[Advances of proteostasis network and its stability maintenance mechanism].

Protein is fundamental to life, as it generates protein variants. The maintenance of a dynamic equilibrium in these protein variants, known as protein homeostasis, is crucial for cellular function. Various factors, both endogenous and exogenous, can disrupt protein homeostasis during protein synthesis. These factors include translational error, and biological functions mediated by regulatory factors, and more. When cell accumulate proteins with folding errors, it impairs protein homeostasis, leading to the development of related diseases. In response to protein folding errors, multiple monitoring mechanisms are activated to mediate pathways that sustain the dynamic equilibrium. This review highlights the complex relationships within the proteostasis network, which are influenced by a variety of factors. These insights potentially provide new directions for studying diseases caused by protein synthesis errors.

Immunosuppressants exert antiviral effects against influenza A(H1N1)pdm09 virus via inhibition of nucleic acid synthesis, mRNA splicing, and protein stability.

Influenza A virus (IAV) poses a threat to patients receiving immunosuppressive medications since they are more susceptible to infection with severe symptoms, and even death. Understanding the direct effects of immunosuppressants on IAV infection is critical for optimizing immunosuppression in these patients who are infected or at risk of influenza virus infection. We profiled the effects of 10 immunosuppressants, explored the antiviral mechanisms of immunosuppressants, and demonstrated the combined effects of immunosuppressants with the antiviral drug oseltamivir in IAV-infected cell models. We found that mycophenolic acid (MPA) strongly inhibits viral RNA replication via depleting cellular guanosine pool. Treatment with 6-Thioguanine (6-TG) promoted viral protein degradation through a proteasomal pathway. Filgotinib blocked mRNA splicing of matrix protein 2, resulting in decreased viral particle assembly. Furthermore, combined treatment with immunosuppressants and oseltamivir inhibits IAV viral particle production in an additive or synergic manner. Our results suggest that MPA, 6-TG, and filgotinib could be the preferential choices for patients who must take immunosuppressants but are at risk of influenza virus infection.

Mechanistic Insights into Water Autoionization through Metadynamics Simulation Enhanced by Machine Learning.

Characterizing the free energy landscape of water ionization has been a great challenge due to the limitations from expensive ab initio calculations and strong rare-event features. Lacking equilibrium sampling of the ionization pathway will cause ambiguities in the mechanistic study. Here, we obtain convergent free energy surfaces through nanosecond timescale metadynamics simulations with classical nuclei enhanced by atomic neural network potentials, which yields good reproduction of the equilibrium constant (pK_{w}=14.14) and ionization rate constant (1.369×10^{-3} s^{-1}). The character of transition state unveils the triple-proton transfer occurs through a concerted but asynchronous mechanism. Conditional ensemble average analyses establish the dual-presolvation mechanism, where a pair of hypercoordinated and undercoordinated waters bridged by one H_{2}O cooperatively constitutes the initiation environment for autoionization, and contributes extremely to the local electric field fluctuation to promote water dissociation.

Analysis for codon usage bias in membrane anchor of nonstructural protein 5A from BVDV.

The nonstructural protein 5A (NS5A) of the bovine viral diarrhea virus (BVDV) is a monotopic membrane protein. This protein can anchor to the cell membrane by an in-plane amphipathic ⍺-helix, which participates in the viral replication complex. In this study, the effects of synonymous codon usage pattern of NS5A and the overall transfer RNA (tRNA) abundance in cells on the formation of the in-plane membrane anchor of NS5A were analyzed, based on NS5A coding sequences of different BVDV genotypes. BVDV NS5A coding sequences represent the most potential for BVDV genotyping. Moreover, the nucleotide usage of BVDV NS5A dominates the genotype-specific pattern of synonymous codon usage. There is an obvious relationship between synonymous codon usage bias and the spatial conformation of the in-plane membrane anchor. Furthermore, the overall tRNA abundance profiling displays that codon positions with a high level of tRNA abundance are more than ones with a low level of tRNA abundance in the in-plane membrane anchor, implying that high translation speed probably acts on the spatial conformation of in-plane membrane anchor of BVDV NS5A. These results give a new opinion on the effect of codon usage bias in the formation of the in-plane membrane anchor of BVDV NS5A.

Nucleotide and codon usage biases involved in the evolution of African swine fever virus: A comparative genomics analysis.

Since African swine fever virus (ASFV) replication is closely related to its host's machinery, codon usage of viral genome can be subject to selection pressures. A better understanding of codon usage can give new insights into viral evolution. We implemented information entropy and revealed that the nucleotide usage pattern of ASFV is significantly associated with viral isolation factors (region and time), especially the usages of thymine and cytosine. Despite the domination of adenine and thymine in the viral genome, we found that mutation pressure alters the overall codon usage pattern of ASFV, followed by selective forces from natural selection. Moreover, the nucleotide skew index at the gene level indicates that nucleotide usages influencing synonymous codon bias of ASFV are significantly correlated with viral protein hydropathy. Finally, evolutionary plasticity is proved to contribute to the weakness in synonymous codons with A- or T-end serving as optimal codons of ASFV, suggesting that fine-tuning translation selection plays a role in synonymous codon usages of ASFV for adapting host. Taken together, ASFV is subject to evolutionary dynamics on nucleotide selections and synonymous codon usage, and our detailed analysis offers deeper insights into the genetic characteristics of this newly emerging virus around the world.

Super-Long SERS Active Single Silver Nanowires for Molecular Imaging in 2D and 3D Cell Culture Models.

Establishing a systematic molecular information analysis strategy for cell culture models is of great significance for drug development and tissue engineering technologies. Here, we fabricated single silver nanowires with high surface-enhanced Raman scattering activity to extract SERS spectra in situ from two-dimensional (2D) and three-dimensional (3D) cell culture models. The silver nanowires were super long, flexible and thin enough to penetrate through multiple cells. A single silver nanowire was used in combination with a four-dimensional microcontroller as a cell endoscope for spectrally analyzing the components in cell culture models. Then, we adopted a machine learning algorithm to analyze the obtained spectra. Our results show that the abundance of proteins differs significantly between the 2D and 3D models, and that nucleic acid-rich and protein-rich regions can be distinguished with satisfactory accuracy.