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We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the cGAS-STING pathway. Multi-omics clustering identified four subtypes with subtype-specific therapeutic vulnerabilities. Cell line and patient-derived xenograft-based drug tests validated the specific therapeutic responses predicted by multi-omics subtyping. This study provides a valuable resource as well as insights to better understand SCLC biology and improve clinical practice.
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Neoplasias Pulmonares , Proteogenómica , Carcinoma Pulmonar de Células Pequeñas , Humanos , Línea Celular , Neoplasias Pulmonares/química , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células Pequeñas/química , Carcinoma Pulmonar de Células Pequeñas/genética , Xenoinjertos , Biomarcadores de Tumor/análisisRESUMEN
We performed the first proteogenomic characterization of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues from 159 patients. Integrated proteogenomic analyses revealed consistency and discordance among multi-omics, activation status of key signaling pathways, and liver-specific metabolic reprogramming in HBV-related HCC. Proteomic profiling identified three subgroups associated with clinical and molecular attributes including patient survival, tumor thrombus, genetic profile, and the liver-specific proteome. These proteomic subgroups have distinct features in metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutics. Two prognostic biomarkers, PYCR2 and ADH1A, related to proteomic subgrouping and involved in HCC metabolic reprogramming, were identified. CTNNB1 and TP53 mutation-associated signaling and metabolic profiles were revealed, among which mutated CTNNB1-associated ALDOA phosphorylation was validated to promote glycolysis and cell proliferation. Our study provides a valuable resource that significantly expands the knowledge of HBV-related HCC and may eventually benefit clinical practice.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virología , Fructosa-Bifosfato Aldolasa/genética , Virus de la Hepatitis B , Hepatitis B Crónica/complicaciones , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , Proteogenómica/métodos , beta Catenina/genética , Animales , Proliferación Celular , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Microambiente Tumoral/genéticaRESUMEN
Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.
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Deshidrocolesteroles , Ferroptosis , Humanos , Membrana Celular/metabolismo , Colesterol/biosíntesis , Colesterol/metabolismo , Sistemas CRISPR-Cas/genética , Deshidrocolesteroles/metabolismo , Genoma Humano , Enfermedades Renales/metabolismo , Membranas Mitocondriales/metabolismo , Metástasis de la Neoplasia , Neoplasias/metabolismo , Neoplasias/patología , Fosfolípidos/metabolismo , Daño por Reperfusión/metabolismoRESUMEN
Genetic alterations are often acquired during prolonged propagation of pluripotent stem cells (PSCs). This ruins the stem cell quality and hampers their full applications. Understanding how PSCs maintain genomic integrity would provide the clues to overcome the hurdle. It has been known that embryonic stem cells (ESCs) utilize high-fidelity pathways to ensure genomic stability, but the underlying mechanisms remain largely elusive. Here, we show that many DNA damage response and repair genes display differential alternative splicing in mouse ESCs compared to differentiated cells. Particularly, Rev1 and Polq, two key genes for mutagenic translesion DNA synthesis (TLS) and microhomology-mediated end joining (MMEJ) repair pathways, respectively, display a significantly higher rate of cryptic exon (CE) inclusion in ESCs. The frequent CE inclusion disrupts the normal protein expressions of REV1 and POLθ, thereby suppressing the mutagenic TLS and MMEJ. Further, we identify an ESC-specific RNA binding protein DPPA5A which stimulates the CE inclusion in Rev1 and Polq. Depletion of DPPA5A in mouse ESCs decreased the CE inclusion of Rev1 and Polq, induced the protein expression, and stimulated the TLS and MMEJ activity. Enforced expression of DPPA5A in NIH3T3 cells displayed reverse effects. Mechanistically, we found that DPPA5A directly regulated CE splicing of Rev1. DPPA5A associates with U2 small nuclear ribonucleoprotein of the spliceosome and binds to the GA-rich motif in the CE of Rev1 to promote CE inclusion. Thus, our study uncovers a mechanism to suppress mutagenic TLS and MMEJ pathways in ESCs.
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Mutágenos , Nucleotidiltransferasas , Animales , Ratones , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Células Madre Embrionarias de Ratones/metabolismo , Células 3T3 NIH , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , ADN , Daño del ADNRESUMEN
Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a critical intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.
