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Nanoparticles have been widely applied to treat emulsion-containing wastewater in the form of chemical demulsifiers, such as SiO2, Fe3O4, and graphene oxide (GO). Owing to their asymmetric structures and selective adsorption, Janus nanoparticles show greater application potential in many fields. In the present work, the novel magnetic Janus graphene oxide (MJGO) nanoparticle was successfully prepared by grafting magnetic Fe3O4 to the surface of the JGO, and its demulsifying ability to treat a crude oil-in-water emulsion was evaluated. The MJGO structure and its magnetic intensity were verified by Fourier-transform infrared spectra (FTIR), transmission electron microscopy (TEM), X-ray diffraction (XRD), and magnetization saturation (MS) tests. Compared with GO and JGO, MJGO displayed the superior efficiency (>96%) to demulsify the crude oil-in-water emulsion, which can be attributed to the reduced electrostatic repulsion between MJGO and the emulsion droplets. Furthermore, the effects of pH and temperature on the demulsification performance of MJGO were also studied. Lastly, the recyclability of MJGO largely reduced the cost of demulsifiers in separating crude oil and water. The current research presents an efficient and recyclable demulsifier, which provides a new perspective for the structural design of nanomaterials and their application in the field of demulsification.
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Heart failure (HF) is associated with high rates of morbidity and mortality. The value of deep learning survival prediction models using chest radiographs in patients with heart failure is currently unclear. The aim of our study is to develop and validate a deep learning survival prediction model using chest X-ray (DLSPCXR) in patients with HF. The study retrospectively enrolled a cohort of 353 patients with HF who underwent chest X-ray (CXR) at our institution between March 2012 and March 2017. The dataset was randomly divided into training (n = 247) and validation (n = 106) datasets. Univariate and multivariate Cox analysis were conducted on the training dataset to develop clinical and imaging survival prediction models. The DLSPCXR was trained and the selected clinical parameters were incorporated into DLSPCXR to establish a new model called DLSPinteg. Discrimination performance was evaluated using the time-dependent area under the receiver operating characteristic curves (TD AUC) at 1, 3, and 5-years survival. Delong's test was employed for the comparison of differences between two AUCs of different models. The risk-discrimination capability of the optimal model was evaluated by the Kaplan-Meier curve. In multivariable Cox analysis, older age, higher N-terminal pro-B-type natriuretic peptide (NT-ProBNP), systolic pulmonary artery pressure (sPAP) > 50 mmHg, New York Heart Association (NYHA) functional class III-IV and cardiothoracic ratio (CTR) ≥ 0.62 in CXR were independent predictors of poor prognosis in patients with HF. Based on the receiver operating characteristic (ROC) curve analysis, DLSPCXR had better performance at predicting 5-year survival than the imaging Cox model in the validation cohort (AUC: 0.757 vs. 0.561, P = 0.01). DLSPinteg as the optimal model outperforms the clinical Cox model (AUC: 0.826 vs. 0.633, P = 0.03), imaging Cox model (AUC: 0.826 vs. 0.555, P < 0.001), and DLSPCXR (AUC: 0.826 vs. 0.767, P = 0.06). Deep learning models using chest radiographs can predict survival in patients with heart failure with acceptable accuracy.
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Noble gas xenon (Xe) is an excellent anesthetic gas, but its rarity, high cost and constrained production prohibits wide use in medicine. Here, we have developed a closed-circuit anesthetic Xe recovery and reusage process with highly effective CO2-specific adsorbent CUPMOF-5 that is promising to solve the anesthetic Xe supply problem. CUPMOF-5 possesses spacious cage cavities interconnected in four directions by confinement throat apertures of ~3.4â Å, which makes it an ideal molecular sieving of CO2 from Xe, O2, N2 with the benchmark selectivity and high uptake capacity of CO2. In situ single-crystal X-ray diffraction (SCXRD) and computational simulation solidly revealed the vital sieving role of the confined throat and the sorbent-sorbate induced-fit strengthening binding interaction to CO2. CUPMOF-5 can remove 5 % CO2 even from actual moist exhaled anesthetic gases, and achieves the highest Xe recovery rate (99.8 %) so far, as verified by breakthrough experiments. This endows CUPMOF-5 great potential for the on-line CO2 removal and Xe recovery from anesthetic closed-circuits.
