RESUMEN

Influenza virus-induced viral pneumonia is a major threat to human health, and specific therapeutic agents for viral pneumonia are still lacking. MoringaA (MA) is an anti-influenza virus active compound isolated from Moringa seeds, which can inhibit influenza virus by activating the TFEB-autophagic lysosomal pathway in host cells. In this study, we obtained exosomes from M2-type macrophages and encapsulated and delivered MA (MA-Exos), and we investigated the efficacy of MA-Exos in antiviral and viral pneumonia in vivo and in vitro, respectively. In addition, we provided insights into the mechanism by which MA-Exos regulates TFEB-lysosomal autophagy by RNA sequencing. The MA-Exos showed broad-spectrum inhibition of IAV, and significant promotion of the autophagic lysosomal pathway. Meanwhile, we found that GCN5 gene and protein were significantly down-regulated in IAV-infected cells after MA-Exos intervention, indicating its blocking the acetylation of TFEB by GCN5. In addition, MA-Exos also significantly promoted autophagy in lung tissue cells of mice with viral pneumonia. MA-Exos can inhibit and clear influenza virus by mediating the TFEB-autophagy lysosomal pathway by a mechanism related to the down-regulation of histone acetyltransferase GCN5. Our study provides a strategy for targeting MA-Exos for the treatment of viral pneumonia from both antiviral and virus-induced inflammation inhibition pathways.

Asunto(s)

Antivirales , Autofagia , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Exosomas , Virus de la Influenza A , Lisosomas , Animales , Ratones , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Lisosomas/virología , Exosomas/metabolismo , Antivirales/farmacología , Autofagia/efectos de los fármacos , Humanos , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/fisiología , Infecciones por Orthomyxoviridae/virología , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Macrófagos/virología , Macrófagos/efectos de los fármacos , Pulmón/virología

RESUMEN

The limited energy density of supercapacitors hampers their widespread application in electronic devices. Metal oxides, employed as electrode materials, suffer from low conductivity and stability, prompting extensive research in recent years to enhance their electrochemical properties. Among these efforts, the construction of core-shell heterostructures and the utilization of oxygen vacancy (VO) engineering have emerged as pivotal strategies for improving material stability and ion diffusion rates. Herein, core-shell composites comprising NiCo2S4 nanospheres and MnO2 nanosheets are grown in situ on carbon cloth (CC), forming nanoflower clusters while introducing VO defects through a chemical reduction method. Density functional theory (DFT) results proves that the existence of VO effectively enhances electronic and structural properties of MnO2, thereby enhancing capacitive properties. The electrochemical test results show that NiCo2S4@MnO2-V3 exhibits excellent 1376 F g-1 mass capacitance and 2.06 F cm-2 area capacitance at 1 A g-1. Moreover, NiCo2S4@MnO2-V3//activated carbon (AC) asymmetric supercapacitor (ASC) can achieve an energy density of 39.7 Wh kg-1 at a power density of 775 W kg-1, and maintains 15.5 Wh kg-1 even at 7749.77 W kg-1. Capacitance retention is 73.1 % after 10,000 cycles at 5 A g-1, and coulombic efficiency reaches 100 %, demonstrating satisfactory cycle stability. In addition, the device's excellent flexibility offers broad application prospects in wearable electronic applications.

