RESUMEN
ATP-hydrolysis-coupled actin polymerization is a fundamental mechanism of cellular force generation1-3. In turn, force4,5 and actin filament (F-actin) nucleotide state6 regulate actin dynamics by tuning F-actin's engagement of actin-binding proteins through mechanisms that are unclear. Here we show that the nucleotide state of actin modulates F-actin structural transitions evoked by bending forces. Cryo-electron microscopy structures of ADP-F-actin and ADP-Pi-F-actin with sufficient resolution to visualize bound solvent reveal intersubunit interfaces bridged by water molecules that could mediate filament lattice flexibility. Despite extensive ordered solvent differences in the nucleotide cleft, these structures feature nearly identical lattices and essentially indistinguishable protein backbone conformations that are unlikely to be discriminable by actin-binding proteins. We next introduce a machine-learning-enabled pipeline for reconstructing bent filaments, enabling us to visualize both continuous structural variability and side-chain-level detail. Bent F-actin structures reveal rearrangements at intersubunit interfaces characterized by substantial alterations of helical twist and deformations in individual protomers, transitions that are distinct in ADP-F-actin and ADP-Pi-F-actin. This suggests that phosphate rigidifies actin subunits to alter the bending structural landscape of F-actin. As bending forces evoke nucleotide-state dependent conformational transitions of sufficient magnitude to be detected by actin-binding proteins, we propose that actin nucleotide state can serve as a co-regulator of F-actin mechanical regulation.
Asunto(s)
Citoesqueleto de Actina , Actinas , Adenosina Difosfato , Microscopía por Crioelectrón , Citoesqueleto de Actina/química , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestructura , Actinas/química , Actinas/metabolismo , Actinas/ultraestructura , Adenosina Difosfato/química , Adenosina Difosfato/metabolismo , Proteínas de Microfilamentos/metabolismo , Solventes , Aprendizaje Automático , Conformación ProteicaRESUMEN
Since the outbreak of monkeypox (mpox) in 2022, widespread concern has been placed on imposing an urgent demand for specific vaccines that offer safer and more effective protection. Using an efficient and scalable circular RNA (circRNA) platform, we constructed four circRNA vaccines that could induce robust neutralizing antibodies as well as T cell responses by expressing different surface proteins of mpox virus (MPXV), resulting in potent protection against vaccinia virus (VACV) in mice. Strikingly, the combination of the four circular RNA vaccines demonstrated the best protection against VACV challenge among all the tested vaccines. Our study provides a favorable approach for developing MPXV-specific vaccines by using a circular mRNA platform and opens up novel avenues for future vaccine research.
Asunto(s)
Anticuerpos Neutralizantes , Monkeypox virus , ARN Circular , Virus Vaccinia , Animales , Ratones , Virus Vaccinia/genética , Virus Vaccinia/inmunología , ARN Circular/genética , Anticuerpos Neutralizantes/inmunología , Monkeypox virus/inmunología , Monkeypox virus/genética , Anticuerpos Antivirales/inmunología , Vaccinia/prevención & control , Vaccinia/inmunología , Mpox/prevención & control , Mpox/inmunología , Vacunas Virales/inmunología , Vacunas Virales/genética , Humanos , Modelos Animales de Enfermedad , Femenino , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
To orchestrate cell mechanics, trafficking, and motility, cytoskeletal filaments must assemble into higher-order networks whose local subcellular architecture and composition specify their functions. Cross-linking proteins bridge filaments at the nanoscale to control a network's µm-scale geometry, thereby conferring its mechanical properties and functional dynamics. While these interfilament linkages are key determinants of cytoskeletal function, their structural mechanisms remain poorly understood. Plastins/fimbrins are an evolutionarily ancient family of tandem calponin-homology domain (CHD) proteins required to construct multiple classes of actin networks, which feature diverse geometries specialized to power cytokinesis, microvilli and stereocilia biogenesis, and persistent cell migration. Here, we focus on the structural basis of actin network assembly by human T-plastin, a ubiquitously expressed isoform necessary for the maintenance of stable cellular protrusions generated by actin polymerization forces. By implementing a machine-learning-enabled cryo-electron microscopy pipeline for visualizing cross-linkers bridging multiple filaments, we uncover a sequential bundling mechanism enabling T-plastin to bridge pairs of actin filaments in both parallel and antiparallel orientations. T-plastin populates distinct structural landscapes in these two bridging orientations that are selectively compatible with actin networks featuring divergent architectures and functions. Our structural, biochemical, and cell biological data highlight inter-CHD linkers as key structural elements underlying flexible but stable cross-linking that are likely to be disrupted by T-plastin mutations that cause hereditary bone diseases.
