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BACKGROUND: Recurrent or metastatic cervical cancer have an extremely low 5-year survival rates about 17% due to limited therapeutic options. CDYL plays a critical role in multiple cancer development, as an oncogene or tumor suppressor in a context-dependent manner. However, the role of CDYL in cervical carcinogenesis has not yet been explored. METHODS: CDYL expression was examined in cervical cancer and cell lines. The effect of CDYL/IRF2BP2/PD-L1 axis on malignant phenotypes of cervical cancer cells were tested with gain-of-function experiments. A mouse model of cervical cancer was developed to validate the in vitro results. RESULTS: Clinical data analysis revealed that CDYL was downregulated and associated with a poor prognosis in cervical cancer patients. CDYL overexpression suppressed cervical cancer cells proliferation and invasion in vitro and vivo assays and enhanced the immune response by decreasing PD-L1 expression and reversing the tumor immunosuppressing microenvironment. Mechanistically, CDYL inhibited the PD-L1 expression through transcriptionally suppressing IRF2BP2 in cervical cancer cells. CONCLUSIONS: Taken together, our findings established the crucial role of CDYL in cervical carcinogenesis and sensitivity for immune checkpoint blockade therapy, and supported the hypothesis that CDYL could be a potential novel immunotherapy response predictive biomarker for cervical cancer patients.
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Platelet-activating factor (PAF) is a potent phospholipid mediator crucial in multiple inflammatory and immune responses through binding and activating the PAF receptor (PAFR). However, drug development targeting the PAFR has been limited, partly due to an incomplete understanding of its activation mechanism. Here, we present a 2.9-Å structure of the PAF-bound PAFR-Gi complex. Structural and mutagenesis analyses unveil a specific binding mode of PAF, with the choline head forming cation-π interactions within PAFR hydrophobic pocket, while the alkyl tail penetrates deeply into an aromatic cleft between TM4 and TM5. Binding of PAF modulates conformational changes in key motifs of PAFR, triggering the outward movement of TM6, TM7, and helix 8 for G protein coupling. Molecular dynamics simulation suggests a membrane-side pathway for PAF entry into PAFR via the TM4-TM5 cavity. By providing molecular insights into PAFR signaling, this work contributes a foundation for developing therapeutic interventions targeting PAF signal axis.
Subject(s)
Platelet Activating Factor , Platelet Membrane Glycoproteins , Receptors, G-Protein-Coupled , Platelet Membrane Glycoproteins/metabolism , Platelet Membrane Glycoproteins/chemistry , Platelet Activating Factor/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/chemistry , Humans , Molecular Dynamics Simulation , Protein Binding , Binding Sites , HEK293 Cells , Signal TransductionABSTRACT
3D graphene porous materials (3GPM), which have low density, large porosity, excellent compressibility, high conductivity, hold huge promise for a wide range of applications. Nevertheless, most 3GPM have brittle and weak network structures, which limits their widespread use. Therefore, the preparation of a robust and elastic graphene porous network is critical for the functionalization of 3GPM. Herein, the recent research of 3GPM with excellent mechanical properties are summarized and the focus is on the effect factors that affect the mechanical properties of 3GPM. Moreover, the applications of elastic 3GPM in various fields, such as adsorption, energy storage, solar steam generation, sensors, flexible electronics, and electromagnetic wave shielding are comprehensively reviewed. At last, the new challenges and perspective for fabrication and functionalization of robust and elastic 3GPM are outlined. It is expected that the perspective will inspire more new ideas in preparation and functionalization of 3GPM.
