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BACKGROUND: Identifying patients at risk of ventilator-associated pneumonia through prediction models can facilitate medical decision-making. Our objective was to evaluate the current models for ventilator-associated pneumonia in patients with mechanical ventilation. METHODS: Nine databases systematically retrieved from establishment to March 6, 2024. Two independent reviewers performed study selection, data extraction, and quality assessment, respectively. The Prediction Model Risk of Bias Assessment Tool was used to evaluate the risk of model bias and applicability. Stata 17.0 was used to conduct a meta-analysis of discrimination of model validation. RESULTS: The total of 34 studies were included, with reported 52 prediction models. The most frequent predictors in the models were mechanical ventilation duration, length of intensive care unit stay, and age. Each study was essentially considered having a high risk of bias. A meta-analysis of 17 studies containing 33 models with validation was performed with a pooled area under the receiver-operating curve of 0.80 (95% confidence interval: 0.78-0.83). CONCLUSIONS: Despite the relatively excellent performance of the models, there is a high risk of bias of the model development process. Enhancing the methodological quality, especially the external validation, practical application, and optimization of the models need urgent attention.
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Microbes strongly affect invasive plant growth. However, how phyllosphere and rhizosphere soil microbes distinctively affect seedling mortality and growth of invaders across ontogeny under varying soil nutrient levels remains unclear. In this study, we used the invader Ageratina adenophora to evaluate these effects. We found that higher proportions of potential pathogens were detected in core microbial taxa in leaf litter than rhizosphere soil and thus leaf inoculation had more adverse effects on seed germination and seedling survival than soil inoculation. Microbial inoculation at different growth stages altered the microbial community and functions of seedlings, and earlier inoculation had a more adverse effect on seedling survival and growth. The soil nutrient level did not affect microbe-mediated seedling growth and the relative abundance of the microbial community and functions involved in seedling growth. The effects of some microbial genera on seedling survival are distinct from those on growth. Moreover, the A. adenophora seedling-killing effects of fungal strains isolated from dead seedlings by non-sterile leaf inoculation exhibited significant phylogenetic signals, by which strains of Allophoma and Alternaria generally caused high seedling mortality. Our study stresses the essential role of A. adenophora litter microbes in population establishment by regulating seedling density and growth.
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Ageratina , Hojas de la Planta , Rizosfera , Plantones , Microbiología del Suelo , Ageratina/microbiología , Plantones/microbiología , Plantones/crecimiento & desarrollo , Hojas de la Planta/microbiología , Hojas de la Planta/crecimiento & desarrollo , Microbiota , Especies Introducidas , GerminaciónRESUMEN
Based on the close relationship between programmed death protein ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR) in glioblastoma (GBM), we designed and synthesized a series of small molecules as potential dual inhibitors of EGFR and PD-L1. Among them, compound EP26 exhibited the highest inhibitory activity against EGFR (IC50 = 37.5 nM) and PD-1/PD-L1 interaction (IC50 = 1.77 µM). In addition, EP26 displayed superior in vitro antiproliferative activities and in vitro immunomodulatory effects by promoting U87MG cell death in a U87MG/Jurkat cell coculture model. Furthermore, EP26 possessed favorable pharmacokinetic properties (F = 22%) and inhibited tumor growth (TGI = 92.0%) in a GBM mouse model more effectively than Gefitinib (77.2%) and NP19 (82.8%). Moreover, EP26 increased CD4+ cells and CD8+ cells in tumor microenvironment. Collectively, these results suggest that EP26 represents the first small-molecule-based PD-L1/EGFR dual inhibitor deserving further investigation as an immunomodulating agent for cancer treatment.
