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Natural killer (NK) cells are commonly reduced in human tumors, enabling many to evade surveillance. Here, we sought to identify cues that alter NK cell activity in tumors. We found that, in human lung cancer, the presence of NK cells inversely correlated with that of monocyte-derived macrophages (mo-macs). In a murine model of lung adenocarcinoma, we show that engulfment of tumor debris by mo-macs triggers a pro-tumorigenic program governed by triggering receptor expressed on myeloid cells 2 (TREM2). Genetic deletion of Trem2 rescued NK cell accumulation and enabled an NK cell-mediated regression of lung tumors. TREM2+ mo-macs reduced NK cell activity by modulating interleukin (IL)-18/IL-18BP decoy interactions and IL-15 production. Notably, TREM2 blockade synergized with an NK cell-activating agent to further inhibit tumor growth. Altogether, our findings identify a new axis, in which TREM2+ mo-macs suppress NK cell accumulation and cytolytic activity. Dual targeting of macrophages and NK cells represents a new strategy to boost antitumor immunity.
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Células Asesinas Naturales , Neoplasias Pulmonares , Humanos , Ratones , Animales , Macrófagos , Células Mieloides , Glicoproteínas de Membrana/genética , Receptores Inmunológicos/genéticaRESUMEN
Lymphoid cells that produce interleukin (IL)-17 cytokines protect barrier tissues from pathogenic microbes but are also prominent effectors of inflammation and autoimmune disease. T helper 17 (Th17) cells, defined by RORγt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4+ T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, Th17 cell behaviors vary markedly according to their environment. Here, we show that SAAs additionally direct a pathogenic pro-inflammatory Th17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting Th17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.
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Síndrome del Colon Irritable/metabolismo , Proteína Amiloide A Sérica/metabolismo , Células Th17/metabolismo , Adulto , Animales , Enfermedades Autoinmunes/metabolismo , Diferenciación Celular/inmunología , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Humanos , Inflamación/metabolismo , Interleucina-17/metabolismo , Síndrome del Colon Irritable/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Células TH1 , Células Th17/inmunologíaRESUMEN
Clinical benefits of cytokine blockade in ileal Crohn's disease (iCD) are limited to a subset of patients. Here, we applied single-cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct network connectivity that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in four independent iCD cohorts (n = 441), and its presence at diagnosis correlated with failure to achieve durable corticosteroid-free remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single-cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities.
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Enfermedad de Crohn/terapia , Citocinas/inmunología , Intestinos/patología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/patología , Humanos , Inmunoterapia/métodos , Fagocitos/patología , Análisis de la Célula Individual , Células del Estroma/patología , Linfocitos T/patologíaRESUMEN
Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.
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Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/patología , Janus Quinasa 1/genética , Síndrome de Respuesta Inflamatoria Sistémica/genética , Síndrome de Respuesta Inflamatoria Sistémica/patología , Adolescente , COVID-19/mortalidad , Dominio Catalítico/genética , Línea Celular , Citocinas/metabolismo , Femenino , Mutación con Ganancia de Función/genética , Genotipo , Células HEK293 , Enfermedades Autoinflamatorias Hereditarias/tratamiento farmacológico , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Mosaicismo , Piperidinas/uso terapéutico , Medicina de Precisión/métodos , Pirimidinas/uso terapéutico , Transducción de Señal/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológicoRESUMEN
An optical antenna can convert a propagative optical radiation into a localized excitation and the reciprocal. Although optical antennas can be readily created using resonant nanoparticles (metallic or dielectric) as elementary building blocks, the realization of antennas sustaining multiple resonances over a broad range of frequencies remains a challenging task. Here, we use aluminum self-similar, fractal-like structures as broadband optical antennas. Using electron energy loss spectroscopy, we experimentally evidence that a single aluminum Cayley tree, a simple self-similar structure, sustains multiple plasmonic resonances. The spectral position of these resonances is scalable over a broad spectral range spanning two decades, from ultraviolet to midinfrared. Such multiresonant structures are highly desirable for applications ranging from nonlinear optics to light harvesting and photodetection, as well as surface-enhanced infrared absorption spectroscopy.
