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The recent revolution in tissue-resident macrophage biology has resulted largely from murine studies performed in C57BL/6 mice. Here, using both C57BL/6 and BALB/c mice, we analyze immune cells in the pleural cavity. Unlike C57BL/6 mice, naive tissue-resident large-cavity macrophages (LCMs) of BALB/c mice failed to fully implement the tissue-residency program. Following infection with a pleural-dwelling nematode, these pre-existing differences were accentuated with LCM expansion occurring in C57BL/6, but not in BALB/c mice. While infection drove monocyte recruitment in both strains, only in C57BL/6 mice were monocytes able to efficiently integrate into the resident pool. Monocyte-to-macrophage conversion required both T cells and interleukin-4 receptor alpha (IL-4Rα) signaling. The transition to tissue residency altered macrophage function, and GATA6+ tissue-resident macrophages were required for host resistance to nematode infection. Therefore, during tissue nematode infection, T helper 2 (Th2) cells control the differentiation pathway of resident macrophages, which determines infection outcome.
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Filariasis , Filarioidea , Infecciones por Nematodos , Ratones , Animales , Filarioidea/fisiología , Células Th2 , Monocitos , Cavidad Pleural , Ratones Endogámicos C57BL , Macrófagos/fisiología , Diferenciación Celular , Ratones Endogámicos BALB CRESUMEN
2'-O-methylation (Nm) is a prominent RNA modification well known in noncoding RNAs and more recently also found at many mRNA internal sites. However, their function and base-resolution stoichiometry remain underexplored. Here, we investigate the transcriptome-wide effect of internal site Nm on mRNA stability. Combining nanopore sequencing with our developed machine learning method, NanoNm, we identify thousands of Nm sites on mRNAs with a single-base resolution. We observe a positive effect of FBL-mediated Nm modification on mRNA stability and expression level. Elevated FBL expression in cancer cells is associated with increased expression levels for 2'-O-methylated mRNAs of cancer pathways, implying the role of FBL in post-transcriptional regulation. Lastly, we find that FBL-mediated 2'-O-methylation connects to widespread 3' UTR shortening, a mechanism that globally increases RNA stability. Collectively, we demonstrate that FBL-mediated Nm modifications at mRNA internal sites regulate gene expression by enhancing mRNA stability.
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Regiones no Traducidas 3' , Estabilidad del ARN , ARN Mensajero , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Metilación , Procesamiento Postranscripcional del ARN , Secuenciación de Nanoporos/métodos , Transcriptoma , Regulación Neoplásica de la Expresión Génica , Aprendizaje AutomáticoRESUMEN
Flowering plants have evolved numerous intraspecific and interspecific prezygotic reproductive barriers to prevent production of unfavourable offspring1. Within a species, self-incompatibility (SI) is a widely utilized mechanism that rejects self-pollen2,3 to avoid inbreeding depression. Interspecific barriers restrain breeding between species and often follow the SI × self-compatible (SC) rule, that is, interspecific pollen is unilaterally incompatible (UI) on SI pistils but unilaterally compatible (UC) on SC pistils1,4-6. The molecular mechanisms underlying SI, UI, SC and UC and their interconnections in the Brassicaceae remain unclear. Here we demonstrate that the SI pollen determinant S-locus cysteine-rich protein/S-locus protein 11 (SCR/SP11)2,3 or a signal from UI pollen binds to the SI female determinant S-locus receptor kinase (SRK)2,3, recruits FERONIA (FER)7-9 and activates FER-mediated reactive oxygen species production in SI stigmas10,11 to reject incompatible pollen. For compatible responses, diverged pollen coat protein B-class12-14 from SC and UC pollen differentially trigger nitric oxide, nitrosate FER to suppress reactive oxygen species in SC stigmas to facilitate pollen growth in an intraspecies-preferential manner, maintaining species integrity. Our results show that SRK and FER integrate mechanisms underlying intraspecific and interspecific barriers and offer paths to achieve distant breeding in Brassicaceae crops.
