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The nuclear pore complex (NPC) has multiple functions beyond the nucleo-cytoplasmic transport of large molecules. Subnuclear compartmentalization of chromatin is critical for gene expression in animals and yeast. However, the mechanism by which the NPC regulates gene expression is poorly understood in plants. Here we report that the Y-complex (Nup107-160 complex, a subcomplex of the NPC) self-maintains its nucleoporin homeostasis and modulates FLOWERING LOCUS C (FLC) transcription via changing histone modifications at this locus. We show that Y-complex nucleoporins are intimately associated with FLC chromatin through their interactions with histone H2A at the nuclear membrane. Fluorescence in situ hybridization assays revealed that Nup96, a Y-complex nucleoporin, enhances FLC positioning at the nuclear periphery. Nup96 interacted with HISTONE DEACETYLASE 6 (HDA6), a key repressor of FLC expression via histone modification, at the nuclear membrane to attenuate HDA6-catalyzed deposition at the FLC locus and change histone modifications. Moreover, we demonstrate that Y-complex nucleoporins interact with RNA polymerase II to increase its occupancy at the FLC locus, facilitating transcription. Collectively, our findings identify an attractive mechanism for the Y-complex in regulating FLC expression via tethering the locus at the nuclear periphery and altering its histone modification.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Histonas/genética , Histonas/metabolismo , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Complejo Poro Nuclear/metabolismo , Poro Nuclear/genética , Poro Nuclear/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Hibridación Fluorescente in Situ , Proteínas de Dominio MADS/genética , Proteínas de Dominio MADS/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , Cromatina/genética , Cromatina/metabolismo , Flores/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismoRESUMEN
Staphylococcus aureus (S. aureus) can evade antibiotics and host immune defenses by persisting within infected cells. Here, we demonstrate that in infected host cells, S. aureus type VII secretion system (T7SS) extracellular protein B (EsxB) interacts with the stimulator of interferon genes (STING) protein and suppresses the inflammatory defense mechanism of macrophages during early infection. The binding of EsxB with STING disrupts the K48-linked ubiquitination of EsxB at lysine 33, thereby preventing EsxB degradation. Furthermore, EsxB-STING binding appears to interrupt the interaction of 2 vital regulatory proteins with STING: aspartate-histidine-histidine-cysteine domain-containing protein 3 (DHHC3) and TNF receptor-associated factor 6. This persistent dual suppression of STING interactions deregulates intracellular proinflammatory pathways in macrophages, inhibiting STING's palmitoylation at cysteine 91 and its K63-linked ubiquitination at lysine 83. These findings uncover an immune-evasion mechanism by S. aureus T7SS during intracellular macrophage infection, which has implications for developing effective immunomodulators to combat S. aureus infections.
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Proteínas Bacterianas , Macrófagos , Proteínas de la Membrana , Infecciones Estafilocócicas , Staphylococcus aureus , Sistemas de Secreción Tipo VII , Ubiquitinación , Staphylococcus aureus/inmunología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/inmunología , Humanos , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Animales , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/metabolismo , Sistemas de Secreción Tipo VII/metabolismo , Sistemas de Secreción Tipo VII/inmunología , Sistemas de Secreción Tipo VII/genética , Ratones , Evasión Inmune , Interacciones Huésped-Patógeno/inmunologíaRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, although disease stratification using in-depth plasma proteomics has not been performed to date. By measuring more than 1000 proteins in the plasma of 147 DLBCL patients using data-independent acquisition mass spectrometry and antibody array, DLBCL patients were classified into four proteomic subtypes (PS-I-IV). Patients with the PS-IV subtype and worst prognosis had increased levels of proteins involved in inflammation, including a high expression of metalloproteinase inhibitor-1 (TIMP-1) that was associated with poor survival across two validation cohorts (n = 180). Notably, the combination of TIMP-1 with the international prognostic index (IPI) identified 64.00% to 88.24% of relapsed and 65.00% to 80.49% of deceased patients in the discovery and two validation cohorts, which represents a 24.00% to 41.67% and 20.00% to 31.70% improvement compared to the IPI score alone, respectively. Taken together, we demonstrate that DLBCL heterogeneity is reflected in the plasma proteome and that TIMP-1, together with the IPI, could improve the prognostic stratification of patients.
