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Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.
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Here, we report inducible mosaic animal for perturbation (iMAP), a transgenic platform enabling in situ CRISPR targeting of at least 100 genes in parallel throughout the mouse body. iMAP combines Cre-loxP and CRISPR-Cas9 technologies and utilizes a germline-transmitted transgene carrying a large array of individually floxed, tandemly linked gRNA-coding units. Cre-mediated recombination triggers expression of all the gRNAs in the array but only one of them per cell, converting the mice to mosaic organisms suitable for phenotypic characterization and also for high-throughput derivation of conventional single-gene perturbation lines via breeding. Using gRNA representation as a readout, we mapped a miniature Perturb-Atlas cataloging the perturbations of 90 genes across 39 tissues, which yields rich insights into context-dependent gene functions and provides a glimpse of the potential of iMAP in genome decoding.
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Sistemas CRISPR-Cas , ARN Guía de Kinetoplastida , Animales , Sistemas CRISPR-Cas/genética , Edición Génica , Genoma , Ratones , ARN Guía de Kinetoplastida/genética , ARN Guía de Kinetoplastida/metabolismo , TransgenesRESUMEN
DNA storage is one of the most promising ways for future information storage due to its high data storage density, durable storage time and low maintenance cost. However, errors are inevitable during synthesizing, storing and sequencing. Currently, many error correction algorithms have been developed to ensure accurate information retrieval, but they will decrease storage density or increase computing complexity. Here, we apply the Bloom Filter, a space-efficient probabilistic data structure, to DNA storage to achieve the anti-error, or anti-contamination function. This method only needs the original correct DNA sequences (referred to as target sequences) to produce a corresponding data structure, which will filter out almost all the incorrect sequences (referred to as non-target sequences) during sequencing data analysis. Experimental results demonstrate the universal and efficient filtering capabilities of our method. Furthermore, we employ the Counting Bloom Filter to achieve the file version control function, which significantly reduces synthesis costs when modifying DNA-form files. To achieve cost-efficient file version control function, a modified system based on yin-yang codec is developed.
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Algoritmos , ADN , Análisis de Secuencia de ADN/métodos , ADN/genética , ADN/química , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Almacenamiento y Recuperación de la InformaciónRESUMEN
BACKGROUND: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9. METHODS: This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing. FINDINGS: Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and five received 1·5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery. INTERPRETATION: AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.
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Dependovirus , Terapia Genética , Humanos , Terapia Genética/métodos , Dependovirus/genética , Niño , Masculino , Preescolar , Femenino , Adolescente , Lactante , Vectores Genéticos , Resultado del Tratamiento , Sordera/genética , Sordera/terapia , Mutación , Proteínas de la MembranaRESUMEN
The endogenous mitochondrial quality control (MQC) system serves to protect mitochondria against cellular stressors. Although mitochondrial dysfunction contributes to cardiac damage during many pathological conditions, the regulatory signals influencing MQC disruption during septic cardiomyopathy (SC) remain unclear. This study aimed to investigate the involvement of pyruvate kinase M2 (PKM2) and prohibitin 2 (PHB2) interaction followed by MQC impairment in the pathogenesis of SC. We utilized LPS-induced SC models in PKM2 transgenic (PKM2TG) mice, PHB2S91D-knockin mice, and PKM2-overexpressing HL-1 cardiomyocytes. After LPS-induced SC, cardiac PKM2 expression was significantly downregulated in wild-type mice, whereas PKM2 overexpression in vivo sustained heart function, suppressed myocardial inflammation, and attenuated cardiomyocyte death. PKM2 overexpression relieved sepsis-related mitochondrial damage via MQC normalization, evidenced by balanced mitochondrial fission/fusion, activated mitophagy, restored mitochondrial biogenesis, and inhibited mitochondrial unfolded protein response. Docking simulations, co-IP, and domain deletion mutant protein transfection experiments showed that PKM2 phosphorylates PHB2 at Ser91, preventing LPS-mediated PHB2 degradation. Additionally, the A domain of PKM2 and the PHB domain of PHB2 are required for PKM2-PHB2 binding and PHB2 phosphorylation. After LPS exposure, expression of a phosphorylation-defective PHB2S91A mutant negated the protective effects of PKM2 overexpression. Moreover, knockin mice expressing a phosphorylation-mimetic PHB2S91D mutant showed improved heart function, reduced inflammation, and preserved mitochondrial function following sepsis induction. Abundant PKM2 expression is a prerequisite to sustain PKM2-PHB2 interaction which is a key element for preservation of PHB2 phosphorylation and MQC, presenting novel interventive targets for the treatment of septic cardiomyopathy.
