Widespread modulation of gene expression by copy number variation in skeletal muscle

Copy number variation (CNV) is a frequently observed deviation from the diploid state due to duplication or deletion of genomic regions. Although intensively analyzed for association with diseases and production traits, the specific mechanisms and extent by which such variations affect the phenotype are incompletely understood. We present an integrative study on CNV and genome-wide gene expression in Brazilian Bos indicus cattle. We analyzed CNVs inferred from SNP-chip data for effects on gene expression measured with RNA-seq in skeletal muscle samples of 183 steers. Local effects, where expression changes coincided with CNVs in the respective genes, were restricted to immune genes. Distal effects were attributable to several high-impact CNVs that modulated remote expression in an orchestrated and intertwined fashion. These CNVs were located in the vicinity of major skeletal muscle pathway regulators and associated genes were enriched for proteolysis, autophagy, and muscle structure development. From association analysis between CNVs and several meat quality and production traits, we found CNV-associated expression effects to also manifest at the phenotype level. Based on genome sequences of the population founders, we further demonstrate that CNVs with impact on expression and phenotype are passed on from one generation to another

Сетевая система контроля технологического процесса выращивания полупроводниковых кристаллов и тонких пленок

Экспериментальное моделирование аппаратно-программного обеспечения показало достаточную надежность работы системы и значительное уменьшение трудоемкости контроля и управления параметрами технологического процесса

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Hsp70 proteins bind Hsp100 regulatory M domains to activate AAA+ disaggregase at aggregate surfaces

Bacteria, fungi and plants rescue aggregated proteins using a powerful bichaperone system composed of an Hsp70 chaperone and an Hsp100 AAA+ disaggregase. In Escherichia coli, the Hsp70 chaperone DnaK binds aggregates and targets the disaggregase ClpB to the substrate. ClpB hexamers use ATP to thread substrate polypeptides through the central pore, driving disaggregation. How ClpB finds DnaK and regulates threading remains unclear. To dissect the disaggregation mechanism, we separated these steps using primarily chimeric ClpB-ClpV constructs that directly recognize alternative substrates, thereby obviating DnaK involvement. We show that ClpB has low intrinsic disaggregation activity that is normally repressed by the ClpB middle (M) domain. In the presence of aggregate, DnaK directly binds M-domain motif 2, increasing ClpB ATPase activity to unleash high ClpB threading power. Our results uncover a new function for Hsp70: the coupling of substrate targeting to AAA+ chaperone activation at aggregate surfaces

TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation

Adaptation of the endoplasmic reticulum (ER) pathway for MHC class I (MHC-I) presentation in dendritic cells enables cross-presentation of peptides derived from phagocytosed microbes, infected cells, or tumor cells to CD8 T cells. How these peptides intersect with MHC-I molecules remains poorly understood. Here, we show that MHC-I selectively accumulate within phagosomes carrying microbial components, which engage Toll-like receptor (TLR) signaling. Although cross-presentation requires Sec22b-mediated phagosomal recruitment of the peptide loading complex from the ER-Golgi intermediate compartment (ERGIC), this step is independent of TLR signaling and does not deliver MHC-I. Instead, MHC-I are recruited from an endosomal recycling compartment (ERC), which is marked by Rab11a, VAMP3/cellubrevin, and VAMP8/endobrevin and holds large reserves of MHC-I. While Rab11a activity stocks ERC stores with MHC-I, MyD88-dependent TLR signals drive IκB-kinase (IKK)2-mediated phosphorylation of phagosome-associated SNAP23. Phospho-SNAP23 stabilizes SNARE complexes orchestrating ERC-phagosome fusion, enrichment of phagosomes with ERC-derived MHC-I, and subsequent cross-presentation during infectio