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Antiinflamatorios/farmacología , Autofagia/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Mitocondrias Hepáticas/efectos de los fármacos , Mitofagia/efectos de los fármacos , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Factor 2 Asociado a Receptor de TNF/metabolismo , Triterpenos/farmacología , Ubiquitinación/efectos de los fármacos , Transporte Activo de Núcleo Celular , Animales , Antiinflamatorios/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Modelos Animales de Enfermedad , Femenino , Genotipo , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Ligandos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias Hepáticas/metabolismo , Mitocondrias Hepáticas/patología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/deficiencia , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Triterpenos Pentacíclicos , Fenotipo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Interferencia de ARN , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismo , Transducción de Señal/efectos de los fármacos , Factor 2 Asociado a Receptor de TNF/genética , Transfección , Triterpenos/metabolismoRESUMEN
Caused by Yersinia pestis, plague ravaged the world through three known pandemics: the First or the Justinianic (6th-8th century); the Second (beginning with the Black Death during c.1338-1353 and lasting until the 19th century); and the Third (which became global in 1894). It is debatable whether Y. pestis persisted in European wildlife reservoirs or was repeatedly introduced from outside Europe (as covered by European Union and the British Isles). Here, we analyze environmental data (soil characteristics and climate) from active Chinese plague reservoirs to assess whether such environmental conditions in Europe had ever supported "natural plague reservoirs". We have used new statistical methods which are validated through predicting the presence of modern plague reservoirs in the western United States. We find no support for persistent natural plague reservoirs in either historical or modern Europe. Two factors make Europe unfavorable for long-term plague reservoirs: 1) Soil texture and biochemistry and 2) low rodent diversity. By comparing rodent communities in Europe with those in China and the United States, we conclude that a lack of suitable host species might be the main reason for the absence of plague reservoirs in Europe today. These findings support the hypothesis that long-term plague reservoirs did not exist in Europe and therefore question the importance of wildlife rodent species as the primary plague hosts in Europe.
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Peste , Yersinia pestis , Humanos , Peste/epidemiología , Peste/historia , Europa (Continente) , Pandemias/historia , Clima , Suelo , Reservorios de EnfermedadesRESUMEN
Developing high-efficiency and stable oxygen evolution reaction (OER) electrocatalysts is an imperative requirement to produce green and clean hydrogen energy. In this work, the FeCoSy /NCDs composite with nitrogen-doped carbon dots (NCDs) modified Fe-Co sulfide (FeCoSy ) nanosheets is prepared by using a facile and mild one-pot solvothermal method. Benefiting from the low crystallinity and the synergistic effect between FeCoSy and NCDs, the optimal FeCoSy /NCDs-3 composite exhibits an overpotential of only 284 mV at 10 mA cm-2 , a small Tafel value of 52.1 mV dec-1 , and excellent electrochemical durability in alkaline solution. Remarkably, unlike ordinary metal sulfide electrocatalysts, the morphology, components, and structure of the FeCoSy /NCDs composite can be well retained after OER test. The NCDs modified FeCoSy composite with excellent electrocatalytic performance provides an effective approach to boost metal sulfide electrocatalysts for practical application.
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Pores and old root-channels are preferentially used by roots to allow them to penetrate hard soils. However, there are few studies that have accounted for the effects of pore-rhizosheath on root growth. In this study, we developed an approach by adding the synthetic root exudates using a porous stainless tube with 0.1-mm micropores through a peristaltic pump to reproduce the rhizosheath around the artificial pore, and investigated the effects of pores with and without rhizosheaths on maize root growth in a dense soil. The results indicated that the artificial rhizosheath was about 2.69 mm wide in the region surrounding the pores. The rhizosheath had a higher content of organic carbon, total nitrogen, and abundance of Actinobacteria than that of the bulk soil. Compared with the artificial macropores, the artificial root-pores with a rhizosheath increased the opportunities for root utilisation of the pores space, promoting steeper and deeper root growth. It is concluded that the pore-rhizosheath has a significant impact on root architecture by enhancing root distribution in macropores.