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Antineoplásicos , Antígeno B7-H1 , Receptores ErbB , Glioblastoma , Animales , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/síntesis química , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/química , Inhibidores de Puntos de Control Inmunológico/síntesis química , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacocinética , Inmunoterapia/métodos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Relación Estructura-ActividadRESUMEN
BACKGROUND: The recovery of upper limb function is of great significance for stroke patients to regain their self-care ability, yet it is still a difficult point in clinical practice of neurological rehabilitation. This study aimed to investigate the effect of Maitland joint mobilization technique on the recovery of upper extremity function in patients with spasticity after stroke. METHODS: From August to December 2023, 71 patients with upper extremity flexor spasm after stroke were recruited and randomly divided into experimental group (nâ =â 35) and control group (nâ =â 36). The control group was given conventional rehabilitation treatment, while the experimental group was treated with Maitland mobilization technique treatment of upper extremity joints on the basis of the control group. The experiment lasted for 8 weeks. Participants of the 2 groups were observed for Fugl-Meyer motor assessment-upper extremity (FMA-UE), box and block test (BBT) and Brunnstrom stage, modified Ashworth scale (MAS), and functional independence measure (FIM) at pre- and post-8 weeks study. RESULTS: There was no significant difference in gender distribution, hemiplegic side, diagnosis, past history, age, duration, body mass index, and mini-mental state examination between the 2 groups (Pâ >â .05). After 8 weeks of intervention, both groups showed significant improvement in FMA-UE, Brunnstrom stage, BBT, FIM, and MAS of the shoulder (Pâ <â .05); however, there was no significant change in MAS of the elbow, wrist, and finger joints (Pâ >â .05). The posttreatment values showed a significant improvement in FMA-UE, BBT, and FIM in the experimental group compared to the control group. Comparing the changes in pretreatment and posttreatment, FMA-UE, BBT, and FIM in the experimental group were significantly improved compared with those in the control group (Pâ <â .05). CONCLUSION: Maitland joint mobilization can improve the motor function of upper extremity and the spasticity of shoulder joint complex in patients with stroke.
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Espasticidad Muscular , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Extremidad Superior , Humanos , Femenino , Masculino , Persona de Mediana Edad , Espasticidad Muscular/etiología , Espasticidad Muscular/rehabilitación , Espasticidad Muscular/fisiopatología , Espasticidad Muscular/terapia , Extremidad Superior/fisiopatología , Rehabilitación de Accidente Cerebrovascular/métodos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/fisiopatología , Recuperación de la Función , Anciano , Resultado del Tratamiento , AdultoRESUMEN
Cell cycle regulation is critical to blood vessel formation and function, but how the endothelial cell cycle integrates with vascular regulation is not well-understood, and available dynamic cell cycle reporters do not precisely distinguish all cell cycle stage transitions in vivo. Here we characterized a recently developed improved cell cycle reporter (PIP-FUCCI) that precisely delineates S phase and the S/G2 transition. Live image analysis of primary endothelial cells revealed predicted temporal changes and well-defined stage transitions. A new inducible mouse cell cycle reporter allele was selectively expressed in postnatal retinal endothelial cells upon Cre-mediated activation and predicted endothelial cell cycle status. We developed a semi-automated zonation program to define endothelial cell cycle status in spatially defined and developmentally distinct retinal areas and found predicted cell cycle stage differences in arteries, veins, and remodeled and angiogenic capillaries. Surprisingly, the predicted dearth of S-phase proliferative tip cells relative to stalk cells at the vascular front was accompanied by an unexpected enrichment for endothelial tip and stalk cells in G2, suggesting G2 stalling as a contribution to tip-cell arrest and dynamics at the front. Thus, this improved reporter precisely defines endothelial cell cycle status in vivo and reveals novel G2 regulation that may contribute to unique aspects of blood vessel network expansion.
