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Abdominal wall scar endometriosis (AWE) is a rare endometriosis that usually occurs after gynecological or obstetric surgery and for which surgical resection is the standard treatment. For large tissue defects after resection, abdominal wall reconstruction is needed. Here, we describe a mesh bridging technique using biological and polypropylene meshes for abdominal wall reconstruction. A 34-year-old woman visited the center with complaints of low abdominal wall pain during menstruation for more than 5 years. Her surgical history included undergoing a cesarean section delivery twice. A mass measuring 6 cm × 5 cm × 3 cm was found above the symphysis pubis in the lower part of the abdominal incision. Endometriosis lesion was considered based on abdominal ultrasound and magnetic resonance imaging findings. After a multidisciplinary discussion that included surgical experts and gynecologists, the decision was made to perform abdominal endometrial focus excision plus abdominal wall reconstruction. Two kinds of mesh were skillfully used in the operation of this patient. Biological mesh was used close to the peritoneal side and covered with polypropylene mesh to reduce the stimulation by the polypropylene mesh of the peritoneum, enhance the strength of the biological mesh, and reduce the incidence of abdominal wall hernia. Our case demonstrates that accurate diagnosis of AWE followed by complete resection and reconstruction of the abdominal wall using a combination of biological and polypropylene mesh bridging can achieve good therapeutic results and patient satisfaction.
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OBJECTIVE: To investigate whether the combination of chemotherapy with staged Chinese herbal medicine (CHM) therapy could enhance health-related quality of life (QoL) in non-small-cell lung cancer (NSCLC) patients and prolong the time before deterioration of lung cancer symptoms, in comparison to chemotherapy alone. METHODS: A prospective, double-blind, randomized, controlled trial was conducted from December 14, 2017 to August 28, 2020. A total of 180 patients with stage I B-IIIA NSCLC from 5 hospitals in Shanghai were randomly divided into chemotherapy combined with CHM (chemo+CHM) group (120 cases) or chemotherapy combined with placebo (chemo+placebo) group (60 cases) using stratified blocking randomization. The European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life-Core 30 Scale (QLQ-C30) was used to evaluate the patient-reported outcomes (PROs) during postoperative adjuvant chemotherapy in patients with early-stage NSCLC. Adverse events (AEs) were assessed in the safety analysis. RESULTS: Out of the total 180 patients, 173 patients (116 in the chemo+CHM group and 57 in the chemo+placebo group) were included in the PRO analyses. The initial mean QLQ-C30 Global Health Status (GHS)/QoL scores at baseline were 57.16 ± 1.64 and 57.67 ± 2.25 for the two respective groups (P>0.05). Compared with baseline, the chemo+CHM group had an improvement in EORTC QLQ-C30 GHS/QoL score at week 18 [least squares mean (LSM) change 17.83, 95% confidence interval (CI) 14.29 to 21.38]. Conversely, the chemo+placebo group had a decrease in the score (LSM change -13.67, 95% CI -22.70 to -4.63). A significant between-group difference in the LSM GHS/QoL score was observed, amounting to 31.63 points (95% CI 25.61 to 37.64, P<0.001). The similar trends were observed in physical functioning, fatigue and appetite loss. At week 18, patients in the chemo+CHM group had a higher proportion of improvement or stabilization in GHS/QoL functional and symptom scores compared to chemo+placebo group (P<0.001). The median time to deterioration was longer in the chemo+CHM group for GHS/QoL score [hazard ratio (HR)=0.33, 95% CI 0.23 to 0.48, P<0.0010], physical functioning (HR=0.43, 95% CI 0.25 to 0.75, P=0.0005), fatigue (HR=0.47, 95% CI 0.30 to 0.72, P<0.0001) and appetite loss (HR=0.65, 95% CI 0.42 to 1.00, P=0.0215). The incidence of AEs was lower in the chemo+CHM group than in the chemo+placebo group (9.83% vs. 15.79%, P=0.52). CONCLUSION: The staged CHM therapy could help improve the PROs of postoperative patients with early-stage NSCLC during adjuvant chemotherapy, which is worthy of further clinical research. (Registry No. NCT03372694).