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OBJECTIVE: To evaluate the impact of previous poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor therapy on the effectiveness of secondary cytoreductive surgery (SCS) in patients with platinum-sensitive recurrent ovarian cancer (PSROC). METHODS: We identified patients with PSROC who underwent SCS at the Cancer Hospital, Chinese Academy of Medical Science, between January 2010 and December 2022. Postoperative complications within 30 days were categorized using the Accordion Severity Grading System. The KaplanâMeier method was used to estimate both overall survival (OS) and progression-free survival (PFS), and multivariate analysis was used to identify independent prognostic factors. RESULTS: Of the 265 patients included, 39 received prior PARP inhibitor therapy (Group A), and 226 did not (Group B). The rates of complete resection after SCS did not significantly differ between the two groups (79.5 % for Group A vs. 81.0 % for Group B; p = 0.766). As of December 2023, Group A exhibited a significantly shorter median PFS (14.2 months) than Group B (22.5 months; p = 0.002). Furthermore, the 3-year OS rate was lower in Group A (72.5 %) than in Group B (82.7 %; p = 0.015). The incidence of severe postoperative complications was comparable between Groups A and B (7.7 % vs. 1.8 %; p = 0.061). Multivariate analysis revealed that prior PARP inhibitor therapy significantly reduced the median PFS (hazard ratio (HR) = 4.434; p = 0.021) and OS (HR = 2.076; p = 0.010). CONCLUSIONS: SCS for PSROC demonstrated reduced efficacy in patients previously treated with PARP inhibitors compared to those without prior PARP inhibitor treatment.
Subject(s)
Cytoreduction Surgical Procedures , Neoplasm Recurrence, Local , Ovarian Neoplasms , Poly(ADP-ribose) Polymerase Inhibitors , Humans , Female , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Middle Aged , Retrospective Studies , Ovarian Neoplasms/surgery , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Aged , Adult , Survival Rate , Progression-Free Survival , Postoperative Complications/epidemiologyABSTRACT
H1N1 influenza virus is a significant global public health concern. Monoclonal antibodies (mAbs) targeting specific viral proteins such as hemagglutinin (HA) have become an important therapeutic strategy, offering highly specific targeting to block viral transmission and infection. This study focused on the development of mAbs targeting HA of the A/Victoria/2570/2019 (H1N1pdm09, VIC-19) strain by utilizing hybridoma technology to produce two mAbs with high binding capacity. Notably, mAb 2B2 has demonstrated a strong affinity for HA proteins in recent H1N1 influenza vaccine strains. In vitro assessments showed that both mAbs exhibited broad-spectrum hemagglutination inhibition and potent neutralizing effects against various vaccine strains of H1N1pdm09 viruses. 2B2 was also effective in animal models, offering both preventive and therapeutic protection against infections caused by recent H1N1 strains, highlighting its potential for clinical application. By individually co-cultivating each of the aforementioned mAbs with the virus in chicken embryos, four amino acid substitution sites in HA (H138Q, G140R, A141E/V, and D187E) were identified in escape mutants, three in the antigenic site Ca2, and one in Sb. The identification of such mutations is pivotal, as it compels further investigation into how these alterations could undermine the binding efficacy and neutralization capacity of antibodies, thereby impacting the design and optimization of mAb therapies and influenza vaccines. This research highlights the necessity for continuous exploration into the dynamic interaction between viral evolution and antibody response, which is vital for the formulation of robust therapeutic and preventive strategies against influenza.
Subject(s)
Antibodies, Monoclonal , Antibodies, Neutralizing , Antibodies, Viral , Hemagglutinin Glycoproteins, Influenza Virus , Influenza A Virus, H1N1 Subtype , Mice, Inbred BALB C , Orthomyxoviridae Infections , Animals , Influenza A Virus, H1N1 Subtype/immunology , Antibodies, Monoclonal/immunology , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Antibodies, Viral/immunology , Mice , Antibodies, Neutralizing/immunology , Orthomyxoviridae Infections/prevention & control , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/virology , Influenza Vaccines/immunology , Influenza Vaccines/administration & dosage , Hemagglutination Inhibition Tests , Humans , Chick Embryo , Female , Influenza, Human/immunology , Influenza, Human/virology , Influenza, Human/prevention & controlABSTRACT
Research on ferroptosis in myocardial ischemia/reperfusion injury (MIRI) using mitochondrial viscosity as a nexus holds great promise for MIRI therapy. However, high-precision visualisation of mitochondrial viscosity remains a formidable task owing to the debilitating electrostatic interactions caused by damaged mitochondrial membrane potential. Herein, we propose a dual-locking mitochondria-targeting strategy that incorporates electrostatic forces and probe-protein molecular docking. Even in damaged mitochondria, stable and precise visualisation of mitochondrial viscosity in triggered and medicated MIRI was achieved owing to the sustained driving forces (e.g., pi-cation, pi-alkyl interactions, etc.) between the developed probe, CBS, and the mitochondrial membrane protein. Moreover, complemented by a western blot, we confirmed that ferrostatin-1 exerts its therapeutic effect on MIRI by improving the system xc-/GSH/GPX4 antioxidant system, confirming the therapeutic value of ferroptosis in MIRI. This study presents a novel strategy for developing robust mitochondrial probes, thereby advancing MIRI treatment.