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Brassicaceae , Flores , Hibridación Genética , Proteínas de Plantas , Polinización , Brassicaceae/genética , Brassicaceae/metabolismo , Depresión Endogámica , Óxido Nítrico/metabolismo , Fosfotransferasas/metabolismo , Fitomejoramiento , Proteínas de Plantas/metabolismo , Polen/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Especificidad de la Especie , Flores/metabolismo , AutofecundaciónRESUMEN
BACKGROUND: The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear. METHODS: Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca2+ influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice. RESULTS: (1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibition peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca2+ influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR (mammalian target of rapamycin) signaling through reducing Akt (protein kinase B) activity, but enhancing inhibitory GSK-3α (glycogen synthase kinase-3α) and GSK-3ß signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic atrial natriuretic peptide (ANP); (7) cPKAi ameliorated established PaCH and improved animal survival. CONCLUSIONS: Cardiomyocyte PKA is a master regulator of PhCH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH.
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Proteínas Quinasas Dependientes de AMP Cíclico , Complejo de la Endopetidasa Proteasomal , Ratones , Ratas , Animales , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Cardiomegalia/metabolismo , Miocitos Cardíacos/metabolismo , Ratones Transgénicos , Péptidos/metabolismo , MamíferosRESUMEN
Stalk lodging is a severe problem that limits maize production worldwide, although little attention has been given to its genetic basis. Here we measured rind penetrometer resistance (RPR), an effective index for stalk lodging, in a multi-parent population of 1948 recombinant inbred lines (RILs) and an association population of 508 inbred lines (AMP508). Linkage and association mapping identified 53 and 29 single quantitative trait loci (QTLs) and 50 and 19 pairs of epistatic interactions for RPR in the multi-parent population and AMP508 population, respectively. Phenotypic variation explained by all identified epistatic QTLs (up to ~5%) was much less than that explained by all single additive QTLs (up to ~33% in the multi-parent population and ~ 60% in the AMP508 population). Among all detected QTLs, only eight single QTLs explained >10% of phenotypic variation in single RIL populations. Alleles that increased RPR were enriched in tropical/subtropical (TST) groups from the AMP508 population. Based on genome-wide association studies in both populations, we identified 137 candidate genes affecting RPR, which were assigned to multiple biological processes, such as the biosynthesis of cell wall components. Sixty-six candidate genes were cross-validated by multiple methods or populations. Most importantly, 23 candidate genes were upregulated or downregulated in high-RPR lines relative to low-RPR lines, supporting the associations between candidate genes and RPR. These findings reveal the complex nature of the genetic basis underlying RPR and provide loci or candidate genes for developing elite varieties that are resistant to stalk lodging via molecular breeding.