RESUMEN

Osteoarthritis (OA) is the most common degenerative joint disease affecting millions of people worldwide. Garlic-derived exosomes (GDEs) are nanoparticles extracted from garlic that exhibit anti-inflammatory effects on other diseases, but the effect of GDEs on OA has not been elucidated. In this study, GDEs were extracted and characterized. Chondrocytes were treated with IL-1ß and incubated with GDEs in vitro, and the expression of cartilage matrix components (collagen II and aggrecan) and matrix degrading enzymes (MMP3 and MMP9) was evaluated via Western blotting. Changes in the MAPK pathway was also examined using Western blotting. The transcriptomic changes associated with GDE intervention were evaluated using high-throughput RNA-seq method. In vivo, we used anterior cruciate ligament transection (ACLT) combined with destabilization of the medial meniscus (DMM) surgery to establish a mouse OA model, and GDEs was intraarticularly injected into the joint cavity. The therapeutic effect of GDE was evaluated by behavioral and histopathological analysis. The results showed that IL-1ß treatment inhibited the expression of collagen II and aggrecan, and upregulated the expression of MMP3 and MMP9, while GDE intervention alleviated these effects. GDEs also inhibited the phosphorylation of ERK, JNK, and P38. In vivo, GDE alleviated the sensitivity to heat stimulation and altered walking gait in a mouse OA model. Histopathological analysis indicated that GDE intervention ameliorated joint destruction in the knee joint without obvious toxicity. The results proved that GDEs alleviated the progression of OA in vitro and in vivo, and may be a potential disease-modifying drug for OA.

RESUMEN

OBJECTIVE: Alloimmunization against red blood cell (RBC) antigen is an important concern in myelodysplastic syndromes (MDSs) patients with chronic transfusion, causing potential risk for hemolytic reaction and limited supply of compatible blood. However, there is little data addressing RBC alloimmunization in this patient cohort among the Chinese population. This study aims to evaluate the incidence, specificity of antibodies, and RBC units transfused before antibody formation and its significance in a population of patients consistently receiving RhD-matched RBC units. METHODS: We retrospectively reviewed the transfusion and clinical information of all transfused patients with MDS enrolled in our hospital from 2012 to 2022. The cumulative incidence of alloimmunization was analyzed by a Kaplan-Meier plot. Alloimmunization incidence was compared based on different transfused RBC units using the log-rank test. RESULTS: A total of 103 patients with MDS were included in this study; alloantibody formed in 8 (7.8%) patients. Before reaching 32 RBC units, 87.5% of the alloimmunized patients had developed their alloantibodies. All but 1 of the alloantibodies developed were antibodies to Rh antigens. The RBC transfusion intensity and frequency were significantly higher following alloimmunization in the alloimmunized patients (P = .008, P = .008, respectively). CONCLUSION: The antibodies detected mostly involve the Rh system among MDS patients in China. The alloimmunization tended to occur early prior to reaching 32 RBC units in patients with MDS. Rh antigen matching should be considered early in the patient's transfusion history and completed before receiving 32 RBC units.

RESUMEN

Degeneracy and symmetry have a profound relation in quantum systems. Here, we report gate-tunable subband degeneracy in PbTe nanowires with a nearly symmetric cross-sectional shape. The degeneracy is revealed in electron transport by the absence of a quantized plateau. Utilizing a dual gate design, we can apply an electric field to lift the degeneracy, reflected as emergence of the plateau. This degeneracy and its tunable lifting were challenging to observe in previous nanowire experiments, possibly due to disorder. Numerical simulations can qualitatively capture our observation, shedding light on device parameters for future applications.

RESUMEN

Understanding building morphology is crucial for accurately simulating interactions between urban structures and hydroclimate dynamics. Despite significant efforts to generate detailed global building morphology datasets, there is a lack of practical solutions using publicly accessible resources. In this work, we present GLAMOUR, a dataset derived from open-source Sentinel imagery that captures the average building height and footprint at a resolution of 0.0009° across urbanized areas worldwide. Validated in 18 cities, GLAMOUR exhibits superior accuracy with median root mean square errors of 7.5 m and 0.14 for building height and footprint estimations, indicating better overall performance against existing published datasets. The GLAMOUR dataset provides essential morphological information of 3D building structures and can be integrated with other datasets and tools for a wide range of applications including 3D building model generation and urban morphometric parameter derivation. These extended applications enable refined hydroclimate simulation and hazard assessment on a broader scale and offer valuable insights for researchers and policymakers in building sustainable and resilient urban environments prepared for future climate adaptation.

