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Rare genetic variants in toll-like receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.
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Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico , Receptor Toll-Like 7 , Lupus Eritematoso Sistémico/genética , Humanos , Animales , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Ratones , Niño , Femenino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Masculino , Edad de Inicio , Variación Genética , FN-kappa B/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Adolescente , Células THP-1 , Interferón Tipo I/metabolismoRESUMEN
Approximately 15 genes have been directly associated with skin pigmentation variation in humans, leading to its characterization as a relatively simple trait. However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed, with genetic architecture varying by latitude. We investigate polygenicity in the KhoeSan populations indigenous to southern Africa who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but known pigmentation loci explain only a small fraction of the variance. Rather, baseline skin pigmentation is a complex, polygenic trait in the KhoeSan. Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13, using a genome-wide association approach complemented by targeted resequencing. By considering diverse, under-studied African populations, we show how the architecture of skin pigmentation can vary across humans subject to different local evolutionary pressures.
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Pigmentación de la Piel , África , Población Negra/genética , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 µm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1ß. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.
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Adenocarcinoma del Pulmón , Contaminantes Atmosféricos , Contaminación del Aire , Transformación Celular Neoplásica , Neoplasias Pulmonares , Animales , Ratones , Adenocarcinoma del Pulmón/inducido químicamente , Adenocarcinoma del Pulmón/genética , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Exposición a Riesgos Ambientales , Receptores ErbB/genética , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Material Particulado/efectos adversos , Material Particulado/análisis , Tamaño de la Partícula , Estudios de Cohortes , Macrófagos Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/patologíaRESUMEN
Genetic lesions in X-linked inhibitor of apoptosis (XIAP) pre-dispose humans to cell death-associated inflammatory diseases, although the underlying mechanisms remain unclear. Here, we report that two patients with XIAP deficiency-associated inflammatory bowel disease display increased inflammatory IL-1ß maturation as well as cell death-associated caspase-8 and Gasdermin D (GSDMD) processing in diseased tissue, which is reduced upon patient treatment. Loss of XIAP leads to caspase-8-driven cell death and bioactive IL-1ß release that is only abrogated by combined deletion of the apoptotic and pyroptotic cell death machinery. Namely, extrinsic apoptotic caspase-8 promotes pyroptotic GSDMD processing that kills macrophages lacking both inflammasome and apoptosis signalling components (caspase-1, -3, -7, -11 and BID), while caspase-8 can still cause cell death in the absence of both GSDMD and GSDME when caspase-3 and caspase-7 are present. Neither caspase-3 and caspase-7-mediated activation of the pannexin-1 channel, or GSDMD loss, prevented NLRP3 inflammasome assembly and consequent caspase-1 and IL-1ß maturation downstream of XIAP inhibition and caspase-8 activation, even though the pannexin-1 channel was required for NLRP3 triggering upon mitochondrial apoptosis. These findings uncouple the mechanisms of cell death and NLRP3 activation resulting from extrinsic and intrinsic apoptosis signalling, reveal how XIAP loss can co-opt dual cell death programs, and uncover strategies for targeting the cell death and inflammatory pathways that result from XIAP deficiency.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Humanos , Apoptosis , Caspasa 1/genética , Caspasa 1/metabolismo , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Caspasa 8/genética , Caspasa 8/metabolismo , Muerte Celular , Inflamasomas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis/fisiología , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.
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Aprendizaje del Sistema de Salud , Medicina de Precisión , Humanos , Bancos de Muestras Biológicas , Colorado , GenómicaRESUMEN
Lithium-ion batteries (LIBs) are widely used in applications ranging from electric vehicles to wearable devices. Before the invention of secondary LIBs, the primary lithium-thionyl chloride (Li-SOCl2) battery was developed in the 1970s using SOCl2 as the catholyte, lithium metal as the anode and amorphous carbon as the cathode1-7. This battery discharges by lithium oxidation and catholyte reduction to sulfur, sulfur dioxide and lithium chloride, is well known for its high energy density and is widely used in real-world applications; however, it has not been made rechargeable since its invention8-13. Here we show that with a highly microporous carbon positive electrode, a starting electrolyte composed of aluminium chloride in SOCl2 with fluoride-based additives, and either sodium or lithium as the negative electrode, we can produce a rechargeable Na/Cl2 or Li/Cl2 battery operating via redox between mainly Cl2/Cl- in the micropores of carbon and Na/Na+ or Li/Li+ redox on the sodium or lithium metal. The reversible Cl2/NaCl or Cl2/LiCl redox in the microporous carbon affords rechargeability at the positive electrode side and the thin alkali-fluoride-doped alkali-chloride solid electrolyte interface stabilizes the negative electrode, both are critical to secondary alkali-metal/Cl2 batteries.
