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Human papillomavirus (HPV) 16 and 18 infections are related to many human cancers. Despite several preventive vaccines for high-risk (hr) HPVs, there is still an urgent need to develop therapeutic HPV vaccines for targeting pre-existing hrHPV infections and lesions. In this study, we developed a lipid nanoparticle (LNP)-formulated mRNA-based HPV therapeutic vaccine (mHTV)-03E2, simultaneously targeting the E2/E6/E7 of both HPV16 and HPV18. mHTV-03E2 dramatically induced antigen-specific cellular immune responses, leading to significant CD8+ T cell infiltration and cytotoxicity in TC-1 tumors derived from primary lung epithelial cells of C57BL/6 mice expressing HPV E6/E7 antigens, mediated significant tumor regression, and prolonged animal survival, in a dose-dependent manner. We further demonstrated significant T cell immunity against HPV16/18 E6/E7 antigens for up to 4 months post-vaccination in immunological and distant tumor rechallenging experiments, suggesting robust memory T cell immunity against relapse. Finally, mHTV-03E2 synergized with immune checkpoint blockade to inhibit tumor growth and extend animal survival, indicating the potential in combination therapy. We conclude that mHTV-03E2 is an excellent candidate therapeutic mRNA vaccine for treating malignancies caused by HPV16 or HPV18 infections.
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Proteínas Oncogénicas Virales , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , ARN Mensajero , Animales , Ratones , Vacunas contra Papillomavirus/inmunología , Humanos , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/terapia , Infecciones por Papillomavirus/prevención & control , Femenino , Proteínas Oncogénicas Virales/inmunología , Proteínas Oncogénicas Virales/genética , ARN Mensajero/genética , ARN Mensajero/inmunología , Nanopartículas/química , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 16/genética , Ratones Endogámicos C57BL , Papillomavirus Humano 18/inmunología , Papillomavirus Humano 18/genética , Proteínas E7 de Papillomavirus/inmunología , Proteínas E7 de Papillomavirus/genética , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Línea Celular Tumoral , Modelos Animales de Enfermedad , Linfocitos T CD8-positivos/inmunología , Proteínas Represoras/inmunología , Proteínas Represoras/genética , Proteínas de Unión al ADN , LiposomasRESUMEN
BACKGROUND: Long noncoding RNAs (lncRNAs) play vital regulatory functions in non-small cell lung cancer (NSCLC). Cisplatin (DDP) resistance has significantly decreased the effectiveness of DDP-based chemotherapy in NSCLC patients. This study aimed to investigate the effects of SH3PXD2A antisense RNA 1 (SH3PXD2A-AS1) on DDP resistance in NSCLC. METHODS: Proliferation and apoptosis of DDP-resistant NSCLC cells were detected using cell counting kit-8 and flow cytometry assays. The interaction between SH3PXD2A-AS1 and sirtuin 7 (SIRT7) was assessed using co-immunoprecipitation (Co-IP), RNA pull-down, RNA immunoprecipitation (RIP), RNA fluorescence in situ hybridization, and immunofluorescence assays, while succinylation (SUCC) of Forkhead Box M1 (FOXM1) was analyzed by IP and Western blot assays. The role of SH3PXD2A-AS1 in vivo was explored using a xenografted tumor model. RESULTS: Expression of SH3PXD2A-AS1 was found elevated in DDP-resistant NSCLC cells, while it's knocking down translated into suppression of cell viability and promotion of apoptosis. Moreover, silencing of SH3PXD2A-AS1 resulted in decreased FOXM1 protein level and enhanced FOXM1-SUCC protein level. The SIRT7 was found to interact with FOXM1, translating into inhibition of FOXM1 SUCC at the K259 site in human embryonic kidney (HEK)-293T cells. Overexpressing of SIRT7 reversed the increase of FOXM1-SUCC protein level and apoptosis, and the decrease of cell viability induced by silencing of SH3PXD2A-AS1. In tumor-bearing mice, SH3PXD2A-AS1 inhibition suppressed tumor growth and the protein levels of Ki67, SIRT7, and FOXM1. CONCLUSION: SH3PXD2A-AS1 promoted DDP resistance in NSCLC cells by regulating FOXM1 SUCC via SIRT7, offering a promising therapeutic approach for NSCLC.