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Linfoma de Células B Grandes Difuso , Inhibidor Tisular de Metaloproteinasa-1 , Humanos , Pronóstico , Proteómica , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Biomarcadores , Estudios RetrospectivosRESUMEN
Hepatocellular carcinoma (HCC) is a prevalent cancer in China, with chronic hepatitis B (CHB) and liver cirrhosis (LC) being high-risk factors for developing HCC. Here, we determined the serum proteomes (762 proteins) of 125 healthy controls and Hepatitis B virus-infected CHB, LC, and HCC patients and constructed the first cancerous trajectory of liver diseases. The results not only reveal that the majority of altered biological processes were involved in the hallmarks of cancer (inflammation, metastasis, metabolism, vasculature, and coagulation) but also identify potential therapeutic targets in cancerous pathways (i.e., IL17 signaling pathway). Notably, the biomarker panels for detecting HCC in CHB and LC high-risk populations were further developed using machine learning in two cohorts comprised of 200 samples (discovery cohort = 125 and validation cohort = 75). The protein signatures significantly improved the area under the receiver operating characteristic curve of HCC (CHB discovery and validation cohort = 0.953 and 0.891, respectively; LC discovery and validation cohort = 0.966 and 0.818, respectively) compared to using the traditional biomarker, alpha-fetoprotein, alone. Finally, selected biomarkers were validated with parallel reaction monitoring mass spectrometry in an additional cohort (n = 120). Altogether, our results provide fundamental insights into the continuous changes of cancer biology processes in liver diseases and identify candidate protein targets for early detection and intervention.
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Carcinoma Hepatocelular , Hepatitis B Crónica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Virus de la Hepatitis B , Neoplasias Hepáticas/patología , Proteómica , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/diagnóstico , Biomarcadores , Curva ROC , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Biomarcadores de TumorRESUMEN
OBJECTIVE: Whether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC. DESIGN: Metabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of AKT1C77S and AKT1C224S knock-in cells, Zdhhc17 and Zdhhc24 knockout mice and Akt1C224S knock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies. RESULTS: By screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis. CONCLUSIONS: Our findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation.
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Carcinoma Hepatocelular , Dieta Alta en Grasa , Lipoilación , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Proteínas Proto-Oncogénicas c-akt , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Humanos , Ácido Palmítico/metabolismo , Carcinogénesis/metabolismo , Ratones Noqueados , Modelos Animales de Enfermedad , Masculino , Transducción de SeñalRESUMEN
The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the emergence of different variants of concerns with immune evasion that have been prevalent over the past three years. Nanobodies, the functional variable regions of camelid heavy-chain-only antibodies, have garnered interest in developing neutralizing antibodies due to their smaller size, structural stability, ease of production, high affinity, and low immunogenicity, among other characteristics. In this work, we describe an integrated proteomics platform for the high-throughput screening of nanobodies against different SARS-CoV-2 spike variants. To demonstrate this platform, we immunized a camel with subunit 1 (S1) of the wild-type spike protein and constructed a nanobody phage library. The binding and neutralizing activities of the nanobodies against 72 spike variants were then measured, resulting in the identification of two nanobodies (C-282 and C-39) with broad neutralizing activity against six non-Omicron variants (D614G, Alpha, Beta, Gamma, Delta, Kappa) and five Omicron variants (BA.1-5). Their neutralizing capability was validated using in vitro pseudovirus-based neutralization assays. All these results demonstrate the utility of our proteomics platform to identify new nanobodies with broad neutralizing capability and to develop a treatment for patients with SARS-CoV-2 variant infection in the future.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , Camelus , Proteómica , SARS-CoV-2 , Anticuerpos de Dominio Único , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos de Dominio Único/inmunología , Anticuerpos de Dominio Único/química , Proteómica/métodos , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Animales , Humanos , COVID-19/inmunología , COVID-19/virología , Anticuerpos Antivirales/inmunología , Pruebas de NeutralizaciónRESUMEN
Patients with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL-3-independent cell proliferation through activation of the p-PDGFRB and p-STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell-derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs).