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Raíces de Plantas , Zea mays , Zea mays/crecimiento & desarrollo , Zea mays/anatomía & histología , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/anatomía & histología , Porosidad , Suelo/química , Nitrógeno/metabolismo , Carbono/metabolismoRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy which characteristically expresses an atypical phenotype including CD123+, CD56+, and CD4+. We are aimed to investigate the clinical and prognostic characteristics of AML patients exhibiting BPDCN-like immunophenotype and provide additional insights for risk stratification of AML. A total of 241 newly diagnosed AML patients were enrolled in this retrospective study and categorized into BPDCN-like positive (n = 125)/negative (n = 116) groups, determined by the present with CD123+ along with either CD56+ or CD4+, or both. Subsequently, an analysis was conducted to examine the general clinical characteristics, genetic profiles, and prognosis of the two respective groups. Patients with BPDCN-like immunophenotype manifested higher frequencies of acute myelomonocytic leukemia and acute monoblastic leukemia. Surprisingly, the presence of the BPDCN-like immunophenotype exhibited an inverse relationship with CEBPA bZIP mutation. Notably, patients with BPDCN-like phenotype had both worse OS and EFS compared to those without BPDCN-like phenotype. In the CN-AML subgroups, the BPDCN-like phenotype was associated with worse EFS. Similarly, a statistically significant disparity was observed in both OS and EFS within the favorable-risk subgroup, while only OS was significant within the adverse-risk subgrouMoreover, patients possessing favorable-risk genetics without BPDCN-like phenotype had the longest survival, whereas those who had both adverse-risk genetics and BPDCN-like phenotype exhibited the worst survival. Our study indicated that BPDCN-like phenotype negatively associated with CEBPA bZIP mutation and revealed a significantly poor prognosis in AML. Moreover, the 2022 ELN classification, in combination with the BPDCN-like phenotype, may better distinguish between different risk groups.
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Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Neoplasias Cutáneas , Humanos , Estudios Retrospectivos , Subunidad alfa del Receptor de Interleucina-3 , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Pronóstico , Enfermedad Aguda , Trastornos Mieloproliferativos/patología , Neoplasias Cutáneas/patología , Células Dendríticas/patología , Mutación , Proteínas Potenciadoras de Unión a CCAAT/genéticaRESUMEN
While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 109/L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 109/L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 109/L and 50 × 109/L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials.
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Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Pirazolonas , Receptores de Trombopoyetina , Humanos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/administración & dosificación , Masculino , Femenino , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Benzoatos/administración & dosificación , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/sangre , Persona de Mediana Edad , Adulto , Anciano , Hidrazinas/uso terapéutico , Hidrazinas/efectos adversos , Hidrazinas/administración & dosificación , Receptores de Trombopoyetina/agonistas , Pirazolonas/uso terapéutico , Sustitución de Medicamentos , Recuento de Plaquetas , Resultado del Tratamiento , HidrazonasRESUMEN
Defective carbon nitride (DCN-x) was synthesized through a dual-surface engineering process consisting of nitric acid treatment followed by high-temperature calcination. This process endowed DCN-x with a porous structure and a larger surface area than that of pure graphite carbon nitride (CN), enhancing its visible light absorption and reducing the electron-hole recombination rate. Consequently, DCN-x demonstrated a significantly more efficient photocatalytic hydrogen evolution, with the optimum sample, DCN-600, achieving an activity 55.9 times greater than that of pure CN, while maintaining excellent photocatalytic stability. Furthermore, the presence of tri-s-triazine (heptazine) structures within the CN's in-plane structure was identified as a critical factor for band gap optimization, suggesting new avenues for the synthesis of carbon nitride variants with enhanced photocatalytic performance.
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Acquired hemophilia A (AHA) is a rare but serious bleeding disorder. Randomized controlled trial (RCT) comparing the efficacy of immunosuppression therapy for AHA lacks. We conducted the first multicenter RCT aiming to establish whether the single-dose rituximab combination regimen was noninferior to the cyclophosphamide combination regimen. From 2017 to 2022, 63 patients with newly diagnosed AHA from five centers were randomly assigned 1:1 to receive glucocorticoid (methylprednisolone 0.8 mg/kg per day for the first 3 weeks and then tapered) plus single-dose rituximab (375 mg/m2 ; n = 31) or plus cyclophosphamide (2 mg/kg per day until inhibitor becomes negative, for a maximum of 5 weeks; n = 32). The primary outcome was complete remission (CR, defined as FVIII activity ≥50 IU/dL, FVIII inhibitor undetectable, immunosuppression tapered and no bleeding for 24 h without bypassing agents) rate measured within 8 weeks. The noninferiority margin was an absolute difference of 20%. Twenty-four (77.4%) patients in the rituximab group and 22 (68.8%) patients in the cyclophosphamide group achieved CR, which showed the noninferiority of the single-dose rituximab-based regimen (absolute difference = -8.67%, lower limit of the 95% confidence interval = -13.11%; Pnoninferiority = 0.005). No difference was found in the incidence of treatment-related adverse events. Single-dose rituximab plus glucocorticoid regimen showed similar efficacy and safety, without a reported risk of secondary malignancies or reproductive toxicity seen in cyclophosphamide, it might be recommended as a first-line therapy for AHA, especially in China where there is a young age trend in AHA patients. This trial was registered at ClinicalTrials.gov as #NCT03384277.