Subject(s)
Ferroptosis , Myocardial Reperfusion Injury , Ferroptosis/drug effects , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Molecular Docking Simulation , Animals , Mitochondria/metabolism , Mitochondria/drug effects , Humans , Cyclohexylamines/chemistry , Cyclohexylamines/pharmacology , Phenylenediamines/chemistry , Phenylenediamines/pharmacologyABSTRACT
Mineral extraction in resource-based cities has caused serious damage to the original ecology, resulting in poor regional vegetation growth, reduced carbon sequestration capacity, and reduced ecosystem resilience. Especially in resource-based cities with fragile ecology, the overall anti-interference ability of the environment is relatively worse. Seeking ecological network optimization solutions that can improve vegetation growth conditions on a large scale is an effective way to enhance the resilience of regional ecosystems. This paper introduces carbon sequestration indicators and designs a differential ecological networks (ENs) optimization model (FTCC model) to achieve the goal of improving ecosystem resilience. The model identifies the patches that need to be optimized and their optimization directions based on the differences in ecological function-topology-connectivity-carbon sequestration of the patches. Finally, the resilience of the ecological network before and after optimization was compared, proving that the model is effective. The results show that the sources in the Yulin ENs form three main clusters, with connectivity between clusters relying on only a few patches. The patches in the northeastern and southwest clusters are large but their ecological functions need to be improved. After optimization, 16 new stepping stones were added, 38 new corridors were added, and the ecological function of 39 patches was enhanced. The optimized ecological network resilience was improved in terms of structure, function, and carbon sinks, and carbon sinks increased by 6364.5 tons. This study provides a reference for measures to optimize landscape space and manage ecosystem resilience enhancement in resource-based cities.
Subject(s)
Ecosystem , Resilience, Psychological , Ecology , Cities , Conservation of Natural Resources , ChinaABSTRACT
Liver disease, a major health concern worldwide, is a serious and progressive disorder. Herein, we not only established a mouse model of DEN+CCl4-induced primary liver disease but also collected clinical human samples to investigate longitudinal alterations in the gut mycobiome. As liver disease advanced, gut integrity was disrupted, and the mycobiota was disturbed in the mouse models. The metabolites associated with hepatocellular carcinoma (HCC) differed from those associated with the cirrhotic phase as follows: levels of stercobilin and aflatoxin B1 dialcohol were reduced, while levels of triterpenoids, bafilomycin A1, and DHEA were increased in the HCC group. The abundance of the phylum Chytridiomycota increased as the chronic liver disease progressed and was then replaced by the phylum Ascomycota in HCC. Based on the results from clinical human samples, the genus Candida (Ascomycota) (in humans) and the genus Kazachstania (Ascomycota) (in mice) occupied a dominant position in the HCC group, while other fungi were depleted. The increased abundance of C. albicans and depletion of S. cerevisiae may be hallmarks of the progression of liver cirrhosis to early HCC. Moreover, the administration of C. albicans and S. cerevisiae in the LC-HCC progression could accelerate or retard the progression of HCC. Therefore, gut fungi have the potential to serve as a noninvasive clinical biomarker and even a treatment method.