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Proteínas de Fusión Oncogénica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Proteína 2 de Unión a Repeticiones Teloméricas , Animales , Humanos , Ratones , Carcinogénesis , Transformación Celular Neoplásica , Mesilato de Imatinib , Inhibidores de Proteínas Quinasas/farmacología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Transducción de Señal , Factor de Transcripción STAT5/genética , Proteína 2 de Unión a Repeticiones Teloméricas/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
Salmonella enterica serovar Abortusovis is a ovine-adapted pathogen that causes spontaneous abortion. Salmonella Abortusovis was reported in poultry in 2009 and has since been reported in human infections in New South Wales, Australia. Phylogenomic analysis revealed a clade of 51 closely related isolates from Australia originating in 2004. That clade was genetically distinct from ovine-associated isolates. The clade was widespread in New South Wales poultry production facilities but was only responsible for sporadic human infections. Some known virulence factors associated with human infections were only found in the poultry-associated clade, some of which were acquired through prophages and plasmids. Furthermore, the ovine-associated clade showed signs of genome decay, but the poultry-associated clade did not. Those genomic changes most likely led to differences in host range and disease type. Surveillance using the newly identified genetic markers will be vital for tracking Salmonella Abortusovis transmission in animals and to humans and preventing future outbreaks.
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Salmonella enterica , Salmonella , Embarazo , Femenino , Humanos , Animales , Ovinos , Aves de Corral , Serogrupo , Nueva Gales del Sur/epidemiología , Australia/epidemiologíaRESUMEN
BACKGROUND: Chimeric antigen receptor (CAR) T cells for refractory or relapsed (r/r) B cell no-Hodgkin lymphoma (NHL) patients have shown promising clinical effectiveness. However, the factors impacting the clinical response of CAR-T therapy have not been fully elucidated. We here investigate the independent influencing factors of the efficacy of CD19 CAR-T cell infusion in the treatment of r/r B-NHL and to establish an early prediction model. METHODS: A total of 43 r/r B-NHL patients were enrolled in this retrospective study. The patients' general data were recorded, and the primary endpoint is the patients' treatment response. The independent factors of complete remission (CR) and partial remission (PR) were investigated by univariate and binary logistic regression analysis, and the prediction model of the probability of CR was constructed according to the determined independent factors. Receiver operating characteristic (ROC) and calibration plot were used to assess the discrimination and calibration of the established model. Furthermore, we collected 15 participators to validate the model. RESULTS: Univariate analysis and binary logistic regression analysis of 43 patients showed that the ratio of central memory T cell (Tcm) and naïve T cell (Tn) in cytotoxic T cells (Tc) was an independent risk factor for response to CD19 CAR-T cell therapy in r/r B-NHL. On this basis, the area under the curve (AUC) of Tcm in the Tc and Tn in the Tc nomogram model was 0.914 (95%CI 0.832-0.996), the sensitivity was 83%, and the specificity was 74.2%, which had excellent predictive value. We did not found the difference of the progression-free survival (PFS). CONCLUSIONS: The ratio of Tcm and Tn in Tc was found to be able to predict the treatment response of CD19 CAR-T cells in r/r B-NHL. We have established a nomogram model for the assessment of the CD19 CAR-T therapy response presented high specificity and sensitivity.
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Receptores Quiméricos de Antígenos , Humanos , Nomogramas , Estudios Retrospectivos , Inmunoterapia Adoptiva , Subgrupos de Linfocitos T , Antígenos CD19RESUMEN
The response rate of anti-PD1 therapy is limited, and the influence of anti-PD1 therapy on cancer patients is unclear. To address these challenges, we conducted a longitudinal analysis of plasma proteomic changes with anti-PD1 therapy in non-small cell lung cancer (NSCLC), alveolar soft part sarcoma (ASPS), and lymphoma patients. We included 339 plasma samples before and after anti-PD1 therapy from 193 patients with NSCLC, ASPS, or lymphoma. The plasma proteins were detected using data-independent acquisition-mass spectrometry and customable antibody microarrays. Differential proteomic characteristics in responders (R) and non-responders (NR) before and after anti-PD1 therapy were elucidated. A total of 1019 proteins were detected using our in-depth proteomics platform and distributed across 10-12 orders of abundance. By comparing the differential plasma proteome expression between R and NR groups, 50, 206, and 268 proteins were identified in NSCLC, ASPS, and lymphoma patients, respectively. Th17, IL-17, and JAK-STAT signal pathways were identified upregulated in NR group, while cellular senescence and transcriptional misregulation pathways were activated in R group. Longitudinal proteomics analysis revealed the IL-17 signaling pathway was downregulated after treatment. Consistently, many proteins were identified as potential combinatorial therapeutic targets (e.g., IL-17A and CD22). Five noninvasive biomarkers (FLT4, SFTPB, GNPTG, F5, and IL-17A) were further validated in an independent lymphoma cohort (n = 39), and another three noninvasive biomarkers (KIT, CCL3, and TNFSF1) were validated in NSCLC cohort (n = 76). Our results provide molecular insights into the anti-PD1 therapy in cancer patients and identify new therapeutic strategies for anti-PD1-resistant patients.