Asunto(s)
Actinas , Glicoproteínas de Membrana , Proteínas de Microfilamentos , Citoesqueleto de Actina/metabolismo , Actinas/química , Microscopía por Crioelectrón , Humanos , Glicoproteínas de Membrana/química , Proteínas de Microfilamentos/química , PolimerizacionRESUMEN
Glioblastoma (GBM) poses a significant therapeutic challenge due to its invasive nature and limited drug penetration through the blood-brain barrier (BBB). In response, here we present an innovative biomimetic approach involving the development of genetically engineered exosome nanocatalysts (Mn@Bi2Se3@RGE-Exos) for efficient GBM therapy via improving the BBB penetration and enzyme-like catalytic activities. Interestingly, a photothermally activatable multiple enzyme-like reactivity is observed in such a nanosystem. Upon NIR-II light irradiation, Mn@Bi2Se3@RGE-Exos are capable of converting hydrogen peroxide into hydroxyl radicals, oxygen, and superoxide radicals, providing a peroxidase (POD), oxidase (OXD), and catalase (CAT)-like nanocatalytic cascade. This consequently leads to strong oxidative stresses to damage GBM cells. In vitro, in vivo, and proteomic analysis further reveal the potential of Mn@Bi2Se3@RGE-Exos for the disruption of cellular homeostasis, enhancement of immunological response, and the induction of cancer cell ferroptosis, showcasing a great promise in anticancer efficacy against GBM with a favorable biosafety profile. Overall, the success of this study provides a feasible strategy for future design and clinical study of stimuli-responsive nanocatalytic medicine, especially in the context of challenging brain cancers like GBM.
Asunto(s)
Exosomas , Glioblastoma , Rayos Infrarrojos , Fototerapia , Glioblastoma/tratamiento farmacológico , Glioblastoma/terapia , Humanos , Exosomas/química , Exosomas/metabolismo , Animales , Fototerapia/métodos , Ratones , Catálisis , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Antineoplásicos/química , Antineoplásicos/farmacología , Manganeso/química , Manganeso/farmacología , Barrera Hematoencefálica/metabolismoRESUMEN
A multicolor electrochemiluminescence (ECL) biosensor based on a closed bipolar electrode (BPE) array was proposed for the rapid and intuitive analysis of three prostate cancer staging indicators. First, [Irpic-OMe], [Ir(ppy)2(acac)], and [Ru(bpy)3]2+ were applied as blue, green, and red ECL emitters, respectively, whose mixed ECL emission colors covered the whole visible region by varying the applied voltages. Afterward, we designed a simple Mg2+-dependent DNAzyme (MNAzyme)-driven tripedal DNA walker (TD walker) to release three output DNAs. Immediately after, three output DNAs were added to the cathodic reservoirs of the BPE for incubation. After that, we found that the emission colors from the anode of the BPE changed as a driving voltage of 8.0 V was applied, mainly due to changes in the interfacial potential and faradaic currents at the two poles of the BPE. Via optimization of the experimental parameters, cutoff values of such three indicators at different clinical stages could be identified instantly with the naked eye, and standard precision swatches with multiple indicators could be prepared. Finally, in order to precisely determine the prostate cancer stage, the multicolor ECL device was used for clinical analysis, and the resulting images were then compared with standard swatches, laying the way for accurate prostate cancer therapy.