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Estudio de Asociación del Genoma Completo , Zea mays , Mapeo Cromosómico , Zea mays/genética , Fenotipo , Ligamiento GenéticoRESUMEN
Following the successful control of poliovirus, the re-emergence of respiratory enterovirus D68 (EV-D68), a prominent non-polio enterovirus, has become a serious public health concern worldwide. Host innate immune responses are the primary defense against EV-D68 invasion; however, the mechanism underlying viral evasion of the antiviral activity of interferons (IFN) remains unclear. In this study, we found that EV-D68 inhibited type I IFN signaling by cleaving signal transducer and activator of transcription 1 (STAT1), a crucial factor in cellular responses to interferons and other cytokines. We observed that the prototype and circulating EV-D68 strains conserved their ability to induce STAT1 cleavage and attenuate IFN signal transduction. Further investigation revealed that EV-D68 3C protease cleaves STAT1 at the 131Q residue. Interestingly, not all enterovirus-encoded 3C proteases exhibited this ability. EV-D68 and poliovirus 3C proteases efficiently induced STAT1 cleavage; whereas, 3C proteases from EV-A71, coxsackievirus A16, and echoviruses did not. STAT1 cleavage also abolished the nuclear translocation capacity of STAT1 in response to IFN stimulation to activate downstream signaling elements. Overall, these results suggest that STAT1, targeted by viral protease 3C, is utilized by EV-D68 to subvert the host's innate immune response.IMPORTANCEEnterovirus D68 (EV-D68) has significantly transformed over the past decade, evolving from a rare pathogen to a potential pandemic pathogen. The interferon (IFN) signaling pathway is an important defense mechanism and therapeutic target for the host to resist viral invasion. Previous studies have reported that the EV-D68 virus blocks or weakens immune recognition and IFN production in host cells through diverse strategies; however, the mechanisms of EV-D68 resistance to IFN signaling have not been fully elucidated. Our study revealed that EV-D68 relies on its own encoded protease, 3C, to directly cleave signal transducer and activator of transcription 1 (STAT1), a pivotal transduction component in the IFN signaling pathway, disrupting the IFN-mediated antiviral response. Previous studies on human enteroviruses have not documented direct cleavage of the STAT1 protein to evade cellular immune defenses. However, not all enteroviral 3C proteins can cleave STAT1. These findings highlight the diverse evolutionary strategies different human enteroviruses employ to evade host immunity.
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Proteasas Virales 3C , Enterovirus Humano D , Interferón Tipo I , Transducción de Señal , Humanos , Proteasas Virales 3C/metabolismo , Antígenos Virales/metabolismo , Antivirales/farmacología , Cisteína Endopeptidasas/metabolismo , Enterovirus Humano D/fisiología , Interacciones Huésped-Patógeno , Evasión Inmune , Inmunidad Innata , Interferón Tipo I/metabolismo , Péptido Hidrolasas/metabolismo , Proteolisis , Factor de Transcripción STAT1/metabolismo , Proteínas Virales/metabolismoRESUMEN
Pyroptosis, a pro-inflammatory programmed cell death, has been implicated in the pathogenesis of coronavirus disease 2019 and other viral diseases. Gasdermin family proteins (GSDMs), including GSDMD and GSDME, are key regulators of pyroptotic cell death. However, the mechanisms by which virus infection modulates pyroptosis remain unclear. Here, we employed a mCherry-GSDMD fluorescent reporter assay to screen for viral proteins that impede the localization and function of GSDMD in living cells. Our data indicated that the main protease NSP5 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) blocked GSDMD-mediated pyroptosis via cleaving residues Q29 and Q193 of GSDMD. While another SARS-CoV-2 protease, NSP3, cleaved GSDME at residue G370 but activated GSDME-mediated pyroptosis. Interestingly, respiratory enterovirus EV-D68-encoded proteases 3C and 2A also exhibit similar differential regulation on the functions of GSDMs by inactivating GSDMD but initiating GSDME-mediated pyroptosis. EV-D68 infection exerted oncolytic effects on human cancer cells by inducing pyroptotic cell death. Our findings provide insights into how respiratory viruses manipulate host cell pyroptosis and suggest potential targets for antiviral therapy as well as cancer treatment.IMPORTANCEPyroptosis plays a crucial role in the pathogenesis of coronavirus disease 2019, and comprehending its function may facilitate the development of novel therapeutic strategies. This study aims to explore how viral-encoded proteases modulate pyroptosis. We investigated the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory enterovirus D68 (EV-D68) proteases on host cell pyroptosis. We found that SARS-CoV-2-encoded proteases NSP5 and NSP3 inactivate gasdermin D (GSDMD) but initiate gasdermin E (GSDME)-mediated pyroptosis, respectively. We also discovered that another respiratory virus EV-D68 encodes two distinct proteases 2A and 3C that selectively trigger GSDME-mediated pyroptosis while suppressing the function of GSDMD. Based on these findings, we further noted that EV-D68 infection triggers pyroptosis and produces oncolytic effects in human carcinoma cells. Our study provides new insights into the molecular mechanisms underlying virus-modulated pyroptosis and identifies potential targets for the development of antiviral and cancer therapeutics.