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BACKGROUND: Endothelial cells regulate their cell cycle as blood vessels remodel and transition to quiescence downstream of blood flow-induced mechanotransduction. Laminar blood flow leads to quiescence, but how flow-mediated quiescence is established and maintained is poorly understood. METHODS: Primary human endothelial cells were exposed to laminar flow regimens and gene expression manipulations, and quiescence depth was analyzed via time-to-cell cycle reentry after flow cessation. Mouse and zebrafish endothelial expression patterns were examined via scRNA-seq (single-cell RNA sequencing) analysis, and mutant or morphant fish lacking p27 were analyzed for endothelial cell cycle regulation and in vivo cellular behaviors. RESULTS: Arterial flow-exposed endothelial cells had a distinct transcriptome, and they first entered a deep quiescence, then transitioned to shallow quiescence under homeostatic maintenance conditions. In contrast, venous flow-exposed endothelial cells entered deep quiescence early that did not change with homeostasis. The cell cycle inhibitor p27 (CDKN1B) was required to establish endothelial flow-mediated quiescence, and expression levels positively correlated with quiescence depth. p27 loss in vivo led to endothelial cell cycle upregulation and ectopic sprouting, consistent with loss of quiescence. HES1 and ID3, transcriptional repressors of p27 upregulated by arterial flow, were required for quiescence depth changes and the reduced p27 levels associated with shallow quiescence. CONCLUSIONS: Endothelial cell flow-mediated quiescence has unique properties and temporal regulation of quiescence depth that depends on the flow stimulus. These findings are consistent with a model whereby flow-mediated endothelial cell quiescence depth is temporally regulated downstream of p27 transcriptional regulation by HES1 and ID3. The findings are important in understanding endothelial cell quiescence misregulation that leads to vascular dysfunction and disease.
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Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Células Endoteliales , Pez Cebra , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Animales , Humanos , Células Endoteliales/metabolismo , Mecanotransducción Celular , Proteínas Inhibidoras de la Diferenciación/metabolismo , Proteínas Inhibidoras de la Diferenciación/genética , Ciclo Celular , Ratones , Células Cultivadas , Factores de Tiempo , Flujo Sanguíneo Regional , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proliferación Celular , Proteínas de NeoplasiasRESUMEN
Bacillus paranthracis, a Gram-positive conditional pathogen of Bacillus cereus group species, is capable of causing foodborne and waterborne illnesses, leading to intestinal diseases in humans characterized by diarrhoea and vomiting. However, documented cases of B. paranthracis infection outbreaks are rare in the world, and the genomic background of outbreak strains is seldom characterized. This study retrospectively analyzed strains obtained from an outbreak in schools, as well as from water systems in peri-urban areas, China, in 2020. In total, 28 B. cereus group isolates were retrieved, comprising 6 from stool samples and 22 from water samples. Epidemiological and phylogenetic investigations indicated that the B. paranthracis isolate from drinking water as the causative agent of the outbreak. The genomic comparison revealed a high degree of consistency among 8 outbreak-related strains in terms of antimicrobial resistance gene profiles, virulence gene profiles, genomic content, and multilocus sequence typing (MLST). The strains related to the outbreak show highly similar genomic ring diagrams and close phylogenetic relationships. Additionally, this study shed light on the pathogenic potential and complexity of B. cereus group through its diversity in virulence genes and mice infection model. The findings highlight the usefulness of B. paranthracis genomes in understanding genetic diversity within specific environments and in tracing the source of pathogens during outbreak situations, thereby enabling targeted infection control interventions.
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Brotes de Enfermedades , Genoma Bacteriano , Filogenia , China/epidemiología , Animales , Humanos , Ratones , Virulencia , Estudios Retrospectivos , Infecciones por Bacterias Grampositivas/epidemiología , Infecciones por Bacterias Grampositivas/microbiología , Bacillus/genética , Bacillus/aislamiento & purificación , Bacillus/clasificación , Bacillus/patogenicidad , Tipificación de Secuencias Multilocus , Enfermedades Transmitidas por el Agua/epidemiología , Enfermedades Transmitidas por el Agua/microbiología , Masculino , Factores de Virulencia/genética , Bacillus cereus/genética , Bacillus cereus/aislamiento & purificación , Bacillus cereus/patogenicidad , Bacillus cereus/clasificación , Femenino , Genómica , Microbiología del AguaRESUMEN
Cell cycle regulation is critical to blood vessel formation and function, but how the endothelial cell cycle integrates with vascular regulation is not well-understood, and available dynamic cell cycle reporters do not precisely distinguish all cell cycle stage transitions in vivo. Here we characterized a recently developed improved cell cycle reporter (PIP-FUCCI) that precisely delineates S phase and the S/G2 transition. Live image analysis of primary endothelial cells revealed predicted temporal changes and well-defined stage transitions. A new inducible mouse cell cycle reporter allele was selectively expressed in postnatal retinal endothelial cells upon Cre-mediated activation and predicted endothelial cell cycle status. We developed a semi-automated zonation program to define endothelial cell cycle status in spatially defined and developmentally distinct retinal areas and found predicted cell cycle stage differences in arteries, veins, and remodeled and angiogenic capillaries. Surprisingly, the predicted dearth of proliferative tip cells at the vascular front was accompanied by an unexpected enrichment for endothelial tip cells in G2, suggesting G2 stalling as a contribution to tip-cell arrest. Thus, this improved reporter precisely defines endothelial cell cycle status in vivo and reveals novel G2 regulation that may contribute to unique aspects of blood vessel network expansion.
