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The anti-Clostridium difficile infection (CDI) drug fidaxomicin is a natural polyketide metabolite mainly produced by Micromonosporaceae, such as Actinoplanes deccanensis, Dactylosporangium aurantiacum, and Micromonospora echinospora. In the present study, we employed a stepwise strategy by combining heterologous expression, chassis construction, promoter engineering, activator and transporters overexpression, and optimization of fermentation media for high-level production of fidaxomicin. The maximum yield of 384 mg/L fidaxomicin was achieved with engineered Streptomyces albus D7-VHb in 5 L-tank bioreactor, and it was approximately 15-fold higher than the native strain Actinoplanes deccanensis YP-1 with higher strain stability and growth rate. This study developed an enhanced chassis strain, and for the first time, achieved the heterologous synthesis of fidaxomicin through a combinatorial metabolic engineering strategy.
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Clathrin-mediated endocytosis (CME) is essential for maintaining cellular homeostasis. Previous studies have reported more than 50 CME accessory proteins; however, the mechanism driving the invagination of clathrin-coated pits (CCPs) remains elusive. Quantitative live cell imaging reveals that CCDC32, a poorly characterized endocytic accessory protein, regulates CCP stabilization and is required for efficient CCP invagination. CCDC32 interacts with the α-appendage domain (AD) of AP2 via its coiled-coil domain to exert this function. Furthermore, we showed that the clinically observed nonsense mutations in CCDC32, which result in the development of cardio-facio-neuro-developmental syndrome (CFNDS), inhibit CME by abolishing CCDC32-AP2 interactions. Overall, our data demonstrates the function and molecular mechanism of a novel endocytic accessory protein, CCDC32, in CME regulation. Significance Statement: Clathrin-mediated endocytosis (CME) happens via the initiation, stabilization, and invagination of clathrin-coated pits (CCPs). In this study, we used a combination of quantitative live cell imaging, ultrastructure electron microscopy and biochemical experiments to show that CCDC32, a poorly studied and functional ambiguous protein, acts as an important endocytic accessory protein that regulates CCP stabilization and invagination. Specifically, CCDC32 exerts this function via its interactions with AP2, and the coiled-coil domain of CCDC32 and the α-appendage domain (AD) of AP2 are essential in mediating CCDC32-AP2 interactions. Importantly, we demonstrate that clinically observed loss-of-function mutations in CCDC32 lose AP2 interaction capacity and inhibit CME, resulting in the development of cardio-facio-neuro-developmental syndrome (CFNDS).
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Efforts on bladder cancer treatment have been shifting from extensive surgery to organ preservation in the past decade. To this end, we herein develop a multifunctional nanoagent for bladder cancer downstaging and bladder-preserving therapy by integrating mucosa penetration, reduced off-target effects, and internal irradiation therapy into a nanodrug. Specifically, an iron oxide nanoparticle was used as a carrier that was coated with hyaluronic acid (HA) for facilitating mucosa penetration. Dibenzocyclooctyne (DBCO) was introduced into the HA coating layer to react through bioorthogonal reaction with azide as an artificial receptor of bladder cancer cells, to improve the cellular internalization of the nanoprobe labeled with 177Lu. Through magnetic resonance imaging, the targeted imaging of both nonmuscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) was realized after intravesical instillation of the multifunctional probe, both NMIBC and MIBC were found downstaged, and the metastasis was inhibited, which demonstrates the potential of the multifunctional nanoprobe for bladder preservation in bladder cancer treatment.
