RESUMEN
The small molecule epiberberine (EPI) is a natural alkaloid with versatile bioactivities against several diseases including cancer and bacterial infection. EPI can induce the formation of a unique binding pocket at the 5' side of a human telomeric G-quadruplex (HTG) sequence with four telomeric repeats (Q4), resulting in a nanomolar binding affinity (KD approximately 26 nM) with significant fluorescence enhancement upon binding. It is important to understand (1) how EPI binding affects HTG structural stability and (2) how enhanced EPI binding may be achieved through the engineering of the DNA binding pocket. In this work, the EPI-binding-induced HTG structure stabilization effect was probed by a peptide nucleic acid (PNA) invasion assay in combination with a series of biophysical techniques. We show that the PNA invasion-based method may be useful for the characterization of compounds binding to DNA (and RNA) structures under physiological conditions without the need to vary the solution temperature or buffer components, which are typically needed for structural stability characterization. Importantly, the combination of theoretical modeling and experimental quantification allows us to successfully engineer Q4 derivative Q4-ds-A by a simple extension of a duplex structure to Q4 at the 5' end. Q4-ds-A is an excellent EPI binder with a KD of 8 nM, with the binding enhancement achieved through the preformation of a binding pocket and a reduced dissociation rate. The tight binding of Q4 and Q4-ds-A with EPI allows us to develop a novel magnetic bead-based affinity purification system to effectively extract EPI from Rhizoma coptidis (Huang Lian) extracts.
Asunto(s)
Berberina , G-Cuádruplex , Berberina/química , Berberina/análogos & derivados , Berberina/farmacología , Humanos , ADN/química , Ácidos Nucleicos de Péptidos/químicaRESUMEN
INTRODUCTION: Linear-array endoscopic ultrasound (EUS) and narrow-band imaging (NBI) are both used to estimate the invasion depth of nonpedunculated rectal lesions (NPRLs). However, it is unclear which procedure is more accurate. This randomized controlled trial aimed to compare the diagnostic accuracy of linear EUS and NBI for estimating the invasion depth of NPRLs. METHODS: This study is a single-center, randomized, tandem trial. Eligible patients with NPRLs were randomly assigned to A group (assessment with EUS followed by NBI) or B group (assessment with NBI followed by EUS). The invasion depth of each lesion was independently measured by each procedure and categorized as mucosal to slight submucosal (M-SM s , invasion depth <1,000 µm) or deep submucosal (SM d , invasion depth ≥1,000 µm) invasion, with postoperative pathology as the standard of measurement. The primary outcome was diagnostic accuracy, and secondary outcomes included sensitivity, specificity, and procedure time. RESULTS: Eighty-six patients with NPRLs were enrolled, and 79 patients were finally analyzed, including 39 cases in the A group and 40 cases in the B group. Comparable diagnostic accuracies were observed between EUS and NBI (96.2% vs 93.7%, P = 0.625). EUS identified lesions with deep submucosal invasion with 81.8% sensitivity while that of NBI was 63.6% ( P = 0.500). The specificity of both EUS and NBI was 98.5%. The procedure time was also similar between EUS and NBI (5.90 ± 3.44 vs 6.4 ± 3.94 minutes, P = 0.450). Furthermore, the combined use of EUS and NBI did not improve diagnostic accuracy compared with EUS or NBI alone (94.9% vs 96.2% vs 93.7%, P = 0.333). DISCUSSION: Linear EUS and NBI measure the invasion depth of NPRLs with comparable accuracy. The combination of the 2 methods does not improve the diagnostic accuracy. Single NBI should be preferred, considering its simplicity and convenience in clinical practice.