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Aging is an important processing step of producing high quality apple brandy. In this study, apple brandies aged by traditional method and using three different toasted oak chips combined with or without ultra-high-pressure (UHP) treatment were prepared to compare their differences in chemical characterization and sensory properties. The results indicated that the brandies aged with toasted oak chip increased the levels of total acidity, volatile acidity and phenolic compounds. It also had the desirable color and taste. The brandy aged with toasted oak chip combined with UHP reached the highest levels of total acidity (1.06 g/L), total phenolic content (284.92 mg/L) and aromatic esters (49.37 %). Therefore, the aging with high toasted oak chip combined with UHP treatment could cut the traditional aging time to meet the same quality as traditional aging method. The results are very useful to develop a fast and efficient aging technique for brandy production.
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Malus , Quercus , Vino , Malus/química , Vino/análisis , Quercus/química , Madera/química , Bebidas Alcohólicas/análisis , Fenoles/análisisRESUMEN
Background: Endothelial cells regulate their cell cycle as blood vessels remodel and transition to quiescence downstream of blood flow-induced mechanotransduction. Laminar blood flow leads to quiescence, but how flow-mediated quiescence is established and maintained is poorly understood. Methods: Primary human endothelial cells were exposed to laminar flow regimens and gene expression manipulations, and quiescence depth was analyzed via time to cell cycle re-entry after flow cessation. Mouse and zebrafish endothelial expression patterns were examined via scRNA seq analysis, and mutant or morphant fish lacking p27 were analyzed for endothelial cell cycle regulation and in vivo cellular behaviors. Results: Arterial flow-exposed endothelial cells had a distinct transcriptome, and they first entered a deep quiescence, then transitioned to shallow quiescence under homeostatic maintenance conditions. In contrast, venous-flow exposed endothelial cells entered deep quiescence early that did not change with homeostasis. The cell cycle inhibitor p27 (CDKN1B) was required to establish endothelial flow-mediated quiescence, and expression levels positively correlated with quiescence depth. p27 loss in vivo led to endothelial cell cycle upregulation and ectopic sprouting, consistent with loss of quiescence. HES1 and ID3, transcriptional repressors of p27 upregulated by arterial flow, were required for quiescence depth changes and the reduced p27 levels associated with shallow quiescence. Conclusions: Endothelial cell flow-mediated quiescence has unique properties and temporal regulation of quiescence depth that depends on the flow stimulus. These findings are consistent with a model whereby flow-mediated endothelial cell quiescence depth is temporally regulated downstream of p27 transcriptional regulation by HES1 and ID3. The findings are important in understanding endothelial cell quiescence mis-regulation that leads to vascular dysfunction and disease.
