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Enterovirus B (EV-B), a major proportion of the genus Enterovirus in the family Picornaviridae, is the causative agent of severe human infectious diseases. Although cellular receptors for coxsackievirus B in EV-B have been identified, receptors mediating virus entry, especially the uncoating process of echovirus and other EV-B remain obscure. Here, we found that human neonatal Fc receptor (FcRn) is the uncoating receptor for major EV-B. FcRn binds to the virus particles in the "canyon" through its FCGRT subunit. By obtaining multiple cryo-electron microscopy structures at different stages of virus entry at atomic or near-atomic resolution, we deciphered the underlying mechanisms of enterovirus attachment and uncoating. These structures revealed that different from the attachment receptor CD55, binding of FcRn to the virions induces efficient release of "pocket factor" under acidic conditions and initiates the conformational changes in viral particle, providing a structural basis for understanding the mechanisms of enterovirus entry.
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Enterovirus Humano B/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase I/ultraestructura , Receptores Fc/metabolismo , Receptores Fc/ultraestructura , Cápside/metabolismo , Microscopía por Crioelectrón , Enterovirus , Enterovirus Humano B/patogenicidad , Infecciones por Enterovirus/metabolismo , Antígenos de Histocompatibilidad Clase I/fisiología , Humanos , Modelos Moleculares , Filogenia , Receptores Fc/fisiología , Virión , Internalización del VirusRESUMEN
Fe-N-C materials have emerged as highly promising non-noble metal catalysts for oxygen reduction reactions (ORRs) in polymer electrolyte membrane fuel cells. However, they still encounter several challenges that need to be addressed. One of these challenges is establishing an atomic environment near the Fe-N4 site, which can significantly affect catalyst activity. To investigate this, herein, we employed density functional theory (DFT). According to our computational analysis of the Gibbs free energy of the reaction based on the computational hydrogen electrode (CHE) model, we successfully determined two C-O-C structures near the Fe-N4 site (referred to as str-11) with the highest limiting potential (0.813 V). Specifically, in the case of O-doped structures, the neighboring eight carbon (C) atoms around nitrogen (N) can be categorized into two distinct types: four C atoms (type A) exhibiting high sensitivity to the limiting potential and the remaining four C atoms (type B) displaying inert behavior. Electronic structure analysis further elucidated that a structure will have strong activity if the valence band maximum (VBM) around its gamma point is mainly contributed by dxz, dyz or dz2 orbitals of Fe atoms. Constant-potential calculations showed that str-11 is suitable for the ORR under both acidic and alkaline conditions with a limiting potential of 0.695 V at pH = 1 and 0.926 V at pH = 14, respectively. Additionally, microkinetic simulations indicated the possibility of str-11 as the active site for the ORR under working potential at pH = 14.
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BACKGROUND: To assess the mortality and outcomes after thoracic endovascular aortic repair (TEVAR) in patients with type B aortic dissection (TBAD) in mainland China, and to compare these outcomes with data from Western countries, while analyzing the potential reasons for differences among different countries. METHODS: An extensive literature search spanning from January 1999 to October 2023 was conducted using PubMed, Cochrane Library, and Embase databases for studies on endovascular treatment for TBAD. This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Data extraction and analysis followed the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Primary outcomes were in-hospital mortality and mid-term (< 5 years) mortality. RESULTS: Based on 25 publications (3,080 patients), pooled estimate for in-hospital mortality was 2.2% (95% confidence interval, 1.6%-2.9%). Major perioperative complications included stroke (2.4% [1.8%-3.3%]), spinal cord ischemia (1.4% [1.0%-2.2%]), retrograde type A aortic dissection (1.2% [0.8%-1.8%]), type I endoleak (5.6% [3.6%-8.6%]), visceral ischemia (1.0% [0.5%-2.1%]), and acute renal failure (2.8% [2.0%-3.8%]). Mid-term mortality was 5.1% (3.6%-7.3%), and secondary intervention rate was 4.9% (4.0%-6.0%) with 1.7% (1.0%-2.9%) conversion rate to open surgery. In subgroup analysis based on uncomplicated TBAD, in-hospital and mid-term mortality was 0.5% (0.2%-1.5%) and 0.6% (0.2-1.7%), respectively. Compared with data from Western countries, mainland Chinese patients had a lower mortality. CONCLUSIONS: In mainland China, the outcomes of endovascular treatment for TBAD are comparable to those of Western countries. The large number of patients undergoing TEVAR in mainland China and its good performance support the use of TEVAR in uncomplicated TBAD.