RESUMEN
Soil-based irrigation and the partial substitution of chemical fertilizers with manure are promising practices to improve water and nitrogen (N) use efficiency. We hypothesize that their combination would simultaneously benefit potato production, tuber quality and profitability. A two-year experiment was conducted in semiarid northern China to investigate the combined effects of three water treatments [rainfed (W0), soil-based irrigation (W1), conventional irrigation (W2)] and three N treatments [no N (N0), chemical N (N1), 25% manure substitution (N2)] on these indicators, and to perform a comprehensive evaluation and correlation analysis. The results showed that water and N treatments separately affected all indicators except vitamin C content. Compared to W2, W1 significantly increased water productivity by 12% and irrigation water use efficiency (IWUE) by 30% due to 10% lower evapotranspiration and 21% lower water use. However, W1 and W2 negatively affected crude protein content. Conversely, this was compensated by the combination with N1 and N2. There were slight differences between N1 and N2 for all indicators on average across water treatments, while under W1, N2 significantly increased leaf area index (LAI) and N recovery efficiency (REN) by 18% and 29.4%, respectively, over N1. Also, comprehensive evaluations showed that W1N2 performed best, with the highest tuber yield, profit and acceptable quality. This can be explained by the increase in LAI, IWUE and REN due to the positive correlations with tuber yield and net return. Consequently, soil-based irrigation combined with 25% manure substitution had complementary effects on tuber quality and synergistic effects on potato productivity and profitability.
RESUMEN
The overuse of antibiotics in animal farming and aquaculture has led to multidrug-resistant methicillin-sensitive Staphylococcus aureus (MR-MSSA) becoming a common pathogen in foodborne diseases. Sophora flavescens Ait. serves as a traditional plant antibacterial agent and functional food ingredient. A total of 30 compounds (1-30) were isolated from the root bark of S. flavescens, consisting of 20 new compounds (1-20). In the biological activity assay, compound 1 demonstrated a remarkable inhibitory effect on MR-MSSA, with an MIC of 2 µg/mL. Furthermore, 1 was found to rapidly eliminate bacteria, inhibit biofilm growth, and exhibit exceptionally low cytotoxicity. Mechanistic studies have revealed that 1 possesses an enhanced membrane-targeting ability, binding to the bacterial cell membrane components phosphatidylglycerol (PG), phosphatidylethanolamine (PE), and cardiolipin (CL). This disruption of bacterial cell membrane integrity increases intracellular reactive oxygen species, protein and DNA leakage, reduced bacterial metabolism, and ultimately bacterial death. In summary, these findings suggest that compound 1 holds promise as a lead compound against MR-MSSA.
Asunto(s)
Antibacterianos , Permeabilidad de la Membrana Celular , Flavonoides , Pruebas de Sensibilidad Microbiana , Corteza de la Planta , Extractos Vegetales , Raíces de Plantas , Sophora , Sophora/química , Antibacterianos/farmacología , Antibacterianos/química , Raíces de Plantas/química , Corteza de la Planta/química , Permeabilidad de la Membrana Celular/efectos de los fármacos , Flavonoides/farmacología , Flavonoides/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Biopelículas/efectos de los fármacos , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Sophora flavescensRESUMEN
Cholangiocarcinoma (CCA), an exceptionally aggressive malignancy originating from the epithelium of the bile duct, poses a formidable challenge in cancer research and clinical management. Currently, attention is focused on exploring the oncogenic role and prognostic implications associated with Bmi1 in the context of CCA. In our study, we assessed the correlation of Bmi1 and Foxn2 expression across all types of CCA and evaluated their prognostic significance. Our results demonstrated that Bmi1 exhibits significantly upregulated expression in CCA tissues, while Foxn2 expression shows an inverse pattern. Simultaneously, the high expression of Bmi1, coupled with the low expression of Foxn2, indicates an unfavorable prognosis. Through in vitro and in vivo experiments, we confirmed the crucial role of Foxn2 in the proliferation, metastasis, and epithelial-mesenchymal transition (EMT) of CCA. Mechanistically, Bmi1 promotes the ubiquitination of histone H2A (H2AUb), leading to chromatin opening attenuation and a decrease in Foxn2 expression, ultimately driving CCA progression. Additionally, we described the potential value of Bmi1 and H2AUb inhibitors in treating CCA through in vitro experiments and orthotopic models. This study is of significant importance in deepening our understanding of the interaction between Bmi1 and Foxn2 in CCA and has the potential to advance the development of precision therapies for CCA.