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Apoptosis , Carcinoma de Pulmón de Células no Pequeñas , Cisplatino , Resistencia a Antineoplásicos , Proteína Forkhead Box M1 , Neoplasias Pulmonares , ARN Largo no Codificante , Sirtuinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteína Forkhead Box M1/metabolismo , Proteína Forkhead Box M1/genética , Cisplatino/farmacología , Cisplatino/uso terapéutico , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Animales , Ratones , Sirtuinas/metabolismo , Sirtuinas/genética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones Desnudos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
An FeCl3-catalyzed oxidative condensation of NH-1,2,3-triazoles, aryl methyl ketones (or acetophenones) and DMF (N,N-dimethylformamide) for the synthesis of ß-(1,2,3-triazolyl)-ketones was developed. DMF serves as a one-carbon source, and the resulting products display diverse reaction selectivity, highlighting the existence of distinct approaches.
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Work from home (WFH) creates work-life integration by moving work into traditional life at home, but its influence on residential greenhouse gas (GHG) emissions remains unclear. In this study, an activity-based bottom-up model was developed to analyze the time-use patterns (activity durations and timeline of a typical day) of participants under WFH and traditional home life and to quantify their residential GHG emissions. Under WFH, participants generated an average of 9.03 kg CO2e/person/day, primarily attributed to space heating and cooling, cooking, grooming, work, and watching TV and movies. Notably, the GHG footprints varied across groups (8.08-9.93 kg CO2e/person/day) due to different work and household responsibilities and leisure time and varied with climate region (4.99-10.63 kg CO2e/person/day) because of emission factors of electricity, space heating and cooling, and cooking. Compared with traditional life at home (10.06 kg CO2e/person/day), WFH participants spent less time on almost all major activities (especially sleeping and watching TV and movies) to focus on work, enabling an 11.34% (1.02 kg CO2e/person/day) mitigation of GHG emissions. The reductions also varied by group and climate region, mainly associated with laundry, cooking, and watching TV and movies. Opportunities to reduce GHG emissions under WFH lie in targeting key activities, balancing the time spent on various activities, and developing group- and spatial-specific strategies. This study provides a systematic and high-resolution estimation of residential GHG emissions under WFH and traditional home life, with a complete system boundary, activity-specific considerations, and countrywide understanding. The findings reveal the environmental impact of work-life integration from the residential perspective and can aid residents and policymakers in utilizing decarbonization opportunities to advance low-carbon living under WFH.
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Gases de Efecto Invernadero , Animales , Humanos , Gases de Efecto Invernadero/análisis , Efecto Invernadero , Carbono/análisisRESUMEN
Observational research shows a link between celiac disease (CeD) and sarcoidosis, but the causal link between CeD and sarcoidosis is still unknown. A two-sample Mendelian randomization (MR) study was conducted to ascertain the causal connection between the 2 disorders. In our two-sample MR analysis, we identified independent genetic variants associated with CeD using publicly accessible GWAS data from people of European ancestry. Summary data for sarcoidosis were obtained from the FinnGen Consortium, the UK-Biobank, and a large GWAS dataset. To assess the association between CeD and sarcoidosis, our MR analysis used inverse variance weighted (IVW) as the primary method, incorporating the MR-Egger, weighted median (WM), and MR-PRESSO (outliers test) as a complementary method. In order to ensure that the findings were reliable, several sensitivity analyses were performed. Our study indicated that CeD had a significant causal relationship with sarcoidosis (IVW odds ratio (OR)â =â 1.13, 95% confidence interval (CI): 1.07-1.20, Pâ =â 5.58E-05; WM ORâ =â 1.12, 95% CI: 1.03-1.23, Pâ =â 1.03E-02; MR-Egger ORâ =â 1.07, 95% CI: 0.96-1.19, Pâ =â 2.20E-01). Additionally, we obtain the same results in the duplicated datasets as well, which makes our results even more reliable. The results of this investigation did not reveal any evidence of horizontal pleiotropy or heterogeneity. Our MR analysis showed a causal effect between CeD and an elevated risk of sarcoidosis. Further study is still needed to confirm the findings and look into the processes underlying these relationships.
