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Osteomyelitis (OM) is a progressive, inflammatory infection of bone caused predominately by Staphylococcus aureus. Herein, we engineered an antibiotic-eluting collagen-hydroxyapatite scaffold capable of eliminating infection and facilitating bone healing. An iterative freeze-drying and chemical crosslinking approach was leveraged to modify antibiotic release kinetics, resulting in a layered dual-release system whereby an initial rapid release of antibiotic to clear infection was followed by a sustained controlled release to prevent reoccurrence of infection. We observed that the presence of microbial collagenase accelerated antibiotic release from the crosslinked layer of the scaffold, indicating that the material is responsive to microbial activity. As exemplar drugs, vancomycin and gentamicin-eluting scaffolds were demonstrated to be bactericidal, and supported osteogenesis in vitro. In a pilot murine model of OM, vancomycin-eluting scaffolds were observed to reduce S. aureus infection within the tibia. Finally, in a rabbit model of chronic OM, gentamicin-eluting scaffolds both facilitated radial bone defect healing and eliminated S. aureus infection. These results show that antibiotic-eluting collagen-hydroxyapatite scaffolds are a one-stage therapy for OM, which when implanted into infected bone defects simultaneously eradicate infection and facilitate bone tissue healing.
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Antibacterianos , Gentamicinas , Osteomielite , Infecções Estafilocócicas , Staphylococcus aureus , Alicerces Teciduais , Animais , Alicerces Teciduais/química , Antibacterianos/farmacologia , Antibacterianos/química , Infecções Estafilocócicas/tratamento farmacológico , Osteomielite/tratamento farmacológico , Coelhos , Staphylococcus aureus/efeitos dos fármacos , Gentamicinas/farmacologia , Gentamicinas/administração & dosagem , Gentamicinas/química , Gentamicinas/uso terapêutico , Camundongos , Vancomicina/farmacologia , Vancomicina/química , Vancomicina/administração & dosagem , Durapatita/química , Cinética , Cicatrização/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Colágeno/química , FemininoRESUMO
BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by its incurable nature and undefined etiology, which is often accompanied by a high prevalence of comorbid depression. The gut-brain axis has emerged as a promising treatment target in recent years. PURPOSE: This study aimed to investigate how vinegar-processed Schisandra Chinensis (VSC) enhances therapeutic effects on depressive behavior in chronic UC mice. METHODS: A chronic UC model was induced in mice using dextran sulfate sodium. The therapeutic effects of both raw and vinegar-processed Schisandra Chinensis on UC and associated depressive symptoms were assessed. Colonic mucosal damage was evaluated using hematoxylin and eosin (H&E) and Alcian blue staining. The integrity of the blood-brain barrier (BBB) and synaptic structures was visualized via transmission electron microscopy (TEM). Enzyme-linked immunosorbent assay (ELISA) was employed to quantify inflammatory cytokine levels in the colon, serum, and brain, while western blotting was performed for protein expression analysis. Additionally, metagenomic analysis was conducted to investigate gut microbiota composition. Nissl staining and immunofluorescence were used to assess hippocampal neuronal damage, and behavioral assessments including the morris water maze, open field test, forced swimming test and tail suspension test, were implemented to evaluate depressive states. Serum metabolites were analyzed using UPLC-MS/MS. RESULTS: Both raw and vinegar-processed Schisandra Chinensis significantly upregulated aryl hydrocarbon receptor (AhR), inhibited NF-κB p-p65 activation, and reduced levels of pro-inflammatory cytokine. These treatments also enhanced the expression of tight junction proteins, restored colonic mucosal and BBB integrity, alleviated damage to hippocampal neurons, and improved synaptic structure. Behavioral assessments indicated that VSC was particularly effective in ameliorating depressive-like behaviors in chronic UC mice. In the gut, both treatments reshaped the gut microbial composition, restoring the relative abundance of Duncaniella, Candidatus_Amulumruptor, Alistipes, Parabacteroides, Lachnospiraceae_bacterium, uncultured_Bacteroides_sp., Candidatus_Amulumruptor_caecigallinarius, with VSC showing more pronounced effects. Serum metabolomics revealed an increase in tryptophan levels and a decrease in kynurenine and xanthurenic acid levels with VSC, indicating that tryptophan metabolism shifted from the kynurenine pathway to the 5-HT or indole pathway. However, this phenomenon did not occur with Schisandra Chinensis (SC). CONCLUSION: This study demonstrated that the disruption of tryptophan metabolic balance served as a biological mechanism underlying the occurrence of depressive behaviors induced by UC. The application of SC following vinegar processing enhanced its regulatory effects on gut microbiota and tryptophan metabolism. This findings provided a new insight for the clinical management of gut-brain comorbidities.