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Layered double hydroxide (LDH)-coated substrates could enhance the removal of various wastewater-born pollutants. However, research on biofilms attached to LDH-coatings and their synergistic purification effects on strongly hydrophobic persistent organic pollutants (POPs) remains limited. This study aims to investigate biofilm formation on MgFe-LDH@quartz sand and its effectiveness in removing tetrabromodiphenyl ether (BDE-47), an emerging halogenated POP in municipal wastewater. Under different C/N ratios (3, 5, and 10), BDE-47 removal rates ranged from 28.0% to 41.6% after 72 h. The optimal performance was achieved with LDH coating at C/N = 5, when substrate biofilm reached its highest extracelluar polymer substances (EPS) content, dehydrogenase activity and relative hydrophobicity. Moreover, distinct distribution patterns of EPS components' fluorescence peaks were observed in the LDH-coating treatment using three dimensional excitation-emission matrix (3D-EEM). While substrate adsorption was the primary mechanism for BDE-47 removal, accounting for 59.6%-83.4% of the total, biofilm adsorption and degradation contributed a relatively lower amount, ranging from 11.5% to 21.4%, and were more dependent on the C/N ratio. Notably, the maximum carrying capacity of protein predicted by the logistic growth model exhibited a strong positive correlation with the total BDE-47 removal rate (R2 = 0.82, p < 0.05), highlighting the importance of biofilm extracelluar proteins.
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Yeast phenylalanine tRNA (tRNAphe) is a paradigmatic model in structural biology. In this work, we combine molecular dynamics simulations and spectroscopy modeling to establish a direct link between its structure, conformational dynamics, and infrared (IR) spectra. Employing recently developed vibrational frequency maps and coupling models, we apply a mixed quantum/classical treatment of the line shape theory to simulate the IR spectra of tRNAphe in the 1600-1800 cm-1 region across its folded and unfolded conformations and under varying concentrations of Mg2+ ions. The predicted IR spectra of folded and unfolded tRNAphe are in good agreement with experimental measurements, validating our theoretical framework. We then elucidate how the characteristic L-shaped tertiary structure of the tRNA and its modulation in response to diverse chemical environments give rise to distinct IR absorption peaks and line shapes. These calculations effectively bridge IR spectroscopy experiments and atomistic molecular simulations, unraveling the molecular origins of the observed IR spectra of tRNAphe. This work presents a robust theoretical protocol for modeling the IR spectroscopy of nucleic acids, which will facilitate its application as a sensitive probe for detecting the fluctuating secondary and tertiary structures of these essential biological macromolecules.
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Simulación de Dinámica Molecular , Conformación de Ácido Nucleico , ARN de Transferencia de Fenilalanina , Espectrofotometría Infrarroja , Espectrofotometría Infrarroja/métodos , ARN de Transferencia de Fenilalanina/química , ARN de Transferencia de Fenilalanina/metabolismo , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/metabolismo , ARN de Hongos/química , ARN de Hongos/metabolismo , Fenilalanina/química , Fenilalanina/metabolismoRESUMEN
BACKGROUND: Atrial fibrosis is associated with the pathogenesis of atrial fibrillation (AF). This study aims to discuss the function of circ_0079480 in atrial fibrosis and its underlying mechanism. METHODS: In vitro and in vivo models of atrial fibrosis were established by using angiotensin II (Ang II) to treat human atrial fibroblasts (HAFs) and C57/B6J mice. qRT-PCR and western blot were used to examine the mRNA and protein expression levels. CCK-8, EdU, cell strach, and transwell assays were performed to determine the proliferation and migration of HAFs. Dual-luciferase reporter and RIP/RNA pull-down assays were explored to identify the interaction of miR-338-3p and circ_0079480/THBS1. HE and Masson's trichrome staining experiments were performed to analyze the histopathological change in mice atrial tissues. RESULTS: Circ_0079480 expression was increased in AF patients' atrial tissues and Ang II-treated HAFs. Silencing circ_0079480 inhibited cell proliferation and migration and reduced fibrosis-associated gene expression in Ang II-treated HAFs. Circ_0079480 could target miR-338-3p to repress its expression. MiR-338-3p inhibitor blocked the inhibitory effects of circ_0079480 knockdown on HAFs proliferation, migration, and fibrosis. Thrombospondin-1 (THBS1) was confirmed as a downstream target of miR-338-3p, and circ_0079480 could sponge miR-338-3p to upregulate THBS1 expression. Moreover, silencing THBS1 suppressed Ang II-induced proliferation, migration, and fibrosis in HAFs. More importantly, depletion of circ_0079480 inactivated the THBS1/TGF-ß1/Smad3 signaling by upregulating miR-338-3p. Mice experiments also confirmed the suppression of circ_0079480 knockdown on atrial fibrosis. CONCLUSION: Circ_0079480 acts as a sponge of miR-338-3p to upregulate THBS1 expression and activate the TGF-ß1/Smad3 signaling, finally promoting Ang II-induced atrial fibrosis.