Subject(s)
Biomarkers , Carcinoma, Hepatocellular , Disease Progression , Gastrointestinal Microbiome , Liver Neoplasms , Animals , Humans , Mice , Biomarkers/metabolism , Liver Neoplasms/microbiology , Liver Neoplasms/metabolism , Carcinoma, Hepatocellular/microbiology , Carcinoma, Hepatocellular/metabolism , Male , Liver Cirrhosis/microbiology , Liver Cirrhosis/metabolism , Disease Models, Animal , Ascomycota , Mice, Inbred C57BL , Liver Diseases/microbiology , Liver Diseases/metabolism , Fungi/classification , Fungi/metabolism , Candida albicans/metabolismABSTRACT
BACKGROUNDS: Immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of an immunogenic niche. Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However, evidence illustrates that targeting FAK is most effective in combination therapy rather than in monotherapy. METHODS: Here, we used drug screening, in vitro and in vivo assays to filter out that doxorubicin and its liposomal form pegylated liposome doxorubicin (PLD) showed synergistic anti-tumor effects in combination with FAK inhibitor IN10018. We hypothesized that anti-tumor immunity and immunogenic cell death (ICD) may be involved in the treatment outcomes through the data analysis of our clinical trial testing the combination of IN10018 and PLD. We then performed cell-based assays and animal studies to detect whether FAK inhibition by IN10018 can boost the ICD of PLD/doxorubicin and further established syngeneic models to test the antitumor effect of triplet combination of PLD, IN10018, and ICB. RESULTS: We demonstrated that the combination of FAK inhibitor IN10018, and PLD/doxorubicin exerted effective antitumor activity. Notably, the doublet combination regimen exhibited response latency and long-lasting treatment effects clinically, outcomes frequently observed in immunotherapy. Our preclinical study confirmed that the 2-drug combination can maximize the ICD of cancer cells. This approach primed the tumor microenvironment, supplementing it with sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. Finally, different animal studies confirmed that the antitumor effects of ICB can be significantly enhanced by this doublet regimen. CONCLUSIONS: We confirmed that targeting FAK by IN10018 can enhance the ICD of PLD/doxorubicin, further benefiting the anti-tumor effect of ICB. The animal tests of the triplet regimen warrant further discovery in the real world.
Subject(s)
Liposomes , Neoplasms , Animals , Humans , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Focal Adhesion Protein-Tyrosine Kinases/antagonists & inhibitors , Focal Adhesion Protein-Tyrosine Kinases/drug effects , Immune Checkpoint Inhibitors/therapeutic use , Immunogenic Cell Death , Neoplasms/drug therapy , Neoplasms/pathology , Polyethylene Glycols , Tumor MicroenvironmentABSTRACT
BACKGROUND: Most patients with ovarian cancer (OC) treated with platinum-based chemotherapy have a dismal prognosis owing to drug resistance. However, the regulatory mechanisms of circular RNA (circRNA) and p53 ubiquitination are unknown in platinum-resistant OC. We aimed to identify circRNAs associated with platinum-resistant OC to develop a novel treatment strategy. METHODS: Platinum-resistant circRNAs were screened through circRNA sequencing and validated using quantitative reverse-transcription PCR in OC cells and tissues. The characteristics of circNUP50 were analysed using Sanger sequencing, oligo (dT) primers, ribonuclease R and fluorescence in situ hybridisation assays. Functional experimental studies were performed in vitro and in vivo. The mechanism underlying circNUP50-mediated P53 ubiquitination was investigated through circRNA pull-down analysis and mass spectrometry, luciferase reporters, RNA binding protein immunoprecipitation, immunofluorescence assays, cycloheximide chase assays, and ubiquitination experiments. Finally, a platinum and si-circNUP50 co-delivery nanosystem (Psc@DPP) was constructed to treat platinum-resistant OC in an orthotopic animal model. RESULTS: We found that circNUP50 contributes to platinum-resistant conditions in OC by promoting cell proliferation, affecting the cell cycle, and reducing apoptosis. The si-circNUP50 mRNA sequencing and circRNA pull-down analysis showed that circNUP50 mediates platinum resistance in OC by binding p53 and UBE2T, accelerating p53 ubiquitination. By contrast, miRNA sequencing and circRNA pull-down experiments indicated that circNUP50 could serve as a sponge for miR-197-3p, thereby upregulating G3BP1 to mediate p53 ubiquitination, promoting OC platinum resistance. Psc@DPP effectively overcame platinum resistance in an OC tumour model and provided a novel idea for treating platinum-resistant OC using si-circNUP50. CONCLUSIONS: This study reveals a novel molecular mechanism by which circNUP50 mediates platinum resistance in OC by modulating p53 ubiquitination and provides new insights for developing effective therapeutic strategies for platinum resistance in OC.