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Lutecio , Radioisótopos , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen , Neoplasias de la Vejiga Urinaria/patología , Humanos , Lutecio/química , Radioisótopos/química , Animales , Línea Celular Tumoral , Imagen por Resonancia Magnética , Ratones , Ácido Hialurónico/químicaRESUMEN
Post-translational modifications (PTMs) have emerged as pivotal regulators of the development of cancers, including esophageal squamous cell carcinoma (ESCC). Here, we conducted a comprehensive analysis of PTM-related genetic variants associated with ESCC risk using large-scale genome-wide and exome-wide association datasets. We observed significant enrichment of PTM-related variants in the ESCC risk loci and identified five variants that were significantly associated with ESCC risk. Among them, rs6780013 in PTPN23 exhibited the highest level of significance in ESCC susceptibility in 9,728 ESCC cases and 10,977 controls (odds ratio [OR] = 0.85, 95 % confidence interval [CI] = 0.81- 0.89, P = 9.77 × 10-14). Further functional investigations revealed that PTPN23[Thr] variant binds to EGFR and modulates its phosphorylation at Thr699. PTPN23[Thr] variant substantially inhibited ESCC cell proliferation both in vitro and in vivo. Our findings underscore the critical role of PTPN23[Thr]-EGFR interaction in ESCC development, providing more insights into the pathogenesis of this cancer.
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Proliferación Celular , Receptores ErbB , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Predisposición Genética a la Enfermedad , Animales , Femenino , Humanos , Ratones , Carcinogénesis/genética , Línea Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Estudio de Asociación del Genoma Completo , Ratones Endogámicos BALB C , Fosforilación , Polimorfismo de Nucleótido Simple , Procesamiento Proteico-PostraduccionalRESUMEN
BACKGROUND: The general sluggish clearance kinetics of functional inorganic nanoparticles tend to raise potential biosafety concerns for in vivo applications. Renal clearance is a possible elimination pathway for functional inorganic nanoparticles delivered through intravenous injection, but largely depending on the surface physical chemical properties of a given particle apart from its size and shape. RESULTS: In this study, three small-molecule ligands that bear a diphosphonate (DP) group, but different terminal groups on the other side, i.e., anionic, cationic, and zwitterionic groups, were synthesized and used to modify ultrasmall Fe3O4 nanoparticles for evaluating the surface structure-dependent renal clearance behaviors. Systematic studies suggested that the variation of the surface ligands did not significantly increase the hydrodynamic diameter of ultrasmall Fe3O4 nanoparticles, nor influence their magnetic resonance imaging (MRI) contrast enhancement effects. Among the three particle samples, Fe3O4 nanoparticle coated with zwitterionic ligands, i.e., Fe3O4@DMSA, exhibited optimal renal clearance efficiency and reduced reticuloendothelial uptake. Therefore, this sample was further labeled with 99mTc through the DP moieties to achieve a renal-clearable MRI/single-photon emission computed tomography (SPECT) dual-modality imaging nanoprobe. The resulting nanoprobe showed satisfactory imaging capacities in a 4T1 xenograft tumor mouse model. Furthermore, the biocompatibility of Fe3O4@DMSA was evaluated both in vitro and in vivo through safety assessment experiments. CONCLUSIONS: We believe that the current investigations offer a simple and effective strategy for constructing renal-clearable nanoparticles for precise disease diagnosis.
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Riñón , Imagen por Resonancia Magnética , Tomografía Computarizada de Emisión de Fotón Único , Animales , Imagen por Resonancia Magnética/métodos , Ratones , Tomografía Computarizada de Emisión de Fotón Único/métodos , Ligandos , Riñón/diagnóstico por imagen , Riñón/metabolismo , Línea Celular Tumoral , Medios de Contraste/química , Femenino , Ratones Endogámicos BALB C , Humanos , Distribución Tisular , Neoplasias/diagnóstico por imagen , Nanopartículas de Magnetita/química , Nanopartículas/químicaRESUMEN
Introduction and importance: Ectopic pancreas is not uncommon, but ileocecal intussusception caused by ectopic pancreas is extremely rare. Thus far, only approximately 10 cases have been reported. Case presentation: Herein, we report a 47-year-old male who presented with abdominal distension and discomfort without apparent cause, accompanied by nausea but no vomiting or other symptoms. The patient's vital signs were stable, and examination revealed increased bowel sounds, tympanic percussion of the abdomen, and tenderness in the lower right abdomen. After laparoscopic exploration, an irreducible intestinal obstruction was found, which subsequently required open surgery. Pathological examination of the resected portion revealed that the patient's ileocecal intussusception was caused by ectopic pancreas. Clinical discussion: Prior to receiving the pathological report, we were not aware that the patient's abdominal pain may have been attributed to ileocecal intussusception induced by ectopic pancreas. This posed challenges in diagnosis and treatment, underscoring the importance of raising awareness among our colleagues through this case report. Conclusion: Our findings emphasize the need to consider the possibility of abdominal pain caused by ileocecal intussusception induced by ectopic pancreas during the investigation of abdominal pain.