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Fibrilación Atrial , Movimiento Celular , Proliferación Celular , Fibroblastos , Fibrosis , Atrios Cardíacos , Ratones Endogámicos C57BL , MicroARNs , ARN Circular , Transducción de Señal , Proteína smad3 , Trombospondina 1 , Factor de Crecimiento Transformador beta1 , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , MicroARNs/genética , MicroARNs/metabolismo , Animales , Proteína smad3/metabolismo , Proteína smad3/genética , Ratones , Proliferación Celular/fisiología , Humanos , Factor de Crecimiento Transformador beta1/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , Trombospondina 1/biosíntesis , Movimiento Celular/fisiología , ARN Circular/genética , ARN Circular/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Atrios Cardíacos/patología , Atrios Cardíacos/metabolismo , Transducción de Señal/fisiología , Masculino , Células CultivadasRESUMEN
Understanding migratory routes is crucial for the conservation of birds and their habitats. Zhejiang is a crucial stopover and wintering area for birds in the East Asian-Australasian Flyway; however, detailed information on this area, and particularly on connections between coastal areas, is limited. By synthesizing ringed and recapture records from local bird-ringing projects and re-sighting community science data (208 records of 35 species), we established migratory connectivity between the Zhejiang coast and nine countries (i.e., Russia, Mongolia, the United States, Korea, Japan, Malaysia, Singapore, Thailand, and Australia), as well as eleven sites within China, and established its crucial role in this flyway. Stopover fidelity was verified by some species with high recapture frequency (seven species exceeded 1%) and species with duplicated re-sighted records (seven Black-faced Spoonbill, one Dalmatian Pelican, and two Spoon-billed Sandpiper individuals). We identified six areas-Hangzhou Bay, Aiwan Bay, Xuanmen National Park, Wenzhou Bay, the reclaimed area between the Ou and Feiyun Rivers, and the Wenzhou Jiangnan Reclamation Area-as crucial stopovers and wintering refuges for waterbirds. Notably, in Xuanmen National Park and the coastal regions along Wenzhou, there were many recovery records for flagship species, such as the Black-faced Spoonbill and Spoon-billed Sandpiper. There were several cases of the recovery of the same individual studied across the years. These findings indicate that these unprotected wetlands require particular attention. Broadly, our findings highlight the feasibility of integrating comprehensive ringing projects with citizen science data to formulate effective conservation strategies and underscore the critical importance of the Zhejiang Coast for migratory waterbirds, particularly those with high conservation concerns, emphasizing the need to mitigate the threats faced by these vulnerable populations.
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Regulating cardiolipin to maintain mitochondrial homeostasis is a promising strategy for addressing Parkinson's disease (PD). Through a comprehensive screening and validation process involving multiple models, ginsenoside Rg3 (Rg3) as a compound capable of enhancing cardiolipin levels is identified. This augmentation in cardiolipin levels fosters mitochondrial homeostasis by bolstering mitochondrial unfolded protein response, promoting mitophagy, and enhancing mitochondrial oxidative phosphorylation. Consequently, this cascade enhances the survival of tyrosine hydroxylase positive (TH+) dopaminergic neurons, leading to an amelioration in motor performance within PD mouse models. Using limited proteolysis-small-molecule mapping combined with molecular docking analysis, it has confirmed Growth Factor Receptor-Bound Protein 2 (GRB2) as a molecular target for Rg3. Furthermore, these investigations reveal that Rg3 facilitates the interaction between GRB2 and TRKA (Neurotrophic Tyrosine Kinase, Receptor, Type 1), thus promotes EVI1 (Ecotropic Virus Integration Site 1 Protein Homolog) phosphorylation by ERK, subsequently increases CRLS1 (Cardiolipin Synthase 1) gene expression and boosts cardiolipin synthesis. The absence of GRB2 or CRLS1 significantly attenuates the beneficial effects of Rg3 on PD symptoms. Finally, Tenofovir Disoproxil Fumarate (TDF) that also promotes the binding between GRB2 and TRKA is further identified. The identified compounds, Rg3 and TDF, exhibit promising potential for the prevention of PD by bolstering cardiolipin expression and reinstating mitochondrial homeostasis.
