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Bats, rodents, and shrews are the most important animal sources of human infectious diseases. However, the evolution and transmission of viruses among them remain largely unexplored. Through the meta-transcriptomic sequencing of internal organ and fecal samples from 2,443 wild bats, rodents, and shrews sampled from four Chinese habitats, we identified 669 viruses, including 534 novel viruses, thereby greatly expanding the mammalian virome. Our analysis revealed high levels of phylogenetic diversity, identified cross-species virus transmission events, elucidated virus origins, and identified cases of invertebrate viruses in mammalian hosts. Host order and sample size were the most important factors impacting virome composition and patterns of virus spillover. Shrews harbored a high richness of viruses, including many invertebrate-associated viruses with multi-organ distributions, whereas rodents carried viruses with a greater capacity for host jumping. These data highlight the remarkable diversity of mammalian viruses in local habitats and their ability to emerge in new hosts.
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The RNA-splicing ligase RNA 2',3'-cyclic phosphate and 5'-OH ligase (RTCB) is a catalytic subunit of the tRNA-splicing ligase complex, which plays an essential role in catalyzing tRNA splicing and modulating the unfolded protein response. However, the function of RTCB in influenza A virus (IAV) replication has not yet been described. In this study, RTCB was revealed to be an IAV-suppressed host factor that was significantly downregulated during influenza virus infection in several transformed cell lines, as well as in primary human type II alveolar epithelial cells, and its knockout impaired the propagation of the IAV. Mechanistically, RTCB depletion led to a robust elevation in the levels of type I and type III IFNs and proinflammatory cytokines in response to IAV infection, which was confirmed by RTCB overexpression studies. Lastly, RTCB was found to compete with DDX21 for RNA helicase DDX1 binding, attenuating the DDX21-DDX1 association and thus suppressing the expression of IFN and downstream IFN-stimulated genes. Our study indicates that RTCB plays a critical role in facilitating IAV replication and reveals that the RTCB-DDX1 binding interaction is an important innate immunomodulator for the host to counteract viral infection.
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Vírus da Influenza A , Influenza Humana , Humanos , RNA Helicases DEAD-box , Imunidade Inata , Vírus da Influenza A/fisiologia , Ligases , RNA Helicases , RNA de Transferência , Replicação ViralRESUMO
Autoimmune diseases are characterized by the immune system's attack on one's own tissues which are highly diverse and diseases differ in severity, causing damage in virtually all human systems including connective tissue (e.g., rheumatoid arthritis), neurological system (e.g., multiple sclerosis) and digestive system (e.g., inflammatory bowel disease). Historically, treatments normally include pain-killing medication, anti-inflammatory drugs, corticosteroids, and immunosuppressant drugs. However, given the above characteristics, treatment of autoimmune diseases has always been a challenge. Artemisinin is a natural sesquiterpene lactone initially extracted and separated from Chinese medicine Artemisia annua L., which has a long history of curing malaria. Artemisinin's derivatives such as artesunate, dihydroartemisinin, artemether, artemisitene, and so forth, are a family of artemisinins with antimalarial activity. Over the past decades, accumulating evidence have indicated the promising therapeutic potential of artemisinins in autoimmune diseases. Herein, we systematically summarized the research regarding the immunoregulatory properties of artemisinins including artemisinin and its derivatives, discussing their potential therapeutic viability toward major autoimmune diseases and the underlying mechanisms. This review will provide new directions for basic research and clinical translational medicine of artemisinins.