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Various members of the viral genera Furovirus and Bymovirus are damaging pathogens of a range of crop species. Infection of the soil-borne plasmodiophorid Polymyxa graminis transmits both Japanese soil-borne wheat mosaic virus (JSBWMV) and the barley yellow mosaic virus (BaYMV) to barley, but their interaction during an episode of their co-infection has not been characterized to date. Here, we present an analysis of the titer of JSBWMV and BaYMV in plants of winter barley growing over a five-month period from late fall until mid-spring. Although JSBWMV was detectable in the plants' roots four weeks earlier than BaYMV, the translocation of both viruses from the root to the leaves occurred nearly simultaneously. Both viruses were co-localized in the roots, leaf sheathes, and leaf blades; however, in some stripes of leaf veins where infection by JSBWMV was prominent, BaYMV was not detectable. A substantial titer of both viruses persisted until early spring, after which JSBWMV became more prominent, being in a range of 10 to 100 times abundant of BaYMV. However, JSBWMV was only able to infect a single wheat accession (cv. Norin 61), whereas all of the wheat entries assayed appeared to be immune to BaYMV infection. Overall, our findings highlight the importance of resistance mechanisms against soil-borne viruses in cereal crops, expanding our understanding of plant-virus interactions and potentially informing strategies for crop protection against viral pathogens.
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Hordeum , Doenças das Plantas , Folhas de Planta , Raízes de Plantas , Potyviridae , Hordeum/virologia , Doenças das Plantas/virologia , Folhas de Planta/virologia , Raízes de Plantas/virologia , Potyviridae/fisiologia , Potyviridae/patogenicidade , Coinfecção/virologia , Vírus do Mosaico/fisiologia , Vírus do Mosaico/patogenicidade , Solo , Triticum/virologia , Microbiologia do Solo , Replicação Viral , População do Leste AsiáticoRESUMO
AIMS: This study aims to explore the concept of future orientation, which encompasses individuals' thoughts about the future, goal-setting, planning, response to challenges and behavioural adjustments in evolving situations. Often viewed as a psychological resource, future orientation is believed to be developed from psychological resilience. The study investigates the curvilinear relationship between childhood maltreatment and future orientation while examining the moderating effects of genotype. METHODS: A total of 14,675 Chinese adults self-reported their experiences of childhood maltreatment and their future orientation. The influence of genetic polymorphism was evaluated through genome-wide interaction studies (GWIS; genome-wide association study [GWAS] using gene × environment interaction) and a candidate genes approach. RESULTS: Both GWAS and candidate genes analyses consistently indicated that rs4498771 and its linked single-nucleotide polymorphisms, located in the intergenic area surrounding CSF3R, significantly interacted with early trauma to influence future orientation. Nonlinear regression analyses identified a quadratic or cubic association between future orientation and childhood maltreatment across some genotypes. Specifically, as levels of childhood maltreatment increased, future orientation declined for all genotypes. However, upon reaching a certain threshold, future orientation exhibited a rebound in individuals with specific genotypes. CONCLUSIONS: The findings suggest that individuals with certain genotypes exhibit greater resilience to childhood maltreatment. Based on these results, we propose a new threshold model of stress-related growth.
