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Background Threats of antimicrobial resistance (AMR) to human health are on the rise worldwide. Airborne fine particulate matter (PM 2.5 ), especially those emitted from hospitals, could serve as a substantial yet lesser-known environmental medium of inhalable antibiotic resistomes. A genome-centric understanding of the hosting bacterial taxa, mobility potential, and consequent risks of the resistomes is needed to reveal the health relevance of PM 2.5 -associated AMR from clinical settings. Results Compared to urban ambient air PM 2.5 , the hospital samples harbored nearly twice the abundance of antibiotic resistantance genes (ARGs, ~ 0.2 log 10 (ARGs/16S rRNA gene)) in the summer and winter sampled. The profiled resistome was closely correlated with the human-source-influenced (~ 30% of the contribution) bacterial community (Procrustes test, P < 0.001), reflecting the potential antibiotic-resistant bacteria (PARB), such as the human commensals Staphylococcus spp. and Corynebacterium spp. Despite the reduced abundance and diversity of the assembled metagenomes from summer to winter, the high horizontal transfer potential of ARGs, such as the clinically relevant bla OXA and bac A, in the human virulent PARB remained unaffected in the hospital air PM samples. The occurring patterns of β-lactam resistance genes and their hosting genomes in the studied hospital-emitting PM 2.5 were closely related to the in-ward β-lactam-resistant infections (SEM, std = 0.62, P < 0.01). Featured with more abundant potentially virulent PARB (2.89 genome copies/m 3 -air), the hospital samples had significantly higher resistome risk index scores than the urban ambient air samples, indicating that daily human exposure to virulent PARB via the inhalation of PM 2.5 was ten times greater than from the ingestion of drinking water. Conclusions The significance of AMR in the studied hospital-emitting PM 2.5 was highlighted by the greater abundance of ARGs, the prevalence of potentially virulent PARB, and the close association with hospital in-ward β-lactam infections. A larger-scale multi-source comparison of genome-resolved antibiotic resistomes is needed to provide a more holistic understanding to evaluate the importance of airborne AMR from the “One-Health” perspective. 39Xa41gPReog5Lijw58oAn Video Abstract

Viruses exploit autophagy to degrade host immune components for their successful infection. However, how viral factors sequester the autophagic substrates into autophagosomes remains largely unknown. In this study, we showed that p20 protein, a viral suppressor of RNA silencing (VSR) encoded by citrus tristeza virus (CTV), mediated autophagic degradation of SUPPRESSOR OF GENE SILENCING 3 (SGS3), a plant-specific RNA-binding protein that is pivotal in antiviral RNA silencing. CTV infection activated autophagy, and the overexpression of p20 was sufficient to induce autophagy. Silencing of autophagy-related genes NbATG5 and NbATG7 attenuated CTV infection in Nicotiana benthamiana plants. In contrast, knockdown of the autophagy negative-regulated genes NbGAPCs led to virus accumulation, indicating the proviral role of autophagy in CTV infection. Further investigation found that p20 interacted with autophagy-related protein ATG8 through two ATG8-interacting motifs (AIMs) and sequestered SGS3 into autophagosomes by forming the ATG8-p20-SGS3 ternary complex. The mutations of the two AIMs in p20 (p20 mAIM1 and p20 mAIM5 ) abolished the interaction of p20 with ATG8, resulting in the deficiency of autophagy induction, SGS3 degradation, and VSR activity. Consistently, N. benthamiana plants infected with mutated CTV mAIM1 and CTV mAIM5 showed milder symptoms and decreased viral accumulation. Taken together, this study uncovers the molecular mechanism underlying how a VSR mediates the interplay between RNA silencing and autophagy to enhance the infection of a closterovirus.

Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.