Subject(s)
MicroRNAs , Ovarian Neoplasms , Ubiquitin-Conjugating Enzymes , Animals , Humans , Female , Cisplatin/pharmacology , Cisplatin/therapeutic use , MicroRNAs/metabolism , RNA, Circular/genetics , RNA, Circular/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , DNA Helicases/genetics , DNA Helicases/metabolism , Cell Line, Tumor , Poly-ADP-Ribose Binding Proteins/genetics , Poly-ADP-Ribose Binding Proteins/metabolism , RNA Helicases/genetics , RNA Helicases/metabolism , RNA Helicases/therapeutic use , RNA Recognition Motif Proteins/genetics , RNA Recognition Motif Proteins/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Ubiquitination , Cell Proliferation , Drug Resistance, NeoplasmABSTRACT
Grass carp (Ctenopharyngodon idellus) is the most productive freshwater fish in China, but its traditional aquaculture model still has problems, such as poor water quality and frequent diseases. We have taken monoculture and 80:20 polyculture grass carp ponds as the research object and used EwE software to build the Ecopath model of two ponds. We analyzed and compared the characteristics of ecological structure and energy flow in two ponds. The result showed the highest effective trophic level in the polyculture pond that was higher than that in the monoculture pond, and fish in polyculture had higher EE values which showed the production of fish in polyculture contributed more to the energy conversion efficiency of the ecosystem. Flows into detritus were the largest component of TST both in the two ponds, which accounted for 49.34% and 50.37%. And the average transfer efficiency in monoculture was 13.07%, while that in polyculture was 15.6%. The ascendency/total development capacity (A/TDC) and overhead/total development capacity (O/TDC) were 0.35 and 0.65 both in the two ponds, respectively, which indicated that both systems had a strong anti-perturbation ability, but the stability could be improved. Finn's cycling index (FCI) in polyculture was higher and showed that the polyculture pond was more mature and stable. Unused energy of functional groups will flow to detritus, and that in the monoculture pond was higher, the energy of C. idellus that flowed to detritus in monoculture was 48.17% higher than that in polyculture; unused energy of bacteria and phytoplankton were also high. The result showed that polyculture could improve energy utilization, increase transfer efficiency, and raise the stability of the ecosystem. Grass carp ponds still need to be improved in the aspects of mixed species and energy consumption. It is necessary to improve the ecological and economic benefits of grass carp ponds by optimizing the aquaculture structure and adjusting the aquaculture proportion.
Subject(s)
Carps , Animals , Ponds/chemistry , Ecosystem , Fresh Water , China , AquacultureABSTRACT
BACKGROUND: Although the elderly constitute more than a third of hepatocellular carcinoma (HCC) patients, they have not been adequately represented in treatment and prognosis studies. Thus, there is not enough evidence to guide the treatment of such patients. The objective of this study is to identify the prognostic factors of older patients with HCC and to construct a new prognostic model for predicting their overall survival (OS). METHODS: 2,721 HCC patients aged ≥ 65 were extracted from the public database-Surveillance, Epidemiology, and End Results (SEER) and randomly divided into a training set and an internal validation set with a ratio of 7:3. 101 patients diagnosed from 2008 to 2017 in the First Affiliated Hospital of Zhejiang University School of Medicine were identified as the external validation set. Univariate cox regression analyses and multivariate cox regression analyses were adopted to identify these independent prognostic factors. A predictive nomogram-based risk stratification model was proposed and evaluated using area under the receiver operating characteristic curve (AUC), calibration curves, and a decision curve analysis (DCA). RESULTS: These attributes including age, sex, marital status, T stage, N stage, surgery, chemotherapy, tumor size, alpha-fetoprotein level, fibrosis score, bone metastasis, lung metastasis, and grade were the independent prognostic factors for older patients with HCC while predicting survival duration. We found that the nomogram provided a good assessment of OS at 1, 3, and 5 years in older patients with HCC (1-year OS: (training set: AUC = 0.823 (95%CI 0.803-0.845); internal validation set: AUC = 0.847 (95%CI 