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INTRODUCTION: Iron and vitamin B12 deficiencies are common in patients with atrophic gastritis, but there are limited data on the prevalence of these deficiencies in different types of atrophic gastritis. METHODS: This multicenter, prospective study assessed micronutrient concentrations in histologically confirmed autoimmune gastritis (AIG, n = 45), Helicobacter pylori-related non-autoimmune gastritis (NAIG, n = 109), and control patients (n = 201). A multivariate analysis was performed to determine factors influencing those deficiencies. RESULTS: The median vitamin B12 concentration was significantly lower in AIG (367.5 pg/mL, Q1, Q3: 235.5, 524.5) than in NAIG (445.0 pg/mL, Q1, Q3: 355.0, 565.0, p = 0.001) and control patients (391.0 pg/mL, Q1, Q3: 323.5, 488.7, p = 0.001). Vitamin B12 deficiency was found in 13.3%, 1.5%, and 2.8% of AIG, NAIG, and control patients, respectively. Similarly, the median ferritin concentration was significantly lower in AIG (39.5 ng/mL, Q1, Q3: 15.4, 98.3 ng/mL) than in NAIG (80.5 ng/mL, Q1, Q3: 43.6, 133.9, p = 0.04) and control patients (66.5 ng/mL, Q1, Q3: 33.4, 119.8, p = 0.007). Iron deficiency and iron deficiency adjusted to CRP were present in 28.9% and 33.3% of AIG, 12.8% and 16.5% of NAIG, and 12.9% and 18.4% of controls, respectively. Multivariate analysis demonstrated that AIG patients had a higher risk of developing vitamin B12 deficiency (OR: 11.52 [2.85-57.64, p = 0.001]) and iron deficiency (OR: 2.92 [1.32-6.30, p = 0.007]) compared to control patients. Factors like age, sex, and H. pylori status did not affect the occurrence of vitamin B12 or iron deficiency. CONCLUSION: Iron and vitamin B12 deficiencies are more commonly observed in patients with AIG than in those with NAIG or control patients. Therefore, it is essential to screen for both iron and vitamin B12 deficiencies in AIG patients and include the treatment of micronutrient deficiencies in the management of atrophic gastritis patients.
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Enfermedades Autoinmunes , Gastritis Atrófica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Deficiencias de Hierro , Deficiencia de Vitamina B 12 , Humanos , Gastritis Atrófica/complicaciones , Gastritis Atrófica/epidemiología , Estudios Prospectivos , Hierro , Gastritis/complicaciones , Gastritis/epidemiología , Deficiencia de Vitamina B 12/complicaciones , Deficiencia de Vitamina B 12/epidemiología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/epidemiología , Vitamina B 12 , Micronutrientes , Enfermedades Autoinmunes/complicacionesRESUMEN
Oil palm, a tropical woody oil crop, is widely used in food, cosmetics, and pharmaceuticals due to its high production efficiency and economic value. Palm oil is rich in free fatty acids, polyphenols, vitamin E, and other nutrients, which are beneficial for human health when consumed appropriately. Therefore, investigating the dynamic changes in free fatty acid content at different stages of development and hypothesizing the influence of regulatory genes on free fatty acid metabolism is crucial for improving palm oil quality and accelerating industry growth. LC-MS/MS is used to analyze the composition and content of free fatty acids in the flesh after 95 days (MS1 and MT1), 125 days (MS2 and MT2), and 185 days (MS3 and MT3) of Seedless (MS) and Tenera (MT) oil palm species fruit pollination. RNA-Seq was used to analyze the expression of genes regulating free fatty acid synthesis and accumulation, with differences in genes and metabolites mapped to the KEGG pathway map using the KEGG (Kyoto encyclopedia of genes and genomes) enrichment analysis method. A metabolomics study identified 17 types of saturated and 13 types of unsaturated free fatty acids during the development of MS and MT. Transcriptomic research revealed that 10,804 significantly different expression genes were acquired in the set differential gene threshold between MS and MT. The results showed that FabB was positively correlated with the contents of three main free fatty acids (stearic acid, myristate acid, and palmitic acid) and negatively correlated with the contents of free palmitic acid in the flesh of MS and MT. ACSL and FATB were positively correlated with the contents of three main free fatty acids and negatively correlated with free myristate acid. The study reveals that the expression of key enzyme genes, FabB and FabF, may improve the synthesis of free myristate in oil palm flesh, while FabF, ACSL, and FATB genes may facilitate the production of free palmitoleic acid. These genes may also promote the synthesis of free stearic acid and palmitoleic acid in oil palm flesh. However, the FabB gene may inhibit stearic acid synthesis, while ACSL and FATB genes may hinder myristate acid production. This study provides a theoretical basis for improving palm oil quality.