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A novel polymeric ionic liquid (PDBA-IL-NH2) using imidazolium ionic liquids with short alkyl chains as monomers and two control ionic liquids (PDBA-IL-OH and PIL-NH2) were synthesized. Their inhibition properties and mechanisms were explored via surface analysis, weight loss tests, electrochemical studies, and adsorption isotherm analysis. The corrosion inhibition efficiency (CIE) of PDBA-IL-NH2 gradually increased with increasing concentration, and the largest efficiency was 94.67% at 100 ppm. At the same concentration (50 ppm), the corrosion inhibition abilities of inhibitors were in the order of PDBA-IL-NH2 > PDBA-IL-OH > PIL-NH2 > IL-NH2. Based on the experimental investigation, the synergistic effect of electrostatic interaction, protonation, and electron donor-acceptor interaction facilitated the intensive entanglement and coverage of PDBA-IL-NH2 with the reticulated form on the metal, and the generated densest films protected the metal from the corrosive media. Ultimately, the theoretical results of molecular dynamics simulations and quantum chemical study were in high agreement with the experimental data, which confirmed the proposed inhibition mechanisms on the microscopic scale. This study contributed valuable perspectives to the design of efficient and ecofriendly corrosion inhibitors.
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Great aqueous dispersibility, a large specific surface area, and high impermeability make graphene oxide (GO) the ideal candidate for a high-performance corrosion inhibitor. Numerous symmetrical modification methods have been reported to enhance the adsorption of GO on metal surfaces in various corrosive media. This work aims to investigate the enhancement and mechanism of unilateral hydrophobic modification on the corrosion inhibition performance of GO. In this study, amphiphilic Janus GO (JGO) was prepared by grafting hydrophobic alkyl chains on one side of GO, and its anticorrosion performance was evaluated via weight loss experiments and electrochemical tests. The results revealed that the corrosion inhibition efficiency for Q235 mild steel (MS) in a 1 M HCl aqueous solution of 25 ppm JGO (81.08%) was much higher than that of GO at the same concentration (22.12%). Furthermore, the Langmuir adsorption isotherm and computational study demonstrated that the synergistic effect of physical adsorption and chemical adsorption promoted the hydrophilic side of JGO close to the surface of the metal, and the dense protective layer was formed by the hydrophobic chains toward the corrosive medium, which effectively hindered the corrosion of MS by the acidic liquid. This study emphasizes the significant role of asymmetrically modified hydrophobic alkyl chains in improving the corrosion prevention performance of GO and provides a perspective for the structural design of GO-based corrosion inhibitors.
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Potentiation of the effects of currently available antibiotics is urgently required to tackle the rising antibiotics resistance. The pyruvate (P) cycle has been shown to play a critical role in mediating aminoglycoside antibiotic killing, but the mechanism remains unexplored. In this study, we investigated the effects of intermediate metabolites of the P cycle regarding the potentiation of gentamicin. We found that α-ketoglutarate (α-KG) has the best synergy with gentamicin compared to the other metabolites. This synergistic killing effect was more effective with aminoglycosides than other types of antibiotics, and it was effective against various types of bacterial pathogens. Using fish and mouse infection models, we confirmed that the synergistic killing effect occurred in vivo. Furthermore, functional proteomics showed that α-KG downregulated thiosulphate metabolism. Upregulation of thiosulphate metabolism by exogenous thiosulphate counteracted the killing effect of gentamicin. The role of thiosulphate metabolism in antibiotic resistance was further confirmed using thiosulphate reductase knockout mutants. These mutants were more sensitive to gentamicin killing, and less tolerant to antibiotics compared to their parental strain. Thus, our study highlights a strategy for potentiating antibiotic killing by using a metabolite that reduces antibiotic resistance.