RESUMEN

Sepsis, a systemic inflammatory response triggered by infection, has a considerably high mortality rate. However, effective prevention and intervention measures against sepsis remain insufficient. Therefore, this study aimed to investigate the mechanisms underlying the protective properties of immune response gene-1 (IRG1) and 4-Octyl itaconate (OI) during acute liver damage in mice with sepsis. A sepsis mouse model was established to compare wild-type and IRG1-/- groups. The impact of IRG1/Itaconate on pro- and anti-inflammatory cytokines was evaluated using J774A.1 cells. IRG1/Itaconate substantially reduced pro-inflammatory cytokines and increased the release of anti-inflammatory cytokines. It reduced pathological damage to liver tissues, preserved normal liver function, decreased the release of reactive oxygen species (ROS) and LDH, and enhanced the GSH/GSSG ratio. Moreover, IRG1 and itaconic acid activated the Nrf2 signaling pathway, regulating the expression of its downstream antioxidative stress-related proteins. Additionally, they inhibited the activity of NLRP3 inflammatory vesicles to suppress the expression of macrophage-associated pyroptosis signaling molecules. Our findings demonstrate that IRG1/OI inhibits NLRP3 inflammatory vesicle activation and macrophage pyroptosis by modulating the Nrf2 signaling pathway, thereby attenuating acute liver injury in mice with sepsis. These findings could facilitate the clinical application of IRG1/Itaconate to prevent sepsis-induced acute liver injury.

Asunto(s)

Macrófagos , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Sepsis , Transducción de Señal , Succinatos , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Succinatos/uso terapéutico , Succinatos/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/inmunología , Piroptosis/efectos de los fármacos , Ratones , Transducción de Señal/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones Noqueados , Hígado/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/inmunología , Línea Celular , Modelos Animales de Enfermedad , Citocinas/metabolismo , Hidroliasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Humanos , Carboxiliasas/metabolismo , Carboxiliasas/genética

RESUMEN

BACKGROUND: Normal bile is sterile. Studies have shown that cholangitis after liver transplantation (LT) was associated with a relatively poor prognosis. It remains unclear whether the bacteriobilia or fungibilia impact the patient outcomes in LT recipients, especially with donation after circulatory death (DCD) allografts, which was correlated with a higher risk of allograft failure. METHODS: This retrospective study included 139 LT recipients of DCD grafts from 2019 to 2021. All patients were divided into two groups according to the presence or absence of bacteriobilia or fungibilia. The prevalence and microbial spectrum of postoperative bacteriobilia or fungibilia and its possible association with outcomes, especially hospital stay were analyzed. RESULTS: Totally 135 and 171 organisms were isolated at weeks 1 and 2, respectively. Among all patients included in this analysis, 83 (59.7%) developed bacteriobilia or fungibilia within 2 weeks post-transplantation. The occurrence of bacteriobilia or fungibilia (ß = 7.43, 95% CI: 0.02 to 14.82, P = 0.049), particularly the detection of Pseudomonas (ß = 18.84, 95% CI: 6.51 to 31.07, P = 0.003) within 2 weeks post-transplantation was associated with a longer hospital stay. However, it did not affect the graft and patient survival. CONCLUSIONS: The occurrence of bacteriobilia or fungibilia, particularly Pseudomonas within 2 weeks post-transplantation, could influence the recovery of liver function and was associated with prolonged hospital stay but not the graft and patient survival.

