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

Proteolytic Processing of Rubella Virus Nonstructural Proteins

AbstractThe genomic RNA of rubella virus contains two long open reading frames (ORF), a 5′-proximal ORF that codes for the nonstructural proteins and a 3′-proximal ORF that encodes the structural proteins. The cDNA encoding the nonstructural protein ORF of the wild-type M33 strain of rubella virus has been obtained and sequenced. Comparison between the nonstructural proteins of the M33 and Therien strains of rubella virus revealed a 98% homology in nucleotide sequence and 98.1% in deduced amino acid sequence. To examine the processing of rubella virus nonstructural protein, the complete nonstructural protein ORF was expressed in BHK cells using a pSFV expression vector. Three nonstructural protein products (p200, p150, and p90) with molecular weights of 200, 150, and 90 kDa were identified using antisera raised against synthetic peptides corresponding to regions of the nonstructural proteins. p200 is the polyprotein precursor, while p150 and p90 are the cleavage products. Site-directed mutagenesis of the Cys-1151 residue (one of the catalytic dyad residues of the viral protease) and of the Gly-1300 residue (the viral protease cleavage site) abrogated protease activity and p200 precursor cleavage, respectively. Coexpression of mutant constructs in BHK cells indicated that rubella virus protease can function both in cis and in trans

Wake interaction between two floating offshore wind turbines with blade deformation

With the increasing size and flexibility of wind turbine blades, the impacts of blade deformation on the aerodynamic performance of wind turbines are becoming more and more important. To better understand the influence of blade flexibility on the wake interaction of FOWTs, a coupled analysis tool composed of an improved ALM and in-house CFD code based on OpenFOAM is employed to perform numerical simulations for two spar-type FOWTs with a tandem layout under given regular wave and uniform wind conditions. Coupled aero-hydroelastic responses of the floating wind turbine are compared for rigid blades and flexible blades scenarios to examine the impacts of blade deformation on the wake interaction. The variations of aerodynamic loads, wake characteristics, and floating platform dynamics motions’ responses are fully examined. Our results show that the blade deformation of downstream FOWT is smaller than that of upstream FOWT due to the turbine wake. The timemean aerodynamic load coefficients of both upstream and downstream FOWT decrease due to the shape deformation of the blade. Moreover, the wake vortexes are found to be more stable when the blade is flexible

Gradient constrained sharpness-aware prompt learning for vision-language models

This paper targets a novel trade-off problem in generalizable prompt learning for vision-language models (VLM), i.e., improving the performance on unseen classes while maintaining the performance on seen classes. Comparing with existing generalizable methods that neglect the seen classes degradation, the setting of this problem is more strict and fits more closely with practical applications. To solve this problem, we start from the optimization perspective, and leverage the relationship between loss landscape geometry and model generalization ability. By analyzing the loss landscapes of the state-of-the-art method and vanilla Sharpness-aware Minimization (SAM) based method, we conclude that the trade-off performance correlates to both loss value and loss sharpness, while each of them is indispensable. However, we find the optimizing gradient of existing methods cannot maintain high relevance to both loss value and loss sharpness during optimization, which severely affects their trade-off performance. To this end, we propose a novel SAM-based method for prompt learning, denoted as Gradient Constrained Sharpness-aware Context Optimization (GCSCoOp), to dynamically constrain the optimizing gradient, thus achieving above two-fold optimization objective simultaneously. Extensive experiments verify the effectiveness of GCSCoOp in the trade-off problem.Comment: 19 pages 11 figure

IRES-Dependent Translational Control during Virus-Induced Endoplasmic Reticulum Stress and Apoptosis

Many virus infections and stresses can induce endoplasmic reticulum (ER) stress response, a host self-defense mechanism against viral invasion and stress. During this event, viral and cellular gene expression is actively regulated and often encounters a switching of the translation initiation from cap-dependent to internal ribosome-entry sites (IRES)-dependent. This switching is largely dependent on the mRNA structure of the 5′ untranslated region (5′ UTR) and on the particular stress stimuli. Picornaviruses and some other viruses contain IRESs within their 5′ UTR of viral genome and employ an IRES-driven mechanism for translation initiation. Recently, a growing number of cellular genes involved in growth control, cell cycle progression and apoptosis were also found to contain one or more IRES within their long highly structured 5′ UTRs. These genes initiate translation usually by a cap-dependent mechanism under normal physiological conditions; however, in certain environments, such as infection, starvation, and heat shock they shift translation initiation to an IRES-dependent modality. Although the molecular mechanism is not entirely understood, a number of studies have revealed that several cellular biochemical processes are responsible for the switching of translation initiation to IRES-dependent. These include the cleavage of translation initiation factors by viral and/or host proteases, phosphorylation (inactivation) of host factors for translation initiation, overproduction of homologous proteins of cap-binding protein eukaryotic initiation factors (eIF)4E, suppression of cap-binding protein eIF4E expression by specific microRNA, activation of enzymes for mRNA decapping, as well as others. Here, we summarize the recent advances in our understanding of the molecular mechanisms for the switching of translation initiation, particularly for the proteins involved in cell survival and apoptosis in the ER stress pathways during viral infections

Large Ecosystem Service Benefits of Assisted Natural Regeneration

China manages the largest monoculture plantations in the world, with 24% being Chinese fir plantations. Maximizing the ecosystem services of Chinese fir plantations has important implications in global carbon cycle and biodiversity protection. Assisted natural regeneration (ANR) is a practice to convert degraded lands into more productive forests with great ecosystems services. However, the quantitative understanding of ANR ecosystem service benefits is very limited. We conducted a comprehensive field manipulation experiment to evaluate the ANR potentials. We quantified and compared key ecosystem services including surface runoff, sediment yield, dissolved organic carbon export, plant diversity, and aboveground carbon accumulation of ANR of secondary forests dominated by Castanopsis carlesii to that of Chinese fir and C. carlesii plantations. Our results showed that ANR of C. carlesii forest reduced surface runoff and sediment yield up to 50% compared with other young plantations in the first 3 years and substantially increased plant diversity. ANR also reduced the export of dissolved organic carbon by 60–90% in the first 2 years. Aboveground biomass of the young ANR forest was approximately 3–4 times of that of other young plantations, while aboveground biomass of mature ANR forests was approximately 1.4 times of that of mature Chinese fir plantations of the same age. If all Chinese fir plantations in China were replaced by ANR forests, potentially 0.7 Pg more carbon will be stored in aboveground in one rotation (25 years). The results indicate that ANR triggers positive feedbacks among soil and water conservation, biodiversity protection, and biomass accumulation and thereby enhances ecosystem services