0.818-0.876); external validation set: AUC = 0.732 (95%CI 0.521-0.943)); 3-year OS: (training set: AUC = 0.813 (95%CI 0.790-0.837); internal validation set: AUC = 0.844 (95%CI 0.812-0.876); external validation set: AUC = 0.780 (95%CI 0.674-0.887)); 5-year OS: (training set: AUC = 0.839 (95%CI 0.806-0.872); internal validation set: AUC = 0.800 (95%CI 0.751-0.849); external validation set: AUC = 0.821 (95%CI 0.727-0.914)). The calibration curves showed that the nomogram was with strong calibration. The DCA indicated that the nomogram can be used as an effective tool in clinical practice. The risk stratification of all subgroups was statistically significant (p < 0.05). In the stratification analysis of surgery, larger resection (LR) achieved a better survival curve than local destruction (LD), but a worse one than segmental resection (SR) and liver transplantation (LT) (p < 0.0001). With the consideration of the friendship to clinicians, we further developed an online interface (OHCCPredictor) for such a predictive function ( https://juntaotan.shinyapps.io/dynnomapp_hcc/ ). With such an easily obtained online tool, clinicians will be provided helpful assistance in formulating personalized therapy to assess the prognosis of older patients with HCC. CONCLUSIONS: Age, sex, marital status, T stage, N stage, surgery, chemotherapy, tumor size, AFP level, fibrosis score, bone metastasis, lung metastasis, and grade were independent prognostic factors for elderly patients with HCC. The constructed nomogram model based on the above factors could accurately predict the prognosis of such patients. Besides, the developed online web interface of the predictive model provide easily obtained access for clinicians.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Lung Neoplasms , Aged , Humans , Risk Assessment , Fibrosis , PrognosisABSTRACT
Meteorological conditions play a key role in the occurrence and evolution of atmospheric complex pollution. Considering the different pollution formation mechanisms of PM2.5 and O3, statistical calculation and in-depth learning methods were used to construct the PM2.5 and O3 meteorological condition indexes based on long-term pollution meteorological observation data. A research method was developed to study the meteorological characteristics and impact contribution of atmospheric complex pollution by using the meteorological condition index, and quantitative analysis of the distribution and variation of pollution excluding the influence of regional meteorological differences was also conducted. The results showed that in the summer of 2021, the pollution meteorological conditions in the key regions in central and eastern China were generally worse in the north and better in the south(index:"2+26" cities>the border area of Jiangsu, Anhui, Shandong, and Henan>the Yangtze River Delta) and the worst in June and the best in July. The "double high" pollution began to appear when the PM2.5 meteorological condition index>30 and O3 meteorological condition index>100; meanwhile, the unfavorable meteorological conditions for O3 also promoted the increase in PM2.5 concentration, resulting in the frequency of "double high" increases with the increase in O3 meteorological condition index. Compared with that during the same period last year, ρ(PM2.5) of each region decreased by 3.9 µg·m-3, 3.3 µg·m-3, and 1.4 µg·m-3 due to the contribution of the improvement in the pollution meteorological conditions, which is nearly 58.5% on average of the total decrease in PM2.5 concentration. However, the change in O3 pollution meteorological conditions was better in the north and worse in the south, and the overall deterioration in the Yangtze River Delta Region led to approximately 2.8 µg·m-3 growth for the O3 concentration. The PM2.5 and O3 concentrations after excluding the impact of meteorological differences showed different distribution characteristics from the air quality monitoring, in which the high concentrations of PM2.5 were distributed along the Bohai Sea, the inter-provincial border, and the south of the region, whereas the high concentrations of O3 were concentrated along the Taihang Mountains, around Mount Tai, and in parts of the Yangtze River Delta. The daily concentration variations in a single city during a specific pollution control period could be used as a basis for evaluating the effectiveness of local supervision and control, which will provide a reference for the dynamic supervision and daily scheduling of local control management.