Asunto(s)
Técnicas Biosensibles , Neoplasias de la Próstata , Masculino , Humanos , Mediciones Luminiscentes/métodos , Fotometría , Neoplasias de la Próstata/diagnóstico , Antígeno Prostático Específico , ADN , Técnicas Biosensibles/métodos , Electrodos , Técnicas Electroquímicas/métodosRESUMEN
Black wolfberry (Lycium ruthenicum Murr.) contains various bioactive metabolites represented by flavonoids, which are quite different among production regions. However, the underlying regulation mechanism of flavonoid biosynthesis governing the bioactivity of black wolfberry remains unclear. Presently, we compared the bioactivity of black wolfberry from five production regions. Multi-omics were performed to construct the regulation network associated with the fruit bioactivity. The detailed regulation mechanisms were identified using genetic and molecular methods. Typically, Qinghai (QH) fruit exhibited higher antioxidant and anti-inflammatory activities. The higher medicinal activity of QH fruit was closely associated with the accumulation of eight flavonoids, especially Kaempferol-3-O-rutinoside (K3R) and Quercetin-3-O-rutinoside (rutin). Flavonoid biosynthesis was found to be more active in QH fruit, and the upregulation of LrFLS, LrCHS, LrF3H and LrCYP75B1 caused the accumulation of K3R and rutin, leading to high medicinal bioactivities of black wolfberry. Importantly, transcription factor LrMYB94 was found to regulate LrFLS, LrCHS and LrF3H, while LrWRKY32 directly triggered LrCYP75B1 expression. Moreover, LrMYB94 interacted with LrWRKY32 to promote LrWRKY32-regulated LrCYP75B1 expression and rutin synthesis in black wolfberry. Transgenic black wolfberry overexpressing LrMYB94/LrWRKY32 contained higher levels of K3R and rutin, and exhibited high medicinal bioactivities. Importantly, the LrMYB94/LrWRKY32-regulated flavonoid biosynthesis was light-responsive, showing the importance of light intensity for the medicinal quality of black wolfberry. Overall, our results elucidated the regulation mechanisms of K3R and rutin synthesis, providing the basis for the genetic breeding of high-quality black wolfberry.
Asunto(s)
Lycium , Lycium/genética , Fitomejoramiento , Flavonoides , Antioxidantes , Rutina , Frutas/genéticaRESUMEN
Nowadays, endoscopic submucosal dissection (ESD) is commonly performed for the removal of large gastrointestinal lesions. Endoscopic mucosal defect closure after ESD is vital to avoid adverse events. In recent years, many innovative instruments have emerged and proved to be beneficial. In this paper, we conducted a thorough literature review and summarized the closure methods for large-size post-ESD mucosal defects over decades. We separated these methods into five categories based on the operational principle: "side closure" method, "ring closure" method, "layered closure" method, "hand suturing closure" method, and "specially designed device closure" method. Side closure with clips assisted by instruments such as threads or loops is applicable for each segment of the gastrointestinal tract to prevent postoperative bleeding. If the defect tension is too large to close with the traditional side closure methods, zigzag closure and ring closure could be applied to gather the bilateral defect edges together and achieve continuous closure. In the stomach and rectum with a high risk of submucosal dead space between the submucosa and muscular layers, side closure methods with muscle layer grasping clip or layered closure methods could enable the involvement of the deep submucosa and muscle layers. The ring closure method and specially designed devices including over-the-scope clip, Overstitch, and X-tack could resolve perforation effectively. Individual closure method requires endoscope reinsertion or sophisticated operation, which may be limited by the deep location and the narrow lumen, respectively. Although specially designed devices are expected to offer promising prospectives, the cost-effectiveness remains to be a problem.
RESUMEN
BACKGROUND: The prevalence of obstructive sleep apnea (OSA) was found to be higher in individuals following COVID-19 infection. However, the intricate mechanisms that underscore this concomitance remain partially elucidated. The aim of this study was to delve deeper into the molecular mechanisms that underpin this comorbidity. METHODS: We acquired gene expression profiles for COVID-19 (GSE157103) and OSA (GSE75097) from the Gene Expression Omnibus (GEO) database. Upon identifying shared feature genes between OSA and COVID-19 utilizing LASSO, Random forest and Support vector machines algorithms, we advanced to functional annotation, analysis of protein-protein interaction networks, module construction, and identification of pivotal genes. Furthermore, we established regulatory networks encompassing transcription factor (TF)-gene and TF-miRNA interactions, and searched for promising drug targets. Subsequently, the expression levels of pivotal genes were validated through proteomics data from COVID-19 cases. RESULTS: Fourteen feature genes shared between OSA and COVID-19 were selected for further investigation. Through functional annotation, it was indicated that metabolic pathways play a role in the pathogenesis of both disorders. Subsequently, employing the cytoHubba plugin, ten hub genes were recognized, namely TP53, CCND1, MDM2, RB1, HIF1A, EP300, STAT3, CDK2, HSP90AA1, and PPARG. The finding of proteomics unveiled a substantial augmentation in the expression level of HSP90AA1 in COVID-19 patient samples, especially in severe conditions. CONCLUSIONS: Our investigation illuminate a mutual pathogenic mechanism that underlies both OSA and COVID-19, which may provide novel perspectives for future investigations into the underlying mechanisms.