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Ago2 differentially regulates oncogenic and tumor-suppressive miRNAs in cancer cells. This discrepancy suggests a secondary event regulating Ago2/miRNA action in a context-dependent manner. We show here that a positive charge of Ago2 K212, that is preserved by SIR2-mediated Ago2 deacetylation in cancer cells, is responsible for the direct interaction between Ago2 and Caveolin-1 (CAV1). Through this interaction, CAV1 sequesters Ago2 on the plasma membranes and regulates miRNA-mediated translational repression in a compartment-dependent manner. Ago2/CAV1 interaction plays a role in miRNA-mediated mRNA suppression and in miRNA release via extracellular vesicles (EVs) from tumors into the circulation, which can be used as a biomarker of tumor progression. Increased Ago2/CAV1 interaction with tumor progression promotes aggressive cancer behaviors, including metastasis. Ago2/CAV1 interaction acts as a secondary event in miRNA-mediated suppression and increases the complexity of miRNA actions in cancer.
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Proteínas Argonautas , Caveolina 1 , MicroARNs , Metástasis de la Neoplasia , Animales , Humanos , Ratones , Proteínas Argonautas/metabolismo , Proteínas Argonautas/genética , Caveolina 1/metabolismo , Caveolina 1/genética , Línea Celular Tumoral , Vesículas Extracelulares/metabolismo , Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , MicroARNs/genética , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patología , Unión Proteica , Sirtuina 2/metabolismo , Sirtuina 2/genéticaRESUMEN
Cancer is driven by somatically acquired point mutations and chromosomal rearrangements, conventionally thought to accumulate gradually over time. Using next-generation sequencing, we characterize a phenomenon, which we term chromothripsis, whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. Rearrangements involving one or a few chromosomes crisscross back and forth across involved regions, generating frequent oscillations between two copy number states. These genomic hallmarks are highly improbable if rearrangements accumulate over time and instead imply that nearly all occur during a single cellular catastrophe. The stamp of chromothripsis can be seen in at least 2%-3% of all cancers, across many subtypes, and is present in â¼25% of bone cancers. We find that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis. This phenomenon has important implications for the origins of genomic remodeling and temporal emergence of cancer.
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Aberraciones Cromosómicas , Neoplasias/genética , Neoplasias/patología , Neoplasias Óseas/genética , Línea Celular Tumoral , Pintura Cromosómica , Femenino , Reordenamiento Génico , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Persona de Mediana EdadRESUMEN
Mitochondrial antiviral signaling platform protein (MAVS) acts as a central hub for RIG-I receptor proximal signal propagation. However, key components in the assembly of the MAVS mitochondrial platform that promote RIG-I mitochondrial localization and optimal activation are still largely undefined. Employing pooled RNAi and yeast two-hybrid screenings, we report that the mitochondrial adaptor protein tripartite motif (TRIM)14 provides a docking platform for the assembly of the mitochondrial signaling complex required for maximal activation of RIG-I-mediated signaling, consisting of WHIP and protein phosphatase PPP6C. Following viral infection, the ubiquitin-binding domain in WHIP bridges RIG-I with MAVS by binding to polyUb chains of RIG-I at lysine 164. The ATPase domain in WHIP contributes to stabilization of the RIG-I-dsRNA interaction. Moreover, phosphatase PPP6C is responsible for RIG-I dephosphorylation. Together, our findings define the WHIP-TRIM14-PPP6C mitochondrial signalosome required for RIG-I-mediated innate antiviral immunity.