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Glucocorticoides , Hemofilia A , Humanos , Ciclofosfamida/uso terapéutico , Glucocorticoides/uso terapéutico , Hemofilia A/tratamiento farmacológico , Metilprednisolona/uso terapéutico , Rituximab/uso terapéutico , Resultado del Tratamiento , Quimioterapia Combinada/efectos adversosRESUMEN
Jaktinib, a novel JAK and ACVR1 inhibitor, has exhibited promising results in treating patients with myelofibrosis (MF). ZGJAK002 is a Phase 2 trial aimed to assess the efficacy and safety of jaktinib 100 mg BID (N = 66) and 200 mg QD (N = 52) in JAK inhibitor-naive patients with intermediate- or high-risk MF. We herein present the long-term data with a median follow-up of 30.7 months. At data cutoff, 30.3% of patients in 100 mg BID and 28.8% in 200 mg QD were still continuing their treatment. The 100 mg BID group displayed a numerically higher best spleen response compared with the 200 mg QD group (69.7% vs. 46.2%), with 50.4% from the BID and 51.2% from the QD group maintaining spleen responses over 120 weeks. The 36-month survival rates were 78.2% in BID and 73.6% in QD group. The tolerability of jaktinib remained well, and common grade ≥3 adverse drug reactions included anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in BID and QD groups, respectively. By comparing the two groups, the incidence of adverse events (AEs) were similar, except for drug-related serious AEs (24.2% vs. 9.6%) and AEs leading to treatment discontinuation (15.2% vs. 7.7%), which were higher in BID group. The percentages of AEs resulting in death were comparable, with 6.1% in BID and 5.8% in QD group. These analyses further support the long-term durable efficacy and acceptable safety of jaktinib at 100 mg BID and 200 mg QD doses for treating MF.
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Mielofibrosis Primaria , Humanos , Estudios de Seguimiento , Mielofibrosis Primaria/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Two rare 8-hydroxysteroid glycosides (6-7), and their downstream metabolites (1-5) with an unprecedented 6/6/5/5/5-pentacyclic scaffold, together with seven known analogues (8-14) were isolated from the twigs and leaves of Strophanthus divaricatus. Their structures were fully assigned by analysis of the spectroscopic and ECD data, NMR calculations, X-ray crystallographic study, and chemical methods. In addition, the inhibitory effects of 1-14 on liver and lung cancer cell lines were evaluated, and preliminary structure-activity relationship was discussed. Data-independent acquisition (DIA)-based quantitative proteomic analysis and biological verification of H1299 cells suggested that this family of compounds may play an anticancer role by suppressing both DNA damage response (DDR) and mTOR/S6K signaling pathways.
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Beta-cypermethrin (ß-CY) residues in food are an important threat to human health. Microorganisms can degrade ß-CY residues during fermentation of fruits and vegetables, while the mechanism is not clear. In this study, a comprehensively investigate of the degradation mechanism of ß-CY in a food microorganism was conducted based on proteomics analysis. The ß-CY degradation bacteria Gordonia alkanivorans GH-1 was derived from fermented Pixian Doubanjiang. Its crude enzyme extract could degrade 77.11% of ß-CY at a concentration of 45 mg/L within 24 h. Proteomics analysis revealed that the ester bond of ß-CY is broken under the action of esterase to produce 3-phenoxy benzoic acid, which was further degraded by oxidoreductase and aromatic degrading enzyme. The up-regulation expression of oxidoreductase and esterase was confirmed by transcriptome and quantitative reverse transcription PCR. Meanwhile, the expression of esterase Est280 in Escherichia coli BL21 (DE3) resulted in a 48.43% enhancement in the degradation efficiency of ß-CY, which confirmed that this enzyme was the key enzyme in the process of ß-CY degradation. This study reveals the degradation mechanism of ß-CY by microorganisms during food fermentation, providing a theoretical basis for the application of food microorganisms in ß-CY residues.
