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Alpha-synuclein ( non A4 component of amyloid precursor, SNCA, ) plays a central role in the pathogenesis of Parkinson's disease (PD) and related Lewy body disorders such as Parkinson's disease dementia, Lewy body dementia, and multiple system atrophy. Since its discovery as a disease-causing gene in 1997, alpha-synuclein has been a central point of scientific interest both at the protein and gene level. Mutations, including copy number variants, missense mutations, short structural variants, and single nucleotide polymorphisms, can be causative for PD and affect conformational changes of the protein, can contribute to changes in expression of alpha-synuclein and its isoforms, and can influence regulation of temporal as well as spatial levels of alpha-synuclein in different tissues and cell types. A lot of progress has been made to understand both the physiological transcriptional and epigenetic regulation of the alpha-synuclein gene and whether changes in transcriptional regulation could lead to disease and neurodegeneration in PD and related alpha-synucleinopathies. Although the histopathological changes in these neurodegenerative disorders are similar, the temporal and spatial presentation and progression distinguishes them which could be in part due to changes or disruption of transcriptional regulation of alpha-synuclein. In this review, we describe different genetic alterations that contribute to PD and neurodegenerative conditions and review aspects of transcriptional regulation of the alpha-synuclein gene in the context of the development of PD.

New technologies, advanced gene engineering and stem cell modeling, are on the horizon to shed further light on a better understanding of gene regulatory processes and exploit them for therapeutic developments. SNCA genomic triplications Copy number variants (CNVs) of the SNCA genomic locus on chromosome 4q21 were first discovered in 2003 in a family with parkinsonism now termed the Iowa kindred (Singleton et al., ).

The mutation is a genomic triplication of the SNCA gene and adjacent genes resulting in a size of ~1.7 Mb. Patients with an SNCA triplication carry four functional copies of the SNCA gene, three copies from the mutant allele and one copy from the wildtype allele, resulting in a 2-fold overexpression of alpha-synuclein mRNA and protein. We recently performed a high-resolution comparative genomic hybridization array and determined that this SNCA triplication was derived in two steps with an underlying region of a slightly larger duplication (Zafar et al.,; Figure, Supplementary Table ). UCSC Genome Browser custom tracks for PD-risk associated variants and regulatory regions impacting SNCA expression. (A) CNVs of SNCA locus on chromosome 4q21.23-q22.3 (GRCh37/hg19, chr4:84,239,011-98,739,011). Programma dlya nakrutki zolotih monet v avatarii.

Colors indicate gene copy numbers. Red: SNCA CNV triplications; blue: SNCA CNV duplications; combination: SNCA triplication (red) and duplication (blue); green: SNCA CNV deletions. IDs given to tracks were either based on family identifiers from literature or are first author's last name of publication where case/family has been reported. (B) Disease variants and regulatory regions of the SNCA genomic locus on chromosome 4q22.1 (GRCh37/hg19, chr4:90,608,984-90,793,984) (details in Supplementary Tables –).

Colors indicate functional changes related to variants. Red: total mRNA expression; blue: affects SNCA splice-isoform; green: SNCA methylation; pink: multiple associated functions. Additional tracks include microRNA and transcription factor binding sites, CpG islands, and integrated regulation from ENCODE (Layered H3K27Ac and DNase Clusters). (Supplementary Table lists all positions to build custom tracks in UCSC Genome Browser). SNCA genomic duplications In addition, there are also families with SNCA genomic duplications (total of three SNCA gene copies) of chromosome 4q21 (Konno et al., ). The length of the genomic regions varies (Ross et al.,; Kara et al.,; Figure ), there are additional cases presenting a combination of duplications and triplications (Ferese et al., ). We mapped size and location of published cases with SNCA triplication and duplications (Figure ) and also identified through database searches CNV deletions of the SNCA locus.

Interestingly, these CNV deletion cases were from large cohorts of children with intellectual disability/developmental delay, multiple congenital anomalies, and/or autism (Miller et al.,; Vulto-van Silfhout et al.,; Coe et al.,; Duyzend et al.,; Figure ). A common primary mechanism underlying the generation of such microdeletions/duplications is non-allelic homologous recombination (NAHR) that give rise to a number of disorders with such reciprocal rearrangements of specific chromosomal regions (Hastings et al.,; Watson et al., ). The SNCA/4q21 locus has been primarily recognized with various forms of parkinsonism as a duplication/triplication, but detailed clinical presentations of SNCA/4q21 microdeletions are pending. Clinically, the SNCA duplications generally present with typical PD, whereas SNCA triplications have an earlier onset of motor symptoms (34.5 ± 7.9 years for triplication vs. 47.2 ± 10.6 years for duplication) and in addition present more frequently with cognitive decline at an earlier age (39.6 ± 5.5 years for triplication vs.