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Cardiomiopatías , Miocitos Cardíacos , Prohibitinas , Piruvato Quinasa , Proteínas Represoras , Sepsis , Animales , Fosforilación , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Ratones , Piruvato Quinasa/metabolismo , Piruvato Quinasa/genética , Sepsis/metabolismo , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Mitocondrias Cardíacas/metabolismo , Ratones Transgénicos , Ratones Endogámicos C57BL , Masculino , Lipopolisacáridos , Humanos , MitofagiaRESUMEN
Electrocatalytic reactions taking place at the electrified electrode-electrolyte interface involve processes of proton-coupled electron transfer. Interfacial protons are delivered to the electrode surface via a H2O-dominated hydrogen-bond network. Less efforts are made to regulate the interfacial proton transfer from the perspective of interfacial hydrogen-bond network. Here, we present quaternary ammonium salt cationic surfactants as electrolyte additives for enhancing the H2O2 selectivity of the oxygen reduction reaction (ORR). Through in situ vibrational spectroscopy and molecular dynamics calculation, it is revealed that the surfactants are irreversibly adsorbed on the electrode surface in response to a given bias potential range, leading to the weakening of the interfacial hydrogen-bond network. This decreases interfacial proton transfer kinetics, particularly at high bias potentials, thus suppressing the 4-electron ORR pathway and achieving a highly selective 2-electron pathway toward H2O2. These results highlight the opportunity for steering H2O-involved electrochemical reactions via modulating the interfacial hydrogen-bond network.
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Müllerian mimicry provides natural replicates ideal for exploring mechanisms underlying adaptive phenotypic divergence and convergence, yet the genetic mechanisms underlying mimetic variation remain largely unknown. The current study investigates the genetic basis of mimetic color pattern variation in a highly polymorphic bumble bee, Bombus breviceps (Hymenoptera, Apidae). In South Asia, this species and multiple comimetic species converge onto local Müllerian mimicry patterns by shifting the abdominal setal color from orange to black. Genetic crossing between the orange and black phenotypes suggested the color dimorphism being controlled by a single Mendelian locus, with the orange allele being dominant over black. Genome-wide association suggests that a locus at the intergenic region between 2 abdominal fate-determining Hox genes, abd-A and Abd-B, is associated with the color change. This locus is therefore in the same intergenic region but not the same exact locus as found to drive red black midabdominal variation in a distantly related bumble bee species, Bombus melanopygus. Gene expression analysis and RNA interferences suggest that differential expression of an intergenic long noncoding RNA between abd-A and Abd-B at the onset setal color differentiation may drive the orange black color variation by causing a homeotic shift late in development. Analysis of this same color locus in comimetic species reveals no sequence association with the same color shift, suggesting that mimetic convergence is achieved through distinct genetic routes. Our study establishes Hox regions as genomic hotspots for color pattern evolution in bumble bees and demonstrates how pleiotropic developmental loci can drive adaptive radiations in nature.