ABSTRACT
BACKGROUND: The aim of this retrospective study was to investigate the outcomes of combining physician-modified endograft (PMEG) and in-situ fenestration (ISF) for aortic arch repair. METHODS: A retrospective analysis was performed in 12 patients with aortic arch pathologies who underwent thoracic endovascular aortic repair with PMEG and ISF between June 2019 and February 2020. RESULTS: Revascularizations of supra-aortic arteries were successfully performed in 91.7% patients (11/12). One patient with aberrant right subclavian artery was unsuccessful because of tortuosity and sharp angle. One patient received endovascular exclusion by Viabahn due to artery injury of the femoral access. During the follow-up (mean 22.7 months), one patient underwent Bentall surgery because of retrograde type A aortic dissection, and one patient received coils embolization due to occurrence of a type I endoleak. In addition, one patient died of myocardial infarction 13 months after surgery. Results obtained after computed tomography angiography conï¬rmed patency of all the supra-aortic arteries. CONCLUSIONS: Combining PMEG and ISF could be a feasible option for aortic arch lesions in selected patients. Long-term durability concerns require further evaluation.
Subject(s)
Aortic Aneurysm, Thoracic , Blood Vessel Prosthesis Implantation , Endovascular Procedures , Humans , Aorta, Thoracic/diagnostic imaging , Aorta, Thoracic/surgery , Blood Vessel Prosthesis , Retrospective Studies , Endovascular Aneurysm Repair , Blood Vessel Prosthesis Implantation/adverse effects , Blood Vessel Prosthesis Implantation/methods , Treatment Outcome , Endovascular Procedures/adverse effects , Endovascular Procedures/methods , Stents , Aortic Aneurysm, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/surgery , Prosthesis DesignABSTRACT
Allelopathic interactions between plants serve as powerful tools for weed control. Despite the increasing understanding of the allelopathic mechanisms between different plant species, the inhibitory effects of B. oleracea on weed growth remain poorly understood. In this study, we conducted experiments to demonstrate that B. oleracea extract can suppress the germination of Panicum miliaceum L.varruderale Kit. seeds as well as of the roots, shoots and hypocotyl elongation of P. miliaceum seedlings. Furthermore, we observed that B. oleracea extract reduced the levels of hydrogen peroxide and superoxide anion in the roots while increasing the activities of catalase and ascorbate peroxidase. In the shoots, B. oleracea extract enhanced the activities of superoxide dismutase and peroxidase. Moreover, the use of the extract led to an increase in the content of phytohormones (indole-3-acetic acid, indole-3-acetaldehyde, methyl indole-3-acetate, N6-isoPentenyladenosine, dihydrozeatin-7-glucoside, abscisic acid and abscisic acid glucose ester) in P. miliaceum seedlings. Interestingly, the aqueous extract contained auxins and their analogs, which inhibited the germination and growth of P. miliaceum. This may contribute to the mechanism of the B. oleracea-extract-induced suppression of P. miliaceum growth.
ABSTRACT
Genetic heterogeneity poses a challenge to research and clinical translation of autism spectrum disorder (ASD). In this study, we conducted a plasma proteomic and metabolomic study of children with ASD with and without risk genes (de novo mutation) and controls to explore the impact of genetic heterogeneity on the search for biomarkers for ASD. In terms of the proteomic and metabolomic profiles, the groups of children with ASD carrying and those not carrying de novo mutation tended to cluster and overlap, and integrating them yielded differentially expressed proteins and differential metabolites that effectively distinguished ASD from controls. The mechanisms associated with them focus on several common and previously reported mechanisms. Proteomics results highlight the role of complement, inflammation and immunity, and cell adhesion. The main pathways of metabolic perturbations include amino acid, vitamin, glycerophospholipid, tryptophan, and glutamates metabolic pathways and solute carriers-related pathways. Integrating the two omics analyses revealed that L-glutamic acid and malate dehydrogenase may play key roles in the pathogenesis of ASD. These results suggest that children with ASD may have important underlying common mechanisms. They are not only potential therapeutic targets for ASD but also important contributors to the study of biomarkers for the disease.