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Aneurisma de la Aorta Torácica , Disección Aórtica , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Mortalidad Hospitalaria , Complicaciones Posoperatorias , Humanos , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Disección Aórtica/cirugía , Disección Aórtica/mortalidad , Disección Aórtica/diagnóstico por imagen , China , Aneurisma de la Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/mortalidad , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/mortalidad , Resultado del Tratamiento , Factores de Tiempo , Complicaciones Posoperatorias/mortalidad , Factores de Riesgo , Medición de Riesgo , Masculino , Femenino , Persona de Mediana Edad , Anciano , Reparación Endovascular de AneurismasRESUMEN
Patients with visceral artery aneurysms are rare, and the reported incidence of left gastric aneurysm (LGA) is only 4%. At present, although there is little knowledge about such disease, it is generally believed that appropriate treatment should be planned to prevent some dangerous aneurysms from rupturing. We introduced a case of 83-year-old patient with LGA who underwent endovascular aneurysm repair. The 6-month follow-up computed tomography angiography showed complete thrombosis in the aneurysm lumen. In addition, to insight the management strategy on LGAs deeply, a literature review concerning this entity published in recent 35 years was performed.
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Aneurisma de la Aorta Abdominal , Implantación de Prótesis Vascular , Embolización Terapéutica , Procedimientos Endovasculares , Humanos , Anciano de 80 o más Años , Artería Gástrica/diagnóstico por imagen , Resultado del Tratamiento , Embolización Terapéutica/métodosRESUMEN
PURPOSE: To explore the role of location, length, and thickness of the intimal flap in the propagation of Stanford type B aortic dissection (TBAD) based on ex vivo porcine aorta models based on ex vivo porcine aorta models. MATERIALS AND METHODS: The porcine aortas were harvested and randomly divided into 6 groups to create various TBAD aortic models. We constructed intimal flaps for different locations (group A [entry tear on outer curvature] and group B [entry tear on inner curvature]), lengths (group C [long] and group D [short]), and thicknesses (group E [thick] and group F [thin]). For the ex vivo perfusion experiments conducted on model aortas, an experimental circulation loop (ECL) was employed. The pressure in false lumen (FL) was constantly monitored. A comparison was made between the morphological data collected before and after the experiment to quantify the changes in the FL after the experiment. RESULTS: Compared the results with group B, the mean peak pressures of the FL in group A were lower (106.87±15.55 vs. 124.01±22.75 mm Hg, p=0.028). The mean axial propagation length in group A was shown to be shorter than that of group B (88.14±33.38 vs. 197.43±41.65 mm, p<0.001). The mean peak pressure was higher in group C than in group D (144.04±19.37 vs. 92.51±26.70 mm Hg, p<0.001). The mean peak pressure of group E was higher than that of group F (160.83±32.83 vs. 109.33±15.62 mm Hg, p<0.001), as was the mean axial propagation length of group E (143.11±39.73 vs. 100.45±35.44 mm, p=0.021). According to the results of multivariable linear regression, axial propagation length=45.873-0.703×length of initial FL+0.863× peak pressure (p<0.001). CONCLUSION: There was a relationship between FL propagation and the location, length, and thickness of the intimal flap. The axial propagation length was related to the length of the intimal flap and the peak pressure of propagation. It may be helpful to evaluate the risk of propagation in patients with TBAD. CLINICAL IMPACT: This study found that the locations, lengths, and thickness of the intimal flap significantly contributed to propagation pressure of FL. Using dissection flap characteristics, a physician can predict FL development in a patient and formulate a treatment plan.The purpose was to investigate the relationship between the dissection flap characteristics (location, length, and thickness) and the propagation of the FL, which is not clear at present. This study employed porcine models to create an experimental circulation loop. The perfusion experiment was conducted using a FL without distal re-entry and a non-pulsating flow.