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Antiinfecciosos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Linfoma , Humanos , Interleucina-17 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteómica , Neoplasias Pulmonares/tratamiento farmacológico , Penicilinas , Biomarcadores , Transferasas (Grupos de Otros Fosfatos Sustitutos)RESUMEN
Previously, a novel Corynebacterium glutamicum strain for the de novo biosynthesis of tailored poly-γ-glutamic acid (γ-PGA) has been constructed by our group. The strain was based on the γ-PGA synthetase complex, PgsBCA, which is the only polyprotein complex responsible for γ-PGA synthesis in Bacillus spp. In the present study, PgsBCA was reconstituted and overexpressed in C. glutamicum to further enhance γ-PGA synthesis. First, we confirmed that all the components (PgsB, PgsC, and PgsA) of γ-PGA synthetase derived from B. licheniformis are necessary for γ-PGA synthesis, and γ-PGA was detected only when PgsB, PgsC, and PgsA were expressed in combination in C. glutamicum. Next, the expression level of each pgsB, pgsC, and pgsA was tuned in order to explore the effect of expression of each of the γ-PGA synthetase subunits on γ-PGA production. Results showed that increasing the transcription levels of pgsB or pgsC and maintaining a medium-level transcription level of pgsA led to 35.44% and 76.53% increase in γ-PGA yield (γ-PGA yield-to-biomass), respectively. Notably, the expression level of pgsC had the greatest influence (accounting for 68.24%) on γ-PGA synthesis, followed by pgsB. Next, genes encoding for PgsC from four different sources (Bacillus subtilis, Bacillus anthracis, Bacillus methylotrophicus, and Bacillus amyloliquefaciens) were tested in order to identify the influence of PgsC-encoding orthologues on γ-PGA production, but results showed that in all cases the synthesis of γ-PGA was significantly inhibited. Similarly, we also explored the influence of gene orthologues encoding for PgsB on γ-PGA production, and found that the titer increased to 17.14 ± 0.62 g/L from 8.24 ± 0.10 g/L when PgsB derived from B. methylotrophicus replaced PgsB alone in PgsBCA from B. licheniformis. The resulting strain was chosen for further optimization, and we achieved a γ-PGA titer of 38.26 g/L in a 5 L fermentor by optimizing dissolved oxygen level. Subsequently, by supplementing glucose, γ-PGA titer increased to 50.2 g/L at 48 h. To the best of our knowledge, this study achieved the highest titer for de novo production of γ-PGA from glucose, without addition of L-glutamic acid, resulting in a novel strategy for enhancing γ-PGA production.
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Corynebacterium glutamicum , Fermentación , Corynebacterium glutamicum/genética , Corynebacterium glutamicum/metabolismo , Ácido Glutámico , Ácido Poliglutámico/genética , Ligasas/metabolismo , Glucosa/metabolismoRESUMEN
Sulfide in sediment porewaters, is toxic to rooted macrophytes in both marine and freshwater environments. Current research on sulfide stress in seagrasses primarily focuses on morphological and physiological aspects, with little known about the molecular response and resistance mechanisms. This study first investigated the damage caused by sulfide to eelgrass (Zostera marina L.) using transcriptomic, metabolomic, and other physiological and biochemical indicators and explored the potential resistance of eelgrass at molecular level through laboratory simulated and in-situ sulfide stress experiments. Comprehensive results showed that sulfide stress severely inhibited the growth, photosynthesis, and antioxidant enzyme activities of eelgrass. Importantly, transcriptome analysis revealed significant activation of pathways related to carbohydrate and sulfur metabolism. This activation served a dual purpose: providing an energy source for eelgrass stress response and achieving detoxification through accelerated sulfur metabolism-a potential resistance mechanism. The toxicity of sulfide increased with rising temperature as evidenced by a decrease in EC50. Results from recovery experiments indicated that when Fv/Fm reduced to about 0 under sulfide stress, the growth and photosynthesis of eelgrass recovered to normal level after timely removal of sulfide. However, prolonged exposure to sulfide resulted in failure to recover, leading ultimately to plant death. This study not only enhances our understanding of the molecular-level impacts of sulfide on seagrasses but also provides guidance for the management and ecological restoration of seagrass meadows under sulfide stress.