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Endopeptidasas , Enterovirus Humano D , Interacciones Microbiota-Huesped , Virus Oncolíticos , Piroptosis , SARS-CoV-2 , Humanos , Línea Celular Tumoral , COVID-19/metabolismo , COVID-19/terapia , COVID-19/virología , Endopeptidasas/genética , Endopeptidasas/metabolismo , Enterovirus Humano D/enzimología , Enterovirus Humano D/genética , Infecciones por Enterovirus/metabolismo , Infecciones por Enterovirus/virología , Gasderminas/antagonistas & inhibidores , Gasderminas/genética , Gasderminas/metabolismo , Viroterapia Oncolítica , Virus Oncolíticos/enzimología , Virus Oncolíticos/genética , SARS-CoV-2/enzimología , SARS-CoV-2/genética , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
RNA expression of a gene is determined by not only transcriptional regulation, but also post-transcriptional regulation of RNA decay. The precise regulation of RNA stability in the cell plays an important role in normal development. Dysregulation of RNA stability can lead to diseases such as cancer. Here we found tumor suppressor RNAs tended to decay fast in normal cell types when compared with other RNAs. Consistent with a negative effect of m6A modification on RNA stability, we observed preferential deposition of m6A on tumor suppressor RNAs. Moreover, abundant m6A and fast decay of tumor suppressor RNAs both tended to be further enhanced in prostate cancer cells relative to normal prostate epithelial cells. Further, knockdown of m6A methyltransferase METTL3 and reader YTHDF2 in prostate cancer cells both posed stronger effect on tumor suppressor RNAs than on other RNAs. These results indicated a strong post transcriptional expression regulatability mediated by abundant m6A modification on tumor suppressor RNAs.
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Genes Supresores de Tumor , Neoplasias de la Próstata , Estabilidad del ARN , ARN Mensajero , Humanos , Masculino , Metiltransferasas/genética , Neoplasias de la Próstata/química , Neoplasias de la Próstata/genética , ARN/genética , ARN Mensajero/químicaRESUMEN
Cell identity genes are distinct from other genes with respect to the epigenetic mechanisms to activate their transcription, e.g. by super-enhancers and broad H3K4me3 domains. However, it remains unclear whether their post-transcriptional regulation is also unique. We performed a systematic analysis of transcriptome-wide RNA stability in nine cell types and found that unstable transcripts were enriched in cell identity-related pathways while stable transcripts were enriched in housekeeping pathways. Joint analyses of RNA stability and chromatin state revealed significant enrichment of super-enhancers and broad H3K4me3 domains at the gene loci of unstable transcripts. Intriguingly, the RNA m6A methyltransferase, METTL3, preferentially binds to chromatin at super-enhancers, broad H3K4me3 domains and their associated genes. METTL3 binding intensity is positively correlated with RNA m6A methylation and negatively correlated with RNA stability of cell identity genes, probably due to co-transcriptional m6A modifications promoting RNA decay. Nanopore direct RNA-sequencing showed that METTL3 knockdown has a stronger effect on RNA m6A and mRNA stability for cell identity genes. Our data suggest a run-and-brake model, where cell identity genes undergo both frequent transcription and fast RNA decay to achieve precise regulation of RNA expression.
