Recent evidence suggests that fibrotic liver injury in patients with chronic hepatitis C correlates with cellular senescence in damaged liver tissue. However, it is still unclear how senescence can affect replication of the hepatitis C virus (HCV). In this work, we report that an inhibitor of cyclin-dependent kinases 4/6, palbociclib, not only induced in hepatoma cells a pre-senescent cellular phenotype, including G1 arrest in the cell cycle, but also accelerated viral replicon multiplication. Importantly, suppression of HCV replication by direct acting antivirals (DAAs) was barely affected by pre-senescence induction, and vice versa, the antiviral activities of host-targeting agents (HTAs), such as inhibitors of human histone deacetylases (HDACi), produced a wide range of reactions—from a dramatic reduction to a noticeable increase. It is very likely that under conditions of the G1 arrest in the cell cycle, HDACi exhibit their actual antiviral potency, since their inherent anticancer activity that complicates the interpretation of test results is minimized.
An algorithm for controlling of commutator’s transistors of a single-phase multi-level voltage inverter is presented. The structure of the power circuit of the considered converter, in contrast to most existing circuits, does not depend on the levels number of the output curve due to the using of an universal source of levels, which are formed by output capacitors of two pulsed DC-converters. The commutator control algorithm ensures the formation of the required output curve of the inverter and excludes the occurrence of emergency situations during level commutating. Features of the converter and commutator operation in modes of active power transmission from pulse converters to the load and perception of the reactive power of the inverter load by them are considered.
The commutator operation algorithm determines the sequence of control pulses, applied to the base of transistors, the sequence being synchronized with the process of the output voltage curve forming, as well as the direction of the inverter input current. At the same time, features of the level commutating are considered. They differ in the transition direction in value of level voltages: «up» from a lower value to a higher one and «down» from a higher value to a lower one. The sequence of supply and removal of pulses from control electrodes of switches and commutations caused by them, when the inverter input current is positive, are given. The similar commutating of levels is realized, when the inverter input current is negative. Wherein indexes of switches are rearranged in accordance with the direction replacement of their switching of the commutator circuit.
A commutator model is realized using Micro-Cap 12 to demonstrate the operation of the algorithm. The transistor MJ15003 model is used as a commutator’s switch. In the model, output capacitors of pulse converters are represented by voltage sources, an autonomous inverter – by an active inductive load. The commutating from a higher voltage level to a lower one with a positive input current of the inverter is considered as an example. Simulation results confirm the performance of the algorithm.
The key role of histone deacetylases (HDACs) in the regulation of the cellular response to infection with the hepatitis C virus (HCV) was first demonstrated in 2008. Studying the metabolism of iron in the liver tissues of patients with chronic hepatitis C, the authors found that the expression of the hepcidin gene (HAMP), a hormone regulator of iron export, is markedly reduced in hepatocytes under conditions of oxidative stress caused by viral infection. HDACs were involved in the regulation of hepcidin expression through the control of acetylation level of histones and transcription factors, primarily STAT3, associated with the HAMP promoter. The purpose of this review is to summarize current data on the functioning of the HCV-HDAC3-STAT3-HAMP regulatory circuit as an example of a well-characterized interaction between the virus and the epigenetic apparatus of the host cell.
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