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Quantum communication networks are crucial for both secure communication and cryptographic networked tasks. Building quantum communication networks in a scalable and cost-effective way is essential for their widespread adoption. Here, we establish a complete polarization entanglement-based fully connected network, which features an ultrabright integrated Bragg reflection waveguide quantum source, managed by an untrusted service provider, and a streamlined polarization analysis module, which requires only one single-photon detector for each user. We perform a continuously working quantum entanglement distribution and create correlated bit strings between users. Within the framework of one-time universal hashing, we provide the experimental implementation of source-independent quantum digital signatures using imperfect keys circumventing the necessity for private amplification. We further beat the 1/3 fault tolerance bound in the Byzantine agreement, achieving unconditional security without relying on sophisticated techniques. Our results offer an affordable and practical route for addressing consensus challenges within the emerging quantum network landscape.
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In organic-inorganic hybrid perovskite solar cells (PSCs), hydrogen defects introduce deep-level trap states, significantly influencing non-radiative recombination processes. Those defects are primarily observed in MA-PSCs rather than FA-PSCs. As a result, MA-PSCs demonstrated a lower efficiency of 23.6% compared to 26.1% of FA-PSCs. In this work, both hydrogen vacancy (VH -) and hydrogen interstitial (Hi -) defects in MAPbI3 bulk and on surfaces, respectively are investigated. i) Bulk VH - defects have dramatic impact on non-radiative recombination, with lifetime varying from 67 to 8 ns, depending on whether deprotonated MA0 are ion-bonded or not. ii) Surface H-defects exhibited an inherent self-healing mechanism through a chemical bond between MA0 and Pb2+, indicating a self-passivation effect. iii) Both VH - and Hi - defects can be mitigated by alkali cation passivation; while large cations are preferable for VH - passivation, given strong binding energy of cation/perovskite, as well as, weak band edge non-adiabatic couplings; and small cations are suited for Hi - passivation, considering the steric hindrance effect. The dual passivation strategy addressed diverse experimental outcomes, particularly in enhancing performance associated with cation selections. The dynamic connection between hydrogen defects and non-radiative recombination is elucidated, providing insights into hydrogen defect passivation essential for high-performance PSCs fabrication.
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Hepatocellular carcinoma (HCC) has become the fourth leading cause of cancer-related deaths worldwide; annually, approximately 830,000 deaths related to liver cancer are diagnosed globally. Since early-stage HCC is clinically asymptomatic, traditional treatment modalities, including surgical ablation, are usually not applicable or result in recurrence. Immunotherapy, particularly immune checkpoint blockade (ICB), provides new hope for cancer therapy; however, immune evasion mechanisms counteract its efficiency. In addition to viral exposure and alcohol addiction, nonalcoholic steatohepatitis (NASH) has become a major cause of HCC. Owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance, NASH-associated HCC patients respond much less efficiently to ICB treatment than do patients with other etiologies. In addition, abnormal inflammation contributes to NASH progression and NASH-HCC transition, as well as to HCC immune evasion. Therefore, uncovering the detailed mechanism governing how NASH-associated immune cells contribute to NASH progression would benefit HCC prevention and improve HCC immunotherapy efficiency. In the following review, we focused our attention on summarizing the current knowledge of the role of CD4+T cells in NASH and HCC progression, and discuss potential therapeutic strategies involving the targeting of CD4+T cells for the treatment of NASH and HCC.