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Enfermedad Celíaca , Sarcoidosis , Humanos , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/epidemiología , Enfermedad Celíaca/genética , Análisis de la Aleatorización Mendeliana , Sarcoidosis/epidemiología , Sarcoidosis/genética , Causalidad , Oportunidad RelativaRESUMEN
Triggering receptor expressed on myeloid cells-2 (TREM2) has been implicated in susceptibility to neurodegenerative disease. Schwann cells (SCs), the predominant glial cell type in the peripheral nervous system (PNS), play a crucial role in myelination, providing trophic support for neurons and nerve regeneration. However, the function of TREM2 in SCs has not been fully elucidated. Here, we found that TREM2 is expressed in SCs but not in neurons in the PNS. TREM2 deficiency leads to disruption of glycolytic flux and oxidative metabolism in SCs, impairing cell proliferation. The energy crisis caused by TREM2 deficiency triggers mitochondrial damage and autophagy by activating AMPK and impairing PI3K-AKT-mTOR signaling. Combined metabolomic analysis demonstrated that energic substrates and energy metabolic pathways were significantly impaired in TREM2-deficient SCs. Moreover, TREM2 deficiency impairs energy metabolism and axonal growth in sciatic nerve, accompanied by exacerbation of neurological deficits and suppression of nerve regeneration in a mouse model of acute motor axonal neuropathy. These results indicate that TREM2 is a critical regulator of energy metabolism in SCs and exerts neuroprotective effects on peripheral neuropathy. TREM2 deficiency impairs glycolysis and oxidative metabolism in Schwann cells, resulting in compromised cell proliferation. The energy crisis caused by TREM2 deficiency induces mitochondrial damage and autophagy by activating AMPK and impairing PI3K-AKT-mTOR signaling. Moreover, TREM2 deficiency disrupts the energy metabolism of the sciatic nerve and impairs support for axonal regeneration, accompanied by exacerbation of neurological deficits and suppression of nerve regeneration in a mouse model of acute motor axonal neuropathy (by FigDraw).
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Enfermedades Neurodegenerativas , Proteínas Proto-Oncogénicas c-akt , Animales , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Metabolismo Energético , Regeneración Nerviosa/fisiología , Enfermedades Neurodegenerativas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células de Schwann/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
OBJECTIVE: Immune checkpoint inhibitor pneumonitis (CIP) is a prevalent form of immunotherapy-induced pulmonary toxicity, ranking among the leading causes of mortality associated with immune checkpoint inhibitors (ICIs). Despite its significance, the risk stratification of CIP in advanced non-small cell lung cancer (NSCLC) remains uncertain. In this study, we conducted a comprehensive analysis, comparing various factors such as histological types, treatment regimens, PD-L1 expression levels, and EGFR/ALK negativity in advanced NSCLC. Our investigation extends to evaluating the relative risk of developing CIP based on previous treatment history. This analysis aims to provide valuable insights for the identification of specific patient subgroups at higher risk, facilitating more effective risk management and precision therapy approaches. METHODS: PubMed, Embase, and Cochrane databases were systematically searched up to February 16, 2023. We conducted a screening of randomized controlled trials (RCTs) that compared ICI monotherapy or its combination with chemotherapy in advanced NSCLC. The trials were categorized based on histological type, treatment regimen, PD-L1 expression level, EGFR/ALK-negative status, and prior treatment history. Subsequently, the data were stratified into five subgroups, and the occurrences of all-grades (1-5) and high-grades (3-5) pneumonia events were extracted. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were then calculated for further analysis. RESULTS: Twenty-two RCTs, encompassing 13,725 patients with advanced NSCLC, were included in this analysis. Regardless of histology (OR = 2.47, 95% CI 1.41-4.33, P = 0.002; OR = 1.84, 95% CI 1.10-3.09, P = 0.02), treatment regimen (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.91, 95% CI 1.98-4.27, P < 0.00001), PD-L1 expression level (OR = 5.11, 95% CI 2.58-10.12, P < 0.00001; OR = 5.15, 95% CI 2.48-10.70, P < 0.0001), negative EGFR/ALK expression (OR = 4.32, 95% CI 2.22-8.41, P < 0.0001; OR = 3.6, 95% CI 1.56-8.28, P = 0.003), whether there is a history of treatment (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.74, 95% CI 1.75-4.29, P < 0.0001), ICI use was associated with a higher risk of