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Arecaceae , Ácidos Grasos no Esterificados , Humanos , Ácidos Grasos no Esterificados/metabolismo , Ácidos Grasos/metabolismo , Aceite de Palma , Cromatografía Liquida , Miristatos/metabolismo , Arecaceae/genética , Arecaceae/metabolismo , Espectrometría de Masas en Tándem , Ácidos Grasos Insaturados/metabolismo , Ácido Palmítico/metabolismo , Perfilación de la Expresión Génica , Ácidos Esteáricos/metabolismo , Aceites de Plantas/metabolismoRESUMEN
Catalases (CATs) play crucial roles in scavenging H2O2 from reactive oxygen species, controlling the growth and development of plants. So far, genome-wide identification and characterization of CAT genes in oil palm have not been reported. In the present study, five EgCAT genes were obtained through a genome-wide identification approach. Phylogenetic analysis divided them into two subfamilies, with closer genes sharing similar structures. Gene structure and conserved motif analysis demonstrated the conserved nature of intron/exon organization and motifs among the EgCAT genes. Several cis-acting elements related to hormone, stress, and defense responses were identified in the promoter regions of EgCATs. Tissue-specific expression of EgCAT genes in five different tissues of oil palm was also revealed by heatmap analysis using the available transcriptome data. Stress-responsive expression analysis showed that five EgCAT genes were significantly expressed under cold, drought, and salinity stress conditions. Collectively, this study provided valuable information on the oil palm CAT gene family and the validated EgCAT genes can be used as potential candidates for improving abiotic stress tolerance in oil palm and other related crops.
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Arecaceae , Peróxido de Hidrógeno , Catalasa/metabolismo , Filogenia , Peróxido de Hidrógeno/metabolismo , Transcriptoma , Arecaceae/genética , Arecaceae/metabolismo , Estrés Fisiológico/genética , Regulación de la Expresión Génica de las Plantas , Aceite de Palma , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
Oil palm (Elaeis guineensis Jacq.) is a typical tropical oil crop with a temperature of 26-28 °C, providing approximately 35% of the total world's vegetable oil. Growth and productivity are significantly affected by low-temperature stress, resulting in inhibited growth and substantial yield losses. To comprehend the intricate molecular mechanisms underlying the response and acclimation of oil palm under low-temperature stress, multi-omics approaches, including metabolomics, proteomics, and transcriptomics, have emerged as powerful tools. This comprehensive review aims to provide an in-depth analysis of recent advancements in multi-omics studies on oil palm under low-temperature stress, including the key findings from omics-based research, highlighting changes in metabolite profiles, protein expression, and gene transcription, as well as including the potential of integrating multi-omics data to reveal novel insights into the molecular networks and regulatory pathways involved in the response to low-temperature stress. This review also emphasizes the challenges and prospects of multi-omics approaches in oil palm research, providing a roadmap for future investigations. Overall, a better understanding of the molecular basis of the response of oil palm to low-temperature stress will facilitate the development of effective breeding and biotechnological strategies to improve the crop's resilience and productivity in changing climate scenarios.