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Cromatina , Regulación de la Expresión Génica , Estabilidad del ARN , Cromatina/genética , Epigénesis Genética , Metiltransferasas/metabolismo , ARN/químicaRESUMEN
Metastasis contributes to the dismal prognosis of bladder cancer (BLCA). The mechanical status of the cell membrane is expected to mirror the ability of cell migration to promote cancer metastasis. However, the mechanical characteristics and underlying molecular profile associated with BLCA metastasis remain obscure. To study the unique cellular architecture and traits associated with cell migration, using a process called cell-based systematic evolution of ligands by exponential enrichment (cell-SELEX) we generated an aptamer-based molecular probe, termed spl3c, which identified cytoskeleton-associated protein 4 (CKAP4). CKAP4 was associated with tumor metastasis in BLCA, but we also found it to be a mechanical regulator of BLCA cells through the maintenance of a central-to-peripheral gradient of stiffness on the cell membrane. Notably, such mechanical traits were transportable through exosome-mediated intercellular CKAP4 trafficking, leading to significant enhancement of migration in recipient cells and, consequently, aggravating metastatic potential in vivo. Taken together, our study shows the robustness of this aptamer-based molecular tool for biomarker discovery, revealing the dominance of a CKAP4-induced central-to-peripheral gradient of membrane stiffness that benefits cell migration and delineating the role of exosomes in mediating mechanical signaling in BLCA metastasis.
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Exosomas , Mecanotransducción Celular , Proteínas de la Membrana , Neoplasias de la Vejiga Urinaria , Línea Celular Tumoral , Movimiento Celular , Exosomas/metabolismo , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Pronóstico , Técnica SELEX de Producción de Aptámeros , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Major depressive disorder is a chronic mental health condition that seriously impacts afflicted individuals. Although electroacupuncture has proven to be an effective therapy for depression, its underlying biological mechanism remains largely unknown. In this study, we aimed to investigate the effects of electroacupuncture on depression-like behavior and to identify potential target genes related to those effects. To achieve this, we subjected rats to chronic unpredictable mild stress (CUMS) and used sucrose preference, forced swimming, and open-field tests to determine their depression-like behavior in the absence or after receipt of electroacupuncture treatment. RNA sequencing technology was then used to reveal the differentially expressed genes associated with depression and electroacupuncture treatment effects in the medial prefrontal cortex (mPFC). Repeated electroacupuncture treatments at the Baihui (GV20) and Taichong (LR3) acupoints significantly alleviated depression-like behavioral defects in the animals. Genomic RNA sequencing revealed several significant changes in the mPFC transcriptome of rats that received treatment. Through differential gene expression analysis, we found that electroacupuncture reversed the CUMS-induced downregulation of 46 genes and upregulation of 13 genes. Among the differentially expressed genes, Casr, Bdkrb2, Gnb3, and Ccl1 were found to be associated with depression and electroacupuncture treatment effects. In conclusion, we verified that electroacupuncture treatment has an effective antidepressant effect, and the underlying mechanism involves multiple systems and targets.
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With more flexible active sites and intermetal interaction, dual-atom catalysts (DACs) have emerged as a new frontier in various electrocatalytic reactions. Constructing a typical p-d orbital hybridization between p-block and d-block metal atoms may bring new avenues for manipulating the electronic properties and thus boosting the electrocatalytic activities. Herein, we report a distinctive heteronuclear dual-metal atom catalyst with asymmetrical FeSn dual atom sites embedded on a two-dimensional C2N nanosheet (FeSn-C2N), which displays excellent oxygen reduction reaction (ORR) performance with a half-wave potential of 0.914 V in an alkaline electrolyte. Theoretical calculations further unveil the powerful p-d orbital hybridization between p-block stannum and d-block ferrum in FeSn dual atom sites, which triggers electron delocalization and lowers the energy barrier of *OH protonation, consequently enhancing the ORR activity. In addition, the FeSn-C2N-based Zn-air battery provides a high maximum power density (265.5 mW cm-2) and a high specific capacity (754.6 mA h g-1). Consequently, this work validates the immense potential of p-d orbital hybridization along dual-metal atom catalysts and provides new perception into the logical design of heteronuclear DACs.