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Based on current laboratory laser parameters and the low density target that is induced by the inevitable prepulse, we propose what we believe to be a new scheme to enhance the proton energy by employing a laser pulse with two different peak intensities. Initially, the lower-intensity peak of the laser pulse P1, irradiates the low-density plasma target induced by the prepulse to form a significantly denser plasma target. Such a compressed high-density target is critical for supporting the subsequent main pulse P2 with higher peak intensity to drive proton acceleration. As an example, particle-in-cell (PIC) simulations reveal that when using a circularly polarized (CP) flat-top P1 with a peak intensity of approximately 1.71 × 10 19 W/cm2, full-width at half-maximum(FWHM) duration of 325 fs and a CP P2 with a peak intensity of 1.54 × 10 22 W/cm2, FWHM duration of 26.5 fs, and focal spot radius of 4â µm successively acting on a target with an initial density of 8nc, protons with cut-off energy of 940 MeV can be obtained from the cascaded acceleration scheme. Compared with the case without P1, the cutoff energy increased by 340 MeV. Owing to the intervention of P1, this scheme overcomes the limitation of laser contrast and is more feasible to be implemented experimentally.
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OBJECTIVE: This study investigates the association between a new insulin resistance indicator, the triglyceride-glucose (TyG) index, and the risk of macrosomia. DESIGN: This is a prospective cohort study. METHODS: This study included 1332 women who delivered at Peking University International Hospital between October 2017 and August 2019. Participants were divided equally into three groups based on the TyG index. Logistic regression and restricted cubic spline (RCS) analyses were used to evaluate the relationship between the TyG index and macrosomia and conducted subgroup analyses. The TyG index's ability to predict macrosomia was assessed using the receiver operating characteristic (ROC) curve. RESULTS: Multivariable logistic regression analysis revealed that the TyG index is an independent risk factor for macrosomia (Odds ratio [OR] 1.84, 95% confidence interval [CI] 1.02-3.30, p < .05). RCS analysis indicates that the risk of macrosomia increases with the rise of the TyG index (p for nonlinearity <.001) when the TyG index is >6.53. Subgroup analysis showed a synergistic additive interaction between the TyG index and gestational diabetes mellitus (GDM) of macrosomia. The area under the ROC curve for the predictive model was 0.733 (95% CI 0.684, 0.781), with a sensitivity of 76.4% and specificity of 66.9%. Incorporating the TyG index alongside traditional risk factors notably enhances macrosomia prediction (p < .05). CONCLUSIONS: The TyG index independently predicts macrosomia, and exhibits an additive interaction with GDM in its occurrence. Integrating the TyG index with traditional risk factors improves the prediction of macrosomia. TRIAL REGISTRY: Clinical trials. gov [NCT02966405].
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BACKGROUND: Microtubule polymerization is usually considered as the upstream of apoptotic cell death induced by taxanes, but recently published studies provide more insights into the mechanisms responsible for the antineoplastic effect of taxanes. In this study, we figure out the role of the stress-related PERK/eIF2α axis in tumor cell death upon taxane treatment along with paclitaxel resistance. METHODS: Utilizing immunoblot assay, the activation status of PERK-eIF2α signaling was detected in a panel of cancer cell lines after the treatment of taxanes. The causal role of PERK-eIF2α signaling in the cancer cell apoptosis induced by taxanes was examined via pharmacological and genetic inhibitions of PERK. The relationship between microtubule polymerization and PERK-eIF2α activation was explored by immunofluorescent and immunoblotting assays. Eventaually, the combined therapeutic effect of paclitaxel (PTX) and CCT020312, a PERK agonist, was investigated in PTX-resistant breast cancer cells in vitro and in vivo. RESULTS: PERK-eIF2α axis was dramatically activated by taxanes in several cancer cell types. Pharmacological or genetic inhibition of PERK efficiently impaired taxane-induced apoptotic cell death, independent of the cellular microtubule polymerization status. Moreover, PTX was able to activate the PERK/eIF2α axis in a very low concentration without triggering microtubule polymerization. In PTX-resistant breast cancer cells, the PERK/eIF2α axis was attenuated in comparison with the PTX-sensitive counterparts. Reactivation of the PERK/eIF2α axis in the PTX-resistant breast cancer cells with PERK agonist sensitized them to PTX in vitro. Combination treatment of the xenografted PTX-resistant breast tumors with PERK agonist and PTX validated the synergic effect of PTX and PERK activation in vivo. CONCLUSION: Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to initiate cancer cell apoptosis, which is independent of the well-known microtubule polymerization-dependent manner. Simultaneous activation of PERK-eIF2α signaling would be a promising therapeutic strategy to overcome PTX resistance in breast cancer or other cancers.