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Identifying high-risk factors (heavy metals (HMs) and pollution sources) by coupling receptor models and health risk assessment model (HRA) is a novel approach within the field of risk assessment. However, this coupled model ignores the contribution of spatial differentiation to high-risk factors, resulting in the assessment being subjective. Taking Dongting Plain (DTP) as an example, a coupling framework by jointly using the positive matrix factorization model (PMF), HRA, Monte Carlo simulation, and geo-detector was developed, aiming to identify high-risk factors in groundwater, and further explore key environmental variables influencing the spatial heterogeneity of high-risk factors. The results showed that at least 82.86 % of non-carcinogenic risks and 97.41 % of carcinogenic risks were unacceptable for people of all ages, especially infants and children. According to the relationships among HMs, pollution sources, and health risks, As and natural sources were defined as high-risk HMs and sources, respectively. The interactions among Holocene thickness, oxidation-reduction potential, and dissolved organic carbon emerged as the primary drivers of spatial variability in high-risk factors, with their combined explanatory power reaching up to 74%. This proposed framework provides a scientific reference for future studies and a practical reference for environmental authorities in developing effective pollution management measures.
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Agua Subterránea , Metales Pesados , Contaminantes Químicos del Agua , Agua Subterránea/química , Metales Pesados/análisis , Contaminantes Químicos del Agua/análisis , Factores de Riesgo , Medición de Riesgo , Monitoreo del Ambiente , Humanos , Método de MontecarloRESUMEN
Aim: The purpose of this study is to examine the design and implementation of a high-fidelity simulation training course for medical and nursing collaboration, based on the Fink integrated course design model. Additionally, the study aims to validate the teaching effectiveness of the course. Background: Previous empirical studies have highlighted the effectiveness of collaborative healthcare education in institutional teaching and hospital training. However, the development of healthcare collaborative education in China has been slow to develop in China. In recent years, Chinese nursing educators and researchers have shown interest in utilizing high-fidelity simulators for healthcare collaborative education. These simulators help address the limitations of traditional nursing teaching and healthcare separation simulation. Nevertheless, a standardized simulation interprofessional education curriculum is still lacking. Therefore, nursing educators need to develop a standardized high-fidelity simulation training curriculum for healthcare collaboration, guided by established science curriculum development theories. Methods: A high-fidelity simulation training course on healthcare collaboration was designed based on the Fink integrated curriculum design model. The course was taught to 14 nursing students and 8 clinical medicine students from March to July 2022. To comprehensively evaluate the effectiveness of the healthcare collaboration high-fidelity simulation training course, several assessment tools were used. These included course grades, satisfaction and self-confidence scales, simulation teaching practice scales, healthcare collaboration attitude scales, critical thinking skills scales, and semi-structured interviews. Results: After the course was implemented, students demonstrated high overall scores (79.19 ± 5.12) and reported high satisfaction ratings (4.44 ± 0.37). They also exhibited increased self-confidence (4.16 ± 0.33). Additionally, students evaluated all four dimensions of the course teaching practice scale positively. Furthermore, the study demonstrated significant improvements in various aspects, such as attitudes toward medical and nursing collaboration (t = -7.135, P < 0.01), shared education and teamwork (t = -3.247, P = 0.002), job autonomy for nurses (t = -1.782, P = 0.000), and reduced physician dominance (t = -6.768, P = 0.000). The critical thinking skills of the students showed significant improvement, with higher scores in truth-seeking (t = -3.052, P = 0.004), analytical ability (t = -2.561, P = 0.014), systematic ability (t = -3.491, P = 0.001), self-confidence in critical thinking (t = -4.024, P = 0.000), and curiosity (t = -5.318, P = 0.000) compared to their scores before the course (all P < 0.05). The interviews showed that the course's student-centered approach enabled active learning. Students suggested enhancing teaching cases and allocating more time for reflection and summarization. Conclusion: The study successfully designed a high-fidelity simulation training course for healthcare collaboration by utilizing the Fink integrated curriculum design model. The findings provide valuable insights for the development of standardized curricula and healthcare collaboration education in China. Moreover, the course adheres to best practice principles, fostering improved attitudes toward healthcare collaboration and enhancing students' healthcare collaboration and clinical thinking skills.