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Selenium (Se) can reduce uptake and translocation of cadmium (Cd) in plants via plenty of ways, including regulation of root morphology. However, the underlying mechanisms on how Se will regulate root morphology under metal(loid) stresses are not fully illustrated. To fill up this knowledge gap, we investigated the effects of 0.5 mg L-1 selenite (Se(IV)) on root exudates, root morphology, root endogenous hormones, and Cd uptake efficiency of rice under the 1 mg L-1 Cd stress condition. The results showed that Se(IV) significantly reduced shoot and root Cd concentrations, and decreased Cd uptake efficiency via root hairs determined by a non-invasive micro-test (NMT) technology. When compared to the 1 mg L-1 Cd (Cd1) treatment, addition of 0.5 mg L-1 Se(IV) (1) significantly reduced root surface area and tip numbers, and non-significantly reduced root length, but significantly enhanced root diameter and root volume; (2) significantly enhanced concentrations of tartaric acid in the root exudate solution, root auxin (IAA) and root jasmonic acid (JA) via a UHPLC or a HPLC analysis; (3) significantly up-regulated metabolites correlated with synthesis of IAA, JA, gibberellin (GA), and salicylic acid, such as GA53, M-SA, (+/-)7-epi-JA, and derivatives of tryptophan and indole in the metabolome analysis. However, results of transcriptome analysis showed that (1) no upregulated differentially expressed genes (DEGs) were enriched in IAA synthesis; (2) some upregulated DEGs were found to be enriched in JA and GA53 synthesis pathways. In summary, although Se(IV) stimulated the synthesis of IAA, JA, and GA53, it significantly inhibited root growth mainly by 1) affecting signal transduction of IAA and GA; 2) altering IAA polar transport and homeostasis; and 3) regulating DEGs including SAUR32, SAUR36, SAUR76, OsSub33, OsEXPA8, OsEXPA18, and Os6bglu24.
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Cadmio , Reguladores del Crecimiento de las Plantas , Tartratos , Reguladores del Crecimiento de las Plantas/farmacología , Reguladores del Crecimiento de las Plantas/metabolismo , Cadmio/metabolismo , Ácido Selenioso/farmacología , Ácido Selenioso/metabolismo , Transcriptoma , Raíces de Plantas/metabolismo , Transducción de Señal , MetabolomaRESUMEN
BMP signaling is crucial to blood vessel formation and function, but how pathway components regulate vascular development is not well-understood. Here, we find that inhibitory SMAD6 functions in endothelial cells to negatively regulate ALK1-mediated responses, and it is required to prevent vessel dysmorphogenesis and hemorrhage in the embryonic liver vasculature. Reduced Alk1 gene dosage rescued embryonic hepatic hemorrhage and microvascular capillarization induced by Smad6 deletion in endothelial cells in vivo. At the cellular level, co-depletion of Smad6 and Alk1 rescued the destabilized junctions and impaired barrier function of endothelial cells depleted for SMAD6 alone. Mechanistically, blockade of actomyosin contractility or increased PI3K signaling rescued endothelial junction defects induced by SMAD6 loss. Thus, SMAD6 normally modulates ALK1 function in endothelial cells to regulate PI3K signaling and contractility, and SMAD6 loss increases signaling through ALK1 that disrupts endothelial cell junctions. ALK1 loss-of-function also disrupts vascular development and function, indicating that balanced ALK1 signaling is crucial for proper vascular development and identifying ALK1 as a 'Goldilocks' pathway in vascular biology that requires a certain signaling amplitude, regulated by SMAD6, to function properly.
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Uniones Adherentes , Células Endoteliales , Humanos , Uniones Adherentes/metabolismo , Células Endoteliales/metabolismo , Hemorragia/metabolismo , Hígado/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína smad6/metabolismoRESUMEN
Purpose: Positive interpersonal interactions are indispensable for employees to engage in organizational citizenship behavior (OCB) that benefits teamwork; however, co-worker ostracism triggers interpersonal isolation, inhibiting OCB. This research aims to leverage the intervention of ethical leadership in the ostracism-OCB relationship to moderate the harmful ostracism and promote ostracized employees' OCB through employee self-identity. Methods: This research chose 122 MBA to participate in Study 1's scenario experiment to verify the causality between variables. Study 2 used 295 valid questionnaires from full-time employees to generalize the experimental results to field settings and compensate for external validity. Two studies used Hayes's conditional process model to test the conditional direct and indirect relationships. Findings: This research revealed that high levels of ethical leadership effectively transitioned the harmful ostracism and promoted ostracized employees' OCB by satisfying ostracized employees' needs for identity recognition. Accordingly, the direct and indirect effects of co-worker ostracism on OCB through employee self-identity would be positive at high levels of ethical leadership, but negative at low levels. Originality: This research first introduces an identity perspective on ethical leadership in moderating the ostracism-OCB relationship. Based on the social identity theory of leadership, this research fills the gap in ostracism and OCB research calling for leadership interventions. It extends a novel insight into inspiring ostracized employees' participation in OCB through employee self-identity. Practical Implications: This research provides the managerial applications of ethical leadership for China organizations to reduce inadvertent inactions, accept employees' identities, and value interpersonal communication for effectively transitioning harmful ostracism.