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L-serine and its derivative L-cysteine have broad industrial applications, and their direct fermentative production from renewable biomass is gaining increasing attention. Corynebacterium glutamicum is an extensively studied and well-established industrial microorganism, which is a predominant microbial host for producing amino acids. In this review, updated information on the genetics and molecular mechanisms underlying L-serine and L-cysteine production using C. glutamicum is presented, including their synthesis and degradation pathways, and other intracellular processes related to their production, as well as the mechanisms underlying substrate import and product export are also analyzed. Furthermore, metabolic strategies for strain improvement are systematically discussed, and conclusions and future perspectives for bio-based L-serine and L-cysteine production using C. glutamicum are presented. This review can provide a thorough understanding of L-serine and L-cysteine metabolic pathways to facilitate metabolic engineering modifications of C. glutamicum and development of more efficient industrial fermentation processes for L-serine and L-cysteine production.
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Corynebacterium glutamicum , Cisteína , Cisteína/metabolismo , Serina/metabolismo , Corynebacterium glutamicum/genética , Aminoácidos/metabolismo , Ingeniería Metabólica , FermentaciónRESUMEN
Chimeric antigen receptor T (CAR-T) cell therapy targeting CLL1 has been considered a potent weapon for patients with acute myeloid leukemia (AML). This study aims to evaluate the efficacy and toxicity of CLL1 CAR-T cell therapy in a larger cohort, with particular attention to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Among the 32 patients assessed for efficacy, complete remission occurred in 71.88% (23/32) of cases and undetectable minimal residual disease in 14 patients. The CRS developed in all patients, with 8 individuals experiencing ICANS. Severe CRS and ICANS were observed in 11 and 2 patients, respectively. Furthermore, the Endothelial Activation and Stress Index (EASIX) and its derivatives measured before and after CLL1 CAR-T cell infusion were employed for predicting the severe complications. Significant differences were observed in EASIX scores on the day before lymphodepletion (Day BL, P = 0.023), -1 (P < 0.001), +1 (P < 0.001), and +3(P = 0.014); sEASIX scores on Day BL (P = 0.007), -1 (P < 0.001), +1 (P < 0.001), and +3 (P < 0.001); and mEASIX score on Day -1 (P = 0.004) between patients with mild and severe CRS/ICANS. Additionally, there was a significant difference in mEASIX scores between responders and non-responders on Day BL (P = 0.004) and Day -1 (P = 0.044). Our findings indicate that pre- and post-infusion assessments of EASIX/mEASIX/sEASIX scores serve as reliable prognostic indicators for severe CRS/ICANS and treatment response following CLL1 CAR-T cell therapy, which can assist physicians in implementing preemptive treatment strategies for potential severe complications and screening patients who are suitable candidates for CLL1 CAR-T cell therapy. EASIX/mEASIX/sEASIX scores serve as reliable prognostic indicators for severe CRS/ICANS following CLL1 CAR-T cell therapy. The preinfusion mEASIX scores of CLL1 CAR-T cells can effectively predict treatment response.
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Leucemia Mieloide Aguda , Síndromes de Neurotoxicidad , Receptores Quiméricos de Antígenos , Humanos , Síndrome de Liberación de Citoquinas , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor expressed predominantly in NK and T-cell subsets that downregulates the activation and proliferation of immune cells and participates in cell-mediated immune responses. Accumulating evidence has demonstrated the importance of KLRG1 as a noteworthy disease marker and therapeutic target that can influence disease onset, progression, and prognosis. Blocking KLRG1 has been shown to effectively mitigate the effects of downregulation in various mouse tumor models, including solid tumors and hematologic malignancies. However, KLRG1 inhibitors have not yet been approved for human use, and the understanding of KLRG1 expression and its mechanism of action in various diseases remains incomplete. In this review, we explore alterations in the distribution, structure, and signaling pathways of KLRG1 in immune cells and summarize its expression patterns and roles in the development and progression of autoimmune diseases, infectious diseases, and cancers. Additionally, we discuss the potential applications of KLRG1 as a tool for tumor immunotherapy.