Asunto(s)
COVID-19 , Apnea Obstructiva del Sueño , Humanos , Proteómica , SARS-CoV-2 , Biomarcadores , Aprendizaje Automático , Apnea Obstructiva del Sueño/genéticaRESUMEN
BACKGROUND: Social well-being impacts cancer patients' health-related quality of life (HRQOL) and coping style. This secondary analysis was conducted to examine whether advanced prostate cancer survivors who had experienced low social well-being would benefit from a web-based cognitive behavioral stress management (CBSM) intervention. METHOD: APC survivors (N = 192) who had received androgen deprivation therapy (ADT) were randomized to a 10-week CBSM or a health promotion (HP) control condition. A subsample of participants (n = 61) with low pre-intervention SWB (measured by social support from and relationship satisfaction with family and friends) was included in the study. Multilevel models compared participants' PC-specific quality of life (sexual, hormonal, urinary), affect-based psychosocial burden (cancer-related anxiety and distress), and coping strategies at baseline, 6 months, and 12 months. Covariates were included in all models as appropriate. RESULTS: Participants randomized to the CBSM condition showed significantly greater improvements in fear of cancer recurrence and cancer-related intrusive thoughts than those in the HP control condition. A significant condition by time interaction was also found, indicating that CBSM improved participants' PC-related fear in both short- (6 months) and long-term (12 months). However, the CBSM intervention did not significantly impact APC-related symptom burden. Only for the urinary domain, clinically meaningful changes (CBSM vs HP) were observed. In addition, all participants, regardless of condition, reported less coping (e.g., emotion-, problem- and avoidance-focused) over time. CONCLUSION: As predicted, the CBSM intervention improved several affect-based psychosocial outcomes for APC survivors with low baseline SWB.
RESUMEN
Although existing 3D object-detection methods have achieved promising results on conventional datasets, it is still challenging to detect objects in data collected under adverse weather conditions. Data distortion from LiDAR and cameras in such conditions leads to poor performance of traditional single-sensor detection methods. Multi-modal data-fusion methods struggle with data distortion and low alignment accuracy, making accurate target detection difficult. To address this, we propose a multi-modal object-detection algorithm, Snow-CLOCs, specifically for snowy conditions. In image detection, we improved the YOLOv5 algorithm by integrating the InceptionNeXt network to enhance feature extraction and using the Wise-IoU algorithm to reduce dependency on high-quality data. For LiDAR point-cloud detection, we built upon the SECOND algorithm and employed the DROR filter to remove noise, enhancing detection accuracy. We combined the detection results from the camera and LiDAR into a unified detection set, represented using a sparse tensor, and extracted features through a 2D convolutional neural network to achieve object detection and localization. Snow-CLOCs achieved a detection accuracy of 86.61% for vehicle detection in snowy conditions.
RESUMEN
Cow milk consumption (CMC) and downstream alterations of serum metabolites are commonly considered important factors regulating human health status. Foods may lead to metabolic changes directly or indirectly through remodelling gut microbiota (GM). We sought to identify the metabolic alterations in Chinese Peri-/Postmenopausal women with habitual CMC and explore if the GM mediates the CMC-metabolite associations. 346 Chinese Peri-/Postmenopausal women participants were recruited in this study. Fixed effects regression and partial least squares discriminant analysis (PLS-DA) were applied to reveal alterations of serum metabolic features in different CMC groups. Spearman correlation coefficient was computed to detect metabolome-metagenome association. 36 CMC-associated metabolites including palmitic acid (FA(16:0)), 7alpha-hydroxy-4-cholesterin-3-one (7alphaC4), citrulline were identified by both fixed effects regression (FDR < 0.05) and PLS-DA (VIP score > 2). Some significant metabolite-GM associations were observed, including FA(16:0) with gut species Bacteroides ovatus, Bacteroides sp.D2. These findings would further prompt our understanding of the effect of cow milk on human health.