Asunto(s)
Neoplasias de los Conductos Biliares , Proliferación Celular , Colangiocarcinoma , Progresión de la Enfermedad , Factores de Transcripción Forkhead , Regulación Neoplásica de la Expresión Génica , Histonas , Complejo Represivo Polycomb 1 , Ubiquitinación , Animales , Femenino , Humanos , Ratones , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismo , Línea Celular Tumoral , Colangiocarcinoma/patología , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Transición Epitelial-Mesenquimal , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Histonas/metabolismo , Ratones Desnudos , Complejo Represivo Polycomb 1/metabolismo , Complejo Represivo Polycomb 1/genética , Pronóstico , Ratones Endogámicos BALB CRESUMEN
The emergence of multidrug-resistant (MDR) bacteria poses a significant challenge to global health. Due to a shortage of antibiotics, alternative therapeutic strategies are urgently needed. Unfortunately, colistin, the last-resort antibiotic, has unavoidable nephrotoxicity and hepatotoxicity, and its single killing mechanism is prone to drug resistance. To address this challenge, a promising combinatorial approach that includes colistin, a membrane-disrupting antimicrobial agent, and chelerythrine (CHE), a FtsZ protein inhibitor is proposed. This approach significantly reduces antibiotic dose and development of resistance, leading to almost complete inactivation of MDR pathogens in vitro. To address solubility issues and ensure transport, the antimicrobial hydrogel system LNP-CHE-CST@hydrogel, which induced reactive oxygen species (ROS) and apoptosis-like cell death by targeting the FtsZ protein, is used. In an in vivo mouse skin infection model, the combination therapy effectively eliminated MDR bacteria within 24 h, as monitored by fluorescence tracking. The findings demonstrate a promising approach for developing multifunctional hydrogels to combat MDR bacterial infections.
Asunto(s)
Antibacterianos , Proteínas Bacterianas , Proteínas del Citoesqueleto , Hidrogeles , Animales , Hidrogeles/química , Hidrogeles/farmacología , Ratones , Proteínas del Citoesqueleto/metabolismo , Antibacterianos/farmacología , Antibacterianos/química , Proteínas Bacterianas/metabolismo , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Infecciones Bacterianas/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , HumanosRESUMEN
Immunotherapy is restricted by a complex tumor immunosuppressive microenvironment (TIM) and low drug delivery efficiency. Herein, a multifunctional adjuvant micelle nanosystem (PPD/MPC) integrated with broken barriers and re-education of three classes of immune-tolerant cells is constructed for cancer immunotherapy. The nanosystem significantly conquers the penetration barrier via the weakly acidic tumor microenvironment-responsive size reduction and charge reversal strategy. The detached core micelle MPC could effectively be internalized by tumor-associated macrophages (TAMs), tumor-infiltrating dendritic cells (TIDCs), and myeloid-derived suppressor cells (MDSCs) via mannose-mediated targeting endocytosis and electrostatic adsorption pathways, promoting the re-education of immunosuppressive cells for allowing them to reverse from pro-tumor to antitumor phenotypes by activating TLR4/9 pathways. This process in turn leads to the remodeling of TIM. In vitro and in vivo studies collectively indicate that the adjuvant micelle-based nanosystem not only relieves the intricate immune tolerance and remodels TIM via reprogramming the three types of immunosuppressive cells and regulating the secretion of relevant cytokines/immunity factors but also strengthens immune response and evokes immune memory, consequently suppressing the tumor growth and metastasis.