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Arecaceae , Metabolómica , Proteómica , Transcriptoma , Metabolómica/métodos , Proteómica/métodos , Arecaceae/metabolismo , Arecaceae/genética , Frío , Regulación de la Expresión Génica de las Plantas , Perfilación de la Expresión Génica/métodos , Estrés Fisiológico , Respuesta al Choque por Frío , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , MultiómicaRESUMEN
AP2/ERF transcription factor genes play an important role in regulating the responses of plants to various abiotic stresses, such as cold, drought, high salinity, and high temperature. However, less is known about the function of oil palm AP2/ERF genes. We previously obtained 172 AP2/ERF genes of oil palm and found that the expression of EgAP2.25 was significantly up-regulated under salinity, cold, or drought stress conditions. In the present study, the sequence characterization and expression analysis for EgAP2.25 were conducted, showing that it was transiently over-expressed in Nicotiana tabacum L. The results indicated that transgenic tobacco plants over-expressing EgAP2.25 could have a stronger tolerance to salinity stress than wild-type tobacco plants. Compared with wild-type plants, the over-expression lines showed a significantly higher germination rate, better plant growth, and less chlorophyll damage. In addition, the improved salinity tolerance of EgAP2.25 transgenic plants was mainly attributed to higher antioxidant enzyme activities, increased proline and soluble sugar content, reduced H2O2 production, and lower MDA accumulation. Furthermore, several stress-related marker genes, including NtSOD, NtPOD, NtCAT, NtERD10B, NtDREB2B, NtERD10C, and NtP5CS, were significantly up-regulated in EgAP2.25 transgenic tobacco plants subjected to salinity stress. Overall, over-expression of the EgAP2.25 gene significantly enhanced salinity stress tolerance in transgenic tobacco plants. This study lays a foundation for further exploration of the regulatory mechanism of the EgAP2.25 gene in conferring salinity tolerance in oil palm.
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Arecaceae , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas , Tolerancia a la Sal , Arecaceae/genética , Arecaceae/metabolismo , Germinación/genética , Nicotiana/genética , Nicotiana/fisiología , Nicotiana/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/genética , Estrés Salino/genética , Tolerancia a la Sal/genética , Estrés Fisiológico/genéticaRESUMEN
BACKGROUND & AIMS: Anti-granulocyte macrophage-colony stimulating factor autoantibodies (aGMAbs) are detected in patients with ileal Crohn's disease (CD). Their induction and mode of action during or before disease are not well understood. We aimed to investigate the underlying mechanisms associated with aGMAb induction, from functional orientation to recognized epitopes, for their impact on intestinal immune homeostasis and use as a predictive biomarker for complicated CD. METHODS: We characterized using enzyme-linked immunosorbent assay naturally occurring aGMAbs in longitudinal serum samples from patients archived before the diagnosis of CD (n = 220) as well as from 400 healthy individuals (matched controls) as part of the US Defense Medical Surveillance System. We used biochemical, cellular, and transcriptional analysis to uncover a mechanism that governs the impaired immune balance in CD mucosa after diagnosis. RESULTS: Neutralizing aGMAbs were found to be specific for post-translational glycosylation on granulocyte macrophage-colony stimulating factor (GM-CSF), detectable years before diagnosis, and associated with complicated CD at presentation. Glycosylation of GM-CSF was altered in patients with CD, and aGMAb affected myeloid homeostasis and promoted group 1 innate lymphoid cells. Perturbations in immune homeostasis preceded the diagnosis in the serum of patients with CD presenting with aGMAb and were detectable in the noninflamed CD mucosa. CONCLUSIONS: Anti-GMAbs predict the diagnosis of complicated CD long before the diagnosis of disease, recognize uniquely glycosylated epitopes, and impair myeloid cell and innate lymphoid cell balance associated with altered intestinal immune homeostasis.