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Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Estresse Psicológico , Humanos , Adulto , Feminino , Masculino , Estresse Psicológico/psicologia , Estresse Psicológico/genética , Resiliência Psicológica , Genótipo , China , Pessoa de Meia-Idade , Maus-Tratos Infantis/psicologia , Povo Asiático/psicologia , Povo Asiático/genética , Desenvolvimento PsicológicoRESUMO
OBJECTIVES: Subjective wellbeing has been defined as an individual's personal appraisal of their quality of life. Subjective wellbeing is associated with positive health behaviours and improved coping abilities. This study aimed to investigate the subjective wellbeing of people living with multiple sclerosis (MS), using the novel Personal Wellbeing Index, and make comparisons with the general population. METHODS: Cross-sectional data was obtained from the Australian Multiple Sclerosis Longitudinal Study and the How Is Your Life Australian general population study in August-October 2020. Subjective wellbeing was measured as life satisfaction using the Personal Wellbeing Index. This instrument measures life satisfaction globally and in seven life domains, allowing the importance of domain-specific life satisfaction to be explored. Descriptive and multivariable regression analyses were conducted. RESULTS: One thousand six hundred eighty-three MS and 1,021 general population participants entered the study (mean age 52.4 and 58.6; female 79.9% and 52.4%, respectively). For people living with MS the most important life domains were standard of living and achieving in life. The domain of personal health was more influential for people living with MS (p < 0.01) than the general population. The life domains most susceptible to MS-related disability were personal health, achieving in life, and community connectedness (p < 0.01 for these domains). CONCLUSION: Personal health and achieving in life are key domains through which the subjective wellbeing of people living with MS is modified. This study recommends the development of interventions to support healthy perceptions of illness and continued employment as paramount in improving the subjective wellbeing of people living with MS.
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Esclerose Múltipla , Satisfação Pessoal , Qualidade de Vida , Humanos , Esclerose Múltipla/psicologia , Feminino , Masculino , Austrália , Pessoa de Meia-Idade , Estudos Transversais , Qualidade de Vida/psicologia , Adulto , Inquéritos e Questionários , Estudos Longitudinais , Idoso , Adaptação PsicológicaRESUMO
Background: The Naples prognostic score (NPS) determined by the nutritional and inflammatory condition of an individual is attracting growing attention for predicting postoperative outcomes in a variety of malignancies. The study aimed to assess the clinical significance of a modified NPS (M-NPS) and establish and validate nomograms incorporating M-NPS in curative stage II-III colon cancer patients. Methods: We retrospectively analyzed 328 stage II-III colon cancer patients receiving radical surgical resection at our hospital from January 2011 to December 2016. Kaplan-Meier (KM) survival analysis and Cox regression analysis were executed for overall survival (OS) and cancer-specific survival (CSS). Independent predictive indicators were applied to develop nomograms. The model's performance was evaluated using many different methods. Results: Of a total of 328 cases, 153 cases were in group 0, 145 in group 1, and 30 in group 2. In terms of OS or CSS, there were obvious differences between groups 0 and 1, and between groups 0 and 2. Age, obstruction, N stage, gross tumor type, and M-NPS group were independent prognostic indicators for OS, while obstruction, gross tumor type, M-NPS group, and N stage were independent predictive parameters for CSS. Furthermore, the training and validation sets were randomly allocated among a cohort of 328 patients. OS and CSS prediction nomograms were developed. In the training and validation cohort, the C-index and ROC analysis showed good discrimination, calibration curves exhibited an excellent level of consistency between model-predicted survival and actual survival outcomes, and DCA curves demonstrated good clinical performance. Conclusion: M-NPS is a reliable survival predictor in patients with curative stage II-III colon cancer. Nomograms incorporating M-NPS for OS and CSS have good predictive performance and clinical utility.
