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Fragrance is a valuable trait in rice varieties, with its aroma significantly influencing consumer preference. In this study, we conducted comprehensive metabolome and transcriptome analyses to elucidate the genetic and biochemical basis of fragrance in the Shangsixiangnuo (SSXN) variety, a fragrant indica rice cultivated in Guangxi, China. Through sensory evaluation and genetic analysis, we confirmed SSXN as strongly fragrant, with an 806 bp deletion in the BADH2 gene associated with fragrance production. In the metabolome analysis, a total of 238, 233, 105 and 60 metabolic compounds exhibited significant changes at the seedling (S), reproductive (R), filling (F), and maturation (M) stages, respectively. We identified four compounds that exhibited significant changes in SSXN across all four development stages. Our analyses revealed a significant upregulation of 2-acetyl-1-pyrroline (2AP), the well-studied aromatic compound, in SSXN compared to the non-fragrant variety. Additionally, correlation analysis identified several metabolites strongly associated with 2AP, including ethanone, 1-(1H-pyrrol-2-yl)-, 1H-pyrrole, and pyrrole. Furthermore, Weighted Gene Co-expression Network Analysis (WGCNA) analysis highlighted the magenta and yellow modules as particularly enriched in aroma-related metabolites, providing insights into the complex aromatic compounds underlying the fragrance of rice. In the transcriptome analysis, a total of 5582, 5506, 4965, and 4599 differential expressed genes (DEGs) were identified across the four developmental stages, with a notable enrichment of the common pathway amino sugar and nucleotide sugar metabolism in all stages. In our correlation analysis between metabolome and transcriptome data, the top three connected metabolites, phenol-, 3-amino-, and 2AP, along with ethanone, 1-(1H-pyrrol-2-yl)-, exhibited strong associations with transcripts, highlighting their potential roles in fragrance biosynthesis. Additionally, the downregulated expression of the P4H4 gene, encoding a procollagen-proline dioxygenase that specifically targets proline, in SSXN suggests its involvement in proline metabolism and potentially in aroma formation pathways. Overall, our study provides comprehensive insights into the genetic and biochemical mechanisms underlying fragrance production in rice, laying the foundation for further research aimed at enhancing fragrance quality in rice breeding programs.
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Regulación de la Expresión Génica de las Plantas , Metaboloma , Oryza , Pirroles , Transcriptoma , Oryza/genética , Oryza/metabolismo , Oryza/crecimiento & desarrollo , Pirroles/metabolismo , Perfilación de la Expresión Génica , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Odorantes/análisisRESUMEN
BACKGROUND: Hepatitis B core antibody (anti-HBc) is commonly present in patients with chronic hepatitis B virus (HBV) infection and serves as a marker of humoral immunity. Herein, we aim to investigate the correlation between anti-HBc and antiviral immune response and its putative role in HBV control. METHODS: Quantitative anti-HBc and levels of anti-HBc subtypes were measured in chronic hepatitis B (CHB) patients. The effects of anti-HBc on immune cells and HBV replication were evaluated using the HBV mouse models and human hepatoma cell lines. RESULTS: Baseline levels of IgG1 and IgG3 anti-HBc were elevated in CHB patients with favorable treatment response, and correlated with the virological response observed at week 52. Additionally, increased levels of IgM and IgG1 anti-HBc were observed exclusively in CHB patients with liver inflammation. Notably, significant correlations were identified between quantitative levels of anti-HBc and the frequencies of HBcAg-specific CD8+ T cells. Intriguingly, HBcAg efficiently activates T cells aided by B cells in vitro experiments. Moreover, anti-HBc inhibits HBV replication either by a direct effect or through complement-mediated cytotoxicity in HBV-producing cell lines. CONCLUSIONS: Anti-HBc reflects the activation of an HBV-specific CD8+ T cell immune response and may have anti-HBV activity.
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The ubiquitous nature of amines in drug compounds, bioactive molecules and natural products has fueled intense interest in their synthesis. Herein, we introduce a nickel-catalyzed enantioconvergent allenylic amination of methanol-activated allenols. This protocol affords a diverse array of functionalized allenylic amines in high yields and with excellent enantioselectivities. The synthetic potential of this method is demonstrated by employing bioactive amines as nucleophiles and conducting gram-scale reactions. Furthermore, mechanistic investigations and DFT calculations elucidate the role of methanol as an activator in the nickel-catalyzed reaction, facilitating the oxidative addition of the C-O bond of allenols through hydrogen-bonding interactions. The remarkable outcomes arise from a rapid racemization of allenols enabled by the nickel catalyst and from highly enantioselective dynamic kinetic asymmetric transformation of η3-alkadienylnickel intermediates.