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Linfocitos T CD4-Positivos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/terapia , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Animales , Inmunoterapia/métodos , Progresión de la EnfermedadRESUMEN
Anesthesia serves as a pivotal tool in modern medicine, creating a transient state of sensory deprivation to ensure a pain-free surgical or medical intervention. While proficient in alleviating pain, anesthesia significantly modulates brain dynamics, metabolic processes, and neural signaling, thereby impairing typical cognitive functions. Furthermore, anesthesia can induce notable impacts such as memory impairment, decreased cognitive function, and diminished intelligence, emphasizing the imperative need to explore the concealed repercussions of anesthesia on individuals. In this investigation, we aggregated gene expression profiles (GSE64617, GSE141242, GSE161322, GSE175894, and GSE178995) from public repositories following second-generation sequencing analysis of various anesthetics. Through scrutinizing post-anesthesia brain tissue gene expression utilizing Gene Set Enrichment Analysis (GSEA), Robust Rank Aggregation (RRA), and Weighted Gene Co-expression Network Analysis (WGCNA), this research aims to pinpoint pivotal genes, pathways, and regulatory networks linked to anesthesia. This undertaking not only enhances comprehension of the physiological changes brought about by anesthesia but also lays the groundwork for future investigations, cultivating new insights and innovative perspectives in medical practice.
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Algoritmos , Anestésicos , Encéfalo , Humanos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Anestésicos/farmacología , Redes Reguladoras de Genes/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , Bases de Datos Genéticas , Perfilación de la Expresión GénicaRESUMEN
The F11 receptor (F11R) gene encoding junctional adhesion molecule A has been associated with gastric cancer (GC) and colorectal cancer (CRC), in which its role and regulation remain to be further elucidated. Recently F11R was also identified as a potential target of adenosine-to-inosine (A-to-I) mediated by the adenosine deaminases acting on RNA (ADARs). Herein, using RNA-Seq and experimental validation, our current study revealed an F11R RNA trinucleotide over-edited by ADAR, with its regulation of gene expression and clinical significance in four GC and three CRC cohorts. Our results found an over-edited AAA trinucleotide in an AluSg located in the F11R 3'-untranslated region (3'-UTR), which showed editing levels correlated with elevated ADAR expression across all GC and CRC cohorts in our study. Overexpression and knockdown of ADAR in GC and CRC cells, followed by RNA-Seq and Sanger sequencing, confirmed the ADAR-mediated F11R 3'-UTR trinucleotide editing, which potentially disrupted an RBM45 binding site identified by crosslinking immunoprecipitation sequencing (CLIP-seq) and regulated F11R expression in luciferase reporter assays. Moreover, the F11R trinucleotide editing showed promising predictive performance for diagnosing GC and CRC across GC and CRC cohorts. Our findings thus highlight both the potential biological and clinical significance of an ADAR-edited F11R trinucleotide in GC and CRC, providing new insights into its application as a novel diagnostic biomarker for both cancers.
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Adenosina Desaminasa , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Edición de ARN , Proteínas de Unión al ARN , Neoplasias Gástricas , Humanos , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Estudios de Cohortes , Regiones no Traducidas 3'/genética , Línea Celular Tumoral , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Masculino , FemeninoRESUMEN
Nod-like receptor family pyrin-containing protein 3 (NLRP3) inflammasome plays a pathologic role in metabolic dysfunction-associated steatohepatitis (MASH), but the molecular mechanism regulating the NLRP3 inflammasome activation in hepatocellular lipotoxicity remains largely unknown. Bromodomain-containing protein 4 (BRD4) has emerged as a key epigenetic reader of acetylated lysine residues in enhancer regions that control the transcription of key genes. The aim of this study is to investigate if and how BRD4 regulated the NLRP3 inflammasome activation and pyroptosis in MASH. Using the AML12 and primary mouse hepatocytes stimulated by palmitic acid (PA) as an in vitro model of hepatocellular lipotoxicity, we found that targeting BRD4 by genetic knockdown or a selective BRD4 inhibitor MS417 protected against hepatosteatosis; and this protective effect was attributed to inhibiting the activation of NLRP3 inflammasome and reducing the expression of Caspase-1, gasdermin D (GSDMD), interleukin (IL)-1ß and IL-6. Moreover, BRD4 inhibition limited the voltage-dependent anion channel-1 (VDAC1) expression and oligomerization in PA-treated AML12 hepatocytes, thereby suppressing the NLRP3 inflammasome activation. Additionally, the expression of BRD4 enhanced in MASH livers of humans. Mechanistically, BRD4 was upregulated during hepatocellular lipotoxicity that in turn modulated the active epigenetic mark H3K27ac at the promoter regions of the Vdac and Gsdmd genes, thereby enhancing the expression of VDAC and GSDMD. Altogether, our data provide novel insights into epigenetic mechanisms underlying BRD4 activating the NLRP3 inflammasome and promoting GSDMD-mediated pyroptosis in hepatocellular lipotoxicity. Thus, BRD4 might serve as a novel therapeutic target for the treatment of MASH.