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Enfermedad de Crohn , Enfermedades del Íleon , Autoanticuerpos , Enfermedad de Crohn/complicaciones , Epítopos , Glicosilación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Enfermedades del Íleon/complicaciones , Inmunidad Innata , Linfocitos , MacrófagosRESUMEN
Phytohormones play an important role in the pollination and fertilization of crops, but the regulatory mechanisms of oil palm pollination and fertilization are unclear. The purpose of this study is to explore the hormonal changes of oil palm pistils during flowering. We used RNA sequencing to evaluate differentially expressed genes (DEGs) in oil palm pistils at the pollination and non-pollination stages. In this study, we found that the hormone contents of oil palm pistil changed drastically after pollination. The transcriptome of the oil palm pistil without pollination and at 2 h, 4 h, 12 h, 24 h, and 48 h after pollination was comprehensively analyzed, and a large number of differential genes and metabolic pathways were explored. Based on the transcriptome data, it could be recognized that the changes of indoleacetic acid (IAA), zeatin riboside (ZR), and abscisic acid (ABA) during pollination were consistent with the changes in the corresponding gene transcripts. Differentially expressed genes during pollination and fertilization of oil palm were mainly related to energy metabolism and hormone signal transduction. It provides new insights to elucidate the interaction and regulation mechanisms of plant hormones before and after oil palm pollination, providing a theoretical basis and reference for the research on sexual reproduction of oil palm.
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Reguladores del Crecimiento de las Plantas , Polinización , Fertilización , Flores/genética , Flores/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Reguladores del Crecimiento de las Plantas/metabolismo , TranscriptomaRESUMEN
BACKGROUND: Oil palm is the most efficient oil-producing crop in the world, and the yield of palm oil is associated with embryonic development. However, a comprehensive understanding of zygotic embryo development at the molecular level remains elusive. In order to address this issue, we report the transcriptomic analysis of zygotic embryo development in oil palm, specifically focusing on regulatory genes involved in important biological pathways. RESULTS: In this study, three cDNA libraries were prepared from embryos at S1 (early-stage), S2 (middle-stage), and S3 (late-stage). There were 16,367, 16,500, and 18,012 genes characterized at the S1, S2, and S3 stages of embryonic development, respectively. A total of 1522, 2698, and 142 genes were differentially expressed in S1 vs S2, S1 vs S3, and S2 vs S3, respectively. Using Gene Ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to identify key genes and pathways. In the hormone signaling pathway, genes related to auxin antagonize the output of cytokinin which regulates the development of embryo meristem. The genes related to abscisic acid negatively regulating the synthesis of gibberellin were strongly up-regulated in the mid-late stage of embryonic development. The results were reported the early synthesis and mid-late degradation of sucrose, as well as the activation of the continuous degradation pathway of temporary starch, providing the nutrients needed for differentiation of the embryonic cell. Moreover, the transcripts of genes involved in fatty acid synthesis were also abundantly accumulated in the zygotic embryos. CONCLUSION: Taken together, our research provides a new perspective on the developmental and metabolic regulation of zygotic embryo development at the transcriptional level in oil palm.
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Arecaceae/crecimiento & desarrollo , Arecaceae/genética , Arecaceae/metabolismo , Semillas/crecimiento & desarrollo , Semillas/genética , Semillas/metabolismo , China , Productos Agrícolas/genética , Productos Agrícolas/crecimiento & desarrollo , Productos Agrícolas/metabolismo , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Redes y Vías Metabólicas , Aceite de PalmaRESUMEN
A single metallic nanodisk is the simplest plasmonic nanostructure, but it is robust enough to generate a Fano resonance in the forward and backward scattering spectra by the increment of nanodisk height in the symmetric and asymmetric dielectric environment. Thanks to the phase retardation effect, the non-uniform distribution of electric field along the height of aluminum (Al) nanodisk generates the out-of-plane higher-order modes, which interfere with the dipolar mode and subsequently result in the Fano-lineshape scattering spectra. Meanwhile, the symmetry-breaking effect by the dielectric substrate and the increment of refractive index of the symmetric dielectric environment further accelerate the phase retardation effect and contribute to the appearance of out-of-plane modes. The experimental results on the periodic Al nanodisk arrays with different heights confirm the retardation-induced higher modes in the asymmetric and symmetric environment. The appearance of higher modes and blueshifted main dips in the transmission spectra prove the dominant role of out-of-plane higher modes on the plasmonic resonances of the taller Al nanodisk.