Asunto(s)
Micelas , Neoplasias , Humanos , Inmunoterapia , Inmunosupresores/farmacología , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Neoplasias/terapia , Microambiente Tumoral , Línea Celular TumoralRESUMEN
ABSTRACT AND AIM: Cholangiocarcinoma (CCA) is a highly aggressive and lethal cancer that originates from the biliary epithelium. Systemic treatment options for CCA are currently limited, and the first targeted drug of CCA, pemigatinib, emerged in 2020 for CCA treatment by inhibiting FGFR2 phosphorylation. However, the regulatory mechanism of FGFR2 phosphorylation is not fully elucidated. APPROACH AND RESULTS: Here we screened the FGFR2-interacting proteins and showed that protein tyrosine phosphatase (PTP) N9 interacts with FGFR2 and negatively regulates FGFR2 pY656/657 . Using phosphatase activity assays and modeling the FGFR2-PTPN9 complex structure, we identified FGFR2 pY656/657 as a substrate of PTPN9, and found that sec. 14p domain of PTPN9 interacts with FGFR2 through ACAP1 mediation. Coexpression of PTPN9 and ACAP1 indicates a favorable prognosis for CCA. In addition, we identified key amino acids and motifs involved in the sec. 14p-APCP1-FGFR2 interaction, including the "YRETRRKE" motif of sec. 14p, Y471 of PTPN9, as well as the PH and Arf-GAP domain of ACAP1. Moreover, we discovered that the FGFR2 I654V substitution can decrease PTPN9-FGFR2 interaction and thereby reduce the effectiveness of pemigatinib treatment. Using a series of in vitro and in vivo experiments including patient-derived xenografts (PDX), we showed that PTPN9 synergistically enhances pemigatinib effectiveness and suppresses CCA proliferation, migration, and invasion by inhibiting FGFR2 pY656/657 . CONCLUSIONS: Our study identifies PTPN9 as a negative regulator of FGFR2 phosphorylation and a synergistic factor for pemigatinib treatment. The molecular mechanism, oncogenic function, and clinical significance of the PTPN9-ACAP1-FGFR2 complex are revealed, providing more evidence for CCA precision treatment.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Morfolinas , Pirimidinas , Pirroles , Humanos , Colangiocarcinoma/tratamiento farmacológico , Epitelio , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Proteínas Activadoras de GTPasaRESUMEN
BACKGROUND AIMS: Cholangiocarcinoma (CCA) is a highly lethal malignancy originating from the biliary ducts. Current CCA diagnostic and prognostic assessments cannot satisfy the clinical requirement. Bile detection is rarely performed, and herein, we aim to estimate the clinical significance of bile liquid biopsy by assessing bile exosomal concentrations and components. APPROACH RESULTS: Exosomes in bile and sera from CCA, pancreatic cancer, and common bile duct stone were identified and quantified by transmission electronmicroscopy, nanoparticle tracking analysis, and nanoFCM. Exosomal components were assessed by liquid chromatography with tandem mass spectrometry and microRNA sequencing (miRNA-seq). Bile exosomal concentration in different diseases had no significant difference, but miR-182-5p and miR-183-5p were ectopically upregulated in CCA bile exosomes. High miR-182/183-5p in both CCA tissues and bile indicates a poor prognosis. Bile exosomal miR-182/183-5p is secreted by CCA cells and can be absorbed by biliary epithelium or CCA cells. With xenografts in humanized mice, we showed that bile exosomal miR-182/183-5p promotes CCA proliferation, invasion, and epithelial-mesenchymal transition (EMT) by targeting hydroxyprostaglandin dehydrogenase in CCA cells and mast cells (MCs), and increasing prostaglandin E2 generation, which stimulates PTGER1 and increases CCA stemness. In single-cell mRNA-seq, hydroxyprostaglandin dehydrogenase is predominantly expressed in MCs. miR-182/183-5p prompts MC to release VEGF-A release from MC by increasing VEGF-A expression, which facilitates angiogenesis. CONCLUSIONS: CCA cells secret exosomal miR-182/183-5p into bile, which targets hydroxyprostaglandin dehydrogenase in CCA cells and MCs and increases prostaglandin E2 and VEGF-A release. Prostaglandin E2 promotes stemness by activating PTGER1. Our results reveal a type of CCA self-driven progression dependent on bile exosomal miR-182/183-5p and MCs, which is a new interplay pattern of CCA and bile.