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BACKGROUND: Taxanes are the basic components of breast cancer chemotherapy. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) shows improved antitumor effects because of more targeted delivery. However, the effects of nab-paclitaxel have not been systematically studied in patients with metastatic breast cancer (MBC) pretreated with taxanes. Considering the limited treatment options for MBC, this study retrospectively evaluated the clinical efficacy and adverse effects of nab-paclitaxel in patients with taxane-pretreated MBC. METHODS: Patients who had previously received taxanes and subsequently received nab-paclitaxel chemotherapy for MBC at Jiangsu Cancer Hospital between October 2014 and April 2022 were included for analysis. The primary end point was progression-free survival (PFS), and the secondary end points were the objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and side effects. RESULTS: A total of 236 female patients with MBC were included. The median PFS was 7.20 months (95% confidence interval [CI], 6.63-7.80 months), and the ORR, DCR, and CBR were 29.55% (95% CI, 23.50%-35.60%), 83.64% (95% CI, 78.70%-88.60%), and 56.36% (95% CI, 49.80%-63.00%), respectively. Following nab-paclitaxel treatment, the median PFS of patients who were sensitive to taxanes during previous treatments was significantly longer than that of patients who were resistant to taxanes (7.57 months vs. 4.43 months, p < .001). The most common adverse events were sensory neuropathy (89.83%), neutropenia (48.73%), leukopenia (46.61%), and anemia (35.59%). CONCLUSION: Nab-paclitaxel demonstrated clinical activity in taxane-pretreated patients with MBC. This beneficial effect was observed both in patients who were sensitive and resistant to taxanes during previous treatments. These results suggest nab-paclitaxel as the preferred chemotherapy regimen in patients with MBC, regardless of their sensitivity to taxanes during previous treatments.
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Neoplasias de la Mama , Hidrocarburos Aromáticos con Puentes , Nanopartículas , Neutropenia , Humanos , Femenino , Neoplasias de la Mama/patología , Paclitaxel Unido a Albúmina/uso terapéutico , Estudios Retrospectivos , Paclitaxel , Taxoides/efectos adversos , Albúminas/efectos adversos , Neutropenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Antibody-drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2-expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti-HER2 ADC therapy. Studies on anti-HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti-HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti-HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti-HER2 ADC therapy in clinical practice.
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Inmunoconjugados , Enfermedades Pulmonares Intersticiales , Receptor ErbB-2 , Humanos , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/inducido químicamente , China , Inmunoconjugados/uso terapéutico , Inmunoconjugados/efectos adversos , Neumonía/tratamiento farmacológico , Femenino , Consenso , Trastuzumab/uso terapéutico , Trastuzumab/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Camptotecina/análogos & derivadosRESUMEN
Transition metal dichalcogenide TiSe2 exhibits a superconducting dome within a low pressure range of 2-4 GPa, which peaks with the maximal transition temperature Tc of ≈1.8 K. Here it is reported that applying high pressure induces a new superconducting state in TiSe2, which starts at ≈16 GPa with a substantially higher Tc that reaches 5.6 K at ≈21.5 GPa with no sign of decline. Combining high-throughput first-principles structure search, X-ray diffraction, and Raman spectroscopy measurements up to 30 GPa, It is found that TiSe2 undergoes a first-order structural transition from the 1T phase under ambient pressure to a new 4O phase under high pressure. Comparative ab initio calculations reveal that while the conventional phonon-mediated pairing mechanism may account for the superconductivity observed in 1T-TiSe2 under low pressure, the electron-phonon coupling of 4O-TiSe2 is too weak to induce a superconducting state whose transition temperature is as high as 5.6 K under high pressure. The new superconducting state found in pressurized TiSe2 requires further study on its underlying mechanism.