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The prevailing opinion emphasizes fronto-parietal network (FPN) is key in mediating general fluid intelligence (gF). Meanwhile, recent studies show that human MT complex (hMT+), located at the occipito-temporal border and involved in 3D perception processing, also plays a key role in gF. However, the underlying mechanism is not clear, yet. To investigate this issue, our study targets visuo-spatial intelligence, which is considered to have high loading on gF. We use ultra-high field magnetic resonance spectroscopy (MRS) to measure GABA/Glu concentrations in hMT+ combining resting-state fMRI functional connectivity (FC), behavioral examinations including hMT+ perception suppression test and gF subtest in visuo-spatial component. Our findings show that both GABA in hMT+ and frontal-hMT+ functional connectivity significantly correlate with the performance of visuo-spatial intelligence. Further, serial mediation model demonstrates that the effect of hMT+ GABA on visuo-spatial gF is fully mediated by the hMT+ frontal FC. Together our findings highlight the importance in integrating sensory and frontal cortices in mediating the visuo-spatial component of general fluid intelligence.
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Lobo Frontal , Inteligência , Imageamento por Ressonância Magnética , Ácido gama-Aminobutírico , Humanos , Lobo Frontal/fisiologia , Lobo Frontal/diagnóstico por imagem , Masculino , Ácido gama-Aminobutírico/metabolismo , Inteligência/fisiologia , Feminino , Adulto Jovem , Adulto , Espectroscopia de Ressonância Magnética/métodos , Percepção Espacial/fisiologiaRESUMO
The gut microbiota plays an important role in the development and treatment of hepatocellular carcinoma (HCC). However, the implication of specific gut microbiota in targeted sorafenib therapy for advanced HCC and the microbiota mode of action, remain to be elucidated. Here, we confirmed that four bacterial genera, Lachnoclostridium, Lachnospira, Enterobacter and Enterococcus, are associated with the therapeutic efficacy of Sorafenib, and that Enterobacter faecium (Efm) plays a crucial role in modulating the sorafenib activity. The effective colonization by Emf induced the IL-12 and IFN-γ production and an increased proportion of IFN-γ+CD8+ T cells in the tumor microenvironment. Finally, exopolysaccharides (EPS) from Efm were the primary inducer to prompt IFN-γ+CD8+ T cells to secrete IFN-γ, which together with sorafenib instigated ferroptosis in HCC cells. Collectively, these results indicate that Efm is a promising probiotics that enhances the efficacy of sorafenib treatment in advanced HCC.
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Linfócitos T CD8-Positivos , Carcinoma Hepatocelular , Enterococcus faecium , Ferroptose , Interferon gama , Neoplasias Hepáticas , Sorafenibe , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/microbiologia , Interferon gama/metabolismo , Interferon gama/imunologia , Humanos , Enterococcus faecium/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Animais , Ferroptose/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Probióticos/farmacologia , Masculino , Microambiente Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/farmacologiaRESUMO
Metal-organic frameworks (MOFs) have been widely used as versatile precursors to fabricate functional nanomaterials with well-defined structures for various applications. Herein, the presynthesized Ni-MOF nanosheets were grown on a Ni foam (NF) substrate, which then guided the nucleation and further growth of Prussian blue analogues (PBA) nanocubes to form MOF-on-MOF of the PBA/Ni-MOF film. This film was subsequently converted into a Co2P/Ni2P heterostructure. The NF-supported Co2P/Ni2P composites exhibited excellent supercapacitor performance, delivering a high specific capacity of 5124.2 mF cm-2 at 1 mA cm-2 and a remarkable capacity retention of 80.69% after 3000 cycles at 10 mA cm-2. An asymmetric supercapacitor assembled using Co2P/Ni2P/NF as the cathode and activated carbon as the anode yielded a maximum energy density of 0.34 mWh cm-2 at a power density of 1.50 mW cm-2. The enhanced supercapacitor performance is attributed to the synergistic effects of the Ni2P and Co2P components with multiple valence states as well as the unique hierarchical structure, which provides efficient pathways for electron and ion transport while mitigating volume expansion during energy storage. This synthetic strategy demonstrates an effective approach to fabricate phosphide-based hybrid materials for high-performance supercapacitor applications.