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The use of hydrogel-based interfacial solar evaporators for desalination is a green, sustainable, and extremely concerned freshwater acquisition strategy. However, developing evaporators that are easy to manufacture, cheap, and have excellent porous structures still remains a considerable challenge. This work proposes a novel strategy for preparing a self-assembling sponge-like poly(vinyl alcohol)/graphite composite hydrogel based on the Hofmeister effect for the first time. The sponge-like hydrogel interfacial solar evaporator (PGCNG) is successfully obtained after combining with graphite. The whole process is environmental-friendly and of low-carbon free of freezing process. The PGCNG can be conventionally dried and stored. PGCNG shows impressive water storage performance and water transmission capacity, excellent steam generation performance and salt resistance. PGCNG has a high evaporation rate of 3.5 kg m-2 h-1 under 1 kW m-2 h-1 solar irradiation and PGCNG demonstrates stable evaporation performance over both 10 h of continuous brine evaporation and 30 cycles of brine evaporation. Its excellent performance and simple, scalable preparation strategy make it a valuable material for practical interface solar seawater desalination devices.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized primarily by cognitive impairment. Recent investigations have highlighted the potential of nutritional interventions that target the gut-brain axis, such as probiotics and prebiotics, in forestalling the onset of AD. In this study, whole-genome sequencing was employed to identify xylan as the optimal carbon source for the tryptophan metabolism regulating probiotic Clostridium sporogenes (C. sporogenes). Subsequent in vivo studies demonstrated that administration of a synbiotic formulation comprising C. sporogenes (1 × 1010 CFU per day) and xylan (1%, w/w) over a duration of 30 days markedly enhanced cognitive performance and spatial memory faculties in the 5xFAD transgenic AD mouse model. The synbiotic treatment significantly reduced amyloid-ß (Aß) accumulation in the cortex and hippocampus of the brain. Importantly, synbiotic therapy substantially restored the synaptic ultrastructure in AD mice and suppressed neuroinflammatory responses. Moreover, the intervention escalated levels of the microbial metabolite indole-3-propionic acid (IPA) and augmented the relative prevalence of IPA-synthesizing bacteria, Lachnospira and Clostridium, while reducing the dominant bacteria in AD, such as Aquabacterium, Corynebacterium, and Romboutsia. Notably, synbiotic treatment also prevented the disruption of gut barrier integrity. Correlation analysis indicated a strong positive association between gut microbiota-generated IPA levels and behavioral changes. In conclusion, this study demonstrates that synbiotic supplementation significantly improves cognitive and intellectual deficits in 5xFAD mice, which could be partly attributed to enhanced IPA production by gut microbiota. These findings provide a theoretical basis for considering synbiotic therapy as a novel microbiota-targeted approach for the treatment of metabolic and neurodegenerative diseases.
