m6A reader proteins: the executive factors in modulating viral replication and host immune response

N6-Methyladenosine (m6A) modification is the most abundant covalent modification of RNA. It is a reversible and dynamic process induced by various cellular stresses including viral infection. Many m6A methylations have been discovered, including on the genome of RNA viruses and on RNA transcripts of DNA viruses, and these methylations play a positive or negative role on the viral life cycle depending on the viral species. The m6A machinery, including the writer, eraser, and reader proteins, achieves its gene regulatory role by functioning in an orchestrated manner. Notably, data suggest that the biological effects of m6A on target mRNAs predominantly depend on the recognition and binding of different m6A readers. These readers include, but are not limited to, the YT521-B homology (YTH) domain family, heterogeneous nuclear ribonucleoproteins (HNRNPs), insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs), and many others discovered recently. Indeed, m6A readers have been recognized not only as regulators of RNA metabolism but also as participants in a variety of biological processes, although some of these reported roles are still controversial. Here, we will summarize the recent advances in the discovery, classification, and functional characterization of m6A reader proteins, particularly focusing on their roles and mechanisms of action in RNA metabolism, gene expression, and viral replication. In addition, we also briefly discuss the m6A-associated host immune responses in viral infection

Experimental Study on Non-Darcian Flow in Phyllite Bimrocks With the Orientation of Blocks

Phyllite bimrocks are widely distributed in the eastern margin of the Tibetan Plateau, and it is the main geomaterial for landslides, slopes, dam basement and subgrades in this area. However, the flow behavior of phyllite bimrocks is unknown, especially the flow behavior of phyllite bimrocks with the orientation of blocks. This paper reports the coupling characteristics of flow and orientation of blocks in phyllite bimrocks. The flow behavior of phyllite bimrocks with different block percentages and block sizes was studied by a series of permeability experiments. A large-scale permeability apparatus was designed, and specimens with varying percentages of block and block sizes were produced by the same dip angle of blocks and compaction degree. Based on the Reynolds number analysis, it was found that the flow in phyllite bimrocks becomes laminar to turbulent under lower hydraulic gradient, and the flow behavior of phyllite bimrocks does not obey Darcy’s law. Furthermore, the Forchheimer equation is better at analyzing the flow behavior of phyllite bimrocks compared with Izbash equation. In addition, based on the coefficients a in the Forchheimer equation, the hydraulic conductivity of phyllite bimrocks can be calculated. The calculation result shows that when the percentage of blocks is 25%, the hydraulic conductivity reaches the minimum. Besides, the hydraulic conductivity increases approximately linear with the block size increase. On the basis of previous studies, coefficients A and B of the Forchheimer equation are detected by the normalized objective function analysis. The results would provide a valuable reference for risk assessment and prevention of phyllite bimrock slope

Influence of Indentation on the Fatigue Strength of Carbonitrided Plain Steel

To study the influence of indentation on the fatigue strength of untreated and carbonitrided specimens of S38C steel, the fatigue limit of specimens with and without indentations was tested. Fracture surfaces were observed using scanning electron microscopy (SEM). The results show that the fatigue strength of the untreated specimen decreases with increasing dimension of indentation, without significant difference compared to the predicted results. Compared to the fatigue limit of the untreated specimen, those of the carbonitrided specimen and the carbonitrided specimen whose compound layer was polished were improved by 12% and 40%, respectively. The fatigue strength of the carbonitrided specimen decreased sharply with increasing indentation size because of the presence of microcracks in the compound layer. When the compound layer was removed, the fatigue limit was observed to be less sensitive to indentation than that of the carbonitrided specimen

Type I interferon signaling and direct cardiomyocyte damages in the pathogenesis of enteroviral myocarditis