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , MicroARNs , Humanos , Animales , Ratones , Dinoprostona , MicroARNs/genética , Bilis/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Colangiocarcinoma/patología , Conductos Biliares Intrahepáticos/patología , Hidroxiprostaglandina Deshidrogenasas/genética , Proliferación Celular , Regulación Neoplásica de la Expresión GénicaRESUMEN
Achieving ultrabright fluorogens is a key issue for fluorescence-guided surgery (FGS). Fluorogens with aggregation-induced emission (AIEgens) are potential agents for FGS on the benefit of the bright fluorescence in physiological conditions. Herein, the fluorescence brightness of AIEgen is further improved by preparing the nanoparticle using a polystyrene-based matrix and utilizing it for tumor FGS with a high signal-to-background ratio. After encapsulating AIEgen into polystyrene-poly (ethylene glycol) (PS-PEG), the fluorescence intensity of the prepared AIE@PS-PEG nanoparticles is multiple times that of nanoparticles in 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-poly (ethylene glycol) (DSPE-PEG), a commonly used polymer matrix for nanoparticle preparation. Molecular dynamics simulations suggest that higher free energy is required for the outer rings of AIEgen to rotate in polystyrene than in the DSPE, indicating that the benzene rings in polystyrene can restrict the intramolecular motions of AIEgen better than the alkyl chain in DSPE-PEG. Fluorescence correlation microscopy detections suggest that the triplet excited state of AIEgens is less in PS-PEG than in DSPE-PEG. The restricted intramolecular motions and suppressed triplet excited state result in ultrabright AIE@PS-PEG nanoparticles, which are more conducive to illuminating tumor tissues in the intestine for FGS. The illumination of metastatic tumors in lungs by AIE@PS-PEG nanoparticles is also tried.
Asunto(s)
Poliestirenos , Poliestirenos/química , Fluorescencia , Polietilenglicoles/química , Humanos , Nanopartículas/química , Cirugía Asistida por Computador/métodos , Simulación de Dinámica Molecular , Animales , Colorantes Fluorescentes/químicaRESUMEN
Hepatocellular carcinoma (HCC) is one of most common and deadliest malignancies. Celastrol (Cel), a natural product derived from the Tripterygium wilfordii plant, has been extensively researched for its potential effectiveness in fighting cancer. However, its clinical application has been hindered by the unclear mechanism of action. Here, we used chemical proteomics to identify the direct targets of Cel and enhanced its targetability and anti-tumor capacity by developing a Cel-based liposomes in HCC. We demonstrated that Cel selectively targets the voltage-dependent anion channel 2 (VDAC2). Cel directly binds to the cysteine residues of VDAC2, and induces cytochrome C release via dysregulating VDAC2-mediated mitochondrial permeability transition pore (mPTP) function. We further found that Cel induces ROS-mediated ferroptosis and apoptosis in HCC cells. Moreover, coencapsulation of Cel into alkyl glucoside-modified liposomes (AGCL) improved its antitumor efficacy and minimized its side effects. AGCL has been shown to effectively suppress the proliferation of tumor cells. In a xenograft nude mice experiment, AGCL significantly inhibited tumor growth and promoted apoptosis. Our findings reveal that Cel directly targets VDAC2 to induce mitochondria-dependent cell death, while the Cel liposomes enhance its targetability and reduces side effects. Overall, Cel shows promise as a therapeutic agent for HCC.