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Enterovirus D68 (EV-D68), which causes severe respiratory diseases and irreversible central nervous system damage, has become a serious public health problem worldwide. However, the mechanisms by which EV-D68 exerts neurotoxicity remain unclear. Thus, we aimed to analyze the effects of EV-D68 infection on the cleavage, subcellular translocation, and pathogenic aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in respiratory or neural cells. The results showed that EV-D68-encoded proteases 2A and 3C induced TDP-43 translocation and cleavage, respectively. Specifically, 3C cleaved residue 327Q of TDP-43. The 3C-mediated cleaved TDP-43 fragments had substantially decreased protein solubility compared with the wild-type TDP-43. Hence, 3C activity promoted TDP-43 aggregation, which exerted cytotoxicity to diverse human cells, including glioblastoma T98G cells. The effects of commercially available antiviral drugs on 3C-mediated TDP-43 cleavage were screened, and the results revealed lopinavir as a potent inhibitor of EV-D68 3C protease. Overall, these results suggested TDP-43 as a conserved host target of EV-D68 3C. This study is the first to provide evidence on the involvement of TDP-43 dysregulation in EV-D68 pathogenesis. IMPORTANCE Over the past decade, the incidence of enterovirus D68 (EV-D68) infection has increased worldwide. EV-D68 infection can cause different respiratory symptoms and severe neurological complications, including acute flaccid myelitis. Thus, elucidating the mechanisms underlying EV-D68 toxicity is important to develop novel methods to prevent EV-D68 infection-associated diseases. This study shows that EV-D68 infection triggers the translocalization, cleavage, and aggregation of TDP-43, an intracellular protein closely related to degenerative neurological disorders. The viral protease 3C decreased TDP-43 solubility, thereby exerting cytotoxicity to host cells, including human glioblastoma cells. Thus, counteracting 3C activity is an effective strategy to relieve EV-D68-triggered cell death. Cytoplasmic aggregation of TDP-43 is a hallmark of degenerative diseases, contributing to neural cell damage and central nervous system (CNS) disorders. The findings of this study on EV-D68-induced TDP-43 formation extend our understanding of virus-mediated cytotoxicity and the potential risks of TDP-43 dysfunction-related cognitive impairment and neurological symptoms in infected patients.
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Proteínas de Unión al ADN , Infecciones por Enterovirus , Humanos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/farmacología , Enterovirus Humano D , Infecciones por Enterovirus/fisiopatología , Infecciones por Enterovirus/virología , Línea Celular Tumoral , Proteasas Virales 3C/metabolismo , Agregación Patológica de Proteínas/genética , Lopinavir/farmacología , Proteolisis/efectos de los fármacos , Silenciador del Gen , Inhibidores de Proteasas/farmacologíaRESUMEN
Endothelial cells (ECs) are widely distributed in the human body and play crucial roles in the circulatory and immune systems. ECs dysfunction contributes to the progression of various chronic cardiovascular, renal, and metabolic diseases. As a key transcription factor in ECs, FLI-1 is involved in the differentiation, migration, proliferation, angiogenesis and blood coagulation of ECs. Imbalanced FLI-1 expression in ECs can lead to various diseases. Low FLI-1 expression leads to systemic sclerosis by promoting fibrosis and vascular lesions, to pulmonary arterial hypertension by promoting a local inflammatory state and vascular lesions, and to tumour metastasis by promoting the EndMT process. High FLI-1 expression leads to lupus nephritis by promoting a local inflammatory state. Therefore, FLI-1 in ECs may be a good target for the treatment of the abovementioned diseases. This comprehensive review provides the first overview of FLI-1-mediated regulation of ECs processes, with a focus on its influence on the abovementioned diseases and existing FLI-1-targeted drugs. A better understanding of the role of FLI-1 in ECs may facilitate the design of more effective targeted therapies for clinical applications, particularly for tumour treatment.
