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关键词： Hypoxia   Melanoma   miRNAs   Dog   Next generation sequencing  

摘要： MicroRNAs (miRNAs) can rapidly respond to cellular stresses, such as hypoxia. This immediate miRNA response regulates numerous genes and influences multiple signaling pathways. Therefore, identifying hypoxia-regulated miRNAs (HRMs) is important in canine oral melanoma (COM) to investigate their clinical significance. The hypoxic and normoxic miRNA profiles of two COM cell lines were investigated by next generation sequencing. HRMs were identified by comparing miRNA expression profiles in these cell lines with that in COM tissue. The HRM profile was different between cell lines of primary and metastatic origin, except for miR-301a and miR-8884. The time course of miRNA expression determined by qRT-PCR, especially for miR-210 and miR-301a, showed that metastatic cells are more resistant to hypoxia than primary cells. Analysis of an experimentally validated human miRNA target database revealed that miR-21 and miR-301a control a complex gene regulatory network in response to hypoxia, which includes pathways of well-known oncogenes, such as VEGF, PTEN, and TGFBR2. In conclusions, we revealed the HRM of COM. Moreover, our study shows the difference in regulation and response of hypoxic miRNAs between primary and metastatic originated melanoma cells.

关键词： Mathematical and Computational Engineering  

摘要： A correction to this paper has been published: https://***/10.1007/s11831-021-09607-5

关键词： Interaction energies   Chemical structure   Peptides and proteins   Molecular dynamics simulations   Computational chemistry  

摘要： Antigen presentation by major histocompatibility complex (MHC) proteins to T-cell receptors (TCRs) plays a crucial role in triggering the adaptive immune response. Most of our knowledge on TCR-peptide-loaded major histocompatibility complex (pMHC) interaction stemmed from experiments yielding static structures, yet the dynamic aspects of this molecular interaction are equally important to understand the underlying molecular mechanisms and to develop treatment strategies against diseases such as cancer and autoimmune diseases. To this end, computational biophysics studies including all-atom molecular dynamics simulations have provided useful insights;however, we still lack a basic understanding of an overall allosteric mechanism that results in conformational changes in the TCR and subsequent T-cell activation. Previous hydrogen-deuterium exchange and nuclear magnetic resonance studies provided clues regarding these molecular mechanisms, including global rigidification and allosteric effects on the constant domain of TCRs away from the pMHC interaction site. Here, we show that molecular dynamics simulations can be used to identify how this overall rigidification may be related to the allosteric communication within TCRs upon pMHC interaction via essential dynamics and nonbonded residue-residue interaction energy analyses. The residues taking part in the rigidification effect are highlighted with an intricate analysis on residue interaction changes, which lead to a detailed outline of the complex formation event. Our results indicate that residues of the C beta domain of TCRs show significant differences in their nonbonded interactions upon complex formation. Moreover, the dynamic cross correlations between these residues are also increased, in line with their nonbonded interaction energy changes. Altogether, our approach may be valuable for elucidating intramolecular allosteric changes in the TCR structure upon pMHC interaction in molecular dynamics simulations.