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Mimetismo Biológico , Estudio de Asociación del Genoma Completo , Abejas/genética , Animales , Fenotipo , Mimetismo Biológico/genética , Edición Génica , ADN Intergénico/genéticaRESUMEN
Programmable A > I RNA editing is a valuable tool for basic research and medicine. A variety of editors have been created, but a genetically encoded editor that is both precise and efficient has not been described to date. The trade-off between precision and efficiency is exemplified in the state of the art editor REPAIR, which comprises the ADAR2 deaminase domain fused to dCas13b. REPAIR is highly efficient, but also causes significant off-target effects. Mutations that weaken the deaminase domain can minimize the undesirable effects, but this comes at the expense of on-target editing efficiency. We have now overcome this dilemma by using a multipronged approach: We have chosen an alternative Cas protein (CasRx), inserted the deaminase domain into the middle of CasRx, and redirected the editor to the nucleus. The new editor created, dubbed REPAIRx, is precise yet highly efficient, outperforming various previous versions on both mRNA and nuclear RNA targets. Thus, REPAIRx markedly expands the RNA editing toolkit and illustrates a novel strategy for base editor optimization.
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Edición Génica/métodos , Edición de ARN , ARN/metabolismo , Adenosina Desaminasa/genética , Células HEK293 , Humanos , Mutación , Proteínas de Unión al ARN/genética , TranscriptomaRESUMEN
Uranyl ions (UO22+) are recognized as important indicators for monitoring sudden nuclear accidents. However, the interferences coexisting in the complicated environmental matrices impart serious constraints on the reliability of current on-site monitoring methods. Herein, a novel ratiometric method for the highly sensitive and selective detection of UO22+ is reported based on a [Eu(diaminoterephthalic acid)] (Eu-DATP) metal-organic framework. Benefiting from the unique chemical structure of Eu-DATP, energy transfer from DATP to UO22+ was enabled, resulting in the up-regulated fluorescence of UO22+ and the simultaneous down-regulated fluorescence of Eu3+. The limit of detection reached as low as 2.7 nM, which was almost 2 orders of magnitude below the restricted limit in drinking water set by the United States Environmental Protection Agency (130 nM). The Eu-DATP probe showed excellent specificity to UO22+ over numerous interfering species, as the intrinsic emissions of UO22+ were triggered. This unprecedentedly high selectivity is especially beneficial for monitoring UO22+ in complicated environmental matrices with no need for tedious sample pretreatment, such as filtration and digestion. Then, by facilely equipping a Eu-DATP-based sampler on a drone, remotely controlled sampling and on-site analysis in real water samples were realized. The concentrations of UO22+ were determined to be from 16.5 to 23.5 nM in the river water of the Guangzhou downtown area, which was consistent with the results determined by the gold-standard inductively coupled plasma mass spectrometry. This study presents a reliable and convenient method for the on-site analysis of UO22+.
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While designing anisotropic noble metal nanoparticles (NPs) can enhance the signal intensity of Raman dyes, more sensitive surface-enhanced Raman scattering (SERS) probes can be designed by oriented self-assembly of noble metal nanomaterials into dimers or higher-order nanoclusters. In this study, we engineered a self-assembly strategy in living cells for real-time fluorescence and SERS dual-channel detection of intracellular microRNAs (miRNAs), using Mg2+-dependent 8-17E DNAzyme sequences as the driving motors, gold nanocubes (AuNCs) as the driver components, and three-branched double-stranded DNA as the linking tool. The assembly selects adenine in DNA as a reporter molecule, simplifying the labeling process of Raman reporter molecules and reducing the synthesis process. In addition, adenine is stably distributed between the faces of AuNCs and the wide hotspot region gives good reproducibility of the adenine SERS signal. In this strategy, the SERS channel was consistently stable and more sensitive compared to the fluorescence channel. Among them, the detection limit of the SERS channel was 2.1 pM and the coefficient of variation was 1.26% in the in vitro liquid phase and 1.49% in MCF-7 cells. The strategy successfully achieved accurate tracking and quantification of miRNA-21 in cancer cells, showing good reproducibility in complex samples as well as cells. The reported strategy provides ideas for exploring intracellular specific triggering of nanoparticles for precise control of self-assembly.