ABSTRACT
Alzheimer's disease (AD) is a severe neurodegenerative disease in older people. Despite some consensus on pathogenesis of AD established by previous researches, further elucidation is still required for better understanding. This study analyzed the eye tissues of 2- and 6-month-old triple transgenic AD (3 × Tg-AD) male mice and age-sex-matched wild-type (WT) mice using a targeted metabolomics approach. Compared with WT mice, 20 and 44 differential metabolites were identified in 2- and 6-month-old AD mice, respectively. They were associated with purine metabolism, pantothenate and CoA biosynthesis, pyruvate metabolism, lysine degradation, glycolysis/gluconeogenesis, and pyrimidine metabolism pathways. Among them, 8 metabolites presented differences in both the two groups, and 5 of them showed constant trend of change. The results indicated that the eye tissues of 3 × Tg-AD mice underwent changes in the early stages of the disease, with changes in metabolites observed at 2 months of age and more pronounced at 6 months of age, which is consistent with our previous studies on hippocampal targeted metabolomics in 3 × Tg-AD mice. Therefore, a joint analysis of data from this study and previous hippocampal study was performed, and the differential metabolites and their associated mechanisms were similar in eye and hippocampal tissues, but with tissue specificity.
Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Humans , Mice , Male , Animals , Aged , Infant , Mice, Transgenic , Metabolomics , GluconeogenesisABSTRACT
In order to study the effects of clean heating measures on the concentration and source of carbonaceous aerosols in PM2.5 in Baoding, we collected PM2.5 samples in Baoding during the winter heating periods of 2014 and 2019. The concentrations of OC and EC in the samples were determined by using a DRI Model 2001A thermo-optical carbon analyzer.The results showed that the average values of ρ(OC) and ρ(EC) in the heating period in 2014 were 60.92 µg·m-3 and 18.15 µg·m-3, and the average values of ρ(OC) and ρ(EC) in the heating period in 2019 were 36.63 µg·m-3 and 6.07 µg·m-3. Compared with those in 2014, the concentrations of OC and EC decreased by 39.87% and 66.56%, respectively, in 2019; the decrease in EC was larger than that in OC, and the meteorological conditions in 2019 were more severe than those in 2014, which was not conducive to the spread of pollutants.The correlation analysis and SOC estimation of OC and EC indicated that the correlation R2 of OC and EC in Baoding in 2014 and 2019 were 0.874 and 0.811, respectively, indicating that OC and EC in Baoding had relatively consistent sources. The average values of ρ(SOC) in 2014 and 2019 were 16.59 µg·m-3 and 11.31 µg·m-3, respectively, and the contribution rates to OC were 27.23% and 30.87%, respectively. This showed that in 2019, compared with that in 2014, the primary pollution decreased, but the secondary pollution increased, and the atmospheric oxidation increased.The analysis of the pollution sources of carbonaceous aerosols revealed that in 2014 and 2019 before and after the implementation of clean heating, the carbonaceous aerosols in the atmosphere were mainly from biomass combustion, coal combustion, and vehicle exhaust emissions. However, the contribution from biomass burning and coal burning decreased in 2019 compared to that in 2014. The decrease in OC and EC concentrations was attributed to the control of coal-fired and biomass-fired sources by clean heating. At the same time, the implementation of clean heating measures reduced the contribution of primary emissions to carbonaceous aerosols in PM2.5 in Baoding City.
ABSTRACT
Bromodomain (BD) is an evolutionarily conserved protein module found in 46 different BD-containing proteins (BCPs). BD acts as a specific reader for acetylated lysine residues (KAc) and serves an essential role in transcriptional regulation, chromatin remodeling, DNA damage repair, and cell proliferation. On the other hand, BCPs have been shown to be involved in the pathogenesis of a variety of diseases, including cancers, inflammation, cardiovascular diseases, and viral infections. Over the past decade, researchers have brought new therapeutic strategies to relevant diseases by inhibiting the activity or downregulating the expression of BCPs to interfere with the transcription of pathogenic genes. An increasing number of potent inhibitors and degraders of BCPs have been developed, some of which are already in clinical trials. In this paper, we provide a comprehensive review of recent advances in the study of drugs that inhibit or down-regulate BCPs, focusing on the development history, molecular structure, biological activity, interaction with BCPs and therapeutic potentials of these drugs. In addition, we discuss current challenges, issues to be addressed and future research directions for the development of BCPs inhibitors. Lessons learned from the successful or unsuccessful development experiences of these inhibitors or degraders will facilitate the further development of efficient, selective and less toxic inhibitors of BCPs and eventually achieve drug application in the clinic.