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Background: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible but causes less severe disease compared to other variants. However, its association with sepsis incidence and outcomes is unclear. This study aimed to investigate the incidence of Omicron-associated sepsis, as per the Sepsis 3.0 definition, in hospitalized patients, and to explore its relationship with clinical characteristics and prognosis. Methods: This multicenter retrospective study included adults hospitalized with confirmed SARS-CoV-2 infection across six tertiary hospitals in Guangzhou, China from November 2022 to January 2023. The Sequential Organ Failure Assessment (SOFA) score and its components were calculated at hospital admission to identify sepsis. Outcomes assessed were need for intensive care unit (ICU) transfer and mortality. Receiver operating characteristic curves evaluated the predictive value of sepsis versus other biomarkers for outcomes. Results: A total of 299 patients (mean age: 70.1±14.4 years, 42.14% female) with SOFA score were enrolled. Among them, 152 were categorized as non-serious cases while the others were assigned as the serious group. The proportion of male patients, unvaccinated patients, patients with comorbidity such as diabetes, chronic cardiovascular disease, and chronic lung disease was significantly higher in the serious than non-serious group. The median SOFA score of all enrolled patients was 1 (interquartile range, 0-18). In our study, 147 patients (64.19%) were identified as having sepsis upon hospital admission, with the majority of these septic patients (113, representing 76.87%) being in the serious group, the respiratory, coagulation, cardiovascular, central nervous, and renal organ SOFA scores were all significantly higher in the serious compared to the non-serious group. Among septic patients, 20 out of 49 (40.81%) had septic shock as indicated by lactate measurement within 24 hours of admission, and the majority of septic patients were in the serious group (17/20, 76.87%). Sepsis was present in 118 out of 269 (43.9%) patients in the general ward, and among those with sepsis, 34 out of 118 (28.8%) later required ICU care during hospitalization. By contrast, none of the patients without sepsis required ICU care. Moreover, the mortality rate was significantly higher in patients with than without sepsis. Conclusions: A considerable proportion of patients infected with Omicron present with sepsis upon hospital admission, which is associated with a poorer prognosis. Therefore, early recognition of viral sepsis by evaluation of the SOFA score in hospitalized coronavirus disease 2019 patients is crucial.
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The purpose of this study was to reduce the length of stay (LOS) for patients stranded in the emergency department (ED) of a Grade III A hospital in China, and to improve patient flow and increase bed capacity. We utilized a pre-/postintervention design and employed the Six Sigma methodology, which is based on the DMAIC cycle (define, measure, analyze, improve, and control), to evaluate and improve the existing process. Data from 18,631 patients who were stranded in the ED were collected and analyzed. The median LOS for stranded patients decreased from 17.21 (6.22, 27.36) hours to 13.45 (5.56, 25.85) hours (P < .05). Similarly, the median LOS for admitted patients decreased from 19.64 (7.77, 27.68) hours to 15.92 (6.19, 26.24) hours (P < .05). The median LOS for patients with an ED triage Level IV decreased from 16.15 (5.80, 26.62) hours to 12.59 (5.20, 24.97) hours (P < .05). In addition, the average hospitalization days of hospitalized patients decreased from 0.92 days to 0.82 days (P < .05). Furthermore, the bed utilization rate increased from 66.79% to 72.29% (P < .05). The number of bed turnovers in the ED resuscitation room increased from 20.30 to 21.96 (P < .05). We had effectively met our goal of minimizing ED patient LOS. Six Sigma method can effectively shorten patient LOS by measuring and analyzing the key factors affecting patient LOS, and by implementing measures such as strict implementation of emergency classification and triage system, establishment of multidisciplinary cooperative team, reasonable allocation of human resources, information management of bed resources, and improvement of performance appraisal scheme to improve and control the effectiveness of patient LOS.