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Oro , Nanopartículas del Metal , MicroARNs , Espectrometría Raman , Oro/química , MicroARNs/análisis , Humanos , Nanopartículas del Metal/química , Células MCF-7 , Fluorescencia , Propiedades de SuperficieRESUMEN
Rapid biodiversity losses under global climate change threaten forest ecosystem functions. However, our understanding of the patterns and drivers of multiple ecosystem functions across biodiversity gradients remains equivocal. To address this important knowledge gap, we measured simultaneous responses of multiple ecosystem functions (nutrient cycling, soil carbon stocks, organic matter decomposition, plant productivity) to a tree species richness gradient of 1, 4, 8, 16, and 32 species in a young subtropical forest. We found that tree species richness had negligible effects on nutrient cycling, organic matter decomposition, and plant productivity, but soil carbon stocks and ecosystem multifunctionality significantly increased with tree species richness. Linear mixed-effect models showed that soil organisms, particularly arbuscular mycorrhizal fungi (AMF) and soil nematodes, elicited the greatest relative effects on ecosystem multifunctionality. Structural equation models revealed indirect effects of tree species richness on ecosystem multifunctionality mediated by trophic interactions in soil micro-food webs. Specifically, we found a significant negative effect of gram-positive bacteria on soil nematode abundance (a top-down effect), and a significant positive effect of AMF biomass on soil nematode abundance (a bottom-up effect). Overall, our study emphasizes the significance of a multitrophic perspective in elucidating biodiversity-multifunctionality relationships and highlights the conservation of functioning soil micro-food webs to maintain multiple ecosystem functions.
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Ecosistema , Micorrizas , Cadena Alimentaria , Árboles , Suelo/química , Biodiversidad , Plantas , CarbonoRESUMEN
Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver. As the global obesity rate rises, non-alcoholic fatty liver disease (NAFLD) has emerged as the most rapidly increasing cause of HCC. Consequently, the regulation of lipid metabolism has become a crucial target for the prevention and treatment of HCC. Liquidambaric acid (LDA), a pentacyclic triterpenoid compound derived from various plants, exhibits diverse biological activities. We found that LDA could inhibit HCC cell proliferation by arresting cell cycle and prompting apoptosis. Additionally, LDA can augment the therapeutic efficacy of Regorafenib in HCC in vitro and vivo. Our study utilized transcriptome analysis, luciferase reporter assays, and co-immunocoprecipitation experiments to elucidate the anti-HCC mechanism of LDA. We discovered that LDA disrupts the formation of the PPARα-RXRα heterodimer, leading to the down-regulation of the ACSL4 gene and subsequently impacting the fatty acid metabolism of HCC cells, ultimately inhibiting HCC proliferation. Our research contributes to the identification of novel therapeutic agents and targets for the treatment of HCC.
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Carcinoma Hepatocelular , Proliferación Celular , Coenzima A Ligasas , Regulación hacia Abajo , Ácidos Grasos , Neoplasias Hepáticas , PPAR alfa , Receptor alfa X Retinoide , PPAR alfa/metabolismo , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Receptor alfa X Retinoide/metabolismo , Receptor alfa X Retinoide/genética , Animales , Ácidos Grasos/metabolismo , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Células Hep G2 , Ratones Desnudos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Ratones , Compuestos de Fenilurea/farmacología , Masculino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones Endogámicos BALB C , Metabolismo de los Lípidos/efectos de los fármacos , PiridinasRESUMEN
BACKGROUND: The association of hepatitis B virus (HBV) DNA levels and liver fibrosis in chronic hepatitis B (CHB) patients with immune-tolerant phase remains unclear. We explored the association between liver fibrosis and HBV DNA levels in HBeAg-positive CHB patients with normal alanine transaminase (ALT) with relatively high HBV DNA. METHODS: Six hundred and twenty-two HBeAg-positive CHB patients with normal ALT were included. Patients were divided into three categories: low (6 log10 IU/mL ≤ HBV DNA < 7 log10 IU/mL), moderate (7 log10 IU/mL ≤ HBV DNA < 8 log10 IU/mL), and high (HBV DNA ≥ 8 log10 IU/mL). APRI, FIB-4, transient elastography, or liver biopsy were used to assess liver fibrosis. RESULTS: The median age of patients was 33.0 years and 57.9% patients were male. 18.8%, 52.1%, and 29.1% of patients had low, moderate, and high HBV DNA levels, respectively. The APRI (0.33 vs. 0.26 vs. 0.26, P < 0.001), FIB-4 (1.03 vs. 0.71 vs. 0.68, P < 0.001), and LSM values (7.6 kPa vs. 5.6 kPa vs. 5.5 kPa, P = 0.086) were higher in low HBV DNA group than other two groups. Low HBV DNA group had higher proportions of significant fibrosis (24.8% vs. 9.9% vs. 3.3%, P < 0.001) and cirrhosis (7.7% vs. 2.5% vs. 1.1%, P = 0.004) than moderate and high HBV DNA groups. Moderate (OR 3.095, P = 0.023) and low (OR 4.968, P = 0.003) HBV DNA were independent risk factors of significant fibrosis. CONCLUSION: Lower HBV DNA level was associated with more severe liver fibrosis in HBeAg-positive CHB patients with ALT.