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Antibacterianos , Gentamicinas , Ácidos Cetoglutáricos , Antibacterianos/farmacología , Animales , Ácidos Cetoglutáricos/metabolismo , Ácidos Cetoglutáricos/farmacología , Ratones , Gentamicinas/farmacología , Sinergismo Farmacológico , Pruebas de Sensibilidad Microbiana , Bacterias/efectos de los fármacos , Bacterias/genética , Bacterias/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Modelos Animales de EnfermedadRESUMEN
In printing, microreactors, and bioassays, the precise control of micrometer-scale droplet generation is essential but challenging, often restricted by the equipment and nozzles used in traditional methods. We introduce a needle-plate electrode corona discharge technique that injects charges into an oil layer, enabling the precise manipulation of droplet polarization and splitting. This method allows for meticulous adjustment of microdroplet formation regarding location, size, and quantity by modulating the discharge voltage, discharge time, and electrode positioning. It enables the immediate initiation and cessation of droplet production, thereby facilitating on-demand droplet generation. Our study on the voltage-dependent droplet stretch coefficient shows that as the voltage increases, the droplets transition from controlled splitting to regular Taylor cone-like ejections, eventually reaching the Rayleigh limit and fully breaking apart. These advancements significantly improve microfluidic droplet manipulation, offering considerable benefits for applications in targeted drug delivery, rapid disease diagnostics, and precise environmental monitoring.
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PURPOSE: The relationship between plaque progression and pericoronary adipose tissue (PCAT) radiomics has not been comprehensively evaluated. We aim to predict plaque progression with PCAT radiomics features and evaluate their incremental value over quantitative plaque characteristics. PATIENTS AND METHODS: Between January 2009 and December 2020, 500 patients with suspected or known coronary artery disease who underwent serial coronary computed tomography angiography (CCTA) ≥2 years apart were retrospectively analyzed and randomly stratified into a training and testing data set with a ratio of 7:3. Plaque progression was defined with annual change in plaque burden exceeding the median value in the entire cohort. Quantitative plaque characteristics and PCAT radiomics features were extracted from baseline CCTA. Then we built 3 models including quantitative plaque characteristics (model 1), PCAT radiomics features (model 2), and the combined model (model 3) to compare the prediction performance evaluated by area under the curve. RESULTS: The quantitative plaque characteristics of the training set showed the values of noncalcified plaque volume (NCPV), fibrous plaque volume, lesion length, and PCAT attenuation were larger in the plaque progression group than in the nonprogression group ( P < 0.05 for all). In multivariable logistic analysis, NCPV and PCAT attenuation were independent predictors of coronary plaque progression. PCAT radiomics exhibited significantly superior prediction over quantitative plaque characteristics both in the training (area under the curve: 0.814 vs 0.615, P < 0.001) and testing (0.736 vs 0.594, P = 0.007) data sets. CONCLUSIONS: NCPV and PCAT attenuation were independent predictors of coronary plaque progression. PCAT radiomics derived from baseline CCTA achieved significantly better prediction than quantitative plaque characteristics.
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Imidacloprid enters the water environment through rainfall and causes harm to aquatic crustaceans. However, the potential chronic toxicity mechanism of imidacloprid in crayfish has not been comprehensively studied. In this study, red claw crayfish (Cherax quadricarinatus) were exposed to 11.76, 35.27, or 88.17 µg/L imidacloprid for 30 days, and changes in the physiology and biochemistry, gut microbiota, and transcriptome of C. quadricarinatus and the interaction between imidacloprid, gut microbiota, and genes were studied. Imidacloprid induced oxidative stress and decreased growth performance in crayfish. Imidacloprid exposure caused hepatopancreas damage and decreased serum immune enzyme activity. Hepatopancreatic and plasma acetylcholine decreased significantly in the 88.17 µg/L group. Imidacloprid reduced the diversity of the intestinal flora, increased the abundance of harmful flora, and disrupted the microbiota function. Transcriptomic analysis showed that the number of up-and-down-regulated differentially expressed genes (DEGs) increased significantly with increasing concentrations of imidacloprid. DEG enrichment analyses indicated that imidacloprid inhibits neurotransmitter transduction and immune responses and disrupts energy metabolic processes. Crayfish could alleviate imidacloprid stress by regulating antioxidant and detoxification-related genes. A high correlation was revealed between GST, HSPA1s, and HSP90 and the composition of gut microorganisms in crayfish under imidacloprid stress. This study highlights the negative effects and provides detailed sequencing data from transcriptome and gut microbiota to enhance our understanding of the molecular toxicity of imidacloprid in crustaceans.