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Servicio de Urgencia en Hospital , Hospitalización , Humanos , Tiempo de Internación , Estudios Prospectivos , Hospitales , Estudios RetrospectivosRESUMEN
Tumors are intricate and heterogeneous systems characterized by mosaic cancer cell populations with diverse expression profiles. Leveraging single-cell technologies, we employed the Scissor algorithm to delineate an epithelial subpopulation associated with the aggressive phenotype in esophageal squamous cell carcinoma (ESCC). This identified subpopulation exhibited elevated expression of genes involved in critical pathways, such as epithelial-mesenchymal transition and PI3K-Akt. Key signature genes within this subpopulation, namely CAV1, COL3A1, COL6A1, POSTN, and TAGLN, demonstrated significant upregulation concomitant with both tumorigenesis and tumor progression across independent single-cell datasets. Furthermore, we selected 1,450 expression quantitative trait loci of the top 62 signature genes of this cell subpopulation to investigate their potential in predicting ESCC risk. The results showed that the POSTN loci were predominantly associated with ESCC susceptibility. Through functional annotation and replication analyses, we identified that the rs1028728 in the POSTN promoter was significantly associated with increased ESCC risk in 7,049 ESCC cases and 8,063 controls (odds ratio = 1.29, 95% confidence interval: 1.18-1.42, p = 4.03 × 10-8). Subsequent biochemical experiments showed that the rs1028728[T] allele enhanced POSTN expression by affecting the binding of PRRX1 in the POSTN promoter. In summary, our meticulous single-cell analysis delineates an invasive epithelial subpopulation in ESCC, with POSTN emerging as an important marker for the aggressive phenotype. These findings offer more insights into potential strategies for the prevention and intervention of ESCC, enriching our understanding of this complex cancer landscape.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Fosfatidilinositol 3-Quinasas/genética , Línea Celular Tumoral , Fenotipo , Proteínas de Homeodominio/genética , Moléculas de Adhesión Celular/genéticaRESUMEN
Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.
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COVID-19 , Microbioma Gastrointestinal , Trombosis , Humanos , Ratones , Animales , Integrina alfa2beta1/genética , Integrina alfa2beta1/metabolismo , Colágeno/metabolismo , Plaquetas/metabolismo , COVID-19/metabolismoRESUMEN
Esophageal squamous cell carcinoma (ESCC) stands as a highly lethal malignancy characterized by pronounced recurrence and metastasis, resulting in a bleak 5-year survival rate. Despite extensive investigations, encompassing genome-wide association studies, the identification of robust prognostic markers has remained elusive. In this study, leveraging four independent data sets comprising 404 ESCC patients, we conducted a systematic analysis to unveil pivotal genes influencing overall survival. our meta-analysis identified 278 genes significantly associated with ESCC prognosis. Further exploration of the prognostic landscape involved an examination of expression quantitative trait loci for these genes, leading to the identification of six tag single nucleotide polymorphisms predictive of overall survival in a cohort of 904 ESCC patients. Notably, functional annotation spotlighted rs11227223, residing in the enhancer region of nuclear paraspeckle assembly transcript 1 (NEAT1), as a crucial variant likely exerting a substantive biological role. Through a series of biochemistry experiments, we conclusively demonstrated that the rs11227223-T allele, indicative of a poorer prognosis, augmented NEAT1 expression. Our results underscore the substantive role of NEAT1 and its regulatory variant in prognostic predictions for ESCC. This comprehensive analysis not only advances our comprehension of ESCC prognosis but also unveils a potential avenue for targeted interventions, offering promise for enhanced clinical outcomes.