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Proteínas Portadoras/inmunología , Proteína 58 DEAD Box/inmunología , Proteínas de Unión al ADN/inmunología , Inmunidad Innata , Mitocondrias/inmunología , Proteínas Mitocondriales/inmunología , Complejos Multiproteicos/inmunología , Fosfoproteínas Fosfatasas/inmunología , Transducción de Señal/inmunología , ATPasas Asociadas con Actividades Celulares Diversas , Animales , Proteínas Portadoras/genética , Línea Celular Tumoral , Chlorocebus aethiops , Proteína 58 DEAD Box/genética , Proteínas de Unión al ADN/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular , Mitocondrias/genética , Proteínas Mitocondriales/genética , Complejos Multiproteicos/genética , Fosfoproteínas Fosfatasas/genética , Receptores Inmunológicos , Transducción de Señal/genética , Proteínas de Motivos Tripartitos , Células Vero , Virosis/genética , Virosis/inmunología , Virus/genética , Virus/inmunologíaRESUMEN
Coupling Weyl quasiparticles and charge density waves (CDWs) can lead to fascinating band renormalization and many-body effects beyond band folding and Peierls gaps. For the quasi-one-dimensional chiral compound (TaSe4)2I with an incommensurate CDW transition at TC = 263 K, photoemission mappings thus far are intriguing due to suppressed emission near the Fermi level. Models for this unconventional behavior include axion insulator phases, correlation pseudogaps, polaron subbands, bipolaron bound states, etc. Our photoemission measurements show sharp quasiparticle bands crossing the Fermi level at T > TC, but for T < TC, these bands retain their dispersions with no Peierls or axion gaps at the Weyl points. Instead, occupied band edges recede from the Fermi level, opening a spectral gap. Our results confirm localization of quasiparticles (holes created by photoemission) is the key physics, which suppresses spectral weights over an energy window governed by incommensurate modulation and inherent phase defects of CDW.
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OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.
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Carcinoma Ductal Pancreático , Células Madre Neoplásicas , Neoplasias Pancreáticas , Animales , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Ratones , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/metabolismo , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Humanos , Línea Celular Tumoral , Escape del Tumor/inmunología , Modelos Animales de Enfermedad , Evasión Inmune , Microambiente Tumoral/inmunologíaRESUMEN
In this study, we investigate the effect of neuregulin 4 (NRG4) on podocyte damage in a mouse model of diabetic nephropathy (DN) and we elucidate the underlying molecular mechanisms. In vivo experiments were conducted using a C57BL/6 mouse model of DN to determine the effect of NRG4 on proteinuria and podocyte injury, and in vitro experiments were performed with conditionally immortalized mouse podocytes treated with high glucose and NRG4 to assess the protective effects of NRG4 on podocyte injury. Autophagy-related protein levels and related signaling pathways were evaluated both in vivo and in vitro. The involvement of the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway was detected using chloroquine or AMPK inhibitors. The results showed that the AMPK/mTOR pathway was involved in the protective roles of NRG4 against high glucose-mediated podocyte injury. Also, NRG4 significantly decreased albuminuria in DN mice. PAS staining indicated that NRG4 mitigated glomerular volume and mesangium expansion in DN mice. Consistently, western blot and RT-PCR analyses confirmed that NRG4 decreased the expression of pro-fibrotic molecules in the glomeruli of DN mice. The immunofluorescence results showed that NRG4 retained expression of podocin and nephrin, whereas transmission electron microscopy revealed that NRG4 alleviated podocyte injury. In DN mice, NRG4 decreased podocyte apoptosis and increased expression of nephrin and podocin, while decreasing the expression of desmin and HIF1α. Overall, NRG4 improved albuminuria, glomerulosclerosis, glomerulomegaly, and hypoxia in DN mice. The in vitro experiments showed that NRG4 inhibited HG-induced podocyte injury and apoptosis. Furthermore, autophagy of the glomeruli decreased in DN mice, but reactivated following NRG4 intervention. NRG4 intervention was found to partially activate autophagy via the AMPK/mTOR signaling pathway. Consequently, when the AMPK/mTOR pathway was suppressed or autophagy was inhibited, the beneficial effects of NRG4 intervention on podocyte injury were diminished. These results indicate that NRG4 intervention attenuates podocyte injury and apoptosis by promoting autophagy in the kidneys of DN mice, in part, by activating the AMPK/mTOR signaling pathway.
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BACKGROUND: Observational studies and meta-analyses have indicated associations between blood lipid profiles and asthma. However, the causal association is unknown. Therefore, this study investigated the causal relationship between blood lipid profiles and asthma using bidirectional Mendelian randomization analysis. METHODS AND MATERIALS: Our analyses were performed using individual data from the Taiwan Biobank and summary statistics from the Asian Genetic Epidemiology Network (AGEN). The causal estimates between all genetic variants, exposures of interest and asthma were calculated using an inverse-variance weighted method based on Taiwan Biobank data from 24,853 participants (mean age, 48.8 years; 49.8% women). Sensitivity analyses, including the weighted median, MR Egger regression, MR-PRESSO, mode-based estimate, contamination mixture methods, and leave-one-out analysis, were applied to validate the results and detect pleiotropy. RESULTS: In the inverse-variance weighted (IVW) analyses, we found evidence of a significant causal effect of an increased level of low-density lipoprotein cholesterol on asthma risk (ßIVW = 1.338, p = 0.001). A genetically decreased level of high-density lipoprotein cholesterol was also associated with asthma risk (ßIVW = -0.338, p = 0.01). We also found that an increased level of total cholesterol was associated with an increased risk of asthma (ßIVW = 1.343, p = 0.001). Several sensitivity analyses generated consistent findings. We did not find evidence to support the causality between asthma and blood lipid profiles in either direction. CONCLUSION: Our results supported the causal relationship between higher levels of LDL cholesterol and total cholesterol and lower levels of HDL cholesterol with an increased risk of asthma.