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Antimaláricos , Artemisininas , Doenças Autoimunes , Humanos , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemeter , Doenças Autoimunes/tratamento farmacológicoRESUMO
Tin diselenide (SnSe2), a layered transition metal dichalcogenide (TMDC), stands out among other TMDCs for its extraordinary photoactive ability and low thermal conductivity. Consequently, it has stimulated many influential researches on photodetectors, ultrafast pulse shaping, thermoelectric devices, etc. However, the carrier mobility in SnSe2, as determined experimentally, remains limited to tens of cm2V-1s-1. This limitation poses a challenge for achieving high-performance SnSe2-based devices. Theoretical calculations, on the other hand, predict that the carrier mobility in SnSe2 can reach hundreds of cm2V-1s-1, approximately one order of magnitude higher than experimental value. Interestingly, the carrier mobility could be underestimated significantly in long-range transportation measurements due to the presence of defects and boundary scattering effects. To address this discrepancy, we employ optic pump terahertz probe spectroscopy to access the photoinduced dynamical THz photoconductivity of SnSe2. Our findings reveal that the intrinsic carrier mobility in conventional SnSe2 single crystal is remarkably high, reaching 353.2 ± 37.7 cm2V-1s-1, consistent with the theoretical prediction. Additionally, dynamical THz photoconductivity measurements reveal that the SnSe2 crystal containing rich defects efficiently capture photoinduced conduction-band electrons and valence-band holes with time constants of â¼20 and â¼200 ps, respectively. Meanwhile, we observe an impulsively stimulated Raman scattering at 0.60 THz. Our study not only demonstrates ultrafast THz spectroscopy as a reliable method for determining intrinsic carrier mobility and detection of low frequency coherent Raman mode in materials but also provides valuable reference for the future application of high-performance SnSe2-based devices.
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Protons (H+) in acidic soils arrest plant growth. However, the mechanisms by which plants optimize their biological processes to diminish the unfavorable effects of H+ stress remain largely unclear. Here, we showed that in the roots of Arabidopsis thaliana, the C2H2-type transcription factor STOP1 in the nucleus was enriched by low pH in a nitrate-independent manner, with the spatial expression pattern of NITRATE TRANSPORTER 1.1 (NRT1.1) established by low pH required the action of STOP1. Additionally, the nrt1.1 and stop1 mutants, as well as the nrt1.1 stop1 double mutant, had a similar hypersensitive phenotype to low pH, indicating that STOP1 and NRT1.1 function in the same pathway for H+ tolerance. Molecular assays revealed that STOP1 directly bound to the promoter of NRT1.1 to activate its transcription in response to low pH, thus upregulating its nitrate uptake. This action improved the nitrogen use efficiency (NUE) of plants and created a favorable rhizospheric pH for root growth by enhancing H+ depletion in the rhizosphere. Consequently, the constitutive expression of NRT1.1 in stop1 mutants abolished the hypersensitive phenotype to low pH. These results demonstrate that STOP1-NRT1.1 is a key module for plants to optimize NUE and ensure better plant growth in acidic media.
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Proteínas de Transporte de Ânions/genética , Proteínas de Arabidopsis/genética , Arabidopsis/fisiologia , Nitratos/metabolismo , Proteínas de Plantas/genética , Rizosfera , Solo/química , Fatores de Transcrição/genética , Adaptação Fisiológica/genética , Proteínas de Transporte de Ânions/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Transporte Biológico , Concentração de Íons de Hidrogênio , Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Posttreatment of pristine metal-organic frameworks (MOFs) with suitable vapor may be an effective way to regulate their structures and properties but has been less explored. Herein, we report an interesting example in which a crystalline nonporous Eu(III)-MOF was transferred to a porous amorphous MOF (aMOF) via iodine vapor adsorption-desorption posttreatment, and the resulting aMOF showed improved turn-on sensing properties with respect to Ag+ ions. The crystalline Eu-MOF, namely, Eu-IPDA, was assembled from Eu(III) and 4,4'-{4-[4-(1H-imidazol-1-yl)phenyl]pyridine-2,6-diyl}dibenzoic acid (H2IPDA) and exhibited a two-dimensional (2D) coordination network based on one-dimensional secondary building blocks. The close packing of the 2D networks gives rise to a three-dimensional supramolecular framework without any significant pores. Interestingly, the nonporous Eu-IPDA could absorb iodine molecules when Eu-IPDA crystals were placed in iodine vapor at 85 °C, and the adsorption capacity was 1.90 g/g, which is comparable to those of many MOFs with large BET surfaces. The adsorption of iodine is attributed to the strong interactions among the iodine molecule, the carboxy group, and the N-containing group and leads to the amorphization of the framework. After immersion of the iodine-loaded Eu-IPDA in EtOH, approximately 89.7% of the iodine was removed, resulting in a porous amorphous MOF, denoted as a-Eu-IPDA. In addition, the remaining iodine in the a-Eu-IPDA framework causes strong luminescent quenching in the fluorescence emission region of the Eu(III) center when compared with that in Eu-IPDA. The luminescence intensity of a-Eu-IPDA in water suspensions was significantly enhanced when Ag+ ions were added, with a detection limit of 4.76 × 10-6 M, which is 1000 times that of pristine Eu-IPDA. It also showed strong anti-interference ability over many common competitive metal ions and has the potential to sense Ag+ in natural water bodies and traditional Chinese medicine preparations. A mechanistic study showed that the interactions between Ag+ and the absorbed iodine, the carboxylate group, and the N atoms all contribute to the sensing performance of a-Eu-IPDA.