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This study aims to determine whether CYP2C19 loss-of-function (LoF) variants were associated with long-term ischemic stroke risk in Chinese primary care patients treated with clopidogrel. Patients treated with clopidogrel were ascertained from Chinese electronic medical records linked with a biobank for a retrospective cohort study. Their medical information was examined for the period from January 2018 to December 2021. Two CYP2C19 major loss of function variants (*2:rs4244285 and *3: rs4986893) were genotyped. The clinical outcome was ischemic stroke event. Cox regression analysis was used to evaluate the association between the occurrence of ischemic stroke events and CYP2C19 LoF variants. Covariates included age, gender, body mass index, prior ischemic stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipoidemia, smoke status, aspirin use, proton-pump inhibitor use, and statin use. Of the 1,141 patients included in the clopidogrel therapy cohort, 61.9% carried at least one CYP2C19 LoF variant. During a median follow-up period of 12 months, 103 patients (9.0%) had an ischemic stroke. After adjusting for other risk factors, carriers of CYP2C19 LoF variants had significantly higher risk of ischemic stroke compared with non-carriers (hazard ratio: 1.64, 95% confidence interval: 1.06-2.53, P = 0.025). This pharmacogenetic study of clopidogrel provides novel insights into the association between the CYP2C19 LoF variant and long-term stroke risk. We established that there is still a need for CYP2C19 genotype-guided personalized antiplatelet therapy in those who have returned to the primary care setting for clopidogrel prescription.
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BACKGROUND: Mitochondrial dysfunction in kidney cells has been implicated in the pathogenesis of chronic kidney disease (CKD). Estimation of mitochondrial DNA copy number (mtDNA-CN) is considered a convenient method for representing mitochondrial function in large samples. However, no study has investigated the association between mtDNA-CN and CKD in older adults with the highest prevalence. The objective is to examine cross-sectional and prospective associations between mtDNA-CN values and CKD risk in older adults to determine whether mtDNA-CN represents a novel potential biomarker for the recognition of CKD risk. PATIENTS AND METHODS: In a Chinese community-based cohort of over 65-year-olds, we included 14,467 participants (52.6% females). CKD was defined by eGFR < 60 mL/min/1.73 m2 or ICD-10 codes (patients = 3831 (26.5%)). Participants had peripheral blood levels of mtDNA-CN calculated from probe intensities of the Axiom CAS Array. RESULTS: The risk of CKD prevalence decreased with mtDNA-CN per 1-SD increment, independent of established risk factors for older CKD (odds ratio [OR] per SD 0.90, 95% confidence interval [CI] 0.86, 0.93, P < 0.001), and has comparable strength of association with these established risk factors. Furthermore, the progression of kidney function was stratified according to the worsening of eGFR categories. The risk of kidney function progression to a more severe stage gradually decreased as the mtDNA-CN increased (P trend < 0.001). Non-CKD participants in the highest quartile of mtDNA-CN had a lower risk of developing CKD compared to the lowest quartile within 2 years of follow-up, reducing the risk of CKD by 36% (95% CI 0.42, 0.97; P = 0.037). CONCLUSIONS: Based on the analysis of the largest sample to date investigating the association between mtDNA-CN and CKD in older adults, higher levels of mtDNA-CN were found to be associated with a lower risk of CKD, suggesting that a reduced level of mtDNA-CN is a potential risk factor for CKD.