RESUMEN

BACKGROUND: Sepsis may be linked to oxidative stress and can be controlled by itaconate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nevertheless, the itaconate impact on sepsis-associated acute kidney injury (SA-AKI) has yet to be definitively established. METHODS: We employed SA-AKI mouse model through a cecal ligation and puncture (CLP) procedure for the in vivo investigation of the potential nephroprotective effect of itaconate in this study. A plasmid was transfected into RAW264.7 cells to examine the Nrf2 pathway function after itaconate administration. Finally, the immune-responsive gene 1-knockout (IRG1-/-) mice were used to study the itaconate impacts on oxidative stress-induced SA-AKI. RESULTS: We have shown that 4-octyl itaconate (OI) significantly reduced CD11b-positive macrophage aggregation and activated the Nrf2 pathway in the bone marrow-derived macrophages (BMDM). The impacts of Nrf2 inhibitor ML385 on the anti-inflammatory and antioxidant properties of itaconate were found to be partial. OI inhibited lipopolysaccharide-induced oxidative stress injury in RAW264.7 macrophages and activated Nrf2 in the nucleus to hinder the expression of nuclear factor kappa B p65, thereby suppressing oxidative stress injury in the macrophages. Additionally, the introduction of the transfected plasmid resulted in a partial inhibition of the anti-inflammatory impact of itaconate. The kidney injury caused by sepsis exhibited greater severity in the IRG1-/- mice than in the wild type mice. Exogenous OI partially attenuated the kidney injury induced by sepsis in the IRG1-/- mice and suppressed the oxidative stress injury in macrophages. CONCLUSIONS: This investigation offers new proof to support the itaconate function in the development and progression of SA-AKI and shows a new possible therapeutic agent for the SA-AKI treatment.

Asunto(s)

Lesión Renal Aguda , Sepsis , Succinatos , Ratones , Animales , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Activación de Macrófagos , Estrés Oxidativo , Lesión Renal Aguda/etiología , Antiinflamatorios/farmacología , Sepsis/complicaciones

RESUMEN

Planar Josephson junctions are predicted to host Majorana zero modes. The material platforms in previous studies are two-dimensional electron gases (InAs, InSb, InAsSb, and HgTe) coupled to a superconductor such as Al or Nb. Here, we introduce a new material platform for planar JJs, the PbTe-Pb hybrid. The semiconductor, PbTe, was grown as a thin film via selective area epitaxy. The Josephson junction was defined by a shadow wall during the deposition of superconductor Pb. Scanning transmission electron microscopy reveals a sharp semiconductor-superconductor interface. Gate-tunable supercurrents and multiple Andreev reflections are observed. A perpendicular magnetic field causes interference patterns of the switching current, exhibiting Fraunhofer-like and SQUID-like behaviors. We further demonstrate a prototype device for Majorana detection wherein phase bias and tunneling spectroscopy are applicable.

RESUMEN

Up to now, the mainstream adoption of renewable energy has brought about substantial transformations in the electricity and energy sector. This shift has garnered considerable attention within the scientific community. Supercapacitors, known for their exceptional performance metrics like good charge/discharge capability, strong power density, as well as extended cycle longevity, have gained widespread traction across various sectors, including transportation and aviation. Metal-organic frameworks (MOFs) with unique traits including adaptable structure, highly customizable synthetic methods, and high specific surface area, have emerged as strong candidates for electrode materials. For enhancing the performance, MOFs are commonly compounded with other conducting materials to increase capacitance. This paper provides a detailed analysis of various common preparation strategies and characteristics of MOFs. It summarizes the recent application of MOFs and their derivatives as supercapacitor electrodes alongside other carbon materials, metal compounds, and conductive polymers. Additionally, the challenges encountered by MOFs in the realm of supercapacitor applications are thoroughly discussed. Compared to previous reviews, the content of this paper is more comprehensive, offering readers a deeper understanding of the diverse applications of MOFs. Furthermore, it provides valuable suggestions and guidance for future progress and development in the field of MOFs.

RESUMEN

Tertiary lymphoid structure (TLS) can predict the prognosis and sensitivity of tumors to immune checkpoint inhibitors (ICIs) therapy, whether it can be noninvasively predicted by radiomics in hepatocellular carcinoma with liver transplantation (HCC-LT) has not been explored. In this study, it is found that intra-tumoral TLS abundance is significantly correlated with recurrence-free survival (RFS) and overall survival (OS). Tumor tissues with TLS are characterized by inflammatory signatures and high infiltration of antitumor immune cells, while those without TLS exhibit uncontrolled cell cycle progression and activated mTOR signaling by bulk and single-cell RNA-seq analyses. The regulators involved in mTOR signaling (RHEB and LAMTOR4) and S-phase (RFC2, PSMC2, and ORC5) are highly expressed in HCC with low TLS. In addition, the largest cohort of HCC patients is studied with available radiomics data, and a classifier is built to detect the presence of TLS in a non-invasive manner. The classifier demonstrates remarkable performance in predicting intra-tumoral TLS abundance in both training and test sets, achieving areas under receiver operating characteristic curve (AUCs) of 92.9% and 90.2% respectively. In summary, the absence of intra-tumoral TLS abundance is associated with mTOR signaling activation and uncontrolled cell cycle progression in tumor cells, indicating unfavorable prognosis in HCC-LT.