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Biomarcadores de Tumor , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Polimorfismo de Nucleótido Simple , Humanos , Pronóstico , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo , ARN Largo no Codificante/genética , Femenino , MasculinoRESUMEN
Background: Leritrelvir is a novel α-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease. A preclinical study has demonstrated leritrelvir poses similar antiviral activities towards different SARS-CoV-2 variants compared with nirmatrelvir. A phase 2 clinical trial has shown a comparable antiviral efficacy and safety between leritrelvir with and without ritonavir co-administration. This trial aims to test efficacy and safety of leritrelvir monotherapy in adults with mild-to-moderate COVID-19. Methods: This was a randomised, double-blind, placebo-controlled, multicentre phase 3 trial at 29 clinical sites in China. Enrolled patients were from 18 to 75 years old, diagnosed with mild or moderate COVID-19 and not requiring hospitalization. Patients had a positive SARS-CoV-2 nucleic acid test (NAT) and at least one of the COVID-19 symptoms within 48 h before randomization, and the interval between the first positive SARS-CoV-2 NAT and randomization was ≤120 h (5 days). Patients were randomly assigned in a 1:1 ratio to receive a 5-day course of either oral leritrelvir 400 mg TID or placebo. The primary efficacy endpoint was the time from the first dose to sustained clinical recovery of all 11 symptoms (stuffy or runny nose, sore throat, shortness of breath or dyspnea, cough, muscle or body aches, headache, chills, fever ≥37 °C, nausea, vomiting, and diarrhea). The safety endpoint was the incidence of adverse events (AE). Primary and safety analyses were performed in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT05620160. Findings: Between Nov 12 and Dec 30, 2022 when the zero COVID policy was abolished nationwide, a total of 1359 patients underwent randomization, 680 were assigned to leritrelvir group and 679 to placebo group. The median time to sustained clinical recovery in leritrelvir group was significantly shorter (251.02 h [IQR 188.95-428.68 h]) than that of Placebo (271.33 h [IQR 219.00-529.63 h], P = 0.0022, hazard ratio [HR] 1.20, 95% confidence interval [CI], 1.07-1.35). Further analysis of subgroups for the median time to sustained clinical recovery revealed that (1) subgroup with positive viral nucleic acid tested ≤72 h had a 33.9 h difference in leritrelvir group than that of placebo; (2) the subgroup with baseline viral load >8 log 10 Copies/mL in leritrelvir group had 51.3 h difference than that of placebo. Leritrelvir reduced viral load by 0.82 log10 on day 4 compared to placebo. No participants in either group progressed to severe COVID-19 by day 29. Adverse events were reported in two groups: leritrelvir 315 (46.46%) compared with placebo 292 (43.52%). Treatment-relevant AEs were similar 218 (32.15%) in the leritrelvir group and 186 (27.72%) in placebo. Two cases of COVID-19 pneumonia were reported in placebo group, and one case in leritrelvir group, none of them were considered by the investigators to be leritrelvir related. The most frequently reported AEs (occurring in ≥5% of participants in at least one group) were laboratory finding: hypertriglyceridemia (leritrelvir 79 [11.7%] vs. placebo 70 [10.4%]) and hyperlipidemia (60 [8.8%] vs. 52 [7.7%]); all of them were nonserious. Interpretation: Leritrelvir monotherapy has good efficacy for mild-to-moderate COVID-19 and without serious safety concerns. Funding: This study was funded by the National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project and R&D Program of Guangzhou Laboratory.
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BACKGROUND: Risk assessment of vascular thrombosis in SLE patients with the presence of antiphospholipid antibodies (aPL) remains a challenge. The adjusted global antiphospholipid syndrome score (aGAPSS) has been validated and used to predict aPL-related thrombosis in SLE patients in some countries. Relevant data of aGAPSS in thrombotic evaluation in SLE population from China has not been reported. We aim to validate aGAPSS in thrombosis assessment in Chinese patients with SLE and to explore the correlations of aGAPSS with routine laboratory parameters and their clinical significance as well. METHODS: A total of 166 consecutive SLE patients were retrospectively analyzed. Multivariate logistic regression analysis was performed to examine the impact of multiple cardiovascular risk factors and laboratory parameters in recurrent thrombosis risk in SLE. ROC was conducted to explore the discriminative ability of aGAPSS and platelet (PLT), activated partial thromboplastin time (APTT), alone or in combination. RESULTS: Significantly higher value of aGAPSS was seen in SLE patients with vascular thrombosis. ROC curve indicated that aGAPSS of 3.5 or more had the best diagnostic accuracy for the prediction of aPL-related thrombosis in SLE patients. PLT with cutoff of 187.5 x 109/L and APTT with 37.5 seconds were predictors of aPL-related thrombosis as well. The combination of aGAPSS with PLT and APTT improved AUC compared to aGAPSS alone. CONCLUSIONS: The aGAPSS could predict the risk of aPL-related vascular thrombosis in SLE patients from China. The combination of aGAPSS with PLT and APTT was first time proved to have better predictive performance in thrombosis risk assessment in SLE.