Asunto(s)
Microbioma Gastrointestinal , Leche , Posmenopausia , Humanos , Femenino , Animales , Persona de Mediana Edad , Posmenopausia/sangre , China , Bovinos , Citrulina/sangre , Anciano , Dieta , Metaboloma , Bacteroides , Pueblos del Este de AsiaRESUMEN
The rapid growth of electronic devices, electric vehicles, and mobile energy storage has produced large quantities of spent batteries, leading to significant environmental issues and a shortage of lithium resources. Recycling spent batteries has become urgent to protect the environment. The key to treating spent lithium-ion batteries is to implement green and efficient regeneration. This study proposes a recycling method for the direct regeneration of spent lithium iron phosphate (LFP) batteries using hydrothermal reduction. Ascorbic acid (AA) was used as a low-cost and environmentally friendly reductant to reduce Fe3+ in spent LiFePO4. We also investigated the role of AA in the hydrothermal process and its effects on the electrochemical properties of the regenerated LiFePO4 cathode material (AA-SR-LFP). The results showed that the hydrothermal reduction direct regeneration method successfully produced AA-SR-LFP with good crystallinity and electrochemical properties. AA-SR-LFP exhibited excellent electrochemical properties, with an initial discharge specific capacity of 144.4 mAh g-1 at 1 C and a capacity retention rate of 98.6% after 100 cycles. In summary, the hydrothermal reduction direct regeneration method effectively repairs the defects in the chemical composition and crystal structure of spent LiFePO4. It can be regarded as a green and effective regeneration approach for spent LiFePO4 cathode materials.
RESUMEN
Sepsis is a systemic inflammatory response syndrome caused by infection, with high morbidity and mortality. Sepsis-induced liver injury(SILI) is one of the manifestations of sepsis-induced multiple organ syndrome. At present, there is no recommended pharmacological intervention for the treatment of SILI. traditional Chinese medicine(TCM), based on the holism and dialectical treatment concept, shows the therapeutic characteristics of multi-target and multi-pathway and can comprehensively prevent and treat SILI by interfering with inflammatory factors, inflammatory signaling pathways, and anti-oxidative stress and inhibiting apoptosis. This article reviewed the experimental studies on the treatment of SILI with TCM to clarify its pathogenic mechanism and therapeutic characteristics, so as to provide more ideas and directions for the development or preparation of new drugs.
Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Medicamentos Herbarios Chinos , Sepsis , Humanos , Medicina Tradicional China , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Apoptosis , Transducción de Señal , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacologíaRESUMEN
The aim of this study was to study the effects of microRNA (miR)-485-3p on the inflammatory response and extracellular matrix deposition of human airway smooth muscle cells (HASMCs). The levels of miR-485-3p and WIF1 in peripheral blood of pediatric asthma (PA) patients and controls were examined by quantitative real-time polymerase chain reaction (qRT-PCR). miR-485-3p inhibitor and mimic, together with negative control (NC) inhibitor/ mimic, were transfected into HASMCs treated with tumor necrosis factor (TNF)-α. The levels of eotaxin, interleukin (IL)-8, and IL-6 were analyzed by enzyme-linked immunosorbent assay (ELISA). Cellular immunofluorescence analysis of fibronectin was also performed. The target genes of miR-485-3p were predicted and validated using TargetScan and dual-luciferase reporter gene assay. The protein levels of IL-6, eotaxin, IL-8, collagen III, collagen I, MMP-9, TIMP-1, MMP-2, axin, ß-catenin, phosphorylated ß-catenin, GSK3ß, p-GSK3ß, and WIF1 were tested by Western blot. The level of miR-485-3p was increased, whereas expression of WIF1 was low in PA patients. In TNF-α-induced HASMCs, miR-485-3p overexpression promoted the inflammatory response and the accumulation of extracellular matrix. WIF1 was a direct target of miR-485-3p. Silencing miR-485-3p inhibited activation of Wnt/ß-catenin signaling. The reductions in the inflammatory response and ECM accumulation caused by silencing miR-485-3p were induced by blocking Wnt/ß-catenin signaling. Thus, miRNA-485-3p targets WIF1 and activates Wnt/ß-catenin signaling, facilitating activation of the inflammatory response and ECM accumulation in HASMCs.