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Change history: In this Article, author Li Liu should be associated with affiliation number 5 (College of Marine Sciences, South China Agricultural University, Guangzhou, Guangdong, China), rather than affiliation number 4 (Wenzhou Center for Disease Control and Prevention, Wenzhou, Zhejiang, China). This has been corrected online.
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Our understanding of the diversity and evolution of vertebrate RNA viruses is largely limited to those found in mammalian and avian hosts and associated with overt disease. Here, using a large-scale meta-transcriptomic approach, we discover 214 vertebrate-associated viruses in reptiles, amphibians, lungfish, ray-finned fish, cartilaginous fish and jawless fish. The newly discovered viruses appear in every family or genus of RNA virus associated with vertebrate infection, including those containing human pathogens such as influenza virus, the Arenaviridae and Filoviridae families, and have branching orders that broadly reflected the phylogenetic history of their hosts. We establish a long evolutionary history for most groups of vertebrate RNA virus, and support this by evaluating evolutionary timescales using dated orthologous endogenous virus elements. We also identify new vertebrate-specific RNA viruses and genome architectures, and re-evaluate the evolution of vector-borne RNA viruses. In summary, this study reveals diverse virus-host associations across the entire evolutionary history of the vertebrates.
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Evolução Molecular , Filogenia , Vírus de RNA/classificação , Vírus de RNA/isolamento & purificação , Vertebrados/classificação , Vertebrados/virologia , Anfíbios/virologia , Animais , Biodiversidade , Peixes/virologia , Genoma Viral/genética , Interações Hospedeiro-Patógeno , Vírus de RNA/genética , Répteis/virologia , TranscriptomaRESUMO
The recombination of photogenerated carrier leads to inefficient Fe2+ regeneration, which limits the extensive application of heterogeneous photo-Fenton. Here, a novel Fe@Fe2O3/BiOBr catalyst with Z-scheme heterojunction structure is designed, and the establishment of the Z-scheme heterojunction facilitates the separation and transfer of photogenerated carrier and maintains the superior redox capability of the system. As-prepared Fe@Fe2O3/BiOBr catalyst exhibits outstanding catalytic performance and stability, especially for the optimum composite FFB-3, its degradation efficiency of tetracycline (TC) achieves 98.22% and the mineralization degree reaches 59.48% within 90 min under natural pH. The preeminent catalytic efficiency benefited from the synergistic of heterogeneous photo-Fenton and Z-scheme carriers transfer mechanism, where Fe2+ regeneration was achieved by photogenerated electrons, and increased hydroxyl radicals were produced with the participation of H2O2 in-situ generated. The results of free-radical scavenging experiment and ESR illustrated that â¢OH, â¢O2-, 1O2 and h+ were active species participating in TC degradation. Furthermore, the TC degradation paths were proposed according to LC-MS, and the toxicity evaluation result showed that the toxicity of TC solutions was markedly decreased after degradation. This study provides an innovative strategy for heterogeneous photo-Fenton degradation of antibiotic contaminations by constructing Z-scheme heterojunctions.