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Síndrome Antifosfolípido , Lupus Eritematoso Sistémico , Trombosis , Humanos , Síndrome Antifosfolípido/complicaciones , Síndrome Antifosfolípido/diagnóstico , Estudios Retrospectivos , Tiempo de Tromboplastina Parcial , Factores de Riesgo , Trombosis/diagnóstico , Trombosis/etiología , Medición de Riesgo , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnósticoRESUMEN
Osteoarthritis (OA) is characterized by degenerative articular cartilage. Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) plays an important role in inflammation. This study aims to investigate whether protective effects of curculigoside on OA are medicated by the regulation of NLRP3 pathway. Destabilization of the medial meniscus (DMM) was performed to build an OA mouse model. After surgery, OA mice were treated with curculigoside. Immunohistochemistry was conducted to evaluate OA cartilage. In addition, human chondrocytes were isolated and treated with curculigoside. The mRNA and protein expression of iNOS, MMP-9, NLRP3 was detected by PCR and Western blot analysis. Curculigoside inhibited mRNA and protein levels of iNOS and MMP-9 induced by DMM surgery in a dose-dependent manner. Furthermore, the expression of NLRP3, NF-κB and PKR was downregulated after curculigoside administration. Moreover, curculigoside reversed the effects of IL-1ß on MMP-9, iNOS and type II collagen expression at mRNA and protein levels in human chondrocytes in a dose-dependent manner. In conclusion, curculigoside exhibits beneficial effect on cartilage via the inhibition of NLRP3 pathway.
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Cartílago Articular , Osteoartritis , Humanos , Ratones , Animales , Metaloproteinasa 9 de la Matriz/metabolismo , Transducción de Señal/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células Cultivadas , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Condrocitos , FN-kappa B/metabolismo , Cartílago Articular/metabolismo , ARN Mensajero/metabolismo , Interleucina-1beta/metabolismoRESUMEN
Our patient, a 48-year-old man from Guangdong's coastal region, worked selling and processing oysters and other seafood. He started experiencing swelling and pain in his left knee on October 4, 2022, and they got worse over time. The findings of mNGS test showed Vibrio vulnificus infection. The patient had AIDS, hepatitis A and hepatitis B concurrently. He was admitted to the hospital's intensive care unit (ICU) for treatment as his symptoms worsened. We refrained from performing an amputation because the family members expressed a desire to keep the limb. The limb was managed with regular dressing changes, thorough debridement, wound closure, ongoing VSD drainage, and local antibiotic irrigation. The patient's organ function eventually returned to normal, and the systemic infection got better. On November 1, the wound's new granulation tissue had grown well and had gradually crept to cover 80% of the wound. The tissue's blood flow had also improved, indicating a trend of growth and healing.