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Enfermedad de Alzheimer , Clostridium , Disfunción Cognitiva , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Indoles , Ratones Transgénicos , Simbióticos , Xilanos , Animales , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/metabolismo , Ratones , Simbióticos/administración & dosificación , Indoles/metabolismo , Disfunción Cognitiva/terapia , Disfunción Cognitiva/metabolismo , Xilanos/metabolismo , Xilanos/farmacología , Clostridium/metabolismo , Masculino , Péptidos beta-Amiloides/metabolismo , Humanos , Propionatos/metabolismo , Eje Cerebro-Intestino/fisiologíaRESUMEN
The surface electromyographic (sEMG) signals reflect human motor intention and can be utilized for human-machine interfaces (HMI). Comparing to the sparse multi-channel (SMC) electrodes, the high-density (HD) electrodes have a large number of electrodes and compact space between electrodes, which can achieve more sEMG information and have the potential to achieve higher performance in myocontrol. However, when the HD electrodes grid shift or damage, it will affect gesture recognition and reduce recognition accuracy. To minimize the impact resulting from the electrodes shift and damage, we proposed an attention deep fast convolutional neural network (attention-DFCNN) model by utilizing the temporary and spatial characteristics of high-density surface electromyography (HD-sEMG) signals. Contrary to the previous methods, which are mostly base on sEMG temporal features, the attention-DFCNN model can improve the robustness and stability by combining the spatial and temporary features. The performance of the proposed model was compared with other classical method and deep learning methods. We used the dataset provided by The University Medical Center Göttingen. Seven able-bodied subjects and one amputee involved in this work. Each subject executed nine gestures under the electrodes shift (10 mm) and damage (6 channels). As for the electrodes shift 10 mm in four directions (inwards; onwards; upwards; downwards) on seven able-bodied subjects, without any pre-training, the average accuracy of attention-DFCNN (0.942 ± 0.04) is significantly higher than LSDA (0.910 ± 0.04, p < 0.01), CNN (0.920 ± 0.05, p < 0.01), TCN (0.840 ± 0.07, p < 0.01), LSTM (0.864 ± 0.08, p < 0.01), attention-BiLSTM (0.852 ± 0.07, p < 0.01), Transformer (0.903 ± 0.07, p < 0.01) and Swin-Transformer (0.908 ± 0.09, p < 0.01). The proposed attention-DFCNN algorithm and the way of combining the spatial and temporary features of sEMG signals can significantly improve the recognition rate when the HD electrodes grid shift or damage during wear.
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Efficient, mild, and reversible adsorption of nucleic acids onto nanomaterials represents a promising analytical approach for medical diagnosis. However, there is a scarcity of efficient and reversible nucleic acid adsorption nanomaterials. Additionally, the lack of comprehension of the molecular mechanisms governing their interactions poses significant challenges. These issues hinder the rational design and analytical applications of the nanomaterials. Herein, we propose an ultra-efficient nucleic acid affinity nanomaterial based on programmable lanthanide metal-organic frameworks (Ln-MOFs). Through experiments and density functional theory calculations, a rational design guideline for nucleic acid affinity of Ln-MOF was proposed, and a modular and flexible preparation scheme was provided. Then, Er-TPA (terephthalic acid) MOF emerged as the optimal candidate due to its pore size-independent adsorption and desorption capabilities for nucleic acids, enabling ultra-efficient adsorption (about 150% mass ratio) within 1 min. Furthermore, we elucidate the molecular-level mechanisms underlying the Ln-MOF adsorption of single- and double-stranded DNA and G4 structures. The affinity nanomaterial based on Ln-MOF exhibits robust nucleic acid extraction capability (4-fold higher than commercial reagent kits) and enables mild and reversible CRISPR/Cas9 functional regulation. This method holds significant promise for broad application in DNA/RNA liquid biopsy and gene editing, facilitating breakthroughs in analytical chemistry, pharmacy, and medical research.
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ADN , Elementos de la Serie de los Lantanoides , Estructuras Metalorgánicas , Estructuras Metalorgánicas/química , Elementos de la Serie de los Lantanoides/química , Adsorción , ADN/química , ADN/aislamiento & purificación , Ácidos Ftálicos/química , Nanoestructuras/química , Teoría Funcional de la Densidad , HumanosRESUMEN
The Lachnospiraceae family holds promise as a source of next-generation probiotics, yet a comprehensive delineation of its diversity is lacking, hampering the identification of suitable strains for future applications. To address this knowledge gap, we conducted an in-depth genomic and functional analysis of 1868 high-quality genomes, combining data from public databases with our new isolates. This data set represented 387 colonization-selective species-level clusters, of which eight genera represented multilineage clusters. Pan-genome analysis, single-nucleotide polymorphism (SNP) identification, and probiotic functional predictions revealed that species taxonomy, habitats, and geography together shape the functional diversity of Lachnospiraceae. Moreover, analyses of associations with atherosclerotic cardiovascular disease (ACVD) and inflammatory bowel disease (IBD) indicated that several strains of potentially novel Lachnospiraceae species possess the capacity to reduce the abundance of opportunistic pathogens, thereby imparting potential health benefits. Our findings shed light on the untapped potential of novel species enabling knowledge-based selection of strains for the development of next-generation probiotics holding promise for improving human health and disease management.