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Lectinas Tipo C , Neoplasias , Receptores Inmunológicos , Humanos , Receptores Inmunológicos/metabolismo , Lectinas Tipo C/metabolismo , Lectinas Tipo C/antagonistas & inhibidores , Animales , Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Biomarcadores/metabolismo , Transducción de Señal , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/tratamiento farmacológico , InmunoterapiaRESUMEN
BACKGROUND: A novel regimen with high-dose dual therapy (HDDT) has emerged, but its impact on the gut microbiota is not well understood. This study aimed to evaluate the impact of HDDT on the gut microbiota and compare it with that of bismuth quadruple therapy (BQT). METHODS: We enrolled outpatients (18-70 years) diagnosed with Helicobacter pylori infection by either histology or a positive 13C-urea breath test (13C-UBT) and randomly assigned to either the BQT or HDDT group. Subjects consented to provide fecal samples which were collected at baseline, Week 2, and Week 14. Amplification of the V1 and V9 regions of the 16S rRNA was conducted followed by high-throughput sequencing. RESULTS: Ultimately, 78 patients (41 patients in the HDDT group and 37 in the BQT group) were enrolled in this study. Eradication therapy significantly altered the diversity of the gut microbiota. However, the alpha diversity rebounded only in the HDDT group at 12 weeks post-eradication. Immediately following eradication, the predominance of Proteobacteria, replacing commensal Firmicutes and Bacteroidetes, did not recover after 12 weeks. Species-level analysis showed that the relative abundances of Klebsiella pneumoniae and Escherichia fergusonii significantly increased in both groups at Week 2. Enterococcus faecium and Enterococcus faecalis significantly increased in the BQT group, with no significant difference observed in the HDDT group. After 12 weeks of treatment, the relative abundance of more species in the HDDT group returned to baseline levels. CONCLUSION: Eradication of H. pylori can lead to an imbalance in gut microbiota. Compared to BQT, the HDDT is a regimen with milder impact on gut microbiota.
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Antibacterianos , Bismuto , Quimioterapia Combinada , Microbioma Gastrointestinal , Infecciones por Helicobacter , Helicobacter pylori , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Bacterias/clasificación , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Bismuto/uso terapéutico , Bismuto/administración & dosificación , Heces/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Helicobacter pylori/efectos de los fármacos , Helicobacter pylori/fisiología , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/administración & dosificación , ARN Ribosómico 16S/genéticaRESUMEN
PURPOSE: Patients with brain cancer and painful symptoms of the disease experience heavy pressure and negative inner experiences, leading to a sense of stigma. Therefore, this study assessed the level of stigma in patients with brain cancer and analyzed the risk factors for stigma to analyze the underlying relationships among depression, social support, low self-esteem, and stigma. METHODS: Patients completed the Social Impact Scale, Self-rating Depression Scale, Rosenberg Self-Esteem Scale, Herth Hope Index, Social Support Rating Scale, and Self-Perceived Burden Scale. Multiple linear regression analysis was used to identify factors independently associated with stigma. Parallel mediation analysis was used to evaluate the mediating role of the relationship between psychoemotional factors and stigma. RESULTS: A multivariate linear regression analysis demonstrated significant associations between age (ß = - 0.189, P = 0.002), treatment (ß = 0.184, P = 0.003), self-esteem (ß = - 0.128, P = 0.046), depression (ß = 0.273, P < 0.001), hope (ß = - 0.217, P = 0.003), and self-perceived burden (ß = 0.260, P < 0.001) with brain cancer. It was observed that the social support received by brain cancer patients directly impacted their stigma (total effect, - 0.851, P = 0.001). Additionally, this relationship was influenced by depression and self-esteem through two distinct pathways. CONCLUSION: Increased stigma among brain cancer patients was found to be associated with severe depression, feelings of inferiority, diminished hope, and a heavy perceived burden. The structural equation modeling (SEM) revealed that social support negatively influenced stigma through depression and self-esteem. It is imperative to grasp patients' inner needs, implement psychological interventions, and cultivate a cancer-friendly social environment to prevent stigmatization and discrimination based on their patient status.