Asunto(s)

Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Transducción de Señal , Serina-Treonina Quinasas TOR , Estructuras Linfoides Terciarias , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Pronóstico , Masculino , Estudios Retrospectivos , Trasplante de Hígado/métodos , Persona de Mediana Edad , Femenino , Estructuras Linfoides Terciarias/genética , Transducción de Señal/genética , Adulto , Anciano , Análisis de Supervivencia

RESUMEN

Li-rich disordered rock-salt oxides (DRX) are considered an attractive cathode material in the future battery field due to their excellent energy density and specific capacity. Nevertheless, anionic redox provides high capacity while causing O2 over-oxidation to O2, resulting in voltage hysteresis and capacity decay. Herein, the crystal structure of Li1.3Mn0.4Ti0.3O1.7F0.3 (LMTOF) cathode is stabilized by using sodium carboxymethylcellulose (CMC) binders replacing traditional polyvinylidene difluoride (PVDF) binders. The electrochemical impedance spectroscopy (EIS) and galvanostatic intermittent titration technique (GITT) reveal that the CMC-based LMTOF electrode has higher electronic conductivity and lithium-ion diffusion kinetics. Moreover, CMC has been demonstrated to improve the O2- reversibility, reduce the amounts of byproducts from electrolyte decomposition and suppress transition metal dissolution by Na+/Li+ exchange reaction. Furthermore, the CMC-based LMTOF electrode also exhibits less volume change upon lithiation/delithiation processes compared to the PVDF-based electrode, resulting in enhanced structural stability during cycling. Benefiting from these features, the CMC binders can effectively improve the cycling life and rate performance of the LMTOF cathode, and the CMC-based LMTOF electrode shows good capacity retention of 94.5 % after 30 cycles at 20 mA/g and 66.7 % after 100 cycles at 200 mA/g. This finding indicates that CMC as a binder can efficiently stabilize the structure and improve the electrochemical performance of Li-rich disordered rock-salt oxides cathode, making it possible for practical Li-ion battery applications.

RESUMEN

Prostate cancer (PCa) is a prevalent malignancy among men worldwide, and biochemical recurrence (BCR) after radical prostatectomy (RP) is a critical turning point commonly used to guide the development of treatment strategies for primary PCa. However, the clinical parameters currently in use are inadequate for precise risk stratification and informing treatment choice. To address this issue, we conducted a study that collected transcriptomic data and clinical information from 1662 primary PCa patients across 12 multicenter cohorts globally. We leveraged 101 algorithm combinations that consisted of 10 machine learning methods to develop and validate a 9-gene signature, named BCR SCR, for predicting the risk of BCR after RP. Our results demonstrated that BCR SCR generally outperformed 102 published prognostic signatures. We further established the clinical significance of these nine genes in PCa progression at the protein level through immunohistochemistry on Tissue Microarray (TMA). Moreover, our data showed that patients with higher BCR SCR tended to have higher rates of BCR and distant metastasis after radical radiotherapy. Through drug target prediction analysis, we identified nine potential therapeutic agents for patients with high BCR SCR. In conclusion, the newly developed BCR SCR has significant translational potential in accurately stratifying the risk of patients who undergo RP, monitoring treatment courses, and developing new therapies for the disease.