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BACKGROUND: The aim of the study was to analyze the clinical characteristics of patients with Stanford type B aortic dissection (TBAD) and risk factors for poor prognosis after thoracic endovascular aortic repair (TEVAR). METHODS: Clinical records for patients with TBAD presenting to a medical center between March 1, 2012 and July 31, 2020 were reviewed. Clinical data including demographics, comorbidities, and postoperative complications were obtained from electronic medical records. Comparative analysis and subgroup analysis were performed. A logistic regression model was used to analyze prognostic factors in patients with TBAD after TEVAR. RESULTS: TEVAR was performed on all 170 patients with TBAD, and poor prognosis was identified in 28.2% (48/170) of cases. Patients with a poor prognosis were younger (38.5 [32.0, 53.8] years vs. 55.0 [48.0, 62.0] years, P < 0.001), had higher systolic blood pressure (SBP) (138.5 [127.8, 152.8] mm Hg vs. 132.0 [120.8, 145.3] mm Hg, P = 0.013) and more complicated aortic dissection patients (19 [60.4] vs. 71 [41.8], P = 0.029) than those without a poor prognosis. According to the results of binary logic regression analysis, the possibility of a poor prognosis after TEVAR decreased with each 10 years increase in age (odds ratio: 0.464, 95% confidence interval: 0.327-0.658, P < 0.001). CONCLUSIONS: There is an association between younger age and a poor prognosis after TEVAR in patients with TBAD, with the condition that those with poor prognoses have higher SBP and more complicated cases. In younger patients, postoperative follow-up should be more frequent, and complications should be managed in time.
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Aneurisma de la Aorta Torácica , Disección Aórtica , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Humanos , Reparación Endovascular de Aneurismas , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/etiología , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/métodos , Resultado del Tratamiento , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/métodos , Factores de Tiempo , Estudios Retrospectivos , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/cirugía , Factores de RiesgoRESUMEN
Metallic conductive 1T phase molybdenum sulfide (MoS2 ) has been identified as promising anode for sodium ion (Na+ ) batteries, but its metastable feature makes it difficult to obtain and its restacking during the charge/discharge processing result in part capacity reversibility. Herein, a synergetic effect of atomic-interface engineering is employed for constructing 2H-MoS2 layers assembled on single atomically dispersed Fe-N-C (SA Fe-N-C) anode material that boosts its reversible capacity. The work-function-driven-electron transfer occurs from SA Fe-N-C to 2H-MoS2 via the Fe-S bonds, which enhances the adsorption of Na+ by 2H-MoS2 , and lays the foundation for the sodiation process. A phase transfer from 2H to 1T/2H MoS2 with the ferromagnetic spin-polarization of SA Fe-N-C occurs during the sodiation/desodiation process, which significantly enhances the Na+ storage kinetics, and thus the 1T/2H MoS2 /SA Fe-N-C display a high electronic conductivity and a fast Na+ diffusion rate.