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Asma , Análisis de la Aleatorización Mendeliana , Humanos , Asma/genética , Asma/sangre , Asma/epidemiología , Femenino , Masculino , Persona de Mediana Edad , HDL-Colesterol/sangre , HDL-Colesterol/genética , Lípidos/sangre , LDL-Colesterol/sangre , Polimorfismo de Nucleótido Simple , Adulto , Taiwán/epidemiología , Factores de Riesgo , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Elizabethkingia spp. are emerging as nosocomial pathogens causing various infections. These pathogens express resistance to a broad range of antibiotics, thus requiring antimicrobial combinations for coverage. However, possible antagonistic interactions between antibiotics have not been thoroughly explored. This study aimed to evaluate the effectiveness of antimicrobial combinations against Elizabethkingia infections, focusing on their impact on pathogenicity, including biofilm production and cell adhesion. METHODS: Double-disc diffusion, time-kill, and chequerboard assays were used for evaluating the combination effects of antibiotics against Elizabethkingia spp. We further examined the antagonistic effects of antibiotic combinations on biofilm formation and adherence to A549 human respiratory epithelial cells. Further validation of the antibiotic interactions and their implications was performed using ex vivo hamster precision-cut lung sections (PCLSs) to mimic in vivo conditions. RESULTS: Antagonistic effects were observed between cefoxitin, imipenem and amoxicillin/clavulanic acid in combination with vancomycin. The antagonism of imipenem toward vancomycin was specific to its effects on the genus Elizabethkingia. Imipenem further hampered the bactericidal effect of vancomycin and impaired its inhibition of biofilm formation and the adhesion of Elizabethkingia meningoseptica ATCC 13253 to human cells. In the ex vivo PCLS model, vancomycin exhibited dose-dependent bactericidal effects; however, the addition of imipenem also reduced the effect of vancomycin. CONCLUSIONS: Imipenem reduced the bactericidal efficacy of vancomycin against Elizabethkingia spp. and compromised its capacity to inhibit biofilm formation, thereby enhancing bacterial adhesion. Clinicians should be aware of the potential issues with the use of these antibiotic combinations when treating Elizabethkingia infections.
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Antibacterianos , Biopelículas , Infecciones por Flavobacteriaceae , Imipenem , Pruebas de Sensibilidad Microbiana , Vancomicina , Animales , Imipenem/farmacología , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Humanos , Vancomicina/farmacología , Infecciones por Flavobacteriaceae/microbiología , Infecciones por Flavobacteriaceae/tratamiento farmacológico , Flavobacteriaceae/efectos de los fármacos , Adhesión Bacteriana/efectos de los fármacos , Células A549 , Cricetinae , Interacciones Farmacológicas , Pulmón/microbiologíaRESUMEN
Akirin is a nuclear protein that controls development in vertebrates and invertebrates. The function of Akirin has not been assessed in any Coleopteran insects. We found that high levels of akirin transcripts in Henosepilachna vigintioctopunctata, a serious Coleopteran potato defoliator (hereafter Hvakirin), were present at prepupal, pupal and adult stages, especially in larval foregut and fat body. RNA interference (RNAi) targeting Hvakirin impaired larval development. The Hvakirin RNAi larvae arrested development at the final larval instar stage. They remained as stunted larvae, gradually blackened and finally died. Moreover, the remodelling of gut and fat body was inhibited in the Hvakirin depleted larvae. Two layers of cuticles, old and newly formed, were noted in the dsegfp-injected animals. In contrast, only a layer of cuticle was found in the dsakirin-injected beetles, indicating the arrest of larval development. Furthermore, the expression of three transforming growth factor-ß cascade genes (Hvsmox, Hvmyo and Hvbabo), a 20-hydroxyecdysone (20E) receptor gene (HvEcR) and six 20E response genes (HvHR3, HvHR4, HvE75, HvBrC, HvE93 and Hvftz-f1) was significantly repressed, consistent with decreased 20E signalling. Conversely, the transcription of a juvenile hormone (JH) biosynthesis gene (Hvjhamt), a JH receptor gene (HvMet) and two JH response genes (HvKr-h1 and HvHairy) was greatly enhanced. Our findings suggest a critical role of Akirin in larval development in H. vigintioctopunctata.