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Alanina Transaminasa , ADN Viral , Antígenos e de la Hepatitis B , Virus de la Hepatitis B , Hepatitis B Crónica , Cirrosis Hepática , Humanos , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/virología , Hepatitis B Crónica/patología , Hepatitis B Crónica/sangre , Masculino , Femenino , Adulto , Cirrosis Hepática/virología , Cirrosis Hepática/sangre , Cirrosis Hepática/patología , ADN Viral/sangre , Alanina Transaminasa/sangre , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Persona de Mediana Edad , Carga Viral , Adulto Joven , Hígado/patología , Hígado/virología , BiopsiaRESUMEN
Microplastics can be ingested by a wide range of aquatic animals. Extensive studies have demonstrated that microplastic ingestion-albeit often not lethal-can affect a range of species life-history traits. However, it remains unclear how the sublethal effects of microplastics on individual levels scale up to influence ecosystem-level dynamics through cascading trophic interactions. Here we employ a well-studied, empirically fed three-species trophic chain model, which was parameterized to mimic a common type of aquatic ecosystems to examine how microplastic ingestion by fish on an intermediate trophic level can produce cascading effects on the species at both upper and lower trophic levels. We show that gradually increasing microplastics in the ingested substances of planktivorous fish may cause population structure effects such as skewed size distributions (i.e. reduced average body length vs. increased maximal body size), and induce abrupt declines in fish biomass and reproduction. Our model analysis demonstrates that these abrupt changes correspond to an ecosystem-level tipping point, crossing which difficult-to-reverse ecosystem degradation can happen. Importantly, microplastic pollution may interact with other anthropogenic stressors to reduce safe operating space of aquatic ecosystems. Our work contributes to better understanding complex effects of microplastic pollution and anticipating tipping points of aquatic ecosystems in a changing world. It also calls attention to an emerging threat that novel microplastic contaminants may lead to unexpected and abrupt degradation of aquatic ecosystems, and invites systematic studies on the ecosystem-level consequences of microplastic exposure.
