Dynamics of the personalities of PCSK9 on missense variants (rs505151 and rs562556) from elderly cohort studies in Brazil.

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptors (LDLR). Gain-of-function (GOF) variants of PCSK9 significantly affects lipid metabolism leading to coronary artery disease (CAD), owing to the raising the plasma low-density lipoprotein (LDL). Considering the public health matter, large-scale genomic studies have been conducted worldwide to provide the genetic architecture of populations for the implementation of precision medicine actions. Nevertheless, despite the advances in genomic studies, non-European populations are still underrepresented in public genomic data banks. Despite this, we found two high-frequency variants (rs505151 and rs562556) in the ABraOM databank (Brazilian genomic variants) from a cohort SABE study conducted in the largest city of Brazil, São Paulo. Here, we assessed the structural and dynamical features of these variants against WT through a molecular dynamics study. We sought fundamental dynamical interdomain relations through Perturb Response Scanning (PRS) and we found an interesting change of dynamical relation between prodomain and Cysteine-Histidine-Rich-Domain (CHRD) in the variants. The results highlight the pivotal role of prodomain in the PCSK9 dynamic and the implications for the development of new drugs depending on patient group genotype.

Metaplasticity in the Visual Cortex: Crosstalk Between Visual Experience and Reactive Oxygen Species.

Metaplasticity is the regulation of synaptic plasticity based on the history of previous synaptic activation. This concept was formulated after observing that synaptic changes in the visual cortex are not fixed, but dynamic and dependent on the history of visual information flux. In visual cortical neurons, sustained synaptic stimulation activate the enzymatic complex NOX2, resulting in the generation of reactive oxygen species (ROS). NOX2 is the main molecular structure responsible for translating neural activity into redox modulation of intracellular signaling pathways involved in plastic changes. Here, we studied the interaction between NOX2 and visual experience as metaplastic factors regulating synaptic plasticity at the supergranular layers of the mouse visual cortex. We found that genetic inhibition of NOX2 reverses the polarizing effects of dark rearing from LTP to LTD. In addition, we demonstrate that this process relies on changes in the NMDA receptor functioning. Altogether, this work indicates a role of ROS in the activity-dependent regulation of cortical synaptic plasticity.SIGNIFICANCE STATEMENT Synaptic plasticity in the visual cortex is modulated by the history of sensory experience and this modulation has been defined as metaplasticity. Dark rearing facilitates synaptic potentiation as a mechanism optimizing the range of synaptic modification. This process requires the production of reactive oxygen species mediated by the enzymatic complex NOX2. If the activity of NOX2 is inhibited, then visual deprivation results in synaptic depression. These findings increase our knowledge about metaplasticity and help in our understanding of how neural activity modulates cellular mechanisms of synaptic change.