RESUMEN
BACKGROUND: Immense attention has been given to the outcome of COVID-19 infection. However, comprehensive studies based on large populational cohort with long-term follow-up are still lacking. This study aimed to investigate the risk of various short-term comorbidities (within one month) and long-term sequelae (above one month) after COVID-19 infection. METHODS: In this large prospective cohort study with 14 months follow-up information based on UK biobank, we included 16,776 COVID-19-positive participants and 58,281 COVID-19-negative participants matched for comparison. The risk of each comorbidity and sequela was evaluated by multivariable logistic regression analysis and presented as hazard ratio (HR) and 95% confidence interval (95% CI). RESULTS: COVID-19-positive individuals had a higher risk of 47 types of comorbidities within one month following COVID-19 infection, especially those who were older, male, overweight/obese, ever-smoked, with more pre-existing comorbidities and hospitalized. About 70.37% of COVID-19 patients with comorbidities had more than one co-occurring comorbidities. Additionally, only 6 high-risk sequelae were observed after one month of COVID-19 infection, and the incidence was relatively low (< 1%). CONCLUSION: In addition to long-term sequelae following COVID-19 infection, plenty of comorbidities were observed, especially in patients with older age, male gender, overweight/obese, more pre-existing comorbidities and severe COVID-19, indicating that more attention should be given to these susceptible persons within this period.
Asunto(s)
COVID-19 , Humanos , Masculino , COVID-19/epidemiología , Estudios Prospectivos , Sobrepeso/epidemiología , SARS-CoV-2 , Comorbilidad , Progresión de la Enfermedad , Obesidad/epidemiologíaRESUMEN
Fluorescent materials with high brightness play a crucial role in the advancement of various technologies such as bioimaging, photonics, and OLEDs. While significant efforts are dedicated to designing new organic dyes with improved performance, enhancing the brightness of existing dyes holds equal importance. In this study, we present a simple supramolecular strategy to develop ultrabright cyanine-based fluorescent materials by addressing long-standing challenges associated with cyanine dyes, including undesired cis-trans photoisomerization and aggregation-caused quenching. Supra-cyanines are obtained by incorporating cyanine moieties in a cyclic peptide-based supramolecular scaffold, and exhibit high fluorescence quantum yields (up to 50 %) in both solution and in the solid state. These findings offer a versatile approach for constructing highly emissive cyanine-based supramolecular materials.
RESUMEN
BACKGROUND: Liver fibrosis caused by chronic liver injury, eventually develops into liver cirrhosis and hepatocellular carcinoma. Currently, there are no effective drugs to relieve liver fibrosis due to the lack of molecular pathogenesis characteristics. Former research demonstrates that the hepatic immune microenvironment plays a key role in the pathogenesis of liver fibrosis, thus macrophages are important immune cells in the liver. Our previous study has found that IDO1 plays an important role in the liver immune microenvironment. CRG is a gallic acid tannin found in medicinal plants of many ethnicities that protects against inflammation, tumors and chronic liver disease. However, the mechanism of by which CRG mediates the interaction of IDO1 with macrophages during hepatic immune maturation is not clear. PURPOSE: To investigate the regulatory mechanism of CRG in liver fibrosis and the intrinsic relationship between IDO1 and macrophage differentiation. METHODS: Zebrafish, RAW264.7 cells and mice were used in the study. IDO1 overexpression and knockdown cell lines were constructed using lentiviral techniques. RESULTS: We discovered that CRG remarkably reduced the AST and ALT serum levels. Histological examination revealed that CRG ameliorates CCL4-induced liver fibrosis and depressed the expression of α-SMA, Lamimin, Collagen-Ι and fibronectin. Besides, we found that CRG promoted increased MerTK expression on partly macrophages. Interestingly, in vitro, we found that CRG suppressed IDO1 expression and regulated macrophage differentiation by upregulating CD86, CD80 and iNOS, while downregulating CD206, CD163, IL-4 and IL-10 expression. Additionally, we found that CRG could inhibit hepatic stellate cell activation by direct or indirect action. CONCLUSION: Our findings suggest that CRG alleviates liver fibrosis by mediating IDO1-mediated M2 macrophage repolarization.