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Bismuto , Peróxido de Hidrogênio , Tetraciclina , Tetraciclina/química , Tetraciclina/toxicidade , Peróxido de Hidrogênio/química , Bismuto/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/toxicidade , Ferro/química , Antibacterianos/química , Antibacterianos/toxicidade , Compostos Férricos/química , Compostos Férricos/toxicidade , Animais , CatáliseRESUMO
Obstructive sleep apnea (OSA) can lead to intestinal injury, endotoxemia, and disturbance of intestinal flora. Additionally, as a crucial component of the endocannabinoid system, some studies have demonstrated that cannabinoid 1 (CB1) receptors are closely linked to the multiple organ dysfunction triggered by OSA. However, the role of the CB1 receptor in alleviating OSA-induced colon injury remains unclear. Here, through the construction of the OSA classic model, we found that the colon tissue of chronic intermittent hypoxia (CIH)-induced mice exhibited an overexpression of the CB1 receptor. The results of hematoxylin-eosin staining and transmission electron microscopy revealed that inhibition of the CB1 receptor could decrease the gap between the mucosa and muscularis mucosae, alleviate mitochondrial swelling, reduce microvilli shedding, and promote the recovery of tight junctions of CIH-induced mice. Furthermore, CB1 receptor inhibition reduced the levels of metabolic endotoxemia and inflammatory responses, exhibiting significant protective effects on the colon injury caused by CIH. At the molecular level, through western blotting and real-time polymerase chain reaction techniques, we found that inhibiting the CB1 receptor can significantly increase the expression of ZO-1 and Occludin proteins, which are closely related to the maintenance of intestinal mucosal barrier function. Through 16S rRNA high-throughput sequencing and short-chain fatty acid (SCFA) determination, we found that inhibition of the CB1 receptor increased the diversity of the microbial flora and controlled the makeup of intestinal flora. Moreover, butyric acid concentration and the amount of SCFA-producing bacteria, such as Ruminococcaceae and Lachnospiraceae, were both markedly elevated by CB1 receptor inhibition. The results of the spearman correlation study indicated that Lachnospiraceae showed a positive association with both ZO-1 and Occludin but was negatively correlated with the colon CB1 receptor, IL-1ß, and TNF-α. According to this study, we found that inhibiting CB1 receptor can improve CIH-induced colon injury by regulating gut microbiota, reducing mucosal damage and promoting tight junction recovery. KEY POINTS: â¢CIH leads to overexpression of CB1 receptor in colon tissue. â¢CIH causes intestinal flora disorder, intestinal mucosal damage, and disruption of tight junctions. â¢Inhibition of CB1 receptor can alleviate the colon injury caused by CIH through regulating the gut microbiota, reducing mucosal injury, and promoting tight junction recovery.
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Colo , Modelos Animais de Doenças , Mucosa Intestinal , Receptor CB1 de Canabinoide , Animais , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/genética , Camundongos , Colo/patologia , Colo/microbiologia , Colo/metabolismo , Masculino , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Hipóxia/metabolismo , Camundongos Endogâmicos C57BL , Proteína da Zônula de Oclusão-1/metabolismo , Ocludina/metabolismo , Ocludina/genética , Microbioma Gastrointestinal , Junções Íntimas/metabolismoRESUMO
BACKGROUND: Endometrial cancer (EC) is one of the most common gynecological cancers. Herein, we aimed to define the role of specific myosin family members in EC because this protein family is involved in the progression of various cancers. METHODS: Bioinformatics analyses were performed to reveal EC patients' prognosis-associated genes in patients with EC. Furthermore, colony formation, immunofluorescence, cell counting kit 8, wound healing, and transwell assays as well as coimmunoprecipitation, cycloheximide chase, luciferase reporter, and cellular thermal shift assays were performed to functionally and mechanistically analyze human EC samples, cell lines, and a mouse model, respectively. RESULTS: Machine learning techniques identified MYH14, a member of the myosin family, as the prognosis-associated gene in patients with EC. Furthermore, bioinformatics analyses based on public databases showed that MYH14 was associated with EC chemoresistance. Moreover, immunohistochemistry validated MYH14 upregulation in EC cases compared with that in normal controls and confirmed that MYH14 was an independent and unfavorable prognostic indicator of EC. MYH14 impaired cell sensitivity to carboplatin, paclitaxel, and progesterone, and increased cell proliferation and metastasis in EC. The mechanistic study showed that MYH14 interacted with MYH9 and impaired GSK3ß-mediated ß-catenin ubiquitination and degradation, thus facilitating the Wnt/ß-catenin signaling pathway and epithelial-mesenchymal transition. Sesamolin, a natural compound extracted from Sesamum indicum (L.), directly targeted MYH14 and attenuated EC progression. Additionally, the compound disrupted the interplay between MYH14 and MYH9 and repressed MYH9-regulated Wnt/ß-catenin signaling. The in vivo study further verified sesamolin as a therapeutic drug without side effects. CONCLUSIONS: Herein, we identified that EC prognosis-associated MYH14 was independently responsible for poor overall survival time of patients, and it augmented EC progression by activating Wnt/ß-catenin signaling. Targeting MYH14 by sesamolin, a cytotoxicity-based approach, can be applied synergistically with chemotherapy and endocrine therapy to eventually mitigate EC development. This study emphasizes MYH14 as a potential target and sesamolin as a valuable natural drug for EC therapy.