all-grade (1-5) and high-grade (3-5) pneumonia compared to chemotherapy. Subgroup analysis revealed that the squamous group, the ICI vs. combination chemotherapy (CT) group, the PD-L1 > 50% group, and the previously untreated group had a higher risk of developing all-grade and grade 3-5 CIP (P < 0.05). CONCLUSIONS: In advanced NSCLC, ICI treatment was linked to an elevated risk of pneumonitis across all grades (1-5) as well as high-grade occurrences (3-5) compared to chemotherapy. Notably, individuals with squamous histology and high PD-L1 expression, along with those lacking a history of prior treatment, demonstrated a heightened susceptibility to developing immune-related pneumonitis of all grades (1-5) and high grades (3-5). These observations provide valuable insights for clinicians seeking to enhance the management of pulmonary toxicity associated with immunotherapy.
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Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Neumonía , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neumonía/inducido químicamente , Ensayos Clínicos Controlados Aleatorios como Asunto , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismoRESUMEN
Nitrous oxide (N2O) generation during composting not only leads to losses of nitrogen (N) but also reduces the agronomic values and environmental benefits of composting. This study aimed to investigate the effect of the C/N ratio on N2O emissions and its underlying mechanisms at the genetic level during the composting of vegetable waste. The experiment was set up with three treatments, including low C/N treatment (LT, C/N = 18), middle C/N treatment (MT, C/N = 30), and high C/N treatment (HT, C/N = 50). The results showed that N2O emission was mainly concentrated in the cooling and maturation periods, and the cumulative N2O emissions decreased as the C/N ratio increased. Specifically, the cumulative N2O emission was 57,401 mg in LT, significantly higher than 2155 mg in MT and 1353 mg in HT. Lowering the C/N ratio led to increasing TN, NH4+-N, and NO3--N contents throughout the composting process. All detected nitrification-related gene abundances in LT continued to increase during composting, significantly surpassing those in MT during the cooling period. By contrast, in HT, there was a slight increase in the abundance of detected nitrification-related genes but a significant decrease in the abundance of narG, napA, and norB genes in the thermophilic and cooling periods. The structural equation model revealed that hao and nosZ genes were vital in N2O emissions. In conclusion, increasing the C/N ratio effectively contributed to N2O reduction during vegetable waste composting.
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Carbono , Compostaje , Nitrógeno , Óxido Nitroso , Verduras , Óxido Nitroso/análisis , Suelo/químicaRESUMEN
Integrins are cell surface nanosized receptors crucial for cell motility and mechanosensing of the extracellular environment, which are often targeted for the development of biomaterials and nanomedicines. As a key feature of integrins, their activity, structure and behavior are highly mechanosensitive, which are regulated by mechanical forces down to pico-Newton scale. Using single-molecule biomechanical approaches, we compared the force-modulated ectodomain bending/unbending conformational changes of two integrin species, α5ß1 and αVß3. It was found that the conformation of integrin α5ß1 is determined by a threshold head-to-tail tension. By comparison, integrin αVß3 exhibits bistability even without force and can spontaneously transition between the bent and extended conformations with an apparent transition time under a wide range of forces. Molecular dynamics simulations observed almost concurrent disruption of â¼2 hydrogen bonds during integrin α5ß1 unbending, but consecutive disruption of â¼7 hydrogen bonds during integrin αVß3 unbending. Accordingly, we constructed a canonical energy landscape for integrin α5ß1 with a single energy well that traps the integrin in the bent state until sufficient force tilts the energy landscape to allow the conformational transition. In contrast, the energy landscape of integrin αVß3 conformational changes was constructed with hexa-stable intermediate states and intermediate energy barriers that segregate the conformational change process into multiple small steps. Our study elucidates the different biomechanical inner workings of integrins α5ß1 and αVß3 at the submolecular level, helps understand their mechanosignaling processes and how their respective functions are facilitated by their distinctive mechanosensitivities, and provides useful design principles for the engineering of protein-based biomechanical nanomachines.