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Plasmonic color using metallic nanostructures has attracted considerable interest because of its subwavelength resolution and long sustainability. Significant efforts have been devoted to expanding the gamut of plasmonic color generation by tuning the composition, shape, and components in the primary pixel. In this study, we develop a novel and straightforward strategy for aluminum plasmonic color printing aimed at practical commercial applications. An array of aluminum nanodisks is designed for the broadband scattering of white pixels instead of the three primary colors. Examples presented include trademark and QR codes, which are common in the market of consumer advertising and item identification, that are encoded and fabricated in experiments with aluminum white color pixels to demonstrate feasibility. This simple and efficient strategy is compatible with cost-effective industrial fabrication methods, such as photolithography and nanoimprinting, and requires relatively simpler manufacturing procedures. Therefore, a new path is opened for the future with the extensive use of plasmonic color printing.
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The continuous spontaneous localization model solves the measurement problem of standard quantum mechanics by coupling the mass density of a quantum system to a white-noise field. Since the mass density is not uniquely defined in general relativity, this model is ambiguous when applied to cosmology. We however show that most natural choices of the density contrast already make current measurements of the cosmic microwave background incompatible with other laboratory experiments.
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Autoimmune regulator (AIRE) deficiency in humans induces a life-threatening generalized autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), and no curative treatments are available. Several models of AIRE-deficient mice have been generated, and although they have been useful in understanding the role of AIRE in central tolerance, they do not reproduce accurately the APECED symptoms, and thus there is still a need for an animal model displaying APECED-like disease. We assessed, in this study, the potential of the rat as an accurate model for APECED. In this study, we demonstrate that in rat, AIRE is expressed by MHC class II (MCH-II)+ and MHC-II- medullary thymic epithelial cells in thymus and by CD4int conventional dendritic cells in periphery. To our knowledge, we generated the first AIRE-deficient rat model using zinc-finger nucleases and demonstrated that they display several of the key symptoms of APECED disease, including alopecia, skin depigmentation, and nail dystrophy, independently of the genetic background. We observed severe autoimmune lesions in a large spectrum of organs, in particular in the pancreas, and identified several autoantibodies in organs and cytokines such as type I IFNs and IL-17 at levels similar to APECED. Finally, we demonstrated a biased Ab response to IgG1, IgM, and IgA isotypes. Altogether, our data demonstrate that AIRE-deficient rat is a relevant APECED animal model, opening new opportunity to test curative therapeutic treatments.
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Enfermedades Autoinmunes/inmunología , Candidiasis/inmunología , Tolerancia Inmunológica/inmunología , Poliendocrinopatías Autoinmunes/inmunología , Animales , Autoanticuerpos/inmunología , Citocinas/inmunología , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Células Epiteliales/inmunología , Femenino , Genes MHC Clase II/inmunología , Masculino , Ratas , Ratas Sprague-Dawley , Timo/inmunologíaRESUMEN
Genome-wide association studies have identified ~170 loci associated with Crohn's disease (CD) and defining which genes drive these association signals is a major challenge. The primary aim of this study was to define which CD locus genes are most likely to be disease related. We developed a gene prioritization regression model (GPRM) by integrating complementary mRNA expression datasets, including bulk RNA-Seq from the terminal ileum of 302 newly diagnosed, untreated CD patients and controls, and in stimulated monocytes. Transcriptome-wide association and co-expression network analyses were performed on the ileal RNA-Seq datasets, identifying 40 genome-wide significant genes. Co-expression network analysis identified a single gene module, which was substantially enriched for CD locus genes and most highly expressed in monocytes. By including expression-based and epigenetic information, we refined likely CD genes to 2.5 prioritized genes per locus from an average of 7.8 total genes. We validated our model structure using cross-validation and our prioritization results by protein-association network analyses, which demonstrated significantly higher CD gene interactions for prioritized compared with non-prioritized genes. Although individual datasets cannot convey all of the information relevant to a disease, combining data from multiple relevant expression-based datasets improves prediction of disease genes and helps to further understanding of disease pathogenesis.