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Extracellular vesicles (EVs) derived from cancer cells are crucial mediators of intercellular communication during tumor progression. The cargo in tumor-derived EVs that facilitates the establishment of a tumor-supportive microenvironment could serve as a therapeutic target to improve cancer treatment. Here, we demonstrated that hepatocellular carcinoma (HCC) cells secreted the acyl-CoA synthetase ACSL4 in large extracellular vesicles (lEVs) to modulate tumor-microenvironment interactions that promote HCC progression. HCC-derived lEV ACSL4 increased the intracellular abundance of polyunsaturated fatty acid-containing lipids and remodeled the lipid profile to potentiate lipid peroxidation in peritumoral hepatocytes, resulting in hepatocyte senescence accompanied by the senescence-associated secretory phenotype (SASP). Depletion of senescent hepatocytes by senolytic treatment suppressed tumor progression. In HCC cells, SREBP2-mediated transcriptional activation upregulated ACSL4 expression, and Akt-mediated phosphorylation of ACSL4 induced its packaging into lEVs by augmenting its interaction with Annexin A2. This study identified the critical regulatory function of ACSL4 secreted from HCC cells in inducing lipid remodeling and senescence in hepatocytes to support HCC progression, suggesting that targeting lEV ACSL4 is a potential therapeutic strategy for HCC.
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The limit of energy saving in the control of small systems has recently attracted much interest due to the concept refinement of the Maxwell demon. Inspired by a newly proposed set of fluctuation theorems, we report the first experimental verification of these equalities and inequalities in an ultracold ^{40}Ca^{+} ion system, confirming the intrinsic nonequilibrium in the system due to involvement of the demon. Based on elaborately designed demon-involved control protocols, such as the Szilard engine protocol, we provide experimentally quantitative evidence of the dissipative information and observe tighter bounds of both the extracted work and the demon's efficacy than the limits predicted by the Sagawa-Ueda theorem. Our results substantiate a close connection between the physical nature of information and nonequilibrium processes at the microscale, which help to further understand the thermodynamic characteristics of information and the optimal design of nanoscale and smaller systems.
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BACKGROUND: Accurate prediction of peritoneal recurrence for gastric cancer (GC) is crucial in clinic. The collagen alterations in tumor microenvironment affect the migration and treatment response of cancer cells. Herein, we proposed multitask machine learning-based tumor-associated collagen signatures (TACS), which are composed of quantitative collagen features derived from multiphoton imaging, to simultaneously predict peritoneal recurrence (TACSPR) and disease-free survival (TACSDFS). METHODS: Among 713 consecutive patients, with 275 in training cohort, 222 patients in internal validation cohort, and 216 patients in external validation cohort, we developed and validated a multitask machine learning model for simultaneously predicting peritoneal recurrence (TACSPR) and disease-free survival (TACSDFS). The accuracy of the model for prediction of peritoneal recurrence and prognosis as well as its association with adjuvant chemotherapy were evaluated. RESULTS: The TACSPR and TACSDFS were independently associated with peritoneal recurrence and disease-free survival in three cohorts, respectively (all P < 0.001). The TACSPR demonstrated a favorable performance for peritoneal recurrence in all three cohorts. In addition, the TACSDFS also showed a satisfactory accuracy for disease-free survival among included patients. For stage II and III diseases, adjuvant chemotherapy improved the survival of patients with low TACSPR and low TACSDFS, or high TACSPR and low TACSDFS, or low TACSPR and high TACSDFS, but had no impact on patients with high TACSPR and high TACSDFS. CONCLUSIONS: The multitask machine learning model allows accurate prediction of peritoneal recurrence and survival for GC and could distinguish patients who might benefit from adjuvant chemotherapy.