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ADN Mitocondrial , Insuficiencia Renal Crónica , Femenino , Humanos , Anciano , Masculino , ADN Mitocondrial/genética , Estudios Transversales , Variaciones en el Número de Copia de ADN/genética , Mitocondrias , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genéticaRESUMEN
Antibiotic abuse is the main reason for the drug resistance of pathogenic bacteria, posing a potential health risk. Antibiotic surveillance is critical for preventing antibiotic contamination. This study aimed to develop a sensitive and broad-spectrum whole-cell biosensor for tetracycline antibiotics (TCs) detection. Wild-type TCs-responsive biosensor was constructed by introducing a tetracycline operon into a sfGFP reporter plasmid. Using error-prone PCR, mutation libraries containing approximately 107 variants of the tetracycline repressor (TetR) gene were generated. The tigecycline-senstive mutants were isolated using high-throughput flow cytometric sorting. After 2 rounds of directed evolution, a mutant epS2-22 of TerR was isolated and assembled as a TCs biosensor. The epS2-22 biosensor was more sensitive and broad-spectrum than the wild-type biosensors. The detection limits of the epS2-22 biosensor for seven TCs were 4- to 62-fold lower than the wild-type biosensor (no response to tigecycline). Meanwhile, the epS2-22 biosensor had a shorter detection time and a stronger signal output than the wild type. In addition, the evolved epS2-22 biosensor showed excellent performance in detecting low traces of TCs in environmental water. These results suggest that directed evolution is a powerful tool for developing high-performance whole-cell biosensors, and the evolved epS2-22 biosensors have the potential for wider applications in real-world TCs detection.
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Antibacterianos , Tetraciclina , Tigeciclina , Tetraciclina/farmacología , Antibacterianos/farmacología , Movimiento Celular , Contaminación de Medicamentos , Factores de TranscripciónRESUMEN
Programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1) is one of the most promising immune checkpoints (ICs) in tumor immunology and has been actively pursued as a target for anticancer drug discovery. Based on our previous research in small molecule PD-1/PD-L1 modulators, we designed and synthesized a series of resorcinol biphenyl ether-bearing macrocyclic compounds and evaluated their anti-PD-1/PD-L1 activities. Among them, compound 8d exhibited the highest inhibitory activity against PD-1/PD-L1 interaction with IC50 of 259.7 nM in the homogenous time-resolved fluorescence (HTRF) assay. In addition, 8d displayed in vitro immunomodulatory effects by promoting HepG2 cell death in a HepG2/Jurkat cell co-culture model. Furthermore, 8d effectively inhibited tumor growth (TGI = 74.6% at 40 mg/kg) in a melanoma tumor model in mice without causing obvious toxicity. Moreover, 8d exhibited favorable pharmacokinetics [e.g. high stability, reasonable half-life, and good oral bioavailability (F = 21.5%)]. Finally, molecular modeling studies showed that 8d bound to PD-L1 with high affinity. These results suggest that 8d may serve as a starting point for further development of macrocyclic small molecule-based PD-1/PD-L1 inhibitors for cancer treatment.
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Antígeno B7-H1 , Neoplasias , Animales , Ratones , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Resorcinoles/farmacología , Resorcinoles/uso terapéutico , ÉteresRESUMEN
Aim: This study examined intronic gene variants for their association with metformin intolerance in a Chinese population, focusing on the plasma monoamine transporter (PMAT) cis-protein expression quantitative trait loci (cis-eQTL) variant rs3889348. Methods: We recruited Type 2 diabetes patients from two hospitals and identified 111 metformin-intolerant patients using a questionnaire, and selected 206 metformin-tolerant patients from 2180 Type 2 diabetes mellitus patients. Genetic testing revealed an association between adverse gastrointestinal (GI) effects and SLC22A1 and PMAT. Results: The single-nucleotide polymorphism rs3889348 is associated with metformin-induced adverse GI effects. Each additional copy of the G allele increases the score by 5.23 (95% CI: 1.82-8.64; p = 0.003). Patients taking more transporter inhibitors were more likely to respond to metformin-induced GI intolerance (p = 0.042). Conclusion: PMAT cis-eQTL rs3889348 was significantly associated with metformin-induced adverse GI effects.