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Studies have shown that poly (ADP-ribose) polymerase 1 (PARP1) is involved in the pathological process of diabetes. Mitophagy is widely acknowledged to be a key regulatory process in maintaining reactive oxygen species homeostasis via lysosome degradation of damaged mitochondria. However, the regulatory role of PARP1 in mitophagy-related mitochondrial oxidative injury and progression of painful diabetic neuropathy (PDN) is unclear. In this study, we studied the in vitro and in vivo mechanisms of PARP1-mediated mitophagy blockade in a leptin gene-mutation (db/db) mouse model of PDN. Db/db mice models of PDN were established by assessing the sciatic nerve conduction velocity (SNCV), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL). The results showed that PARP1 activity and mitochondrial injury of dorsal root ganglion (DRG) neurons were increased, and mitophagy was impaired in PDN mice. PARP1 was found to mediate the impairment of mitophagy in DRG neurons isolated from PDN mice. PARP1 inhibitors (PJ34 or AG14361) attenuated diabetes-induced peripheral nerve hyperalgesia, restored DRG neuron mitophagy function and decreased mitochondrial oxidative injury. Mitophagy impairment induced by lysosome deacidificant (DC661) aggravated diabetes-induced DRG neuron mitochondrial oxidative stress and injury. Taken together, our data revealed that PARP1-induced defective mitophagy of DRG neurons is a key mechanism in diabetes-induced peripheral neuropathic injury. Inhibition of PARP1 and restoration of mitophagy function are potential therapeutic targets for PDN.
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Diabetes Mellitus , Neuropatías Diabéticas , Adenosina Difosfato/metabolismo , Animales , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Ganglios Espinales/metabolismo , Ratones , Mitofagia , RibosaRESUMEN
OBJECTIVE: N6-methyladenosine (m6A) mRNA modification triggers malignant behaviors of tumor cells and thereby drives malignant progression in gastric cancer (GC). However, data regarding the prognostic values of m6A RNA methylation-related long non-coding RNAs (lncRNAs) in GC are very limited in the literature. We aimed to investigate the prognostic potential of m6A-related lncRNAs in predicting prognosis and monitoring immunotherapy efficacy in GC patients. METHODS: Transcriptome and clinical data were obtained from GC biopsies from Cancer Genome Atlas (TCGA). M6A-related lncRNAs associated with GC were identified by constructing a co-expression network, and the gene pairs differentially expressed in GC were selected using univariate analysis. We constructed a risk model based on prognosis-related lncRNA pairs selected using the LASSO algorithm and quantified the best cutoff by comparing the area under the curve (AUC) for risk stratification. A risk model with the optimal discrimination between high- and low-risk GC patients was established. Its feasibility for overall survival prediction and discrimination of clinicopathological features, tumor-infiltrating immune cells, and biomarkers of immune checkpoint inhibitors between high- and low-risk groups were assessed. RESULTS: Finally, we identified 11 m6A-related lncRNA pairs associated with GC prognosis based on transcriptome analysis of 375 GC specimens and 32 normal tissues. A risk model was constructed with an AUC of 0.8790. We stratified GC patients into high- and low-risk groups at a cutoff of 1.442. As expected, patients in the low-risk group had longer overall survival versus the high-risk group. Infiltration of cancer-associated fibroblasts, endothelial cells, macrophages, particularly M2 macrophages, and monocytes was more severe in high-risk patients than low-risk individuals, who exhibited high CD4+ Th1 cell infiltration in GC. Altered expressions of immune-related genes were observed in both groups. PD-1 and LAG3 expressions were found higher in low-risk patients than high-risk patients. Immunotherapy, either single or combined use of PD-1 or CTLA4 inhibitors, had better efficacy in low-risk patients than high-risk patients. CONCLUSION: The new risk model based on a 11-m6A-related lncRNA signature can serve as an independent predictor for GC prognosis prediction and may aid in the development of personalized immunotherapy strategies for patients.
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ARN Largo no Codificante , Neoplasias Gástricas , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Células Endoteliales/metabolismo , Humanos , Inmunoterapia , Pronóstico , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapiaRESUMEN
Low molecular weight fucoidan (LMWF) has been reported to have immunomodulation effects through the increase of the activation and function of macrophages. In this study, the regulating effect of LMWF from Undaria pinnatifida grown in New Zealand on dendritic cells (DCs) was investigated. We discovered that LMWF could stimulate DCs' maturation and migration, as well as CD4+ and CD8+ T cells' proliferation in vitro. We proved that this immune promoting activity is activated through TLR4 and its downstream MAPK and NF-κB signaling pathways. Further in vivo (mouse model) investigation showed that LMWF has a strong immunological boosting effect, such as facilitating the proliferation of immune cells and increasing the index of immune organs. These findings suggest that LMWF has a positive immunomodulatory effect and is a promising candidate to supplement cancer immunotherapy.