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Neoplasias do Endométrio , Glicogênio Sintase Quinase 3 beta , Cadeias Pesadas de Miosina , beta Catenina , Humanos , Feminino , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Cadeias Pesadas de Miosina/metabolismo , Cadeias Pesadas de Miosina/genética , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Linhagem Celular Tumoral , beta Catenina/metabolismo , beta Catenina/genética , Camundongos , Proliferação de Células/efeitos dos fármacos , Camundongos Nus , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Prognóstico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Pessoa de Meia-Idade , Naftoquinonas/farmacologiaRESUMO
OBJECTIVES: To study chest computed tomography (CT) manifestations in neonates with chronic granulomatous disease (CGD) to provide clues for early diagnosis of this disease. METHODS: A retrospective analysis was conducted on the clinical data and chest CT scan results of neonates diagnosed with CGD from January 2015 to December 2022 at Anhui Provincial Children's Hospital. RESULTS: Nine neonates with CGD were included, with eight presenting respiratory symptoms as the initial sign. Chest CT findings included: consolidation in all 9 cases; nodules in all 9 cases, characterized by multiple, variably sized scattered nodules in both lungs; masses in 4 cases; cavities in 3 cases; abscesses in 6 cases; bronchial stenosis in 2 cases; pleural effusion, interstitial changes, and mediastinal lymphadenopathy each in 1 case. CT enhancement scans showed nodules and masses with uneven or ring-shaped enhancement; no signs of pulmonary emphysema, lung calcification, halo signs, crescent signs, bronchiectasis, or scar lesions were observed. There was no evidence of rib or vertebral bone destruction. Fungal infections were present in 8 of the 9 cases, including 6 with Aspergillus infections; three of these involved mixed infections with Aspergillus, with masses most commonly associated with mixed Aspergillus infections (3/4). CONCLUSIONS: The primary manifestations of neonatal CGD on chest CT are consolidation, nodules, and/or masses, with Aspergillus as a common pathogen. These features can serve as early diagnostic clues for neonatal CGD.
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Doença Granulomatosa Crônica , Tomografia Computadorizada por Raios X , Humanos , Doença Granulomatosa Crônica/diagnóstico por imagem , Recém-Nascido , Masculino , Feminino , Estudos Retrospectivos , Tórax/diagnóstico por imagemRESUMO
G protein subunit ß1 (GNB1), the beta subunit of the G protein family, plays an important role in regulating transmembrane signal transduction. Although a recent study has demonstrated that GNB1 can bind the matrix protein 1 (M1) to facilitate M1 transport to budding sites and promote the release of progeny influenza A virus (IAV), whether the GNB1 protein has other functions in IAV replication requires further study. Here, we found that GNB1 promoted IAV replication, as virus yield decreased in GNB1 knockdown or knockout cells. GNB1 interacted with polymerase subunits PB2, PB1, and PA. Overexpressed GNB1 facilitated PB2 binding to importin α3, α5, and α7 promoting the nuclear import of PB2, enhancing viral RNA synthesis and polymerase activity. Altogether, our results demonstrated that GNB1 positively regulates virus replication by interacting with polymerase subunits and facilitating the nuclear import of PB2, which provide novel insights into the molecular mechanism of IAV. IMPORTANCE Until now, there has been only one article on the role of GNB1 in IAV budding. No study has investigated the role of GNB1 in IAV replication. In this study, our research demonstrated that GNB1 could increase the interaction between PB2 and the importin α isoform and mediate the nuclear import of PB2. Therefore, GNB1 could promote viral replication and transcription. Our results provide a better understanding of the molecular mechanisms of viral replication and provide potential antiviral drug targets.