Asunto(s)
Asma , MicroARNs , Niño , Humanos , Glucógeno Sintasa Quinasa 3 beta , beta Catenina , Interleucina-6 , MicroARNs/metabolismo , Asma/genética , Miocitos del Músculo Liso/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Proliferación CelularRESUMEN
BACKGROUND: Obesity is highly influenced by heritability and variant effects. While previous genome-wide association studies (GWASs) have successfully identified numerous genetic loci associated with obesity-related traits [body mass index (BMI) and waist-to-hip ratio (WHR)], most causal variants remain unidentified. The high degree of linkage disequilibrium (LD) throughout the genome makes it extremely difficult to distinguish the GWAS-associated SNPs that exert a true biological effect. OBJECTIVE: This study was to identify the potential causal variants having a biological effect on obesity-related traits. METHODS: We used Probabilistic Annotation INTegratOR, a Bayesian fine-mapping method, which incorporated genetic association data (GWAS summary statistics), LD structure, and functional annotations to calculate a posterior probability of causality for SNPs across all loci of interest. Moreover, we performed gene expression analysis using the available public transcriptomic data to validate the corresponding genes of the potential causal SNPs partially. RESULTS: We identified 96 SNPs for BMI and 43 SNPs for WHR with a high posterior probability of causality (> 99%), including 49 BMI SNPs and 24 WHR SNPs which did not reach genome-wide significance in the original GWAS. Finally, we partially validated some genes corresponding to the potential causal SNPs. CONCLUSION: Using a statistical fine-mapping approach, we identified a set of potential causal variants to be prioritized for future functional validation and also detected some novel trait-associated variants. These results provided novel insight into our understanding of the genetics of obesity and also demonstrated that fine mapping may improve upon the results identified by the original GWASs.
Asunto(s)
Estudio de Asociación del Genoma Completo , Obesidad , Humanos , Mapeo Cromosómico/métodos , Estudio de Asociación del Genoma Completo/métodos , Teorema de Bayes , Desequilibrio de Ligamiento , Obesidad/genéticaRESUMEN
Exquisite design of RuO2 -based catalysts to simultaneously improve activity and stability under harsh conditions and reduce the Ru dosage is crucial for advancing energy conversion involving oxygen evolution reaction (OER). Herein, a distinctive cobalt-doped RuOx framework is constructed on Co3 O4 nanocones (Co3 O4 @CoRuOx ) as a promising strategy to realize above urgent desires. Extensive experimental characterization and theoretical analysis demonstrate that cobalt doped in RuOx lattice brings the oxygen vacancies and lattice contraction, which jointly redistribute the electron configuration of RuOx . The optimized d-band center balances the adsorption energies of oxygenated intermediates, lowing the thermodynamical barrier of the rate-determining step; and meanwhile, the over-oxidation and dissolution of Ru species are restrained because of the p-band down-shifting of the lattice oxygen. Co3 O4 @CoRuOx with 3.7 wt.% Ru delivers the extremely low OER overpotentials at 10 mA cm-2 in alkaline (167 mV), neutral (229 mV), and acidic electrolytes (161 mV), and super operating stability over dozens of hours. The unprecedented activity ranks first in all pH-universal OER catalysts reported so far. These findings provide a route to produce robust low-loading Ru catalysts and an engineering approach for regulating the central active metal through synergy of co-existing defects to improve the catalytic performance and stability.