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Células Dendríticas/efectos de los fármacos , Factores Inmunológicos/farmacología , Polisacáridos/farmacología , Undaria , Animales , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Dendríticas/metabolismo , Factores Inmunológicos/química , Subunidad p40 de la Interleucina-12/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Peso Molecular , FN-kappa B/metabolismo , Nueva Zelanda , Polisacáridos/química , Bazo/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Targeted genome editing technologies are powerful tools for studying biology and disease, and have a broad range of research applications. In contrast to the rapid development of toolkits to manipulate individual genes, large-scale screening methods based on the complete loss of gene expression are only now beginning to be developed. Here we report the development of a focused CRISPR/Cas-based (clustered regularly interspaced short palindromic repeats/CRISPR-associated) lentiviral library in human cells and a method of gene identification based on functional screening and high-throughput sequencing analysis. Using knockout library screens, we successfully identified the host genes essential for the intoxication of cells by anthrax and diphtheria toxins, which were confirmed by functional validation. The broad application of this powerful genetic screening strategy will not only facilitate the rapid identification of genes important for bacterial toxicity but will also enable the discovery of genes that participate in other biological processes.
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Proteínas Asociadas a CRISPR/genética , Células/metabolismo , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Biblioteca de Genes , Genómica/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Antígenos Bacterianos/farmacología , Toxinas Bacterianas/farmacología , Línea Celular , Células/efectos de los fármacos , Toxina Diftérica/farmacología , Humanos , Mutación INDEL/genética , Lentivirus/genética , Transportador 1 de Catión Orgánico/genética , Reproducibilidad de los Resultados , ARN Pequeño no TraducidoRESUMEN
Optical axis pointing accuracy is an important index of airborne electro-optical (EO) platforms. In this work, we aim to correct the optical axis pointing angle of an airborne EO platform by digital compensation. First, a basic parameter model (BPM) of pointing error with clear physical significance is established by analyzing the physical structure and error source of the EO platform. Then, to suppress the nonlinear factors in the error, we propose an improved algorithm of a semi-parametric regression model based on the BPM. Numerical simulation analysis shows that the improved algorithm inherits the advantages of the BPM, such as fewer model parameters and clear physical significance, and can improve the correction effect. Finally, experimental results show that the mean square error of the azimuth angle is reduced from more than 110'' to less than 4'', and that of the elevation angle is reduced from more than 75'' to less than 3''. According to the results obtained, the proposed correction model can improve the optical axis pointing accuracy of an airborne EO platform quickly and effectively, which has significant application value.
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BACKGROUND: Cistanche tubulosa (Schenk) R. Wight is a traditional Chinese medicine that parasitizes the roots of the Tamarix plant and has been used to treat male impotence, sterility, body weakness, and as a tonic. However, its antitumor effect on hepatocellular carcinoma is still elusive. Here, we investigated the antitumor effect of C. tubulosa phenylethanoid glycosides (CTPG) on H22 hepatocellular carcinoma cells both in vitro and in vivo and its mechanisms. METHODS: The morphology, viability, apoptosis, cell cycle and mitochondrial membrane potential (Δψm) of H22 cells were analyzed by inverted microscopy, MTT assay and flow cytometry, respectively. The expression and activation of proteins in apoptosis pathway were detected by Western blot. The in vivo antitumor effect was evaluated in tumor mouse model established using male Kunming mice. RESULTS: CTPG treatment significantly suppressed H22 cell growth in a dose- and time-dependent manner, which was correlated with the increased apoptosis and cell cycle arrest at G0/G1 and G2/M phases. Moreover, the chromosomal condensation was observed in CTPG-treated H22 cells. CTPG treatment significantly increased Bax/Bcl-2 ratio, reduced Δψm and enhanced the release of cytochrome c. The levels of cleaved caspase-8 and caspase-9 in both extrinsic and intrinsic signaling pathways were significantly increased that sequentially activated caspase-7 and -3 to cleave PARP. Finally, CTPG inhibited the growth of H22 cells in mice and improved the survival rate of tumor mice. CONCLUSIONS: These results suggested that CTPG suppressed H22 cell growth through both extrinsic and intrinsic apoptosis pathways.