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Integrina alfa5beta1 , Integrinas , Integrina alfa5beta1/metabolismo , Integrinas/metabolismo , Simulación de Dinámica Molecular , Integrina alfaVbeta3/metabolismoRESUMEN
Human papillomavirus (HPV) infections account for several human cancers. There is an urgent need to develop therapeutic vaccines for targeting preexisting high-risk HPV (such as HPV 16 and 18) infections and lesions, which are insensitive to preventative vaccines. In this study, we developed a lipid nanoparticle-formulated mRNA-based HPV therapeutic vaccine (mHTV), mHTV-02, targeting the E6/E7 of HPV16 and HPV-18. mHTV-02 dramatically induced antigen-specific cellular immune response and robust memory T-cell immunity in mice, besides significant CD8+ T-cell infiltration and cytotoxicity in TC-1 tumors expressing HPV E6/E7, resulting in tumor regression and prolonged survival in mice. Moreover, evaluation of routes of administration found that intramuscular or intratumoral injection of mHTV-02 displayed significant therapeutic effects. In contrast, intravenous delivery of the vaccine barely showed any benefit in reducing tumor size or improving animal survival. These data together support mHTV-02 as a candidate therapeutic mRNA vaccine via specific administration routes for treating malignancies caused by HPV16 or HPV18 infections.
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Neoplasias , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Ratones , Animales , Humanos , Vacunas de ARNm , Infecciones por Papillomavirus/prevención & control , Proteínas E7 de Papillomavirus/genética , Neoplasias/terapia , Vacunas contra Papillomavirus/genéticaRESUMEN
A recently emerging cell death pathway, known as copper-induced cell death, has demonstrated significant potential for treating infections. Existing research suggests that cells utilizing aerobic respiration, as opposed to those reliant on glycolysis, exhibit greater sensitivity to copper-induced death. Herein, a MnO2-loaded copper metal-organic frameworks platform is developed denoted as MCM, to enhance bacterial cuproptosis-like death via the remodeling of bacterial respiratory metabolism. The reversal of hypoxic microenvironments induced a cascade of responses, encompassing the reactivation of suppressed immune responses and the promotion of osteogenesis and angiogenesis. Initially, MCM catalyzed O2 production, alleviating hypoxia within the biofilm and inducing a transition in bacterial respiration mode from glycolysis to aerobic respiration. Subsequently, the sensitized bacteria, characterized by enhanced tricarboxylic acid cycle activity, underwent cuproptosis-like death owing to increased copper concentrations and aggregated intracellular dihydrolipoamide S-acetyltransferase (DLAT). The disruption of hypoxia also stimulated suppressed dendritic cells and macrophages, thereby strengthening their antimicrobial activity through chemotaxis and phagocytosis. Moreover, the nutritional effects of copper elements, coupled with hypoxia alleviation, synergistically facilitated the regeneration of bones and blood vessels. Overall, reshaping the infection microenvironment to enhance cuproptosis-like cell death presents a promising avenue for eradicating biofilms.