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Astacoidea , Microbioma Gastrointestinal , Neonicotinoides , Nitrocompuestos , Transcriptoma , Contaminantes Químicos del Agua , Animales , Neonicotinoides/toxicidad , Astacoidea/efectos de los fármacos , Astacoidea/genética , Microbioma Gastrointestinal/efectos de los fármacos , Nitrocompuestos/toxicidad , Transcriptoma/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Insecticidas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Hepatopáncreas/efectos de los fármacos , Hepatopáncreas/metabolismoRESUMEN
The utilization of solar-thermal energy and universal cold energy has led to many innovative designs that achieve effective temperature regulation in different application scenarios. Numerous studies on passive solar heating and radiation cooling often operate independently (or actively control the conversion) and lack a cohesive framework for deep connections. This work provides a concise overview of the recent breakthroughs in solar heating and radiation cooling by employing a mechanism material in the application model. Furthermore, the utilization of dynamic Janus-like behavior serves as a novel nexus to elucidate the relationship between solar heating and radiation cooling, allowing for the analysis of dynamic conversion strategies across various applications. Additionally, special discussions are provided to address specific requirements in diverse applications, such as optimizing light transmission for clothing or window glass. Finally, the challenges and opportunities associated with the development of solar heating and radiation cooling applications are underscored, which hold immense potential for substantial carbon emission reduction and environmental preservation. This work aims to ignite interest and lay a solid foundation for researchers to conduct in-depth studies on effective and self-adaptive regulation of cooling and heating.
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Hydrate-based CO2 storage in the ocean is considered a potential method for mitigating the greenhouse effect. Numerous studies demonstrated that NaCl exhibited the dual effects of promotion and inhibition in the nucleation and growth processes of CO2 hydrate, whose mechanisms remain unclear. In this study, the effects of NaCl at various concentrations on the CO2 hydrate growth and crystal are investigated. The independent gradient model based on Hirshfeld partition, electrostatic potential, and binding energy is conducted to study the interaction between ions and water molecules. The motion trajectories of ions are observed at the molecular level to reflect the impact of ion motion on hydrate growth. The results show that the influence of NaCl on hydrate growth depends on a delicate balance of dual promotion-inhibition effects. NaCl can combine more water molecules and provide a transport channel of CO2 to promote hydrate growth at low concentrations. Meanwhile, the promoting effects shift toward inhibition with increasing NaCl concentrations. In a word, this paper proposes a novel mechanism for the dual promotion-inhibition effects of NaCl on hydrate growth, which is significant for further research on hydrate-based CO2 storage in the ocean.
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Rising wide bandgap semiconductor gallium oxide (Ga2O3) displays huge potential in performing solar-blind photodetection, with constraint in narrow detection wavebands in nature, whereas bandgap modulation through the introduction of exotic atoms into Ga2O3 has an essential effect on the tunable performance of photodetectors and the detection waveband. Here, a novel method for the preparation of (InxGa1-x)2O3 alloy films is proposed, and the continuous tuning of the bandgap in the range of 3.70-4.99 eV is achieved by varying the In-doping content. Alloy-based metal-semiconductor-metal photodetectors were fabricated, achieving a peak responsivity between 254 and 295 nm, superior performance compared to Ga2O3 photodetectors, with a photo-to-dark current ratio as high as 106, and a better optical image-sensing capability. This study offers new insight for high-performance detection of full solar-blind waveband ultraviolet light.