RESUMEN
The renewable electricity-driven hydrogen evolution reaction (HER) coupled with biomass oxidation is a powerful avenue to maximize the energy efficiency and economic feedback, but challenging. Herein, porous Ni-VN heterojunction nanosheets on nickel foam (Ni-VN/NF) are constructed as a robust electrocatalyst to simultaneously catalyze HER and 5-hydroxymethylfurfural electrooxidation reaction (HMF EOR). Benefiting from the surface reconstruction of Ni-VN heterojunction during the oxidation process, the derived NiOOH-VN/NF energetically catalyzes HMF into 2,5-furandicarboxylic acid (FDCA), yielding the high HMF conversion (>99%), FDCA yield (99%), and Faradaic efficiency (>98%) at the lower oxidation potential along with the superior cycling stability. Ni-VN/NF is also surperactive for HER, exhibiting an onset potential of ≈0 mV and Tafel slope of 45 mV dec-1 . The integrated Ni-VN/NF||Ni-VN/NF configuration delivers a compelling cell voltage of 1.426 V at 10 mA cm-2 for the H2 O-HMF paired electrolysis, about 100 mV lower than that for water splitting. Theoretically, for Ni-VN/NF, the superiority in HMF EOR and HER is mainly dominated by the local electronic distribution at the heterogenous interface, which accelerates the charge transfer and optimize the adsorption of reactants/intermediates by modulating the d-band center, therefore being an advisable thermodynamic and kinetic process.
RESUMEN
BACKGROUND: The dose-effect relationship of Long-snake-like moxibustion for chronic fatigue syndrome (CFS) remains poorly understood. In order to address this gap, we designed this trial to assess the association between different treatment duration of Long-snake-like moxibustion and its effects on CFS based on the combination measurements of the subjective patient-reported scales with objective medical infrared imaging technologyâThermal Texture Maps (TTM). METHODS: From December 2020 to January 2022, 60 female CFS patients were recruited and equally allocated to two groups: Group A, receiving 60-min Long-snake-like moxibustion per treatment, and Group B, receiving 30-min Long-snake-like moxibustion per treatment. The treatment was administered 3 times per week for a total of 4 weeks. The primary outcome was defined as the improvement of symptoms measured by the Fatigue scale-14 (FS-14), and secondary outcomes were designated as the improvement in Symptoms Scale of Spleen-Kidney Yang Deficiency, Self-rating depression scale, and Self-rating anxiety scale. TTM scanning was employed twice for CFS patients (before and after 4-week treatment) and once for Healthy control subjects (HCs). RESULTS: At week 4, the scores of FS-14 and Symptoms Scale of Spleen-Kidney Yang Deficiency in Group A were significantly lower than those in Group B (physical fatigue: 5.00 vs. 6.00, with 95%CI - 2.00 to 0.00, p = 0.003; FS-14 total score: 8.00 vs. 9.00, with 95%CI - 3.00 to 0.00, p = 0.012; total score of Symptoms Scale of Spleen-Kidney Yang Deficiency: 9.80 vs. 13.07, with 95%CI - 5.78 to - 0.76, P = 0.012). All thermal radiation values of the two groups increased, and statistical differences in ΔTs between Group A and HCs were not obtained. More significant correlations between symptoms improvements and ΔT changes were observed in Group A, and its ΔT changes in Upper Jiao, Shenque (CV8), Zhongwan (CV12), Danzhong (CV17), Zhiyang (GV9), Dazhui (GV14), upper arm, thoracic segments, lumbar segments, renal region, popliteal fossa strongly correlated with the improvement of Spleen-Kidney Yang Deficiency symptoms. CONCLUSIONS: In the same course of treatment, the positive dose-effect relationship was found between the treatment duration of Long-snake-like moxibustion and CFS effect assessment. 60-min Long-snake-like moxibustion per treatment were associated with optimal clinical response and TTM improvement. TRIAL REGISTRATION: Chinese Clinical Trail Registry (No. ChiCTR2000041000, date of registration: 16 December 2020), http://www.chictr.org.cn/showproj.aspx?proj=62488.