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Degeneracy and symmetry have a profound relation in quantum systems. Here, we report gate-tunable subband degeneracy in PbTe nanowires with a nearly symmetric cross-sectional shape. The degeneracy is revealed in electron transport by the absence of a quantized plateau. Utilizing a dual gate design, we can apply an electric field to lift the degeneracy, reflected as emergence of the plateau. This degeneracy and its tunable lifting were challenging to observe in previous nanowire experiments, possibly due to disorder. Numerical simulations can qualitatively capture our observation, shedding light on device parameters for future applications.
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Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.
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Fusobacterium vincentii brain abscesses are relatively rare. Here, we report our treatment of an anaerobic brain abscess caused by a mixed infection of Parvimonas micra, Streptococcus constellatus, Fusobacterium vincentii, and Bacteroides heparinolyticus diagnosed by metagenomic next-generation sequencing (mNGS). This is the first reported case of Fusobacterium vincentii in a brain abscess. This case highlights the possibility that oral anaerobic microbes can cause a brain abscess and demonstrates that mNGS has the potential to be deployed to provide rapid infection diagnosis and rationalize antimicrobial therapy for brain abscesses.
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Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria as guardian in cytosol' (MAGIC) whereby cytosolic misfolded proteins (MPs) are imported into and degraded inside mitochondria. In this study, a genome-wide screen in Saccharomyces cerevisiae uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of MPs into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by MPs such as those associated with neurodegenerative diseases.
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Mitocondrias , Pliegue de Proteína , Transporte de Proteínas , Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Mitocondrias/metabolismo , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Glucosa/metabolismoRESUMEN
To maintain protein homeostasis, X-box binding protein 1 (XBP1) undergoes splicing following the activation of the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress. Although targeting ER stress represents a promising therapeutic strategy, a comprehensive understanding of XBP1 at the cellular level and the link between XBP1 and the innate nervous system is lacking. Here, TCGA pancancer datasets from 33 cancer types, scRNA pancancer datasets from 454 patients and bulk RNA-seq datasets from 155 paired esophageal squamous cell carcinoma (ESCC) patients were analyzed. To cope with ER stress, plasma cells tend to activate XBP1 after undergoing bacterial infection and inflammatory signaling from the innate immune system. Patients with high XBP1 expression in their plasma cells have a higher tumor grade and worse survival. However, activation of the innate immune system with increased XBP1 expression in plasma cells correlates with an increased lymphocyte ratio, indicative of a more robust immune response. Moreover, XBP1 activation appears to initiate leukocyte migration at the transcriptional level. Our study revealed that the XBP1-induced UPR could mediate the crosstalk between optimal acquired humoral immune responses and innate immunity in ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Inmunidad Innata , Células Plasmáticas , Respuesta de Proteína Desplegada , Proteína 1 de Unión a la X-Box , Humanos , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismo , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Masculino , Femenino , Estrés del Retículo Endoplásmico/inmunología , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Anciano , PronósticoRESUMEN
Radiation-induced brain injury (RIBI) is a significant challenge in radiotherapy for head and neck tumors, impacting patients' quality of life. In exploring potential treatments, this study focuses on memantine hydrochloride and hydrogen-rich water, hypothesized to mitigate RIBI through inhibiting the NLRP3/NLRC4/Caspase-1 pathway. In a controlled study involving 40 Sprague-Dawley rats, divided into five groups including a control and various treatment groups, we assessed the effects of these treatments on RIBI. Post-irradiation, all irradiated groups displayed symptoms like weight loss and salivation, with notable variations among different treatment approaches. Particularly, hydrogen-rich water showed a promising reduction in these symptoms. Histopathological analysis indicated substantial hippocampal damage in the radiation-only group, while the groups receiving memantine and/or hydrogen-rich water exhibited significant mitigation of such damage. Molecular studies, revealed a decrease in oxidative stress markers and an attenuated inflammatory response in the treatment groups. Immunohistochemistry further confirmed these molecular changes, suggesting the effectiveness of these agents. Echoing recent scientific inquiries into the protective roles of specific compounds against radiation-induced damages, our study adds to the growing body of evidence on the potential of memantine and hydrogen-rich water as novel therapeutic strategies for RIBI.