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Apoptosis/efectos de los fármacos , Cistanche/química , Glicósidos/farmacología , Neoplasias Hepáticas/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Reparación del ADN/efectos de los fármacos , Glicósidos/química , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Extractos Vegetales/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
An enantioselective synthesis of ß-chiral amides through asymmetric and redox-neutral hydroamidation of enals is reported. In this reaction, a chiral N-heterocyclic carbene (NHC) catalyst reacts with enals to generate the homoenolate intermediate. Upon highly enantioselective ß-protonation through proton-shuttle catalysis, the resulting azolium intermediate reacts with imidazole to yield the key ß-chiral acyl species. This transient intermediate provides access to diversified ß-chiral carbonyl derivatives, such as amides, hydrazides, acids, esters, and thioesters. In particular, ß-chiral amides can be prepared in excellent yield and ee (40 chiral amides, up to 95 % yield and 99 % ee). This modular strategy overcomes the challenge of disruption of the highly selective proton-shuttling process by basic amines.
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Remote asymmetric protonation is a longstanding challenge due to the small size of protons. Reactions involving electron-deficient olefins pose a further difficulty due to the electrophilic nature of these substrates. We report a shuttling system that delivers a proton in a highly enantioselective manner to the ß-carbon of enals using a chiral N-heterocyclic carbene (NHC) catalyst. Choices of a Brønsted base shuttle and a Brønsted acid cocatalyst are critical for highly stereoselective ß-protonation of the homoenolate intermediate and regeneration of the NHC catalyst results in functionalization of the carbonyl group. Thioesters with a ß-chiral center were prepared in a redox-neutral transformation with an excellent yield and ee.
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The germinal center response requires cooperation between Ag-specific T and B lymphocytes, which takes the form of long-lasting cell-cell conjugation in vivo. Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is required for stable cognate T-B cell conjugation, whereas SLAM family transmembrane (TM) receptor Ly108 may negatively regulate this process. We show that, other than phosphotyrosine-binding, SAP does not harbor motifs that recruit additional signaling intermediates to stabilize T-B adhesion. Ly108 dampens T cell adhesion to not only Ag-presenting B cells, but also dendritic cells by inhibiting CD3ζ phosphorylation through two levels of regulated Ly108-CD3ζ interactions. Constitutively associated with Src homology 2 domain-containing tyrosine phosphatase-1 even in SAP-competent cells, Ly108 is codistributed with the CD3 complex within a length scale of 100-200 nm on quiescent cells and can reduce CD3ζ phosphorylation in the absence of overt TCR stimulation or Ly108 ligation. When Ly108 is engaged in trans during cell-cell interactions, Ly108-CD3ζ interactions are promoted in a manner that uniquely depends on Ly108 TM domain, leading to more efficient CD3ζ dephosphorylation. Whereas replacement of the Ly108 TM domain still allows the constitutive, colocalization-dependent inhibition of CD3ζ phosphorylation, it abrogates the ligation-dependent Ly108-CD3ζ interactions and CD3ζ dephosphorylation, and it abolishes the suppression on Ag-triggered T-B adhesion. These results offer new insights into how SAP and Ly108 antagonistically modulate the strength of proximal TCR signaling and thereby control cognate T cell-APC interactions.