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Coinfección , Infecciones por VIH , Hepatitis B , Hepatitis C , Vibriosis , Vibrio vulnificus , Masculino , Humanos , Persona de Mediana Edad , Coinfección/diagnóstico , Coinfección/complicaciones , Vibriosis/diagnóstico , Vibriosis/terapia , Infecciones por VIH/complicacionesRESUMEN
Introduction: For middle-aged and older people, depression is a frequent and prevalent illness. The purpose of this study was to examine the moderating function of living arrangements in the mediating model as well as the mediating role of life satisfaction in the association between chronic diseases and depressive symptoms. Methods: The China Health and Retirement Longitudinal Study (CHARLS) provided the data for this investigation (2018). Respondents were grouped according to depression status to compare the differences between middle-aged and older people with different depression statuses. The moderating effect of living arrangements and the mediating effect of life satisfaction were tested using the Bootstrap program and the simple slope approach. Results: The population's total prevalence of depressive symptoms was 30.3%. According to the mediating effect research, middle-aged and older people with chronic diseases experienced substantial direct effects on depressive symptoms (ß = 1.011, p < 0.001). It has been established that life satisfaction has an 18.6% mediation effect between depressive symptoms and chronic diseases. Regarding the further moderating influence, it was discovered that chronic diseases had a more significant impact on the life satisfaction of middle-aged and older people who are in live alone than those who are living with others (ß = 0.037, p < 0.05). Conclusion: In middle-aged and older people, chronic diseases have a major influence on depressive symptoms. Life satisfaction mediated the relationship between chronic diseases and depressive symptoms, and living arrangements moderated the first part of the route in the mediation model. Therefore, life satisfaction and living arrangements should be important considerations to decrease the prevalence of depressive symptoms in middle-aged and older people.
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IMPORTANCE: Cascade regulation networks are almost present in various kinds of microorganisms, but locating and systematically elucidating specific pleiotropic regulators related to a certain gene cluster can be a tricky problem. Here, based on the promoter of the fidaxomicin pathway-specific regulator FadR1, we utilized a "DNA to Proteins" affinity purification method and captured a global regulator MtrA, which positively regulates fidaxomicin biosynthesis. In the mtrA overexpressed strain, the production of fidaxomicin was improved by 37% compared to the native strain. Then, we combined the "Protein to DNAs" affinity purification method (DAP-seq) with the results of RNA-seq and systematically elucidated the primary and secondary metabolic processes in which MtrA directly or indirectly participates. Thus, our work brought up a new way to improve fidaxomicin production from the perspective of global regulation and analyzed the regulatory mechanism of MtrA. Meanwhile, we provided a novel methodology for the research of cascade regulation networks and vital secondary metabolites.
Asunto(s)
Transportadoras de Casetes de Unión a ATP , Regulación Bacteriana de la Expresión Génica , Fidaxomicina , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Familia de Multigenes , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismoRESUMEN
Background: Large number of patients with prior coronary artery bypass grafting (CABG) need repeat revascularization yearly, and percutaneous coronary intervention (PCI) is the optimal treatment strategy for such patients. However, it is still controversial whether PCI of native coronary artery or bypass graft is more beneficial. The aim of the study was to compare the clinical outcomes between native coronary artery vs. bypass graft PCI in patients with prior CABG. Methods: A total of 1,276 patients with prior CABG who underwent index PCI of native coronary artery (n=1,072) or bypass graft (n=204) were retrospectively examined. Patients were divided into native group and graft group according to the target vessel. The outcomes of the two groups were compared by using inverse probability of treatment weighting (IPTW) and Cox regression analysis. The primary endpoint was the composite of major adverse cardiac and cerebrovascular events (MACCEs), which included all-cause death, non-fatal stroke, non-fatal myocardial infarction (MI), or target vessel revascularization (TVR). Results: Compared with native group, patients in graft group had higher risk of slow-flow/no-reflow phenomenon (1.5% vs. 0.1%, P=0.011 before IPTW, and 2.2% vs. 0.1%, P<0.001 after IPTW) and peri-procedural stroke (0.3% vs. 0, P=0.021 after IPTW). During a median follow-up period of 43 months, there was similar risk of MACCE between two groups. Notably, patients in graft group had a significantly higher incidence of non-fatal MI compared with native group regardless with or without IPTW (7.8% vs. 3.8%, P=0.018 and 8.3% vs. 3.9%, P=0.030, separately). After adjusting for confounding by using Cox regression, bypass graft PCI was associated with a higher risk of non-fatal MI (HR: 2.091, 95% CI: 1.069-4.089; P=0.031), but similar results in MACCE (HR: 1.077, 95% CI: 0.817-1.419; P=0.599) compared with native group. Conclusions: This study found that native coronary artery might be preferred for PCI in patients with prior CABG because of lower rates of slow-flow/no-reflow, peri-procedural stroke, and non-fatal MI at follow-up.