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Células Endoteliales , Proteína Proto-Oncogénica c-fli-1 , Humanos , Proteína Proto-Oncogénica c-fli-1/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Enfermedad , AnimalesRESUMEN
BACKGROUND AND AIMS: Cross talk between tumor cells and immune cells enables tumor cells to escape immune surveillance and dictate responses to immunotherapy. Previous studies have identified that downregulation of the glycolytic enzyme fructose-1,6-bisphosphate aldolase B (ALDOB) in tumor cells orchestrated metabolic programming to favor HCC. However, it remains elusive whether and how ALDOB expression in tumor cells affects the tumor microenvironment in HCC. APPROACH AND RESULTS: We found that ALDOB downregulation was negatively correlated with CD8 + T cell infiltration in human HCC tumor tissues but in a state of exhaustion. Similar observations were made in mice with liver-specific ALDOB knockout or in subcutaneous tumor models with ALDOB knockdown. Moreover, ALDOB deficiency in tumor cells upregulates TGF-ß expression, thereby increasing the number of Treg cells and impairing the activity of CD8 + T cells. Consistently, a combination of low ALDOB and high TGF-ß expression exhibited the worst overall survival for patients with HCC. More importantly, the simultaneous blocking of TGF-ß and programmed cell death (PD) 1 with antibodies additively inhibited tumorigenesis induced by ALDOB deficiency in mice. Further mechanistic experiments demonstrated that ALDOB enters the nucleus and interacts with lysine acetyltransferase 2A, leading to inhibition of H3K9 acetylation and thereby suppressing TGFB1 transcription. Consistently, inhibition of lysine acetyltransferase 2A activity by small molecule inhibitors suppressed TGF-ß and HCC. CONCLUSIONS: Our study has revealed a novel mechanism by which a metabolic enzyme in tumor cells epigenetically modulates TGF-ß signaling, thereby enabling cancer cells to evade immune surveillance and affect their response to immunotherapy.
RESUMEN
Patellogastropoda, the true limpets, is a major group of gastropods widely distributed in marine habitats from the intertidal to deep sea. Though important for understanding their evolutionary radiation, the phylogenetic relationships among the patellogastropod families have always been challenging to reconstruct, with contradictory results likely due to insufficient sampling. Here, we obtained mitogenomic and phylogenomic data (transcriptomic or genomic) from six species representing the three predominantly deep-water patellogastropod families: Lepetidae, Neolepetopsidae, and Pectinodontidae. By using various phylogenetic methods, we show that mitogenome phylogeny recovers monophyly of eight families in most of the trees, though the relationships among families remain contentious. Meanwhile, a more robust family-level topology consistent with morphology was achieved by phylogenomics. This also reveals that these mainly deep-water families are monophyletic, suggesting a single colonisation of the deep water around the Jurassic. We also found a lack of significant correlation between genome size and habitat depth, despite some deep-water species exhibiting larger genome sizes. Our phylogenomic tree provides a stable phylogenetic backbone for Patellogastropoda that includes seven of the nine recognized families and paves the way for future evolutionary analyses in this major group of molluscs.
Asunto(s)
Evolución Biológica , Gastrópodos , Humanos , Animales , Filogenia , Genómica , Gastrópodos/genética , Tamaño del GenomaRESUMEN
Cobalt phosphosulphide (CoPS) has recently been recognized as a potentially effective electrocatalyst for the hydrogen evolution reaction (HER). However, there have been no research on the design of CoPS-based heterojunctions to boost their HER performance. Herein, CoPS/Co4S3 heterojunction was prepared by phosphating treatment based on defect-rich flower-like Co1-xS precursors. The high specific surface area of nanopetals, together with the heterojunction structure with inhomogeneous strain, exposes more active sites in the catalyst. The electronic structure of the catalyst is reconfigured as a result of the interfacial interactions, which promote the catalyst's ability to adsorb hydrogen and conduct electricity. The synergistic effect of the Co and S dual-site further enhance the catalytic activity. The catalyst has overpotentials of 61 and 70â mV to attain a current density of 10â mA cm-2 in acidic and alkaline media, respectively, which renders it competitive with previously reported analogous catalysts. This work proposes an effective technique for constructing transition metal phosphosulfide heterojunctions, as well as the development of an efficient HER electrocatalyst.