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Hepatocitos , Inflamasomas , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas de Unión a Fosfato , Piroptosis , Factores de Transcripción , Animales , Humanos , Masculino , Ratones , Proteínas que Contienen Bromodominio , Proteínas de Ciclo Celular , Hígado Graso/metabolismo , Hígado Graso/patología , Furanos , Gasderminas , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Indenos/farmacología , Inflamasomas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Nucleares , Ácido Palmítico/farmacología , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Piroptosis/efectos de los fármacos , Sulfonamidas/farmacología , Factores de Transcripción/metabolismo , Factores de Transcripción/genéticaRESUMEN
Lanthanide (Ln) based mononuclear single-molecule magnets (SMMs) provide probably the finest ligand regulation model for magnetic property. Recently, the development of such SMMs has witnessed a fast transition from coordination to organometallic complexes because the latter provides a fertile, yet not fully excavated soil for the development of SMMs. Especially those SMMs with heterocyclic ligands have shown the potential to reach higher blocking temperature. In this minireview, we give an overview of the design principle of SMMs and highlight those "shining stars" of heterocyclic organolanthanide SMMs based on the ring sizes of ligands, analysing how the electronic structures of those ligands and the stiffness of subsequently formed molecules affect the dynamic magnetism of SMMs. Finally, we envisaged the future development of heterocyclic Ln-SMMs.
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Immunotherapy exhibited potential effects for advanced hepatocellular carcinoma, unfortunately, the clinical benefits are often countered by cancer adaptive immune suppressive response. Uncovering the mechanism how cancer cells evade immune surveillance would help to develop new immunotherapy approaches and combination therapy. In this article, by analyzing the transcriptional factors which modulate the differentially expressed genes between T cell infiltration high group and low group, we identified oncoprotein B cell lymphoma 6 (BCL6) suppresses the infiltration and activation of tumor infiltrating T lymphocytes, thus correlated with poorer clinical outcome. By using antibody deletion experiment, we further demonstrated that CD4+T cells but not CD8+T cells are the main lymphocyte population suppressed by Bcl6 to promote HCC development. Mechanistically, BCL6 decreases cancer cell expression of pro-inflammatory cytokines and T lymphocyte chemokines such as IL6, IL1F6, and CCL5. Moreover, BCL6 upregulates Endothelial cell-specific molecule 1 (ESM1) to inhibit T lymphocyte recruitment and activation possibly through ICAM-1/LFA-1 signaling pathway. Our findings uncovered an unappreciated paracrine mechanism how cancer cell-derived BCL6 assists cancer cell immune evasion, and highlighted the role of CD4+T cells in HCC immune surveillance.
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In this work, a highly accurate neural network potential (NNP) is presented, named PtNNP, and the exploration of the reconstruction of the Pt(001) surface and its vicinal surfaces with it. Contrary to the most accepted understanding of the Pt(001) surface reconstruction, the study reveals that the main driving force behind Pt(001) quasi-hexagonal reconstruction is not the surface stress relaxation but the increased coordination number of the surface atoms resulting in stronger intralayer binding in the reconstructed surface layer. In agreement with experimental observations, the optimized supercell size of the reconstructed Pt(001) surface contains (5 × 20) unit cells. Surprisingly, the reconstruction of the vicinal Pt(001) surfaces leads to a smooth shell-like surface layer covering the whole surface and diminishing sharp step edges.
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In many real-world phenomena, such as the reconstruction of disaster areas after an earthquake or the stock market's recovery after an economic crisis, damaged networks are spontaneously active after receiving assistance. To reveal how the recovery process, the research of dynamic network recovery has become a hot topic in the field of network science. Previous studies on network recovery have been limited to simple networks with pairwise interactions. However, real-world systems are usually networks with higher-order interactions that are composed of multiple units. To better understand the recovery phenomenon on complex networks in the real world, we propose a novel spontaneous recovery model applied to hypergraphs. The model considers two types of recovery, internal recovery and fast recovery, where inactive nodes in the network can either recover internally with independent probabilities or receive sufficient resources from the hyperedge for fast recovery. We find that the number of active nodes in the system shows a phase change from continuous to discontinuous as the fast recovery condition is relaxed. Moreover, under the influence of higher-order interactions, increasing both average hyperedge cardinality and network heterogeneity contribute to increasing the network resilience. These findings help us understand the recovery mechanisms of complex networks and provide essential insights into designing highly resilient systems.