Asunto(s)
Neoplasias Hepáticas , Pez Cebra , Animales , Ratones , Cirrosis Hepática/tratamiento farmacológico , Macrófagos , Microambiente TumoralRESUMEN
Anatomical and functional heterogeneous substantia nigra (SN) has been extensively studied in humans and animals like rhesus monkeys given its crucial role in modulating a broad range of behaviors. Increasingly important cross-species research of SN may require connectionally homogeneous and homologous subregions of SN as objective and stable starting points from which the evolutionary characteristics of brain could be inspected. However, existing atlases of SN were all inaccurate mappings as a cross-species connectome atlas due to inadequate homology constraint during their constructions, and arbitrary paired use of these atlases might cause unreliable findings. In this study, a reliable blind-source cross-species parcellation of SN was developed based on the following rationale: striatonigrostriatal circuits form major structure of nigral connectivity; different nigral components have unique striatonigrostriatal connectivity; and inter-species corresponding human and macaque nigral components have similar striatonigrostriatal connectivity. Specifically, all voxels in human and macaque SN were grouped together and then classified based on inter-species identically characterized striatonigrostriatal connectivity attributes. Our results delineated a pars compacta-pars reticulate-like parcellation and further demonstrated its reliability by illustrating best-matched whole-brain structural and functional connectivity profiles of inter-species corresponding nigral subregions. Detailed inter-species and inter-regional differences in multi-aspect connectivities of these nigral subregions were inspected. It is expected that this cross-species connectome atlas of SN can offer biologically reliable cornerstones and important information to facilitate future cross-species research.
Asunto(s)
Conectoma , Imagen por Resonancia Magnética , Animales , Humanos , Imagen por Resonancia Magnética/métodos , Reproducibilidad de los Resultados , Sustancia Negra/diagnóstico por imagen , Conectoma/métodos , Macaca mulattaRESUMEN
Hepatocellular carcinoma (HCC) is a common malignancy affecting many people worldwide. Baicalin is a flavonoid extracted from the dried root of Scutellaria baicalensis Georgi. It can effectively inhibit the occurrence and development of HCC. Nonetheless, the mechanism through which Baicalin inhibits HCC growth and metastasis remain unknown. This work discovered that Baicalin inhibited HCC cell proliferation, invasion, metastasis while inducing cell cycle arrest at the G0/G1 phase and apoptosis. In vivo HCC xenograft results indicated that Baicalin inhibited HCC growth. Western blotting analysis indicated that Baicalin suppressed the expressions of ROCK1, p-GSK-3ß, and ß-catenin, whereas it up-regulated the expressions of GSK-3ß and p-ß-catenin. Baicalin also reduced the expressions of Bcl-2, C-myc, Cyclin D1, MMP-9, and VEGFA, while increasing the expression of Bax. Molecular docking revealed that Baicalin docked in the binding site of the ROCK1 agonist, with a binding energy of -9 kcal/mol between the two. In addition, lentivirus-mediated suppression of ROCK1 expression improved the inhibitory effect of Baicalin on the proliferation, invasion, and metastasis of HCC and the expression of proteins associated with ROCK1/GSK-3ß/ß-catenin signaling pathway. Moreover, restoring ROCK1 expression decreased the anti-HCC efficacy of Baicalin. These findings suggest that Baicalin may decrease HCC proliferation and metastasis by suppressing ROCK1/GSK-3ß/ß-catenin signaling.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , beta Catenina/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Transducción de Señal , Flavonoides/farmacología , Proliferación Celular , Quinasas Asociadas a rhoRESUMEN
To date, reliable biomarkers remain unclear that could link functional connectivity to patients' symptoms for detecting and predicting the process from normal aging to Alzheimer's disease (AD) in elderly people with specific genotypes. To address this, individual-specific functional connectivity is constructed for elderly participants with/without APOE ε4 allele. Then, we utilize recursive feature selection-based machine learning to reveal individual brain-behavior relationships and to predict the symptom transition in different genotypes. Our findings reveal that compared with conventional atlas-based functional connectivity, individual-specific functional connectivity exhibits higher classification and prediction performance from normal aging to AD in both APOE ε4 groups, while no significant performance is detected when the data of two genotyping groups are combined. Furthermore, individual-specific between-network connectivity constitutes a major contributor to assessing cognitive symptoms. This study highlights the essential role of individual variation in cortical functional anatomy and the integration of brain and behavior in predicting individualized symptoms.