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Previous studies have indicated that various blood cell traits are associated with a higher risk of venous thromboembolism (VTE). However, the causal relationship remains uncertain. We collected data from the China pulmonary thromboembolism registry study and the China pulmonary health study, using propensity score matching and two-sample Mendelian randomization analyses with summary statistics from genome-wide association studies of blood cell traits and VTE in the East Asian population. Our findings revealed that platelet (PLT) count and hemoglobin (Hb) levels were significantly higher in VTE patients compared to the general population (p value <0.01). Genetically predicted Hb levels were positively associated with VTE, with an odds ratio (OR) of 2.38 (1.13-5.01), p value = 0.022. Similarly, genetically predicted PLT count was positively correlated with VTE, with an OR of 1.33 (1.02-1.74), p value = 0.038. These results suggest a causal relationship and potential targets for prevention.
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Chronic pain induced by pathological insults to the sensorimotor system is a typical form of neuropathic pain (NP), and the underlying mechanism is complex. Currently, there are no successful therapeutic interventions for NP. Orexin B is a neuropeptide with a wide range of biological functions. However, the pharmacological function of orexin B in chronic neuropathic pain has been less studied. Here, we aim to examine the neuroprotective effects of orexin B in chronic constriction injury (CCI)- induced NP. Firstly, we found that orexin type 2 receptor (OX2R) but not orexin type 1 receptor (OX1R) was reduced in the spinal cord (SC) of CCI-treated rats. Mechanical withdrawal threshold and thermal withdrawal latency assays display that administration of orexin B clearly ameliorated CCI-evoked neuropathic pain dose-dependently. Notably, orexin B treatment also effectively prevented microglia activation by reducing the levels of IBA1. Additionally, orexin B was also found to suppress the inflammatory response in the SC tissue by reducing the levels of IL-6, TNF-α, iNOS, and COX-2 as well as the production of NO and PGE2 in CCI-treated rats. Furthermore, orexin B administration attenuated oxidative stress (OS) by increasing the activity of SOD and the levels of GSH. Mechanically, orexin B prevented activation of JNK/NF-κB signaling in the SC of CCI-treated rats. Based on these findings, we conclude that orexin B might have a promising role in ameliorating CCI-evoked neuropathic pain through the inhibition of microglial activation and inflammatory response.
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Background: Thoracoscopic surgery is a primary treatment for lung cancer, with lobectomy and mediastinal lymph node dissection being the predominant surgical approaches for invasive lung cancer. While many thoracic surgeons can proficiently perform lobectomy, thorough and standardized lymph node dissection remains challenging. This study aimed to explore a safer and more efficient surgical method for mediastinal lymph node dissection in lung cancer. Methods: A prospective randomized controlled study was conducted, involving 100 patients with right lung cancer who were admitted to our hospital from January 2021 to April 2024 and met the inclusion criteria. These patients were randomly divided into an observation group (tissue pneumoperitoneum technique around lymph nodes group) and a control group (conventional surgery group). Thoracoscopic lobectomy and mediastinal lymph node dissection were performed. Intraoperative and postoperative related indicators were observed to validate the effectiveness and safety of the tissue pneumoperitoneum technique around lymph nodes. Results: The observation group showed a significantly shorter lymph node dissection surgery time compared to the control group, with a statistically significant difference (p < 0.05). The number of lymph nodes dissected in the observation group was significantly higher than that in the control group, with a statistically significant difference (p < 0.05). Although the observation group had slightly more mediastinal lymph node stations dissected than the control group, the difference was not statistically significant (p > 0.05). The total drainage volume within three days postoperatively was comparable between the two groups, with no statistically significant difference (p > 0.05). The observation group had shorter chest tube indwelling time and postoperative hospital stay than the control group, with statistically significant differences (p < 0.05). The incidence of surgical complications was similar between the two groups, and there were no perioperative deaths. Conclusion: The tissue pneumoperitoneum technique around lymph nodes is a more efficient method for mediastinal lymph node dissection in lung cancer, demonstrating safety and feasibility, and is worthy of promotion.