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Renal cell carcinoma (RCC) is considered a "metabolic disease" characterized by elevated glycolysis in patients with advanced RCC. Tyrosine kinase inhibitor (TKI) therapy is currently an important treatment option for advanced RCC, but drug resistance may develop in some patients. Combining TKI with targeted metabolic therapy may provide a more effective approach for patients with advanced RCC. An analysis of 14 RCC patients (including three needle biopsy samples with TKI resistance) revealed by sing-cell RNA sequencing (scRNA-seq) that glycolysis played a crucial role in poor prognosis and drug resistance in RCC. TCGA-KIRC and glycolysis gene set analysis identified DEPDC1 as a target associated with malignant progression and drug resistance in KIRC. Subsequent experiments demonstrated that DEPDC1 promoted malignant progression and glycolysis of RCC, and knockdown DEPDC1 could reverse TKI resistance in RCC cell lines. Bulk RNA sequencing (RNA-seq) and non-targeted metabolomics sequencing suggested that DEPDC1 may regulate RCC glycolysis via AKT/mTOR/HIF1α pathway, a finding supported by protein-level analysis. Clinical tissue samples from 98 RCC patients demonstrated that DEPDC1 was associated with poor prognosis and predicted RCC metastasis. In conclusion, this multi-omics analysis suggests that DEPDC1 could serve as a novel target for TKI combined with targeted metabolic therapy in advanced RCC patients with TKI resistance.
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Carcinoma de Células Renales , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Renales , Proteínas Proto-Oncogénicas c-akt , Serina-Treonina Quinasas TOR , Animales , Femenino , Humanos , Masculino , Ratones , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/tratamiento farmacológico , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Glucólisis/efectos de los fármacos , Proteínas Activadoras de GTPasa/metabolismo , Proteínas Activadoras de GTPasa/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Ratones Desnudos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Breast cancer (BC) is a heterogeneous disease, with the ductal subtype exhibiting significant cellular diversity that influences prognosis and response to treatment. Single-cell RNA sequencing data from the GEO database were utilized in this study to investigate the underlying mechanisms of cellular heterogeneity and to identify potential prognostic markers and therapeutic targets. METHODS: Bioinformatics analysis was conducted using R packages to analyze the single-cell sequencing data. The presence of highly variable genes and differences in malignant potency within the same BC samples were examined. Differential gene expression and biological function between Type 1 and Type 2 ductal epithelial cells were identified. Lasso regression and Cox proportional hazards regression analyses were employed to identify genes associated with patient prognosis. Experimental validation was performed in vitro and in vivo to confirm the functional relevance of the identified genes. RESULTS: The analysis revealed notable heterogeneity among BC cells, with the presence of highly variable genes and differences in malignant behavior within the same samples. Significant disparities in gene expression and biological function were identified between Type 1 and Type 2 ductal epithelial cells. Through regression analyses, CYP24A1 and TFPI2 were identified as pivotal genes associated with patient prognosis. Kaplan-Meier curves demonstrated their prognostic significance, and experimental validation confirmed their inhibitory effects on malignant behaviors of ductal BC cells. CONCLUSION: This study highlights the cellular heterogeneity in ductal subtype breast cancer and delineates the differential gene expressions and biological functions between Type 1 and Type 2 ductal epithelial cells. The genes CYP24A1 and TFPI2 emerged as promising prognostic markers and therapeutic targets, exhibiting inhibitory effects on BC cell malignancy in vitro and in vivo. These findings offer the potential for improved BC management and the development of targeted treatment strategies.
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Despite the emergence of various treatment strategies for rectal cancer based on neoadjuvant chemoradiotherapy, there is currently a lack of reliable biomarkers to determine which patients will respond well to neoadjuvant chemoradiotherapy. Through collecting hematological and biochemical parameters data of patients prior to receiving neoadjuvant chemoradiotherapy, we evaluated the predictive value of systemic inflammatory indices for pathological response and prognosis in rectal cancer patients. We found that baseline GRIm-Score was an independent predictor for MPR in rectal cancer patients. However, no association was observed between several commonly systemic inflammation indices and long-term outcome.