Viral myocarditis is an inflammatory heart disease caused by viral infection. CVB3 (coxsackievirus B3) is the predominant pathogen for myocarditis. It is generally proposed that both direct cardiac injury and virus-activated immune response contribute to the pathogenesis of viral myocarditis. However, the molecular determinants mediating the underlying mechanisms remain unclear. ICDs (Intercalated Discs) are substantial connections maintaining cardiac structure and mediating signal communication among cardiomyocytes. NFAT5 (Nuclear factor of activated T-cells 5) is an osmosensitive transcription factor that has been studied well in kidney but rarely in the heart, an organ usually not presented to hypertonic condition as the kidney. Previous studies have shown that NFAT5 protein has antiviral activity but is cleaved during CVB3 infection. Thus, the main objective of this dissertation is to delineate the interplay between direct cardiac damage and NFAT5-mediated innate immune response in CVB3 infected conditions. I hypothesize that 1) CVB3 infection induces destruction of ICD structure by decreasing its key proteins and thus damaging cardiomyocytes; 2) CVB3-induced reduction of NFAT5 leads to the perturbation of immune response, which benefits viral replication and enhances viral pathogenesis. In this dissertation, I first performed studies using HL-1 mouse cardiomyocytes and found that desmosomal proteins, γ-catenin, desmocollin-2, and desmoglein-2, were reduced after CVB3 infection. Since γ-catenin shares high sequence homology with β-catenin in binding with the TCF/LEF transcription factor, I further determined that degradation of γ-catenin benefited Wnt/β-catenin signaling and supressed activation of IFNB1 (type I interferon beta). I further generated a cardiac specific NFAT5 knockout (KO) mouse model by using a tamoxifen-inducible Cre-LoxP system. RNA-seq results showed that IFNB1 and many other antiviral cytokines and chemokines were downregulated due to the deficiency of NFAT5. Also, more cardiac damages and inflammatory immune infiltrates were observed in CVB3-infected NFAT5 KO mice heart than in control mice. Finally, I found that NFAT5 deficiency suppressed the formation of antiviral stress granules and benefited viral replication. Taken together, my study shed light on the mechanisms underlying how CVB3 induces viral myocarditis by both direct cardiac injury and perturbation of innate immune response, and thus provided potential therapeutic strategies against CVB3-induced heart diseases.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

Assessment of the possibility of using point-to-point radio links in the mimo system for constructing the local area network backbone

The article presents the results of the research conducted to assess the possibility of replacing the wiring in the connection system of the local network backbone for constructing backup connections or for the localizations where architectonic conditions do not allow performing installation works related to structural wiring of a building. Testing laboratory environment has been developed using radio devices operating in the IEEE 802.11n standard. The paper reports the results of the transmission tests in the systems of point-to-point links using the MIMO technique to determine parameters of the data transmission performance-throughput and latency. The transfer tests in the MIMO system were conducted in the indoor and outdoor environment.W artykule przedstawiono wyniki prac badawczych prowadzonych w celu oceny możliwości zastąpienia okablowania w układach połączeń szkieletu sieci lokalnej dla realizacji połączeń rezerwowych lub dla lokalizacji z uwarunkowaniami architektonicznymi, które nie zezwalają na prace instalacyjne w zakresie okablowania strukturalnego budynku. Opracowano badawcze środowisko laboratoryjne z wykorzystaniem sprzętu radiowego działającego w standardzie IEEE 802.11n. Przedstawiono ponadto wyniki badań transmisji w układach łączy punkt-punkt z zastosowaniem techniki MIMO przeprowadzonych w celu określenia parametrów wydajności transmisji danych w postaci przepustowości oraz opóźnienia transmisji. Badania transmisji w układzie MIMO zostały wykonane w środowisku wewnątrzbudynkowym i w wolnej przestrzeni

FRET Ratiometric Nanoprobes for Nanoparticle Monitoring

Fluorescence labelling is often used for tracking nanoparticles, providing a convenient assay for monitoring nanoparticle drug delivery. However, it is difficult to be quantitative, as many factors affect the fluorescence intensity. Förster resonance energy transfer (FRET), taking advantage of the energy transfer from a donor fluorophore to an acceptor fluorophore, provides a distance ruler to probe NP drug delivery. This article provides a review of different FRET approaches for the ratiometric monitoring of the self-assembly and formation of nanoparticles, their in vivo fate, integrity and drug release. We anticipate that the fundamental understanding gained from these ratiometric studies will offer new insights into the design of new nanoparticles with improved and better-controlled properties