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Programmed death-ligand 1 (PD-L1) on tumor-derived small extracellular vesicles (sEVs) limits therapeutic effectiveness by interacting with the PD-1 receptor on host immune cells. Targeting the secretion of sEV PD-L1 has emerged as a promising strategy to enhance immunotherapy. However, the lack of small-molecule inhibitors poses a challenge for clinical translation. In this study, we developed a target and phenotype dual-driven high-throughput screening strategy that combined virtual screening with nanoflow-based experimental verification. We identified ibuprofen (IBP) as a novel inhibitor that effectively targeted sEV PD-L1 secretion. IBP disrupted the biogenesis and secretion of PD-L1+ sEVs in tumor cells by physically interacting with a critical regulator of sEV biogenesis, hepatocyte growth factor-regulated tyrosine kinase substrate. Notably, the mechanism of action of IBP is distinct from its commonly known targets, cyclooxygenases. Administration of IBP stimulated antitumor immunity and enhanced the efficacy of anti-PD-1 therapy in melanoma and oral squamous cell carcinoma mouse models. To address potential adverse effects, we further developed an IBP gel for topical application, which demonstrated remarkable therapeutic efficacy when combined with anti-PD-1 treatment. The discovery of this specific small inhibitor provides a promising avenue for establishing durable, systemic antitumor immunity.
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Optical flow has made great progress in clean scenes, while suffers degradation under adverse weather due to the violation of the brightness constancy and gradient continuity assumptions of optical flow. Typically, existing methods mainly adopt domain adaptation to transfer motion knowledge from clean to degraded domain through one-stage adaptation. However, this direct adaptation is ineffective, since there exists a large gap due to adverse weather and scene style between clean and real degraded domains. Moreover, even within the degraded domain itself, static weather (e.g., fog) and dynamic weather (e.g., rain) have different impacts on optical flow. To address above issues, we explore synthetic degraded domain as an intermediate bridge between clean and real degraded domains, and propose a cumulative homogeneous-heterogeneous adaptation framework for real adverse weather optical flow. Specifically, for clean-degraded transfer, our key insight is that static weather possesses the depth-association homogeneous feature which does not change the intrinsic motion of the scene, while dynamic weather additionally introduces the heterogeneous feature which results in a significant boundary discrepancy in warp errors between clean and degraded domains. For synthetic-real transfer, we figure out that cost volume correlation shares a similar statistical histogram between synthetic and real degraded domains, benefiting to holistically aligning the homogeneous correlation distribution for synthetic-real knowledge distillation. Under this unified framework, the proposed method can progressively and explicitly transfer knowledge from clean scenes to real adverse weather. In addition, we further collect a real adverse weather dataset with manually annotated optical flow labels and perform extensive experiments to verify the superiority of the proposed method. Both the code and the dataset will be available at https://github.com/hyzhouboy/CH2DA-Flow.