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Biopelículas , Cobre , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Animales , Cobre/metabolismo , Ratones , Óxidos/farmacología , Compuestos de Manganeso , Modelos Animales de Enfermedad , Hipoxia/metabolismoRESUMEN
p62, also known as SQSTM1, has been shown to be closely related to the coronavirus. However, it remains unclear on the relationship between p62 and NIBV infection. Moreover, there are no available antibodies against the chicken p62 protein. Thus, this study aimed to prepare p62 polyclonal antibody and investigate the correlation between the p62 protein and NIBV infection. Here, PET-32a-p62 prokaryotic fusion expression vector was constructed for prokaryotic protein expression, and then p62 polyclonal antibody was prepared by immunizing rabbits. Lastly, these antibodies were then utilized in Western blotting (WB), immunohistochemistry (IHC), and immunofluorescence (IF) assays. The results showed that we successfully prepared chicken p62 polyclonal antibody. Meanwhile, WB and IF demonstrated that the expression of p62 showed a trend of first increase and then decrease after NIBV infection. IHC showed that the expression of p62 in the spleen, lung, kidney, bursa of Fabricius and trachea of chickens infected with NIBV in 11 dpi was significantly higher than that of normal chickens. Taken together, this study successfully prepared a polyclonal antibody for chicken p62 protein and confirmed its application and expression in chickens, as well as the expression of p62 in tissues after NIBV infection.
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Pollos , Infecciones por Coronavirus , Virus de la Bronquitis Infecciosa , Animales , Virus de la Bronquitis Infecciosa/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Enfermedades de las Aves de Corral/inmunología , Enfermedades de las Aves de Corral/virología , Proteína Sequestosoma-1/metabolismo , Proteína Sequestosoma-1/inmunología , Proteína Sequestosoma-1/genética , Anticuerpos/inmunología , Conejos , Anticuerpos Antivirales/inmunologíaRESUMEN
Goose astrovirus (GoAstV) is an emerging avian pathogen that induces gout in goslings with a mortality of up to 50%. Organ damage caused by GoAstV infection was considered the cause of gout, but it is still unclear whether other factors are involved. Human and murine studies have linked the gut microbiome-derived urate and gout, thus we hypothesized that gut microbiome may also play an important role in gout induced by GoAstV infection. This study tested the pathogenicity of our isolated GoAstV genotype 2 strain on goslings, while the appearance of clinical signs, histopathological changes, viral distribution and the blood level of cytokines were monitored for 18 d postinfection (dpi). The dynamics in the gut microbiome were profiled by 16S sequencing and then correlated with GoAstV infection. Results showed that this study successfully developed an experimental infection model for studying the pathogenicity of the GoAstV infection which induces typical symptoms of gout. GoAstV infection significantly altered the gut microbiome of goslings with the enrichment of potential proinflammatory bacteria and depletion of beneficial bacteria that can produce short-chain fatty acids. More importantly, the microbial pathway involved in urate production was significantly increased in goslings infected with GoAstV, suggesting that gut microbiome-derived urate may also contribute to the gout symptoms. Overall, this study demonstrated the role of gut microbiome in the pathogenesis of GoAstV infection, highlighting the potential of gut microbiome-based therapeutics against gout symptoms.
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Infecciones por Astroviridae , Avastrovirus , Microbioma Gastrointestinal , Gansos , Enfermedades de las Aves de Corral , Animales , Infecciones por Astroviridae/veterinaria , Infecciones por Astroviridae/virología , Enfermedades de las Aves de Corral/virología , Enfermedades de las Aves de Corral/microbiología , Avastrovirus/fisiología , Gota/veterinaria , Gota/virología , Gota/microbiologíaRESUMEN
Straw return utilizes waste resources to reduce the use of chemical fertilizers worldwide. However, information is still lacking on the relative impact of straw return on soil fertility, the nutrient composition of different soil aggregates, and soil microbial communities. Therefore, this study aimed to understand the effects of different management practices on the crop yield, soil fertility, and soil community composition in a 14-year wheat-rice rotation system. The treatments included a control (without fertilizer and straw addition), chemical fertilization (NPK), straw return without fertilizer (S), and straw addition with chemical fertilizer (NPKS). The results showed that NPKS improved the wheat and rice yield by 185.12% and 88.02%, respectively, compared to the CK treatment. Additionally, compared to the CK treatment, the N, P, and K contents of the wheat stem were increased by 39.02%, 125%, and 20.23% under the NPKS treatment. Compared to the CK treatment, SOM, TN, TP, AN, AP, AK, CEC, AFe, AMn, ACu, and AZn were increased by 49.12%, 32.62%, 35.06%, 22.89%, 129.36%, 48.34%, 13.40%, 133.95%, 58.98%, 18.26% and 33.33% under the NPKS treatment, respectively. Moreover, straw addition promoted the creation and stabilization of macro-aggregates in crop soils. The relative abundance of macro-aggregates (0.25-2 mm) increased from 37.49% to 52.97%. Straw addition was associated with a higher proportion of aromatic and carbonyl carbon groups in the soil, which, in turn, promoted the formation of macro-aggregates. Redundancy analysis showed that straw return significantly increased the microbial community diversity. These findings demonstrate that straw addition together with chemical fertilizer could increase the crop yield by improving soil fertility, soil aggregate stability, and the diversity of fungi.