Background The common carp ( Cyprinus carpio ) might best represent the domesticated allopolyploid animals. Although subgenome divergence which is well-known to be a key to allopolyploid domestication has been comprehensively characterized in common carps, the link between genetic architecture underlying agronomic traits and subgenome divergence is unknown in the selective breeding of common carps globally. Results We utilized a comprehensive SNP dataset in 13 representative common carp strains worldwide to detect genome-wide genetic variations associated with scale reduction, vibrant skin color, and high growth rate in common carp domestication. We identified numerous novel candidate genes underlie the three agronomically most desirable traits in domesticated common carps, providing potential molecular targets for future genetic improvement in the selective breeding of common carps. We found that independently selective breeding of the same agronomic trait (e.g., fast growing) in common carp domestication could result from completely different genetic variations, indicating the potential advantage of allopolyploid in domestication. We observed that candidate genes associated with scale reduction, vibrant skin color, and/or high growth rate are repeatedly enriched in the immune system, suggesting that domestication of common carps was often accompanied by the disease resistance improvement. Conclusions In common carp domestication, asymmetric subgenome selection is prevalent, while parallel subgenome selection occurs in selective breeding of common carps. This observation is not due to asymmetric gene retention/loss between subgenomes but might be better explained by reduced pleiotropy through transposable element-mediated expression divergence between ohnologs. Our results demonstrate that domestication benefits from polyploidy not only in plants but also in animals.

We study the generalized Dyson Brownian motion (GDBM) of an interacting N -particle system with logarithmic Coulomb interaction and general potential V . Under reasonable condition on V , we prove the existence and uniqueness of strong solution to SDE for GDBM. We then prove that the family of the empirical measures of GDBM is tight on C ( [ 0 , T ] , P ( R ) ) and all the large N limits satisfy a nonlinear McKean–Vlasov equation. Inspired by previous works due to Biane and Speicher, Carrillo, McCann and Villani, and Blower, we prove that the McKean–Vlasov equation is indeed the gradient flow of the Voiculescu free entropy on the Wasserstein space of probability measures over R . Using the optimal transportation theory, we prove that if V ′ ′ ≥ K for some constant K ∈ R , the McKean–Vlasov equation has a unique weak solution in the space of probability measures P ( R ) . This establishes the Law of Large Numbers and the propagation of chaos for the empirical measures of GDBM with non-quadratic external potentials which are not necessarily convex. Finally, we prove the longtime convergence of the McKean–Vlasov equation for C 2 -convex potentials V .

Class V myosin (myosin-5) is a molecular motor that functions as an organelle transporter. The activation of myosin-5′s motor function has long been known to be associated with a transition from the folded conformation in the off-state to the extended conformation in the on-state, but only recently have we begun to understand the underlying mechanism. The globular tail domain (GTD) of myosin-5 has been identified as the inhibitory domain and has recently been shown to function as a dimer in regulating the motor function. The folded off-state of myosin-5 is stabilized by multiple intramolecular interactions, including head–GTD interactions, GTD–GTD interactions, and interactions between the GTD and the C-terminus of the first coiled-coil segment. Any cellular factor that affects these intramolecular interactions and thus the stability of the folded conformation of myosin-5 would be expected to regulate myosin-5 motor function. Both the adaptor proteins of myosin-5 and Ca 2+ are potential regulators of myosin-5 motor function, because they can destabilize its folded conformation. A combination of these regulators provides a versatile scheme in regulating myosin-5 motor function in the cell.

Eukaryotic translation initiation factor 4E (eIF4E), which plays a pivotal role in initiating translation in eukaryotic organisms, is often hijacked by the viral genome‐linked protein to facilitate the infection of potyviruses. In this study, we found that the naturally occurring amino acid substitution D71G in eIF4E is widely present in potyvirus‐resistant watermelon accessions and disrupts the interaction between watermelon eIF4E and viral genome‐linked protein of papaya ringspot virus‐watermelon strain, zucchini yellow mosaic virus or watermelon mosaic virus. Multiple sequence alignment and protein modelling showed that the amino acid residue D71 located in the cap‐binding pocket of eIF4E is strictly conserved in many plant species. The mutation D71G in watermelon eIF4E conferred resistance against papaya ringspot virus‐watermelon strain and zucchini yellow mosaic virus, and the equivalent mutation D55G in tobacco eIF4E conferred resistance to potato virus Y. Therefore, our finding provides a potential precise target for breeding plants resistant to multiple potyviruses. The amino acid substitution D71G in the cap‐binding pocket of watermelon eIF4E and its equivalent substitution D55G in tobacco eIF4E confers resistance to multiple potyviruses by disrupting the interaction between eIF4E and VPg.