Asunto(s)
Enfermedad de Alzheimer , Apolipoproteína E4 , Humanos , Anciano , Apolipoproteína E4/genética , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Genotipo , Encéfalo/diagnóstico por imagen , Mapeo EncefálicoRESUMEN
Somatic hypermutation (SHM), initiated by activation-induced cytidine deaminase (AID), generates mutations in the antibody-coding sequence to allow affinity maturation. Why these mutations intrinsically focus on the three nonconsecutive complementarity-determining regions (CDRs) remains enigmatic. Here, we found that predisposition mutagenesis depends on the single-strand (ss) DNA substrate flexibility determined by the mesoscale sequence surrounding AID deaminase motifs. Mesoscale DNA sequences containing flexible pyrimidine-pyrimidine bases bind effectively to the positively charged surface patches of AID, resulting in preferential deamination activities. The CDR hypermutability is mimicable in in vitro deaminase assays and is evolutionarily conserved among species using SHM as a major diversification strategy. We demonstrated that mesoscale sequence alterations tune the in vivo mutability and promote mutations in an otherwise cold region in mice. Our results show a non-coding role of antibody-coding sequence in directing hypermutation, paving the way for the synthetic design of humanized animal models for optimal antibody discovery and explaining the AID mutagenesis pattern in lymphoma.
Asunto(s)
Citidina Desaminasa , Hipermutación Somática de Inmunoglobulina , Animales , Ratones , Anticuerpos/genética , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , ADN/genética , ADN de Cadena Simple , Mutación , Evolución Molecular , Regiones Determinantes de Complementariedad/genética , Motivos de NucleótidosRESUMEN
OBJECTIVES: The disposable esophagogastroduodenoscopy (EGD) system is a novel endoscopic device which is highly portable and is designed to eliminate the risk of cross-infection caused by reusable EGD. This study aimed to investigate the feasibility and safety of disposable EGD in emergency, bedside, and intraoperative settings. METHODS: This was a prospective, single-center, noncomparative study. Disposable EGD was used for emergency, bedside, and intraoperative endoscopies in 30 patients. The primary end-point was the technical success rate of the disposable EGD. Secondary end-points included technical performance indicators including clinical operability, image quality score, procedure time, the incidence of device malfunction and/or failure, and the incidence of adverse events. RESULTS: A total of 30 patients underwent diagnosis and/or treatment with disposable EGD. Therapeutic EGD was performed on 13/30 patients, including hemostasis (n = 3), foreign body retrieval (n = 6), nasoenteric tube placement (n = 3), and percutaneous endoscopic gastrostomy (n = 1). The technical success rate was 100%: all procedures and indicated interventions were completed without changing to a conventional upper endoscope. The mean image quality score obtained immediately after procedure completion was 3.72 ± 0.56. The mean (± SD) procedure time was 7.4 (± 7.6) min. There were no device malfunctions or failures, device-related adverse events, or overall adverse events. CONCLUSION: The disposable EGD may be a feasible alternative to the traditional EGD in emergency, bedside, and intraoperative settings. Preliminary data show that it is a safe and effective tool for diagnosis and treatment in emergency and bedside upper gastrointestinal cases. TRIAL REGISTRATION: Chinese Clinical Trial Registry (Trial ID: ChiCTR2100051452, https://www.chictr.org.cn/showprojen.aspx?proj=134284).