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Transporte Ativo do Núcleo Celular , Subunidades beta da Proteína de Ligação ao GTP , Vírus da Influenza A , Influenza Humana , Proteínas Virais , Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/fisiologia , Influenza Humana/genética , Carioferinas/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Replicação ViralRESUMO
The M1 of influenza A virus (IAV) is important for the virus life cycle, especially for the assembly and budding of viruses, which is a multistep process that requires host factors. Identifying novel host proteins that interact with M1 and understanding their functions in IAV replication are of great interest in antiviral drug development. In this study, we identified 19 host proteins in DF1 cells suspected to interact with the M1 protein of an H5N6 virus through immunoprecipitation (IP)/mass spectrometry. Among them, PSMD12, a 26S proteasome regulatory subunit, was shown to interact with influenza M1, acting as a positive host factor in IAV replication in avian and human cells. The data showed that PSMD12 promoted K63-linked ubiquitination of M1 at the K102 site. H5N6 and PR8 with an M1-K102 site mutant displayed a significantly weaker replication ability than the wild-type viruses. Mechanistically, PSMD12 promoted M1-M2 virus-like particle (VLP) release, and an M1-K102 mutation disrupted the formation of supernatant M1-M2 VLPs. An H5N6 M1-K102 site mutation or knockdown PSMD12 disrupted the budding release of the virus in chicken embryo fibroblast (CEF) cells, which was confirmed by transmission electron microscopy. Further study confirmed that M1-K102 site mutation significantly affected the virulence of H5N6 and PR8 viruses in mice. In conclusion, we report the novel host factor PSMD12 which affects the replication of influenza virus by mediating K63-linked ubiquitination of M1 at K102. These findings provide novel insight into the interactions between IAV and host cells, while suggesting an important target for anti-influenza virus drug research. IMPORTANCE M1 is proposed to play multiple biologically important roles in the life cycle of IAV, which relies largely on host factors. This study is the first one to identify that PSMD12 interacts with M1, mediates K63-linked ubiquitination of M1 at the K102 site, and thus positively regulates influenza virus proliferation. PSMD12 promoted M1-M2 VLP egress, and an M1-K102 mutation affected the M1-M2 VLP formation. Furthermore, we demonstrate the importance of this site to the morphology and budding of influenza viruses by obtaining mutant viruses, and the M1 ubiquitination regulator PSMD12 has a similar function to the M1 K102 mutation in regulating virus release and virus morphology. Additionally, we confirm the reduced virulence of H5N6 and PR8 (H1N1) viruses carrying the M1-K102 site mutation in mice. These findings provide novel insights into IAV interactions with host cells and suggest a valid and highly conserved candidate target for antiviral drug development.
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Interações Hospedeiro-Patógeno , Vírus da Influenza A , Complexo de Endopeptidases do Proteassoma , Ubiquitinação , Proteínas da Matriz Viral , Replicação Viral , Animais , Antivirais , Linhagem Celular , Embrião de Galinha , Fibroblastos , Humanos , Vírus da Influenza A Subtipo H1N1/química , Vírus da Influenza A Subtipo H1N1/crescimento & desenvolvimento , Vírus da Influenza A Subtipo H1N1/metabolismo , Vírus da Influenza A/genética , Vírus da Influenza A/crescimento & desenvolvimento , Vírus da Influenza A/metabolismo , Vírus da Influenza A/patogenicidade , Camundongos , Mutação , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismo , Virulência/genéticaRESUMO
Novel immune escape variants have emerged as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide. Many of the variants cause breakthrough infections in vaccinated populations, posing great challenges to current antiviral strategies targeting the immunodominance of the receptor-binding domain within the spike protein. Here, we found that a novel broadly neutralizing monoclonal antibody (mAb), G5, provided efficient protection against SARS-CoV-2 variants of concern (VOCs) in vitro and in vivo. A single dose of mAb G5 could significantly inhibit the viral burden in mice challenged with the mouse-adapted SARS-CoV-2 or SARS-CoV-2 Omicron BA.1 variant, as well as the body weight loss and cytokine release induced by mouse-adapted SARS-CoV-2. The refined epitope recognized by mAb G5 was identified as 1148 FKEELDKYF1156 in the stem helix of subunit S2. In addition, a human-mouse chimeric mAb was generated based on the variable region of heavy chain and VL genes of mAb G5. Our study provides a broad antibody drug candidate against SARS-CoV-2 VOCs and reveals a novel target for developing pan-SARS-CoV-2 vaccines.