Asunto(s)

Antígeno Prostático Específico , Neoplasias de la Próstata , Masculino , Humanos , Benchmarking , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/metabolismo , Próstata/patología

RESUMEN

Prostate cancer is the second most common malignancy among men in the world, posing a serious threat to men's health and lives. RB1 is the first human tumor suppressor gene to be described, and it is closely associated with the development, progression, and suppression of a variety of tumors. It was found that the loss of RB1 is an early event in prostate cancer development and is closely related to prostate cancer development, progression and treatment resistance. This paper reviews the current status of research on the relationship between RB1 and prostate cancer from three aspects: RB1 and prostate cell lineage plasticity; biological behavior; and therapeutic resistance. Providing a novel perspective for developing new therapeutic strategies for RB1-loss prostate cancer.

Asunto(s)

Resistencia a Antineoplásicos , Neoplasias de la Próstata , Proteínas de Unión a Retinoblastoma , Ubiquitina-Proteína Ligasas , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Resistencia a Antineoplásicos/genética , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Plasticidad de la Célula/efectos de los fármacos , Linaje de la Célula

RESUMEN

Wannanhua (WH) is a pig breed indigenous to Anhui Province, China. This breed has a high intramuscular fat (IMF) content, making it an ideal model for investigating lipid deposition mechanisms in pigs. IMF content is one of the main indicators of meat quality in pigs and is regulated by multiple genes and metabolic pathways. Building upon our prior transcriptomic investigation, the present study focused on the longissimus dorsi muscle tissue of Wannanhua (WH) pigs in the rapid fat-deposition stages (120 and 240 days of age). Employing 4D label-free quantitative proteomic analysis, we identified 106 differentially expressed proteins (DEPs). Parallel reaction monitoring (PRM) technology was used to verify the DEPs, and the results showed that the 4D label-free results were reliable and valid. Functional enrichment and protein-protein interaction analyses showed that the DEPs were mainly involved in the skeletal-muscle-associated structural proteins, mitochondria, energy metabolism, and fatty acid metabolism. By integrating transcriptomic data, we identified seven candidate genes including ACADL, ACADM, ANKRD2, MYOZ2, TNNI1, UCHL1, and ART3 that play a regulatory role in fat deposition and muscle development. These findings establish a theoretical foundation for future analyses of lipid deposition traits, contributing to potential enhancements in pig meat quality during breeding and advancing the selection process for Chinese indigenous breeds.

RESUMEN

Load forecasting is critical to the task of energy management in power systems, for example, balancing supply and demand and minimizing energy transaction costs. There are many approaches used for load forecasting such as the support vector regression (SVR), the autoregressive integrated moving average (ARIMA), and neural networks, but most of these methods focus on single-step load forecasting, whereas multistep load forecasting can provide better insights for optimizing the energy resource allocation and assisting the decision-making process. In this work, a novel sequence-to-sequence (Seq2Seq)-based deep learning model based on a time series decomposition strategy for multistep load forecasting is proposed. The model consists of a series of basic blocks, each of which includes one encoder and two decoders; and all basic blocks are connected by residuals. In the inner of each basic block, the encoder is realized by temporal convolution network (TCN) for its benefit of parallel computing, and the decoder is implemented by long short-term memory (LSTM) neural network to predict and estimate time series. During the forecasting process, each basic block is forecasted individually. The final forecasted result is the aggregation of the predicted results in all basic blocks. Several cases within multiple real-world datasets are conducted to evaluate the performance of the proposed model. The results demonstrate that the proposed model achieves the best accuracy compared with several benchmark models.