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Caspasa 1 , Hidrógeno , Memantina , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Ratas Sprague-Dawley , Agua , Animales , Memantina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Hidrógeno/farmacología , Piroptosis/efectos de los fármacos , Ratas , Caspasa 1/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Lesiones Encefálicas/etiología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/prevención & control , Lesiones Encefálicas/patología , Traumatismos por Radiación/tratamiento farmacológico , Traumatismos por Radiación/metabolismo , Traumatismos por Radiación/patología , Estrés Oxidativo/efectos de los fármacos , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/prevención & controlRESUMEN
The stable and site-specific operation of transmission lines is a crucial safeguard for grid functionality. This study introduces a comprehensive optimization design method for transmission line crossing frame structures based on the Biogeography-Based Optimization (BBO) algorithm, which integrates size, shape, and topology optimization. By utilizing the BBO algorithm to optimize the truss structure's design variables, the method ensures the structure's economic and practical viability while enhancing its performance. The optimization process is validated through finite element analysis, confirming the optimized structure's compliance with strength, stiffness, and stability requirements. The results demonstrate that the integrated design of size, shape, and topology optimization, as opposed to individual optimizations of size or shape and topology, yields the lightest structure mass and a maximum stress of 151.4 MPa under construction conditions. These findings also satisfy the criteria for strength, stiffness, and stability, verifying the method's feasibility, effectiveness, and practicality. This approach surpasses traditional optimization methods, offering a more effective solution for complex structural optimization challenges, thereby enhancing the sustainable utilization of structures.
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Algoritmos , Análisis de Elementos FinitosRESUMEN
Postoperative cognitive dysfunction (POCD) is a kind of serious postoperative complication in surgery with general anesthesia and it may affect patients' normal lives. Activated microglia are thought to be one of the key factors in the regulation of POCD process. Once activated, resident microglia change their phenotype and secrete kinds of cytokines to regulate inflammatory response in tissues. Among these secretory factors, brain-derived neurotrophic factor (BDNF) is considered to be able to inhibit inflammation response and protect nervous system. Therefore, the enhancement of BDNF expression derived from resident microglia is suggested to be potential treatment for POCD. In our study, we focused on the role of C8-ceramide (a kind of interventional drug) and assessed its regulatory effect on improving the expression of BDNF secreted from microglia to treat POCD. According to the results of our study, we observed that C8-ceramide stimulated primary microglia to up-regulate the expression of BDNF mRNA after being treated with lipopolysaccharide (LPS) in vitro. We proved that C8-ceramide had ability to effectively improve POCD of mice after being accepted carotid artery exposure and their abnormal behavior recovered better than that of mice from the surgery group. Furthermore, we also demonstrated that C8-ceramide enhanced the cognitive function of mice via the PKCδ/NF-κB signaling pathway. In general, our study has confirmed a potential molecular mechanism that led to the occurrence of POCD caused by surgery and provided a new clinical strategy to treat POCD.
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Factor Neurotrófico Derivado del Encéfalo , Ceramidas , Microglía , FN-kappa B , Complicaciones Cognitivas Postoperatorias , Proteína Quinasa C-delta , Transducción de Señal , Animales , Microglía/efectos de los fármacos , Microglía/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Ratones , FN-kappa B/metabolismo , Complicaciones Cognitivas Postoperatorias/metabolismo , Complicaciones Cognitivas Postoperatorias/prevención & control , Ceramidas/metabolismo , Proteína Quinasa C-delta/metabolismo , Masculino , Ratones Endogámicos C57BLRESUMEN
Considerable progress has recently been made in cancer immunotherapy, including immune checkpoint blockade, cancer vaccine, and adoptive T cell methods. The lack of effective targets is a major cause of the low immunotherapy response rate in colorectal cancer (CRC). Here, we used a proteogenomic strategy comprising immunopeptidomics, whole exome sequencing, and 16â¯S ribosomal DNA sequencing analyses of 8 patients with CRC to identify neoantigens and bacterial peptides that can serve as antitumor targets. This study directly identified several personalized neoantigens and bacterial immunopeptides. Immunoassays showed that all neoantigens and 5 of 8 bacterial immunopeptides could be recognized by autologous T cells. Additionally, T cell receptor (TCR) αß sequencing revealed the TCR repertoire of epitope-reactive CD8+ T cells. Functional studies showed that T cell receptor-T (TCR-T) could be activated by epitope pulsed lymphoblastoid cells. Overall, this study comprehensively profiled the CRC immunopeptidome, revealing several neoantigens and bacterial peptides with potential to serve as immunotherapy targets in CRC.