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Microplásticos , Contaminantes Químicos del Agua , Animales , Ecosistema , Plásticos/efectos adversos , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/análisis , Monitoreo del Ambiente , Peces , Ingestión de AlimentosRESUMEN
BACKGROUND AND AIM: Triggering receptor expressed on myeloid cells 2 (TREM2) plays crucial roles in metabolic homeostasis and inflammatory response. Altered metabolic function in macrophages could modulate their activation and immune phenotype. The present study aimed to investigate the expression of TREM2 in non-alcoholic fatty liver disease (NAFLD) and to clarify the underlying mechanism of TREM2 on macrophages lipid metabolism and oxidative stress. METHODS: Hepatic TREM2 expression and its relationship with NAFLD progression were analyzed in patients with NAFLD and mice fed a high-fat diet. Lipid metabolism and oxidative stress were investigated in macrophages from NAFLD mice or stimulated with saturated fatty acids. Knockdown and overexpression of TREM2 were further explored. RESULTS: Triggering receptor expressed on myeloid cells 2+ macrophages were increased along with NAFLD development, characterized by aggravated steatosis and liver damage in humans and mice. TREM2 expression was upregulated and lipid metabolism was changed in macrophages from NAFLD mice or metabolically activated by saturated fatty acid in vitro, as demonstrated by increased lipid uptake and catabolism, but reduced de novo synthesis of fatty acids (FAs). Regulation of TREM2 expression in lipid-laden macrophages reprogrammed lipid metabolism, especially the fatty acid oxidation capacity of mitochondria. TREM2 knockdown promoted oxidative stress by aggravating FAs deposition in mitochondria. Intervention of mitochondrial FAs transport in lipid-laden macrophages alleviated FA deposition and reactive oxygen species production induced by TREM2 knockdown. CONCLUSIONS: Triggering receptor expressed on myeloid cells 2 expression was associated with the lipid metabolic profile and reactive oxygen species production in macrophages. High expression of TREM2 in macrophages may protect the liver from oxidative stress in NAFLD.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Ratones , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos , Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Células Mieloides/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: The shift work schedule is a common work arrangement that can disrupt typical sleep-wake rhythms and lead to negative health consequences. The present study aims to examine the effect of shift work on health-related quality of life (QoL) and explore potential behaviorial mediators (i.e., sleep, eating, exercise, smoking, drinking). METHODS: A cross-sectional survey was conducted among 4,449 petroleum workers in southwest China. Data on shift work status, health behaviors, and physical and mental health QoL were collected. We tested our model using path analysis and the Monte Carlo approach among 2,129 included participants. RESULTS: After adjusting for covariates, shift work did not exhibit a significant direct association with QoL. However, shift work indirectly related to poorer physical health quality of life via less frequent healthy food consumption; shift work also indirectly related to poorer mental health QoL via both less frequent healthy food consumption and physical exercise. No significant indirect effects were found via sleeping, smoking, or drinking. CONCLUSIONS: Results suggest that shift work presents a challenge for QoL among Chinese petroleum workers due to their lesser engagement in two specific health behaviors: healthy eating and physical exercise. Healthy eating and exercise may present an even more prominent threat to shift workers' QoL than sleep and substance use. Strategies targeting shift work schedule as well as eating and exercise behaviors may help protect against poor QoL and adverse physical and mental health outcomes in this vulnerable group.
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Ejercicio Físico , Conductas Relacionadas con la Salud , Calidad de Vida , Horario de Trabajo por Turnos , Humanos , Calidad de Vida/psicología , Masculino , Femenino , Estudios Transversales , Adulto , China , Persona de Mediana Edad , Horario de Trabajo por Turnos/psicología , Horario de Trabajo por Turnos/efectos adversos , Ejercicio Físico/psicología , Encuestas y Cuestionarios , Sueño , Petróleo , Tolerancia al Trabajo Programado/psicologíaRESUMEN