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This study aims to investigate the mechanism of Xuanbai Chengqi Decoction in treating acute lung injury(ALI) based on network pharmacology and animal experiments. The potential targets and signaling pathways of Xuanbai Chengqi Decoction in regulating ALI were predicted by network pharmacology. The rat model of ALI was constructed and administrated with different doses of Xuanbai Chengqi Decoction. The pathological changes in the lung tissue of rats were observed by hematoxylin-eosin(HE) staining. The levels of interleukin-6(IL-6), interleukin-1ß(IL-1ß), and tumor necrosis factor-α(TNF-α) in the peripheral blood were measured by enzyme-linked immunosorbent assay(ELISA). The mRNA and protein levels of factors in the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR) signaling pathway were determined by quantitative real-time PCR(qPCR) and Western blot, respectively. A total of 52 compounds from Xuanbai Chengqi Decoction were predicted to be involved in the treatment of ALI, including ß-sitosterol, emodin, stigmasterol, glabridin, and aloe-emodin, which corresponded to 112 targets,and 4 723 targets of ALI were predicted. The compounds and ALI shared 94 common targets. The key targets included TNF, IL-1ß,prostaglandin-endoperoxide synthase 2(PTGS2), and tumor protein 53(TP53). Lipids and atherosclerosis, p53 signaling pathway,IL-17 signaling pathway, and PI3K/Akt signaling pathway were mainly involved in the treatment. Animal experiments showed that compared with the model group, Xuanbai Chengqi Decoction alleviated the pathological changes in the lung tissue, lowered the serum levels of IL-6, IL-1ß, and TNF-α, down-regulated the mRNA and protein levels of PI3K, Akt, and mTOR, and reduced the p-PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR ratios in ALI rats. The results showed that Xuanbai Chengqi Decoction exerted its therapeutic effects on ALI via multiple components, targets, and pathways. Meanwhile, Xuanbai Chengqi Decoction may reduce the inflammation and attenuate the lung injuries of ALI rats by inhibiting the PI3K/Akt/mTOR signaling pathway.
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Lesão Pulmonar Aguda , Medicamentos de Ervas Chinesas , Interleucina-1beta , Farmacologia em Rede , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Masculino , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismoRESUMO
Pneumonia is a common postoperative complication in patients with aneurysmal subarachnoid hemorrhage (aSAH), which is associated with poor prognosis and increased mortality. The aim of this study was to develop a predictive model for postoperative pneumonia (POP) in patients with aSAH. A retrospective analysis was conducted on 308 patients with aSAH who underwent surgery at the Neurosurgery Department of the First Affiliated Hospital of Soochow University. Univariate and multivariate logistic regression and lasso regression analysis were used to analyze the risk factors for POP. Receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the constructed model. Finally, the effectiveness of modeling these six variables in different machine learning methods was investigated. In our patient cohort, 23.4% (n = 72/308) of patients experienced POP. Univariate, multivariate logistic regression analysis and lasso regression analysis revealed age, Hunt-Hess grade, mechanical ventilation, leukocyte count, lymphocyte count, and platelet count as independent risk factors for POP. Subsequently, these six factors were used to build the final model. We found that age, Hunt-Hess grade, mechanical ventilation, leukocyte count, lymphocyte count, and platelet count were independent risk factors for POP in patients with aSAH. Through validation and comparison with other studies and machine learning models, our novel predictive model has demonstrated high efficacy in effectively predicting the likelihood of pneumonia during the hospitalization of aSAH patients.
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Aprendizado de Máquina , Pneumonia , Complicações Pós-Operatórias , Hemorragia Subaracnóidea , Humanos , Hemorragia Subaracnóidea/cirurgia , Hemorragia Subaracnóidea/complicações , Feminino , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Adulto , Fatores de Risco , IdosoRESUMO
This study develops an observational model to assess kidney function recovery and xenogeneic immune responses in kidney xenotransplants, focusing on gene editing and immunosuppression. Two brain-dead patients undergo single kidney xenotransplantation, with kidneys donated by minipigs genetically modified to include triple-gene knockouts (GGTA1, ß4GalNT2, CMAH) and human gene transfers (hCD55 or hCD55/hTBM). Renal xenograft functions are fully restored; however, immunosuppression without CD40-CD154 pathway blockade is ineffective in preventing acute rejection by day 12. This rejection manifests as both T cell-mediated rejection and antibody-mediated rejection (AMR), confirmed by natural killer (NK) cell and macrophage infiltration in sequential xenograft biopsies. Despite donor pigs being pathogen free before transplantation, xenografts and recipient organs test positive for porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) by the end of the observation period, indicating reactivation and contributing to significant immunopathological changes. This study underscores the critical need for extended clinical observation and comprehensive evaluation using deceased human models to advance xenograft success.