Asunto(s)
Síndrome de Fatiga Crónica , Moxibustión , Humanos , Femenino , Moxibustión/métodos , Síndrome de Fatiga Crónica/terapia , Deficiencia Yang/terapia , Puntos de Acupuntura , BazoRESUMEN
BACKGROUND: Bladder cancer is one of the most common malignant tumors of the urinary system and is associated with a poor prognosis once invasion and distant metastases occur. Epithelial-mesenchymal transition (EMT) drives metastasis and invasion in bladder cancer. Transforming growth factor ß1 (TGF-ß1) and stromal fibroblasts, especially cancer-associated fibroblasts (CAFs), are positive regulators of EMT in bladder cancer. However, it remains unclear how TGF-ß1 mediates crosstalk between bladder cancer cells and CAFs and how it induces stromal fibroblast-mediated EMT in bladder cancer. We aimed to investigate the mechanism of TGF-ß1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells. METHODS: Primary CAFs with high expression of fibroblast activation protein (FAP) were isolated from bladder cancer tissue samples. Subsequently, different conditioned media were used to stimulate the bladder cancer cell line T24 in a co-culture system. Gene set enrichment analysis, a human cytokine antibody array, and cytological assays were performed to investigate the mechanism of TGF-ß1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells. RESULTS: Among the TGF-ß family, TGF-ß1 was the most highly expressed factor in bladder cancer tissue and primary stromal fibroblast supernatant. In the tumor microenvironment, TGF-ß1 was mainly derived from stromal fibroblasts, especially CAFs. In stimulated bladder cells, stromal fibroblast-derived TGF-ß1 promoted bladder cancer cell migration, invasion, and EMT. Furthermore, TGF-ß1 promoted the activation of stromal fibroblasts, inducing CAF-like features, by upregulating FAP in primary normal fibroblasts and a normal fibroblast cell line. Stromal fibroblast-mediated EMT was induced in bladder cancer cells by TGF-ß1/FAP. Versican (VCAN), a downstream molecule of FAP, plays an essential role in TGF-ß1/FAP axis-induced EMT in bladder cancer cells. VCAN may also function through the PI3K/AKT1 signaling pathway. CONCLUSIONS: TGF-ß1 is a critical mediator of crosstalk between stromal fibroblasts and bladder cancer cells. We revealed a new mechanism whereby TGF-ß1 dominated stromal fibroblast-mediated EMT of bladder cancer cells via the FAP/VCAN axis and identified potential biomarkers (FAP, VCAN, N-cadherin, and Vimentin) of bladder cancer. These results enhance our understanding of bladder cancer invasion and metastasis and provide potential strategies for diagnosis, treatment, and prognosis.
Asunto(s)
Factor de Crecimiento Transformador beta1 , Neoplasias de la Vejiga Urinaria , Humanos , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Fibroblastos/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismo , Microambiente Tumoral , Vejiga Urinaria/metabolismo , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Versicanos/metabolismoRESUMEN
Children are the high-risk group for COVID-19, and in need of vaccination. However, humoral and cellular immune responses of COVID-19 vaccine remain unclear in vaccinated children. To establish the rational immunization strategy of inactivated COVID-19 vaccine for children, the immunogenicity of either one dose or two doses of the vaccine in children was evaluated. A prospective cohort study of 322 children receiving inactivated COVID-19 vaccine was established in China. The baseline was conducted after 28 days of the first dose, and the follow-up was conducted after 28 days of the second dose. The median titers of receptor binding domain (RBD)-IgG, and neutralizing antibody (NAb) against prototype strain and Omicron variant after the second dose increased significantly compared to those after the first dose (first dose: 70.0, [interquartile range, 30.0-151.0] vs. second dose: 1261.0 [636.0-2060.0] for RBD-IgG; 2.5 [2.5-18.6] vs. 252.0 [138.6-462.1] for NAb against prototype strain; 2.5 [2.5-2.5] vs. 15.0 [7.8-26.5] for NAb against Omicron variant, all p < 0.05). The flow cytometry results showed that the first dose elicited SARS-CoV-2 specific cellular immunity, while the second dose strengthened SARS-CoV-2 specific IL-2+ or TNF-α+ monofunctional, IFN-γ+ TNF-α+ bifunctional, and IFN-γ- IL-2+ TNF-α+ multifunctional CD4+ T cell responses (p < 0.05). Moreover, SARS-CoV-2 specific memory T cells were generated after the first vaccination, including the central memory T cells and effector memory T cells. The present findings provide scientific evidence for the vaccination strategy of the inactive vaccines among children against COVID-19 pandemic.