The aberrant activation of NLRP3 inflammasome has been observed in various human diseases. Targeting the NLRP3 protein with small molecule inhibitors shows immense potential as an effective strategy for disease intervention. Herein, a series of novel biphenyl-sulfonamide NLRP3 inflammasome inhibitors were designed and synthesized. The representative compound H28 was identified as potent and specific NLRP3 inflammasome inhibitor with IC50 values of 0.57 µM. Preliminary mechanistic studies have revealed that compound H28 exhibits direct binding to the NLRP3 protein (KD: 1.15 µM), effectively inhibiting the assembly and activation of the NLRP3 inflammasome. The results in a mouse acute peritonitis model revealed that H28 effectively inhibit the NLRP3 inflammasome pathway, demonstrating their anti-inflammatory properties. Our findings strongly support the further development of H28 as potential lead compound for treating NLRP3-related diseases.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Ratones , Animales , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Compuestos de Bifenilo , Sulfonamidas/farmacología , Sulfanilamida , Ratones Endogámicos C57BLRESUMEN
Background: The single nucleotide polymorphism (SNP) of Gastrokine-1 (GKN1) is associated with lung cancer but its association with prognosis is not clear. Methods: Genomic DNA was extracted from the blood samples of 888 patients with lung cancer. The association between GKN1 polymorphism rs4254535 and prognostic was analyzed by the Kaplan-Meier (KM) method, Log-rank test, and Cox proportional hazards model. Results: In females and patients diagnosed with late-stage lung cancer, the CC genotype (CC vs TT, adjusted odds ratio [HR] = 0.57, 95% Confidence Interval [CI]: 0.33-0.99, P = 0.045; HR = 0.66, 95% CI: 0.48-0.92, P = 0.014) and recessive CC genotype (CC vs TT + TC, HR = 0.55, 95% CI: 0.32-0.94, P = 0.028; HR = 0.64, 95% CI: 0.47-0.89, P = 0.006) of rs4254535 conferred a better prognosis, compared with the TT and TT + TC genotype. Rs4254535 dominate TC + CC genotype, recessive CC genotype, and C allele who were adenocarcinoma patients had a significantly better prognosis. The recessive CC genotype of non-smoking patients has a better prognosis, compared to the TT + TC genotype. Additionally, in the dominant TT + TC genotype and C allele, no family history patients had a significantly better prognosis, compared to the TT genotype. Conclusion: For lung cancer patients, GKN1 polymorphism rs4254535 may be a protective genetic marker and predicts the prognosis of lung cancer patients.
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Neoplasias Pulmonares , Hormonas Peptídicas , Femenino , Humanos , Pronóstico , Neoplasias Pulmonares/genética , Genotipo , Polimorfismo de Nucleótido Simple/genética , ChinaRESUMEN
BACKGROUND: Seoul virus (SEOV) is a significant causative pathogen of hemorrhagic fever with renal syndrome (HFRS). Accurate discrimination of SEOV infection from other viral or bacterial infections holds vital clinical importance. METHODS: Our study utilized quantitative real-time PCR (qRT-PCR), metagenomic next-generation sequencing (mNGS), and immunological assays to identify the pathogen causing HFRS. RESULTS: For the case, mNGS identified SEOV and suspected host or environmental microorganisms at 5 days from symptom onset. qRT-PCR detected SEOV between 5 to 8 days from symptom onset. Anti-hantavirus IgM antibodies reached positive criteria at 7 days and IgG antibodies at 9 days from symptom onset. CONCLUSIONS: qRT-PCR, mNGS, and immunological assays each have merits and drawbacks. Optimal selection depends on laboratory conditions and clinical requirements.
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Fiebre Hemorrágica con Síndrome Renal , Virus Seoul , Humanos , Virus Seoul/genética , Fiebre Hemorrágica con Síndrome Renal/diagnóstico , Anticuerpos Antivirales , Inmunoglobulina GRESUMEN
BACKGROUND: Normal hemoglobin is a tetrameric structure, consisting of two alpha-globin chains and two nonalpha (beta, gamma, delta) chains. Hemoglobinopathies occur when the presence of gene mutations affect the molecular structure or expression of the globin chains. METHODS: We reported the case of a 9-year-old Chinese girl who presented with abnormal low oxygen saturation values on pulse oximetry and no oximetry results were obtained during blood gas analysis (BGA). RESULTS: High-performance liquid chromatography (HPLC) and capillary electrophoresis demonstrated that the presence of a low oxygen affinity hemoglobin variant, characterized as hemoglobin Titusville, was proven by gene sequencing. The patient's mother and aunt also carry the hemoglobin variant, representing the first Chinese family case reported. CONCLUSIONS: Hemoglobin Titusville is a rare genetic hemoglobin structural defect. early diagnosis can help patients and clinicians avoid unnecessary anxiety and costly or excessive clinical investigations.