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The creation of self-healing polymers with superior strength and stretchability from biodegradable materials is attracting increasing attention. In this study, we synthesized new biomass-derived cellulose acetate (CA) derivatives by ring-opening graft polymerization of δ-valerolactone followed by the introduction of ureidopyrimidinone (Upy) groups in the polymer side chains. Due to the semicrystalline aliphatic characteristics of the side chain poly(δ-valerolactone) (PVL) and quadruple hydrogen bonds formed by the Upy groups, the stretchability of the resulting polymers was significantly enhanced. Moreover, the shape memory ability and self-healing property (58.3% of self-healing efficiency) were successfully imparted to the polymer. This study demonstrates the great significance of using biomass sources to create self-healing polymers.
This paper describes the first successful demonstration of self-healing polymers with superior strength and stretchability from a biodegradable material, cellulose acetate (CA). We initially introduced the ureidopyrimidinone (Upy) groups in the side chains of CA. However, the resulting polymer was not soluble and processable. In order to solve this issue, a new strategy based on the ring-opening graft polymerization of δ-valerolactone followed by the introduction of ureidopyrimidinone (Upy) groups was adopted. Due to the semicrystalline aliphatic characteristics of the side chain poly(δ-valerolactone) (PVL), the resulting polymers were soluble and processable. In addition, the quadruple hydrogen bonds formed by the Upy groups enhanced the stretchability of the resulting polymers. Moreover, the shape memory ability and self-healing property were successfully achieved due to the presence of PVL and Upy. The developed new strategy can be applied to a variety of polymers including biomass-based polymers and materials.
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The increasing volume of electronic waste (e-waste) poses significant challenges for efficient collection in China. Despite many measures were taken over the past two decades, the e-waste collection rate was still not high. To this end, the Chinese government issued a new policy, the collection target responsibility (CTR) policy. Under the CTR policy, however, it is essential for participants to know how to share the responsibility of collection and how much reasonable targets are set to ensure the efficiency of the collection models. Therefore, the purpose of this paper is to explore the determination of optimal collection targets and the corresponding performance from the perspective of responsibility sharing to support the successful implementation of the CTR. Firstly, the study focuses on participants including the government, manufacturers, and recyclers, and develops three CTR models, independent collection model, government cost-sharing model, and enterprise collaboration model. Secondly, collection target equations for each model are established by employing dynamic differential game analysis, and corresponding collection performances are derived. Thirdly, through practical case simulations, the evolution of collection performance is dynamically analyzed to determine reasonable collection targets for the three models, as 23.8%, 32.3%, and 34.4%, respectively. The findings highlight the effectiveness of CTR in improving e-waste collection targets and performance, with the highest levels attained when the collection responsibilities are shared by government cost-sharing and enterprise collaboration. This study provides theoretical support for setting reasonable collection targets under CTR, and assists decision-makers in developing targeted CTR implementation measures.
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Residuos Electrónicos , Administración de Residuos , Humanos , Reciclaje , ChinaRESUMEN
Cellular RNA is asymmetrically distributed in cells and the regulation of RNA localization is crucial for proper cellular functions. However, limited chemical tools are available to capture dynamic RNA localization in complex biological systems with high spatiotemporal resolution. Here, we developed a new method for RNA proximity labeling activated by near-infrared (NIR) light, which holds the potential for deep penetration. Our method, termed FAP-seq, utilizes a genetically encoded fluorogen activating protein (FAP) that selectively binds to a set of substrates known as malachite green (MG). FAP binding restricts the rotation of MG and rapidly activates its fluorescence in a wash-free manner. By introducing a monoiodo modification to MG, we created a photosensitizer (MG-HI) with the highest singlet oxygen generation ability among various MG derivatives, enabling both protein and RNA proximity labeling in live cells. New insights are provided in the transcriptome analysis with FAP-seq, while a deeper understanding of the symmetry-breaking structural arrangement of FAP-MG-HI was obtained through molecular dynamics simulations. Overall, our wash-free and NIR light-inducible RNA proximity labeling method (FAP-seq) offers a powerful and versatile approach for investigating complex mechanisms underlying RNA-related biological processes.