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OBJECTIVES: Lung adenocarcinoma (LUAD) is a malignant tumor originating from the bronchial mucosa or glands of the lung, with the fastest increasing morbidity and mortality. Therefore, the prognosis of lung cancer remains poor. Glycerol-3-phosphate dehydrogenase 2 (GPD2) is a widely existing protein pattern sequence in biology and is closely related to tumor progression. The therapy values of GPD2 inhibitor in LUAD were unclear. Therefore, we aimed to analyze the therapy values of GPD2 inhibitor in LUAD. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA)-LUAD database was used to analyze the expression levels of GPD2 in LUAD tissues. The relationship between GPD2 expression and LUAD patient survival was analyzed by Kaplan-Meier method. Moreover, KM04416 as a target inhibitor of GPD2 was used to further investigate the therapy value of GPD2 inhibitor in LUAD cells lines (A549 cell and H1299 cell). The TISIDB website was used to investigate the associations between GPD2 expression and immune cell infiltration in LUAD. RESULTS: The results showed that GPD2 is overexpressed in LUAD tissues and significantly associated with poor survival. KM04416 can suppress the progression of LUAD cells by targeting GPD2. Low expression of GPD2 is related to high infiltration of immune cells. CONCLUSIONS: In summary, our present study found that targeting inhibition of GPD2 by KM04416 can suppress LUAD progression via adjusting immune cell infiltration.
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Adenocarcinoma del Pulmón , Progresión de la Enfermedad , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Pronóstico , Regulación Neoplásica de la Expresión GénicaRESUMEN
Generating an infectious non-human primate (NHP) model using a prevalent monkeypox virus (MPXV) strain has emerged as a crucial strategy for assessing the efficacy of vaccines and antiviral drugs against human MPXV infection. Here, we established an animal model by infecting cynomolgus macaques with the prevalent MPXV strain, WIBP-MPXV-001, and simulating its natural routes of infection. A comprehensive analysis and evaluation were conducted on three animals, including monitoring clinical symptoms, collecting hematology data, measuring viral loads, evaluating cellular and humoral immune responses, and examining histopathology. Our findings revealed that initial skin lesions appeared at the inoculation sites and subsequently spread to the limbs and back, and all infected animals exhibited bilateral inguinal lymphadenopathy, eventually leading to a self-limiting disease course. Viral DNA was detected in post-infection blood, nasal, throat, rectal and blister fluid swabs. These observations indicate that the NHP model accurately reflects critical clinical features observed in human MPXV infection. Notably, the animals displayed clinical symptoms and disease progression similar to those of humans, rather than a lethal outcome as observed in previous studies. Historically, MPXV was utilized as a surrogate model for smallpox. However, our study contributes to a better understanding of the dynamics of current MPXV infections while providing a potential infectious NHP model for further evaluation of vaccines and antiviral drugs against mpox infection. Furthermore, the challenge model closely mimics the primary natural routes of transmission for human MPXV infections. This approach enhances our understanding of the precise mechanisms underlying the interhuman transmission of MPXV.