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Antígenos Ly/inmunología , Complejo CD3/inmunología , Adhesión Celular/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Animales , Linfocitos B/inmunología , Complejo CD3/metabolismo , Comunicación Celular/inmunología , Células Cultivadas , Células Dendríticas/inmunología , Centro Germinal/inmunología , Células HEK293 , Humanos , Activación de Linfocitos/inmunología , Ratones , Fosforilación , Estructura Terciaria de Proteína , Receptores de Antígenos de Linfocitos T/inmunología , Proteínas Adaptadoras de la Señalización Shc , Transducción de Señal/inmunología , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria , Linfocitos T/inmunología , Dominios Homologos src/inmunologíaRESUMEN
Employing first-principles combined with hybrid functional calculations, the electronic and optical properties of GaAs alloyed with isovalent impurities Bi and N are investigated. As GaAsBiN alloy is a quaternary alloy, the band gap and the lattice constant of the alloy can be individually tuned. Both impurities are important to the valence band and conduction band of the alloy, with the band gap of the alloy being dramatically reduced by Bi 6p states and N localized 2s states. Interestingly, the calculated optical properties of the quaternary alloy are similar to those of undoped GaAs except that the absorption edge has a redshift toward lower energy. These results suggest potential interest in the long-wavelength applications of GaAsBiN alloy.
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Current evidence suggests that hyperactivated or impaired autophagy can lead to neuronal death. The effect of local anesthetics on painful diabetic neuropathy (PDN) and the role of autophagy in the above pathological process remain unclear, warranting further studies. So, PDN models were established by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in leptin gene-mutation (db/db) mice. Wild type (WT) and PDN mice received intrathecal 0.75% bupivacaine or/with intraperitoneal drug treatment (rapamycin or bafilomycin A1). Subsequently, the PWT and PWL were measured to assess hyperalgesia at 6 h, 24 h, 30 h, and 48 h after intrathecal bupivacaine. Also, sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) were measured before and 48 h after intrathecal bupivacaine treatment. The spinal cord tissue of L4-L6 segments and serum were harvested to evaluate the change of autophagy, oxidative stress, oxidative injury, and apoptosis. We found that bupivacaine induced the activation of autophagy but did not affect the pain threshold, SNCV and MNCV in WT mice at predefined time points. Conversely, bupivacaine lowered autophagosome generation and degradation, slowed SNCV and aggravated spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. The autophagy activator (rapamycin) could decrease spinal dorsal horn neuron oxidative injury, alleviate the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Meanwhile, the autophagy inhibitor (bafilomycin A1) could exacerbate spinal dorsal horn neuron oxidative injury, the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Our results showed that bupivacaine could induce defective autophagy, slowed SNCV and aggravate spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. Restoring autophagy may represent a potential therapeutic approach against nerve injury in PDN patients with local anesthesia and analgesia.
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Diabetes Mellitus , Neuropatías Diabéticas , Macrólidos , Ratas , Ratones , Humanos , Animales , Hiperalgesia/metabolismo , Ratas Sprague-Dawley , Neuropatías Diabéticas/inducido químicamente , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/metabolismo , Bupivacaína/toxicidad , Sirolimus , AutofagiaRESUMEN