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Colorantes Fluorescentes , Rayos Infrarrojos , Fármacos Fotosensibilizantes , ARN , Colorantes de Rosanilina , Colorantes de Rosanilina/química , Fármacos Fotosensibilizantes/química , Humanos , Colorantes Fluorescentes/química , ARN/química , ARN/metabolismo , Oxígeno Singlete/metabolismo , Oxígeno Singlete/química , Simulación de Dinámica Molecular , Células HeLaRESUMEN
What is already known about this topic?: The prevalence of monkeypox (mpox) infections is primarily observed among young men who engage in sexual activities with other men, and there is a possibility of sexual transmission. Co-occurring sexually transmitted infections have also been documented. What is added by this report?: In this report, we present a case of a patient in China who was simultaneously diagnosed with mpox, and acute human immunodeficiency virus (HIV) infection. The patient exhibited symptoms of fever and widespread papules on the trunk, face, and genital area. What are the implications for public health practice?: It is crucial for health agencies to prioritize HIV testing when mpox is suspected or diagnosed in individuals with recent engagement in high-risk sexual behavior.
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Inorganic thick-film dielectric capacitors with ultrahigh absolute recovered energy at low electric fields are extremely desired for their wide application in pulsed power systems. However, a long-standing technological bottleneck exists between high absolute energy and large recovered energy density. A new strategy is offered to fabricate selected all-inorganic 0-3 composite thick films up to 10 µm by a modified sol-slurry method. Here, the ceramic powder is dispersed into the sol-gel matrix to form a uniform suspension, assisted by powder, therefore, the 2 µm-thickness after single layer spin coating. To enhance the energy-storage performances, the composites process is thoroughly optimized by ultrafine powder (<50 nm) technique based on a low-cost coprecipitation method instead of the solid-state and sol-gel methods. 0D coprecipitation powder has a similar dielectric constant to the corresponding 3D films, thus uneven electrical field distributions is overcome. Moreover, the increase of interfacial polarization is realized due to the larger specific surface area. A maximum recoverable energy density of 14.62 J cm-3 is obtained in coprecipitation thick films ≈2.2 times that of the solid-state powder and ≈1.3 times for sol-gel powder. This study provides a new paradigm for further guiding the design of composite materials.
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Heat stroke (HS) is a severe medical condition characterized by a systemic inflammatory response that may precipitate multi-organ dysfunction, with a particular predilection for inducing profound central nervous system impairments. We aim to employ bioinformatics techniques for the retrieval and analysis of genes associated with heat stroke-induced neurological damage. We performed a comprehensive analysis of the GSE64778 dataset from the Sequence Read Archive, resulting in the identification of 1178 significantly differentially expressed genes (DEGs). We retrieved 2914 genes associated with heat stroke from the GeneCards database and 2377 genes associated with heat stroke from the Comparative Toxicogenomics Database (CTD). The intersection of the top 300 DEGs in the GSE64778 dataset intersected with the search results of GeneCards and CTD, yielding 25 final candidates for DEGs associated with heat stroke. Gene Ontology functional annotation results indicated that the target genes were mainly involved in apoptosis, stress response, and negative regulation of cellular processes and function in processes such as protein dimerization and protein binding. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed a predominant enrichment of candidate target genes within the PI3K-AKT signaling pathway. Subsequent protein-protein interaction network analysis highlighted HSP90aa1 as a central gene, indicating its pivotal role by possessing the highest number of edges among the genes enriched in the PI3K-AKT signaling pathway. Quantitative reverse transcription-polymerase chain reaction analysis performed on blood samples from patients validated the expression of Hsp90aa1 in individuals exhibiting early neurological damage in HS, consistent with the findings from the mRNA bioinformatics analysis. Additionally, the bioinformatics analysis of the upstream microRNAs (miRNAs) regulating HSP90aa1 and the target miRNAs associated with candidate long non-coding RNAs (lncRNAs) identified three lncRNAs, eight miRNAs, and one mRNA in the regulatory network. The DIANA Tools database and algorithms were employed for pathway enrichment and correlation analysis, revealing a significant association between LOC102547734 and MIR-206-3p, with the latter being identified as a target binding site Moreover, the analysis unveiled a correlation between MIR-206-3p and HSP90aa1, implicating the latter as a potential target binding site within the regulatory network.