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Antígenos de Neoplasias , Neoplasias Colorrectales , Inmunoterapia , Proteogenómica , Humanos , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/genética , Proteogenómica/métodos , Inmunoterapia/métodos , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Masculino , Femenino , Anciano , Persona de Mediana Edad , Péptidos/inmunología , Linfocitos T CD8-positivos/inmunologíaRESUMEN
Birinapant, an antagonist of the inhibitor of apoptosis proteins, upregulates MHCs in tumor cells and displays a better tumoricidal effect when used in combination with immune checkpoint inhibitors, indicating that Birinapant may affect the antigen presentation pathway; however, the mechanism remains elusive. Based on high-resolution mass spectrometry and in vitro and in vivo models, we adopted integrated genomics, proteomics, and immunopeptidomics strategies to study the mechanism underlying the regulation of tumor immunity by Birinapant from the perspective of antigen presentation. Firstly, in HT29 and MCF7 cells, Birinapant increased the number and abundance of immunopeptides and source proteins. Secondly, a greater number of cancer/testis antigen peptides with increased abundance and more neoantigens were identified following Birinapant treatment. Moreover, we demonstrate the existence and immunogenicity of a neoantigen derived from insertion/deletion mutation. Thirdly, in HT29 cell-derived xenograft models, Birinapant administration also reshaped the immunopeptidome, and the tumor exhibited better immunogenicity. These data suggest that Birinapant can reshape the tumor immunopeptidome with respect to quality and quantity, which improves the presentation of CTA peptides and neoantigens, thus enhancing the immunogenicity of tumor cells. Such changes may be vital to the effectiveness of combination therapy, which can be further transferred to the clinic or aid in the development of new immunotherapeutic strategies to improve the anti-tumor immune response.
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Presentación de Antígeno , Dipéptidos , Indoles , Masculino , Animales , Humanos , Terapia Combinada , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Tumor treating fields (TTFields) therapy has shown effectiveness in glioblastoma treatment and holds potential for other cancers. However, its application in pancreatic cancer and the distribution of electric fields in pancreas remain unexplored. This study aims to investigate the electric field distributions in pancreatic regions using different array configurations for TTFields therapy. METHODS: Computational modelling was employed to simulate electric field distributions, and quantitative analysis was conducted. Human body impedance measurements were used to optimize the electric properties of the model. Various array configurations were examined to assess their impact on the electric field distributions. RESULTS: The study revealed that well-positioned arrays, specifically the combination of 20-piece transducer arrays in anterior-posterior orientation and 13-piece transducer arrays in left-right orientation, consistently achieved electric fields exceeding the 1V/cm threshold in over 99.4% of the pancreas. Even with a reduced number of transducers (13 pieces for both orientations), sufficient electric field coverage was achieved, exceeding the threshold in over 92.9% of the pancreas. Additionally, different array placements within the same orientation were explored to address clinical challenges such as skin rash and patient anatomical variations. CONCLUSIONS: This research lays the groundwork for understanding TTFields distribution within the abdomen, offering insights into optimizing array configurations for improved electric field delivery. The findings have the potential to guide practical designs of TTFields devices, enhance treatment efficacy, and improve patient outcomes. These results offer promises of advancing TTFields therapy for pancreatic cancer towards clinical applications, and potentially enhancing treatment efficacy and patient outcomes.
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Planar Josephson junctions are predicted to host Majorana zero modes. The material platforms in previous studies are two-dimensional electron gases (InAs, InSb, InAsSb, and HgTe) coupled to a superconductor such as Al or Nb. Here, we introduce a new material platform for planar JJs, the PbTe-Pb hybrid. The semiconductor, PbTe, was grown as a thin film via selective area epitaxy. The Josephson junction was defined by a shadow wall during the deposition of superconductor Pb. Scanning transmission electron microscopy reveals a sharp semiconductor-superconductor interface. Gate-tunable supercurrents and multiple Andreev reflections are observed. A perpendicular magnetic field causes interference patterns of the switching current, exhibiting Fraunhofer-like and SQUID-like behaviors. We further demonstrate a prototype device for Majorana detection wherein phase bias and tunneling spectroscopy are applicable.