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Macrophages play a pivotal role in the response to injury, contributing significantly to the repair and regrowth of damaged tissues. The external lateral line system in aquatic organisms offers a practical model for studying regeneration, featuring interneuromast cells connecting sensory neuromasts. Under normal conditions, these cells remain dormant, but their transformation into neuromasts occurs when overcoming inhibitory signals from Schwann cells and posterior lateral line nerves. The mechanism enabling interneuromast cells to evade inhibition by Schwann cells remains unclear. Previous observations suggest that macrophages physically interact with neuromasts, nerves, and Schwann cells during regeneration. This interaction leads to the regeneration of neuromasts in a subset of zebrafish with ablated neuromasts. To explore whether macrophages achieve this effect through secreted cytokines, we conducted experiments involving tail amputation in zebrafish larvae and tested the impact of cytokine inhibitors on neuromast regeneration. Most injured larvae remarkably regenerated a neuromast within 4 days post-amputation. Intriguingly, removal of macrophages and inhibition of the anti-inflammatory cytokine transforming growth factor-beta (TGF-ß) significantly delayed neuromast regeneration. Conversely, inhibition of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) had minor effects on the regeneration process. This study provides insights into how macrophages activate interneuromast cells, elucidating the pathways underlying neuromast regeneration.
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Sistema de la Línea Lateral , Pez Cebra , Animales , Pez Cebra/fisiología , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
BACKGROUND: Among patients with chronic obstructive pulmonary disease (COPD), some have features of both asthma and COPD-a condition categorized as asthma-COPD overlap (ACO). Our aim was to determine whether asthma- or COPD-related microRNAs (miRNAs) play a role in the pathogenesis of ACO. METHODS: A total of 22 healthy subjects and 27 patients with ACO were enrolled. We selected 6 miRNAs that were found to correlate with COPD and asthma. The expression of miRNAs and target genes was analyzed using quantitative reverse-transcriptase polymerase chain reaction. Cell apoptosis and intracellular reactive oxygen species production were evaluated using flow cytometry. In vitro human monocytic THP-1 cells and primary normal human bronchial epithelial (NHBE) cells under stimuli with cigarette smoke extract (CSE) or ovalbumin (OVA) allergen or both were used to verify the clinical findings. RESULTS: We identified the upregulation of miR-125b-5p in patients with ACO and in THP-1 cells stimulated with CSE plus OVA allergen. We selected 16 genes related to the miR-125b-5p pathway and found that IL6R and TRIAP1 were both downregulated in patients with ACO and in THP-1 cells stimulated with CSE plus OVA. The percentage of late apoptotic cells increased in the THP-1 cell culture model when stimulated with CSE plus OVA, and the effect was reversed by transfection with miR-125b-5p small interfering RNA (siRNA). The percentage of reactive oxygen species-producing cells increased in the NHBE cell culture model when stimulated with CSE plus OVA, and the effect was reversed by transfection with miR-125b-5p siRNA. In NHBE cells, siRNA transfection reversed the upregulation of STAT3 under CSE+OVA stimulation. CONCLUSIONS: Our study revealed that upregulation of miR-125b-5p in patients with ACO mediated late apoptosis in THP-1 cells and oxidative stress in NHBE cells via targeting IL6R and TRIAP1. STAT3 expression was also regulated by miR-125b-5p.