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Ontología de Genes , Golpe de Calor , Golpe de Calor/genética , Humanos , Mapas de Interacción de Proteínas/genética , Proteínas HSP90 de Choque Térmico/genética , Redes Reguladoras de Genes , Perfilación de la Expresión Génica , Bases de Datos Genéticas , Biología Computacional/métodos , Estudios de Asociación Genética , Transducción de Señal/genética , Reproducibilidad de los ResultadosRESUMEN
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis. TNBCs with high homologous recombination deficiency (HRD) scores benefit from DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, whereas those with low HRD scores still lack therapeutic options. Therefore, we sought to exploit metabolic alterations to induce HRD and sensitize DNA-damaging agents in TNBCs with low HRD scores. We systematically analyzed TNBC metabolomics and identified a metabolite, guanosine diphosphate (GDP)-mannose (GDP-M), that impeded homologous recombination repair (HRR). Mechanistically, the low expression of the upstream enzyme GDP-mannose-pyrophosphorylase-A (GMPPA) led to the endogenous up-regulation of GDP-M in TNBC. The accumulation of GDP-M in tumor cells further reduced the interaction between breast cancer susceptibility gene 2 (BRCA2) and ubiquitin-specific peptidase 21 (USP21), which promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HRR. Therapeutically, we illustrated that the supplementation of GDP-M sensitized DNA-damaging agents to impair tumor growth in both in vitro (cancer cell line and patient-derived organoid) and in vivo (xenograft in immunodeficient mouse) models. Moreover, the combination of GDP-M with DNA-damaging agents activated STING-dependent antitumor immunity in immunocompetent syngeneic mouse models. Therefore, GDP-M supplementation combined with PARP inhibition augmented the efficacy of anti-PD-1 antibodies. Together, these findings suggest that GDP-M is a crucial HRD-related metabolite and propose a promising therapeutic strategy for TNBCs with low HRD scores using the combination of GDP-M, PARP inhibitors, and anti-PD-1 immunotherapy.
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Neoplasias de la Mama Triple Negativas , Animales , Ratones , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Reparación del ADN por Recombinación , Manosa/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Recombinación Homóloga , Guanosina Difosfato Manosa , Proteína BRCA1/genética , ADN , Ubiquitina Tiolesterasa/metabolismoRESUMEN
OBJECTIVE: To compare intra- and postoperative outcomes between off-clamp and on-clamp robot-assisted partial nephrectomy (RAPN), using data from randomised controlled trials (RCTs) or covariate-matched studies (propensity score-matched or matched-pair analysis). METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant literature review was conducted on PubMed, EMBASE, Scopus and CENTRAL for relevant studies comparing off-clamp to on-clamp RAPN. Primary outcomes were estimated blood loss, postoperative percentage decrease in estimated glomerular filtration rate (eGFR), and margin positive rate. Secondary outcomes were operative time, postoperative eGFR, length of stay, all postoperative complications, major complications, and need for transfusion. Random-effects meta-analyses were performed to generate mean differences (MDs) or odds ratios (ORs). RESULTS: A total of 10 studies (2307 patients) were shortlisted for analysis. There was no significant difference in estimated operative blood loss between off-clamp and on-clamp RAPN (MD 21.9 mL, 95% confidence interval [CI] -0.9 to 44.7 mL; P = 0.06, I2 = 58%). Off-clamp RAPN yielded a smaller postoperative eGFR deterioration (MD 3.10%, 95% CI 1.05-5.16%; P = 0.008, I2 = 13%) and lower odds of margin positivity (OR 0.62, 95% CI 0.40-0.94; P = 0.03, I2 = 0%). No significant differences were found for all secondary outcomes. CONCLUSIONS: Off-clamp and on-clamp RAPN are similarly effective approaches for selected renal masses. Within the classic trifecta of PN outcomes, off-clamp RAPN yields similar rates of perioperative complications and may possibly offer better preservation of renal function and reduced margin-positive rates.