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Esterasas , Proteómica , Piretrinas , Piretrinas/metabolismo , Esterasas/metabolismo , Esterasas/genética , Alimentos Fermentados/microbiología , Fermentación , Escherichia coli/metabolismo , Escherichia coli/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genéticaRESUMEN
BACKGROUND: The maturation of microRNAs (miRNAs) successively undergoes Drosha, Dicer, and Argonaute -mediated processing, however, the intricate regulations of the individual miRNA maturation are largely unknown. Retinoid x receptor alpha (RXRα) belongs to nuclear receptors that regulate gene transcription by binding to DNA elements, however, whether RXRα binds to miRNAs to exert physiological functions is not known. RESULTS: In this work, we found that RXRα directly binds to the precursor of miR-103 (pre-miR-103a-2) via its DNA-binding domain with a preferred binding sequence of AGGUCA. The binding of RXRα inhibits the processing of miR-103 maturation from pre-miR-103a-2. Mechanistically, RXRα prevents the nuclear export of pre-miR-103a-2 for further processing by inhibiting the association of exportin-5 with pre-miR-103a-2. Pathophysiologically, the negative effect of RXRα on miR-103 maturation correlates to the positive effects of RXRα on the expression of Dicer, a target of miR-103, and on the inhibition of breast cancer. CONCLUSIONS: Our findings unravel an unexpected role of transcription factor RXRα in specific miRNA maturation at post-transcriptional level through pre-miRNA binding, and present a mechanistic insight regarding RXRα role in breast cancer progression.
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MicroARNs , Receptores Citoplasmáticos y Nucleares , Factores de Transcripción , Proteínas Argonautas , MicroARNs/genéticaRESUMEN
Membranes have been extensively studied and applied in various fields owing to their high energy efficiency and small environmental impact. Further conferring membranes with stimuli responsiveness can allow them to dynamically tune their pore structure and/or surface properties for efficient separation performance. This review summarizes and discusses important developments and achievements in stimuli-responsive membranes. The most commonly utilized stimuli, including light, pH, temperature, ions, and electric and magnetic fields, are discussed in detail. Special attention is given to stimuli-responsive control of membrane pore structure (pore size and porosity/connectivity) and surface properties (wettability, surface topology, and surface charge), from the perspective of determining the appropriate membrane properties and microstructures. This review also focuses on strategies to prepare stimuli-responsive membranes, including blending, casting, polymerization, self-assembly, and electrospinning. Smart applications for separations are also reviewed as well as a discussion of remaining challenges and future prospects in this exciting field. This review offers critical insights for the membrane and broader materials science communities regarding the on-demand and dynamic control of membrane structures and properties. We hope that this review will inspire the design of novel stimuli-responsive membranes to promote sustainable development and make progress toward commercialization.
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Polyurethane/silk protein-bismuth halide oxide composite films were fabricated using a blending-wet phase transformationin situsynthesis method. The crystal structure, micromorphology, and optical properties were conducted using XRD, SEM, and UV-Vis DRS characterize techniques. The results indicated that loaded silk protein enhanced the hydrophilicity and pore structure of the polyurethane composite films. The active species BiOX were observed to grow as nanosheets with high dispersion on the internal skeleton and silk protein surface of the polyurethane-silk protein film. The photocatalytic efficiency of BiOX/PU-SF composite films was assessed through the degradation of Rhodamine B under visible light irradiation. Among the tested films, the BiOBr/PU-SF composite exhibited the highest removal rate of RhB at 98.9%, surpassing the removal rates of 93.7% for the BiOCl/PU-SF composite and 85.6% for the BiOI/PU-SF composite. Furthermore, an active species capture test indicated that superoxide radical (â¢O2-) and hole (h+) species played a predominant role in the photodegradation process.
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Bismuto , Interacciones Hidrofóbicas e Hidrofílicas , Fotólisis , Poliuretanos , Poliuretanos/química , Bismuto/química , Catálisis , Seda/química , Rodaminas/química , Colorantes/química , Óxidos/química , Porosidad , LuzRESUMEN
BACKGROUND: Unsafe sex is recognized as an important risk factor for cervical cancer (CC). Understanding the global disease burden of CC attributable to unsafe sex can assist policymakers in allocating healthcare resources. METHODS: Data were obtained from the 2019 global burden of disease database (GBD). We examined global, regional, and national levels of CC mortality, disability-adjusted life years (DALYs), and age-standardized rates (ASRs) caused by unsafe sex. ASRs were evaluated using estimated annual percentage changes (EAPCs). RESULTS: Attributable to unsafe sex, there were 280,479 CC-related deaths in 2019 and 8,955,013 CC-related DALYs. In the period 1990-2019, the global ASRs of CC due to unsafe sex decreased around the world; for age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR), the EAPCs were -0.93 and -0.95. The highest ASMRs and ASDRs were found in central sub-Saharan Africa and the lowest in Australasia. CONCLUSION: In the past few decades, the ASMR and ASDR of CC caused by unsafe sexual practices have decreased over time, with significant variations observed among different countries and regions. Increased focus is needed on spreading awareness about sexual health and promoting CC prevention and screening, particularly in low- and middle-income nations.