Transport and localization of melanosome at the periphery region of melanocyte are depended on myosin-5a (Myo5a), which associates with melanosome by interacting with its adaptor protein melanophilin (Mlph). Mlph contains four functional regions, including Rab27a-binding domain, Myo5a GTD-binding motif (GTBM), Myo5a exon F-binding domain (EFBD), and actin-binding domain (ABD). The association of Myo5a with Mlph is known to be mediated by two specific interactions: the interaction between the exon-F-encoded region of Myo5a and Mlph-EFBD and that between Myo5a-GTD and Mlph-GTBM. Here, we identify a third interaction between Myo5a and Mlph, that is, the interaction between the exon-G-encoded region of Myo5a and Mlph-ABD. The exon-G/ABD interaction is independent from the exon-F/EFBD interaction and is required for the association of Myo5a with melanosome. Moreover, we demonstrate that Mlph-ABD interacts with either the exon-G or actin filament, but cannot interact with both of them simultaneously. Based on above findings, we propose a new model for the Mlph-mediated Myo5a transportation of melanosomes.

Class II myosin (myosin-2) is an actin-based motor protein found in nearly all eukaryotes. One critical question is how the motor function of myosin-2 is regulated. Vertebrate myosin-2 comprises non-muscle myosin, smooth muscle myosin and striated muscle myosin. Recent studies have shown that smooth muscle myosin, in its inhibited state, adopts a folded conformation in which the two heads interact with each other asymmetrically, and the tail is folded into three segments that wrap around the two heads. It has been proposed that the asymmetric head-to-head interaction is a conserved, fundamental structure essential for the regulation of all types of myosin-2. Nearly all insects have only a single striated muscle myosin heavy chain (MHC) gene, which produces all MHC isoforms through alternative splicing of mutually exclusive exons. Most of the alternative exon-encoded regions in insect MHC are located in the motor domain and are critical for generating isoform-specific contraction velocity and force production. However, it remains unclear whether these alternative exon-encoded regions participate in the regulation of insect striated muscle myosin. Here, we review the recently resolved structure of the inhibited state of smooth muscle myosin and discuss its implications on the regulation of insect striated muscle myosin. We propose that the alternative exon-encoded regions in insect MHC not only affect motor properties but also contribute to stabilizing the folded conformation and play a crucial role in regulating insect striated muscle myosin.

Tomato cultivars containing the Tm‐22 resistance gene have been widely known to resist tobacco mosaic virus (TMV) and tomato mosaic virus. Tomato brown rugose fruit virus (ToBRFV), a new emerging tobamovirus, can infect tomato plants carrying the Tm‐22 gene. However, the virulence determinant of ToBRFV that overcomes the resistance conferred by the Tm‐22 gene remains unclear. In this study, we substituted the movement protein (MP) encoding sequences between ToBRFV and TMV infectious clones and conducted infectivity assays. The results showed that MP was the virulence determinant for ToBRFV to infect Tm‐22 transgenic Nicotiana benthamiana plants and Tm‐22‐carrying tomato plants. A TMV MP chimera with amino acid residues 60–186 of ToBRFV MP failed to induce hypersensitive cell death in the leaves of Tm‐22 transgenic N. benthamiana plants. Chimeric TMV containing residues 60–186 of ToBRFV MP could, but chimeric ToBRFV containing 61–187 residues of TMV MP failed to infect Tm‐22 transgenic N. benthamiana plants, indicating that 60–186 residues of MP were important for ToBRFV to overcome Tm‐22 gene‐mediated resistance. Further analysis showed that six amino acid residues, H67, N125, K129, A134, I147, and I168 of ToBRFV MP, were critical in overcoming Tm‐22‐mediated resistance in transgenic N. benthamiana plants and tomato plants. These results increase our understanding of the mechanism by which ToBRFV overcomes Tm‐22‐mediated resistance. Six amino acid residues, H67, N125, K129, A134, I147, and I168, located in the central region of the movement protein are involved in tomato brown rugose fruit virus to evade Tm‐22‐mediated resistance.