RESUMEN

Sepsis is a multiple organ dysfunction syndrome due to a dysregulated response to infection with unacceptably high mortality. Currently, no effective treatment exists for sepsis. IRG1/itaconate has been considered to play a protective role for various inflammatory diseases. In the present study, we explored the protective role and mechanisms of IRG1/itaconate on lipopolysaccharide (LPS)-induced multi-organ injury. The LPS-induced sepsis model was used. IRG1-/- and wild type mice were used to explore the protective role of IRG1/itaconate on multi-organ injury. GSDMD-/- mice were used to explore the effect of GSDMD-mediated pyroptosis on LPS-induced model. RAW264.7 cells and bone-marrow-derived macrophages (BMDMs) were used for in vitro studies. In vivo experiments, we found IRG1 deficiency aggravated LPS-induced multi-organ injury especially lung injury. 4-Octyl itaconate (4-OI), a derivative of itaconate, significantly ameliorated LPS-induced acute lung, liver, and kidney injury. Furthermore, IRG1/4-OI decreased serum interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α) level, macrophage infiltration, and TUNEL-positive cells in lung and liver tissue. Western blot showed IRG1/itaconate decreased the expressions of p-ERK, p-P38, p-JNK, and p-P65 and increased the expression of Nrf2/HO-1 in lung tissue. Meanwhile, 4-OI inhibited the expression of GSDMD-N. In vitro experiments, 4-OI inhibited ROS production and promoted apoptosis under LPS stimulation in RAW264.7 cells. Furthermore, 4-OI inhibited nuclear factor-kappaB/mitogen-activated protein kinase pathways and GSDMD-medicated pyroptosis in BMDMs. Finally, we used GSDMD-/- mice to explore the effect of pyroptosis on LPS-induced multi-organ injury. The results showed that GSDMD deficiency significantly ameliorated lung injury. In conclusion, our data demonstrated that IRG1/itaconate protect against multi-organ injury via inhibiting inflammation response and GSDMD-indicated pyroptosis, which may be a promising agent for protecting against sepsis.

Asunto(s)

Lesión Pulmonar , Sepsis , Succinatos , Animales , Ratones , Piroptosis , Gasderminas , Lipopolisacáridos/farmacología , Sepsis/tratamiento farmacológico , Inmunidad

RESUMEN

Metabolic states greatly influence functioning and differentiation of immune cells. Regulating the metabolism of immune cells can effectively modulate the host immune response. Itaconate, an intermediate metabolite derived from the tricarboxylic acid (TCA) cycle of immune cells, is produced through the decarboxylation of cis-aconitate by cis-aconitate decarboxylase in the mitochondria. The gene encoding cis-aconitate decarboxylase is known as immune response gene 1 (IRG1). In response to external proinflammatory stimulation, macrophages exhibit high IRG1 expression. IRG1/itaconate inhibits succinate dehydrogenase activity, thus influencing the metabolic status of macrophages. Therefore, itaconate serves as a link between macrophage metabolism, oxidative stress, and immune response, ultimately regulating macrophage function. Studies have demonstrated that itaconate acts on various signaling pathways, including Keap1-nuclear factor E2-related factor 2-ARE pathways, ATF3-IκBζ axis, and the stimulator of interferon genes (STING) pathway to exert antiinflammatory and antioxidant effects. Furthermore, several studies have reported that itaconate affects cancer occurrence and development through diverse signaling pathways. In this paper, we provide a comprehensive review of the role IRG1/itaconate and its derivatives in the regulation of macrophage metabolism and functions. By furthering our understanding of itaconate, we intend to shed light on its potential for treating inflammatory diseases and offer new insights in this field.

Asunto(s)

Factor 2 Relacionado con NF-E2 , Succinatos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Succinatos/farmacología , Succinatos/metabolismo , Inmunidad

RESUMEN

Disorder is the primary obstacle in the current Majorana nanowire experiments. Reducing disorder or achieving ballistic transport is thus of paramount importance. In clean and ballistic nanowire devices, quantized conductance is expected, with plateau quality serving as a benchmark for disorder assessment. Here, we introduce ballistic PbTe nanowire devices grown by using the selective-area-growth (SAG) technique. Quantized conductance plateaus in units of 2e2/h are observed at zero magnetic field. This observation represents an advancement in diminishing disorder within SAG nanowires as most of the previously studied SAG nanowires (InSb or InAs) have not exhibited zero-field ballistic transport. Notably, the plateau values indicate that the ubiquitous valley degeneracy in PbTe is lifted in nanowire devices. This degeneracy lifting addresses an additional concern in the pursuit of Majorana realization. Moreover, these ballistic PbTe nanowires may enable the search for clean signatures of the spin-orbit helical gap in future devices.