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Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Metformina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Pueblos del Este de Asia/genética , Hipoglucemiantes/efectos adversos , Metformina/efectos adversos , Polimorfismo de Nucleótido Simple/genética , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/genéticaRESUMEN
Background: Overweight and obese older adults have a high risk for developing cardiovascular disease. Aerobic exercise is a valuable strategy to improve vascular health, but the effects of aerobic exercise on vascular endothelial function in obese and overweight older adults remain controversial. The purpose of this meta-analysis was to investigate the effects of aerobic exercise on vascular function in obese and overweight older adults with or without comorbidity. Methods: A systematic literature search for related studies published in English was conducted between January 1989 and October 30, 2022, in the PubMed, Embase, and Cochrane Library databases. A random effects model was chosen for meta-analysis, which calculated the effect sizes of control and intervention groups after exercise intervention using standardized mean differences (SMDs) corrected for Hedges' g bias and 95% confidence intervals (95% CIs). Results: Twenty-six studies containing 1418 participants were included in the study. After excluding three studies contributing to higher heterogeneity by sensitivity analysis, there are small effects of regular aerobic exercise on vascular function of obese and overweight older adults, including flow-mediated dilation (FMD) [SMD = 0.21, 95% CI (0.02, 0.41), z = 2.16, df = 19, I2 = 52.2%, P = 0.031] and pulse wave velocity (PWV) [SMD = -0.24, 95% CI (-0.46, -0.02), z = 2.17, df = 10, I2 = 8.6%, P = 0.030], and no significant effect was observed on augmentation index (Aix). Subgroup analysis showed small effects of regular aerobic exercise on FMD [SMD = 0.37, 95% CI (0.13, 0.61), z = 3.05, df = 9, I2 = 52.6%, P = 0.002] in the overweight not obese subgroup (25 = BMI <30 kg/m2), but no significant effect on the obese subgroup (BMI ≥30 kg/m2). Regular aerobic exercise for more than 24 weeks improved FMD by small effect sizes [SMD = 0.48, 95% CI (0.04, 0.93), z = 2.12, df = 5, I2 = 56.4%, P = 0.034] and for more than three times per week improved FMD by moderate effect sizes [SMD = 0.55, 95% CI (0.12, 0.98), z = 2.50, df = 3, I2 = 31.1%, P = 0.012] in obese and overweight older adults with or without CVD. Conclusion: In obese and overweight older adults with or without comorbidity, regular aerobic exercise for more than 24 weeks improved FMD by small effect sizes and exercise for more than three times per week improved FMD by moderate effect sizes and regular aerobic exercise reduced PWV by small effect sizes and had no influence on Aix. Taken together, it was recommended that obese and overweight older adults should adhere to regular aerobic exercise, training at least 3 times per week for better results.
RESUMEN
BACKGROUND: Biological laboratories and companies involved in antibody development need convenient and versatile methods to detect highly active antibodies. METHODS: To develop a mammalian cell-based ZZ display system for antibody quantification, the eukaryotic ZZ-displayed plasmid was constructed and transfected into CHO cells. After screening by flow cytometric sorting, the stable ZZ display cells were incubated with reference IgG and samples with unknown IgG content for 40 min at 4â, the relative fluorescence intensity of cells was analyzed and the concentration of IgG was calculated. RESULTS: By investigating the effects of different display-associated genetic elements, a eukaryotic ZZ-displaying plasmid with the highest display efficiency were constructed. After transfection and screening, almost 100% of the cells were able to display the ZZ peptide (designated CHO-ZZ cells). These stable CHO-ZZ cells were able to capture a variety of IgG, including human, rabbit, donkey and even mouse and goat. CHO-ZZ cells could be used to quantify human IgG in the range of approximately 12.5-1000 ng/mL, and to identify high-yielding engineered monoclonal cell lines. CONCLUSIONS: We have established a highly efficient CHO-ZZ display system in this study, which enables the quantification of IgG from various species under physiological conditions. This system offers the advantage of eliminating the need for antibody purification and will contribute to antibody development.