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Anticorpos Monoclonais , COVID-19 , Humanos , Animais , Camundongos , Anticorpos Monoclonais/uso terapêutico , Vacinas contra COVID-19 , SARS-CoV-2/genética , Imunossupressores , Glicoproteína da Espícula de Coronavírus/genética , Anticorpos Neutralizantes , Anticorpos Antivirais/uso terapêuticoRESUMO
Though the evidence for antibiotic resistance spread via plant microbiome is mounting, studies regarding antibiotic resistome in the plant seed, a reproductive organ and important food resource, are still in their infancy. This study investigated the effects of long-term organic fertilization on seed bacterial endophytes, resistome, and their intergenerational transfer in the microcosm. A total of 99 antibiotic resistance genes (ARGs) and 26 mobile genetic elements (MGEs) were detected by high-throughput quantitative PCR. The amount of organic fertilizer applied was positively correlated to the number and relative abundance of seed-associated ARGs and MGEs. Moreover, the transmission of ARGs from the rhizosphere to the seed was mainly mediated by the shared bacteria and MGEs. Notably, the rhizosphere of progeny seedlings derived from seeds harboring abundant ARGs was found to have a higher relative abundance of ARGs. Using structural equation models, we further revealed that seed resistome and MGEs were key factors affecting the ARGs in the progeny rhizosphere, implying the seed was a potential resistome reservoir for rhizosphere soil. This study highlights the overlooked role of seed endophytes in the dissemination of resistome in the soil-plant continuum, and more attention should be paid to plant seeds as vectors of ARGs within the "One-Health" framework.
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Antibacterianos , Genes Bacterianos , Antibacterianos/farmacologia , Solo/química , Resistência Microbiana a Medicamentos/genética , Bactérias/genética , Sementes/química , Microbiologia do Solo , EstercoRESUMO
This experiment aimed to analyze the salidroside effect on lipopolysaccharide (LPS)-induced inflammatory activation in young rats with acute lung injury (ALI) via PI3K/Akt signaling pathway. In this study, sixty SD young rats were divided into 5 groups (control, model, salidroside low-dose, salidroside medium-dose and salidroside high-dose), with 12 rats in each group. ALI rat model was established. In the control and model group, rats were intraperitoneally injected with normal saline, while the salidroside low-, medium-, and high-dose groups were intraperitoneally injected with 5, 20, and 40 mg/kg salidroside, then the pathological changes of lung tissue, lung injury score, wet/dry lung weight ratio, neutrophils and TNF-α, MPO, MDA, NO, p-PI3K and p-AKT were detached and compared between these groups. Results showed that the ALI rat model was successfully established. The lung injury score, wet/dry lung weight ratio, neutrophils and TNF-α in alveolar lavage fluid, MPO, MDA, NO, p-PI3K and p-AKT in the lung tissue of the model group were increased than the control group. With the increase of salidroside dose, lung injury score, wet lung weight/dry lung weight ratio, neutrophils and TNF-α in alveolar lavage fluid, and the levels of MPO, MDA, NO, p-PI3K and p-AKT in lung tissues of the salidroside group were decreased then model group (P < 0.05). In conclusion, salidroside may reduce the activation of inflammatory cells in the lung tissue of young rats with LPS-induced ALI by activating PI3K/AKT signaling pathway, thereby exerting a certain protective effect on the lung tissue with LPS-induced ALI.
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Lesão Pulmonar Aguda , Glucosídeos , Animais , Ratos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Pulmão/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Glucosídeos/uso terapêuticoRESUMO
Black phosphorene has attracted widespread attention because of its great potential as a high-performance anode material for sodium-ion batteries (SIBs). However, almost all theoretical studies on sodium (Na) atom adsorption and diffusion in it have not taken temperature into account. Actually, the structural stability of an anode material at room temperature is vital in practical applications. In this work, employing first-principles calculations, we investigate the stability of AA-, AB-, AC- and AD-stacked bilayered black phosphorene (BBP) at ground state, and Na adsorption and diffusion within BBPs. Using ab initio molecular-dynamics (AIMD) calculations, dynamic stabilities of pristine BBP and Na-adsorbed BBP systems at room temperature are discussed. Our calculations show that only AB-stacked BBP is stable. Na atoms generally prefer to intercalate within BBP, making all BBPs exhibit metallic properties, which provides good electrical conductivity required for an ideal anode of SIBs. In particular, our AIMD results indicate that the temperature effect on the structural stability of Na-adsorbed BBP could not be neglected. It increases Na capacity loss at room temperature. This provides an important reference for further theoretical and experimental exploration of anode materials for SIBs. Additionally, the AC-stacked structure facilitates Na intercalation within BBP, and Na diffusion exhibits a strong directional preference, diffusing very fast along the zigzag direction. Our results suggest that AC-stacked BBP is a potential anode material of SIBs.