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Apoptosis , Asma , MicroARNs , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Alérgenos , Apoptosis/genética , Asma/genética , Asma/complicaciones , Péptidos y Proteínas de Señalización Intracelular/metabolismo , MicroARNs/metabolismo , Estrés Oxidativo/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Especies Reactivas de Oxígeno , Receptores de Interleucina-6/metabolismo , ARN Interferente Pequeño/metabolismo , Masculino , AncianoRESUMEN
Dry eye disease is a multifactorial dysfunction of the tear film and ocular surface, with etiology involving inflammation and oxidative stress on the ocular surface. Pterostilbene (PS) is a secondary metabolite extracted from plants, which possesses remarkable anti-inflammatory and antioxidant effects. However, its application is limited by light instability and very poor water solubility. We modified fat-soluble PS into a biparental pterostilbene-glutaric anhydride-arginine-glycine-aspartic acid (PS-GA-RGD) nanomedicine by prodrug ligation of functional peptides. The aim of this study was to explore the protective effect and potential mechanism of PS-GA-RGD on dry eye disease in vitro and in vivo. We demonstrated good long-term biocompatibility of PS-GA-RGD through rabbit eye stimulation test. Lipopolysaccharide (LPS) was used to induce murine macrophages RAW 264.7 to establish an inflammation and oxidative stress model. In this model, PS-GA-RGD effectively reduced the production of ROS and 8-OHdG, enhancing the expression of antioxidant factor Nrf2 and antioxidant enzyme heme oxygenase-1. In addition, the expression of NF-κB inflammatory pathway significantly increased in LPS-induced RAW 264.7 cells, while PS-GA-RGD could significantly reduce this pathway. Hypertonic saline was utilized to establish a hypertonic model of human corneal epithelial cells. PS-GA-RGD was found to significantly reduce the production of ROS and NLRP3 inflammasomes in this model, exhibiting superior efficacy compared to PS. Experimental dry eye animal models were co-induced with subcutaneous injection of scopolamine and an intelligently controlled environmental system. We demonstrated that PS-GA-RGD nano drugs can prevent and reduce corneal epithelial cell defects and apoptosis, protect conjunctival goblet cells, and have an excellent anti-inflammatory effect. Finally, we demonstrated that RGD sequence in PS-GA-RGD can enhance cellular uptake, corneal retention, and penetration, thereby increasing their bioavailability and efficacy by a cell uptake assay and rabbit corneal drug retention experiment. Overall, this study highlights the potential of PS-GA-RGD nanomedicines in the treatment of dry eyes.
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Antioxidantes , Síndromes de Ojo Seco , Ratones , Humanos , Animales , Conejos , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Lipopolisacáridos , Síndromes de Ojo Seco/metabolismo , Inflamación/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Oligopéptidos/farmacología , Oligopéptidos/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
The present work reports the rapid sweat detection inside a PPE kit using a flexible humidity sensor based on hydrothermally synthesized ZnO (zinc oxide) nanoflowers (ZNFs). Physical characterization of ZNFs was done using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transmission infrared spectroscopy (FTIR), UV-visible, particle size analysis, Raman analysis, and X-ray photoelectron spectroscopy (XPS) analysis, and the hydrophilicity was investigated by using contact angle measurement. Fabrication of a flexible sensor was done by deposition on the paper substrate using the spin coating technique. It exhibited high sensitivity and low response and recovery times in the humidity range 10-95%RH. The sensor demonstrated the highest sensitivity of 296.70 nF/%RH within the humidity range 55-95%RH, and the rapid response and recovery times were also calculated and found as 5.10/1.70 s, respectively. The selectivity of the proposed sensor was also analyzed, and it is highly sensitive to humidity. The humidity sensing characteristics were theoretically witnessed in terms of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and electronic properties of sensing materials in ambient and humid conditions. These theoretical results are evidence of the interaction of ZnO with humidity. Overall, the present study provides a scope of architecture-enabled paper-based humidity sensors for the detection of sweat levels inside PPE kits for health workers.
RESUMEN
Previous studies reported that auditory cortices (AC) were mostly activated by sounds coming from the contralateral hemifield. As a result, sound locations could be encoded by integrating opposite activations from both sides of AC ("opponent hemifield coding"). However, human auditory "where" pathway also includes a series of parietal and prefrontal regions. It was unknown how sound locations were represented in those high-level regions during passive listening. Here, we investigated the neural representation of sound locations in high-level regions by voxel-level tuning analysis, regions-of-interest-level (ROI-level) laterality analysis, and ROI-level multivariate pattern analysis. Functional magnetic resonance imaging data were collected while participants listened passively to sounds from various horizontal locations. We found that opponent hemifield coding of sound locations not only existed in AC, but also spanned over intraparietal sulcus, superior parietal lobule, and frontal eye field (FEF). Furthermore, multivariate pattern representation of sound locations in both hemifields could be observed in left AC, right AC, and left FEF. Overall, our results demonstrate that left FEF, a high-level region along the auditory "where" pathway, encodes sound locations during passive listening in two ways: a univariate opponent hemifield activation representation and a multivariate full-field activation pattern representation.