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Mpox , Vacunas , Animales , Humanos , Monkeypox virus/genética , Antivirales/farmacología , MacacaRESUMEN
This study aimed to compare the effect of different phosphate additives including superphosphate (CP) and MP [Mg(OH)2 + H3PO4] on nitrogen conversion, humus fractions formation and bacterial community in food waste compost. The results showed the ratio of humic acid nitrogen in total nitrogen (HA-N/TN) in CP increased by 49 %. Ammonium nitrogen accumulation was increased by 75 % (CP) and 44 % (MP). Spectroscopic techniques proved that phosphate addition facilitated the formation of complex structures in HA. CP enhanced the dominance of Saccharomonospora, while Thermobifida and Bacillus were improved in MP. Structural equation modeling and network analysis demonstrated that ammonium nitrogen can be converted to HA-N and has positive effects on bacterial composition, reducing sugars and amino acids, especially in CP with more clustered network and synergic bacterial interactions. Therefore, the addition of phosphate provides a new idea to regulate the retained nitrogen toward humification in composting.
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Compuestos de Amonio , Compostaje , Eliminación de Residuos , Sustancias Húmicas , Fosfatos , Carbono , Nitrógeno/química , Alimentos , Eliminación de Residuos/métodos , Suelo , Bacterias , Esqueleto/química , EstiércolRESUMEN
This study aimed to compare the process of maturity and humus fraction evolution as well as bacterial community dynamics in composting from different domestic organic wastes (food waste (FW), and vegetable waste (VW)) and decipher the key biotic influencing factors of humic acid formation through correlation analysis and ecological network. The results showed that organic carbon components in FW with high ratio of soluble organic carbon and hemicellulose were more easily to be degraded in composting compared to VW. After 30 days of composting, the content of HA-C generated by VW was 35.41%, higher than 29.01% of FW, and the growth rate of HA-C generated was 38.42% and 28.34%, respectively. PARAFAC analysis showed that the structure of HA generated in VW was more complex, and the proportion of humic acid-like components (C3 + C4) was 60.32%, while FW only accounted for 43.86%. However, the evolution growth rate of aromatic components in HA in FW was 26.88% in 30 days of compost, which was higher than 15.17% in VW. High-throughput sequencing indicated that Lactobacillus was the initial dominated genera in composting from different domestic wastes. Thermobifida, Thermovum, and Pusillimas as well as Aeribacillus were core bacterial genera that promoted the humification process in FW and VW, respectively. Network analysis showed that there was higher bacterial interacted connection degree and complexity in FW compared to VW. This study was of great significance for optimizing organics conversion and humification efficiency of household waste composting.
RESUMEN
Arterial thrombosis, which represents a critical complication of cardiovascular diseases, is a leading cause of death and disability worldwide with no effective bioassay for clinical prediction. As a symbolic feature of arterial thrombosis, severe stenosis in the blood vessel creates a high-shear, high-gradient flow environment that effectively facilitates platelet aggregation towards vessel occlusion even with platelet amplification loops inhibited. However, no approach is currently available to comprehensively characterize the size, composition and platelet activation status of thrombi forming under this biorheological condition. Here, we present a thrombus profiling assay that monitors the multi-dimensional attributes of thrombi forming in conditions mimicking the physiological scenario of arterial thrombosis. Using this platform, we demonstrate that different receptor-ligand interactions contribute distinctively to the composition and activation status of the thrombus. Our investigation into hypertensive and older individuals reveals intensified biomechanical thrombogenesis and multi-dimensional thrombus profile abnormalities, demonstrating a direct contribution of mechanobiology to arterial thrombosis and endorsing the diagnostic potential of the assay. Furthermore, we identify the hyperactivity of GPIbα-integrin αIIbß3 mechanosensing axis as a molecular mechanism that contributes to hypertension-associated arterial thrombosis. By studying the interactions between anti-thrombotic inhibitors and hypertension, and the inter-individual variability in personal thrombus profiles, our work reveals a critical need for personalized anti-thrombotic drug selection that accommodates each patient's pathological profile.