OBJECTIVES: To observe the effect and safety of acupuncture on quality of life, pain, and prostate symptoms in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: Seventy patients with CP/CPPS were randomly divided into an acupuncture group (35 cases, 1 case was eliminated) and a sham acupuncture group (35 cases, 3 cases dropped out). The patients in the acupuncture group were treated with routine acupuncture at bilateral Zhongliao (BL 33), Huiyang (BL 35), Shenshu (BL 23) and Sanyinjiao (SP 6), while the patients in the sham acupuncture group were treated with shallow needling at non-meridian and non-acupoint points beside bilateral Zhongliao (BL 33), Huiyang (BL 35), Shenshu (BL 23) and Sanyinjiao (SP 6),without manipulation to induce arrival of qi (deqi). Both groups retained the needles for 30 min, with one session every other day, three times a week, for a total of 8 weeks (24 sessions). Before and after treatment, and at the follow-up of 24 weeks after treatment completion, the scores of MOS 36-item short-form health survey (SF-36, including 8 dimensions of physical function [PF], role physical function [RP], bodily pain [BP], general health status [GH], vitality [VT], social function [SF], role emotional [RE], and mental health [MH], which can be summarized as physical component summary [PCS] and mental component summary [MCS]), pelvic pain visual analogue scale (VAS), National Institutes of Health chronic prostatitis symptom index (NIH-CPSI), and international prostate symptom score (IPSS) were evaluated, and safety of both groups was assessed. RESULTS: After treatment and at the follow-up, the scores of each dimension and PCS, MCS scores of SF-36 in the acupuncture group were higher than those before treatment (P<0.05, P<0.01); compared before treatment, the RP, BP, and SF scores and PCS score in the sham acupuncture group were increased after treatment (P<0.05, P<0.01). After treatment, the acupuncture group had higher scores in RP, BP, GH, MH and PCS, MCS than those in the sham acupuncture group (P<0.05, P<0.01); at the follow-up, except for PF and RE dimensions, the scores in each dimension and PCS, MCS scores in the acupuncture group were higher than those in the sham acupuncture group (P<0.05, P<0.01). After treatment and at the follow-up, pelvic pain VAS, NIH-CPSI, IPSS scores in the acupuncture group were lower than those before treatment (P<0.01); in the sham acupuncture group, pelvic pain VAS, NIH-CPSI scores were lower after treatment, and NIH-CPSI score at the follow-up was lower compared with those before treatment (P<0.01). After treatment and at the follow-up, pelvic pain VAS, NIH-CPSI, IPSS scores in the acupuncture group were lower than those in the sham acupuncture group (P<0.01, P<0.05). No significant adverse reactions were observed in both groups, and the incidence rates of adverse reactions had no significant difference (P>0.05). CONCLUSIONS: Acupuncture could effectively improve the quality of life, reduce pain levels, alleviate prostate symptoms, and shows favorable long-term efficacy in patients with CP/CPPS.
Asunto(s)
Terapia por Acupuntura , Dolor Crónico , Prostatitis , Masculino , Humanos , Dolor Crónico/terapia , Calidad de Vida , Prostatitis/terapia , Enfermedad Crónica , Terapia por Acupuntura/métodos , Dolor Pélvico/terapiaRESUMEN
Cancer immunotherapy has emerged as a promising approach to cancer treatment in recent years. The physical and chemical properties of nanocarriers are critical factors that regulate the immune activation of antigen-presenting cells (APCs) in the tumor microenvironment (TME). Herein, we extensively investigated the behavior of liposome nanoparticles (Lipo-NPs) with different elasticities, focusing on their interaction with immune cells and their transport mechanisms from tumors to tumor-draining lymph nodes (tdLNs). Successfully preparing Lipo-NPs with distinct elastic properties, their varied behaviors were observed, concerning immune cell interaction. Soft Lipo-NPs exhibited an affinity to cell membranes, while those with medium elasticity facilitated the cargo delivery to macrophages through membrane fusion. Conversely, hard Lipo-NPs enter macrophages via classical cellular uptake pathways. Additionally, it was noted that softer Lipo-NPs displayed superior transport to tdLNs in vivo, attributed to their deformable nature with lower elasticity. As a result, the medium elastic Lipo-NPs with agonists (cGAMP), by activating the STING pathway and enhancing transport to tdLNs, promoted abundant infiltration of tumor-infiltrating lymphocytes (TILs), leading to notable antitumor effects and extended survival in a melanoma mouse model. Furthermore, this study highlighted the potential synergistic effect of medium elasticity Lipo-NPs with immune checkpoint blockade (ICB) therapy in preventing tumor immune evasion. These findings hold promise for guiding immune-targeted delivery systems in cancer immunotherapy, particularly in vaccine design for tdLNs targeting and eradicating metastasis within tdLNs.