RESUMO
Hepatocellular carcinoma (HCC) is a type of cancer characterized by high recurrence rates. Overcoming chemoresistance can reduce HCC recurrence and improve patients' prognosis. This work aimed to identify HCC chemoresistance-associated long non-coding RNA (lncRNA) and find an effective drug targeting the identified lncRNA for ameliorating the chemoresistance. In this investigation, bioinformatics analysis based on The Cancer Genome Atlas revealed a new chemoresistance index and suggested LINC02331 as an HCC chemoresistance and patients' prognosis-associated lncRNA that served as an independent prognostic indicator. Moreover, LINC02331 promoted DNA damage repair, DNA replication, and epithelial-mesenchymal transition as well as attenuated cell cycle arrest and apoptosis through regulating Wnt/ß-catenin signaling, thus stimulating HCC resistance to cisplatin cytotoxicity, proliferation, and metastasis. Interestingly, we developed a novel oxidative coupling approach to synthesize a dimeric oxyberberine CT4-1, which exerted superior anti-HCC activities without obvious side effects measured by in vivo mice model and could downregulate LINC02331 mice model and could downregulate LINC02331 to mitigate LINC02331-induced HCC progression by suppressing Wnt/ß-catenin signaling. RNA sequencing analyses verified the involvement of CT4-1-affected differential expression genes in dysregulated pathways and processes, including Wnt, DNA damage repair, cell cycle, DNA replication, apoptosis, and cell adhesion molecules. Furthermore, CT4-1 was demonstrated to be an effective cytotoxic drug in ameliorating HCC patients' prognosis with a prediction model constructed based on RNA-sequencing data from CT4-1-treated cancer cells and public cancer database. In summary, HCC chemoresistance-associated LINC02331 independently predicted poor patients' prognosis and enhanced HCC progression by promoting resistance to cisplatin cytotoxicity, proliferation, and metastasis. Targeting LINC02331 by the dimeric oxyberberine CT4-1 that exhibited synergistic cytotoxicity with cisplatin could alleviate HCC progression and improve patients' prognosis. Our study identified LINC02331 as an alternative target and suggested CT4-1 as an effective cytotoxic drug in HCC treatment.
Assuntos
Antineoplásicos , Berberina , Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Animais , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , beta Catenina/genética , beta Catenina/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/genética , Via de Sinalização Wnt , Berberina/análogos & derivados , Berberina/farmacologiaRESUMO
Simultaneous dysregulation of multiple microRNAs (miRs) affects various pathological pathways related to cardiac failure. In addition to being potential cardiac disease-specific markers, miR-23b/27b/24-1 were reported to be responsible for conferring cardiac pathophysiological processes. In this study, we identified a conserved guanine-rich RNA motif within the miR-23b/27b/24-1 cluster that can form an RNA G-quadruplex (rG4) in vitro and in cells. Disruption of this intragenic rG4 significantly increased the production of all three miRs. Conversely, a G4-binding ligand tetrandrine (TET) stabilized the rG4 and suppressed miRs production in human and rodent cardiomyocytes. Our further study showed that the rG4 prevented Drosha-DGCR8 binding and processing of the pri-miR, suppressing the biogenesis of all three miRs. Moreover, CRISPR/Cas9-mediated G4 deletion in the rat genome aberrantly elevated all three miRs in the heart in vivo, leading to cardiac contractile dysfunction. Importantly, loss of the G4 resulted in reduced targets for the aforementioned miRs critical for normal heart function and defects in the L-type Ca2+ channel-ryanodine receptor (LCC-RyR) coupling in cardiomyocytes. Our results reveal a novel mechanism for G4-dependent regulation of miR biogenesis, which is essential for maintaining normal heart function.