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Recently, aqueous zinc-ion batteries with conversion mechanisms have received wide attention in energy storage systems on account of excellent specific capacity, high power density, and energy density. Unfortunately, some characteristics of cathode material, zinc anode, and electrolyte still limit the development of aqueous zinc-ion batteries possessing conversion mechanism. Consequently, this paper provides a detailed summary of the development for numerous aqueous zinc-based batteries: zinc-sulfur (Zn-S) batteries, zinc-selenium (Zn-Se) batteries, zinc-tellurium (Zn-Te) batteries, zinc-iodine (Zn-I2) batteries, and zinc-bromine (Zn-Br2) batteries. Meanwhile, the reaction conversion mechanism of zinc-based batteries with conversion mechanism and the research progress in the investigation of composite cathode, zinc anode materials, and selection of electrolytes are systematically introduced. Finally, this review comprehensively describes the prospects and outlook of aqueous zinc-ion batteries with conversion mechanism, aiming to promote the rapid development of aqueous zinc-based batteries.
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BACKGROUND: Data on long-term cancer survivors treated with apatinib are lacking. This study aimed to describe the characteristics of long-term cancer survivors after apatinib-based therapy, and to know about their satisfaction degree with apatinib and severity of depression and insomnia. METHODS: Patients with solid tumors who had received apatinib-based therapy for at least 5 years were invited to complete an online questionnaire. Characteristics of patients and treatment, knowledge of apatinib, satisfaction degree, and severity of depression and insomnia assessed by Patient Health Questionnaire-9 and Insomnia Severity Index were collected. RESULTS: Between December 8, 2023 and March 1, 2024, a total of 436 patients completed the online questionnaire. Most patients were satisfied with the efficacy (96.6%) and safety (93.1%) of apatinib, were willing to continue apatinib treatment (99.5%), and would recommend apatinib to other patients (93.3%). Continuous apatinib treatment resulted in significant negative impact on daily life, work, or study in only two (0.5%) patients. Almost all patients currently had no or mild depression (97.0%) and insomnia (97.9%) problems. The most common patient-reported adverse events were hand-foot syndrome (21.3%) and hypertension (18.3%). CONCLUSIONS: Our survey showed a high satisfaction degree with apatinib in long-term cancer survivors. Long-term apatinib treatment resulted in almost no negative impact on patient's quality of life.
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Supervivientes de Cáncer , Neoplasias , Medición de Resultados Informados por el Paciente , Piridinas , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Supervivientes de Cáncer/psicología , Neoplasias/tratamiento farmacológico , Anciano , Adulto , Encuestas y Cuestionarios , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Depresión/inducido químicamente , Satisfacción del Paciente , Calidad de VidaRESUMEN
Cetuximab [the epidermal growth factor receptor (EGFR)-targeting mAb] improves clinical outcomes when added to standard chemotherapy used in the treatment of metastatic colorectal cancer. Patients with hotspot mutations in Kirsten rat sarcoma viral oncogene ( KRAS ) mutation in exon 2 were not recommended to be treated with cetuximab. However, there is still a lack of clinical data for those unreported non-hotspot KRAS mutations in exon 2 and their response to cetuximab. In this study, we reported a 35-year-old woman who was diagnosed with stage IVA CRC with liver metastases. An exceptionally uncommon KRASP34R mutation in KRAS exon 2 was detected in tumor specimens by next-generation sequencing. This patient obtained limited benefit from first-line chemotherapy and did not respond to cetuximab in the second-line course. In the third-line course, the patient also did not respond to the combination treatment of furaquitinib and cindilimab. The patient died 8 months after treatment initiation. In this study, we found amplification of the rare oncogenic KRASP34R was not only associated with an aggressive phenotype, but also supported cancer resistance to cetuximab, chemotherapy, and immunotherapy.
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Antineoplásicos , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Femenino , Humanos , Adulto , Cetuximab/uso terapéutico , Antineoplásicos/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , MutaciónRESUMEN
A straightforward methodology for the assembly of polysubstituted naphthalenes from ortho-alkynyl benzyl alcohols, enabled by using catalytic amounts of Tf2O, has been developed. This transformation not only features transition-metal free and without using other bases and additives but also provides a new synthetic application for ortho-alkynyl benzyl alcohols, i.e., as C6 synthons for the construction of PAHs.
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Rainwater Harvesting (RWH) is increasingly recognized as a vital sustainable practice in urban environments, aimed at enhancing water conservation and reducing energy consumption. This study introduces an innovative integration of nano-composite materials as Silver Nanoparticles (AgNPs) into RWH systems to elevate water treatment efficiency and assess the resulting environmental and energy-saving benefits. Utilizing a regression analysis approach with Support Vector Machines (SVM) and K-Nearest Neighbors (KNN), this study will reach the study objective. In this study, the inputs are building attributes, environmental parameters, sociodemographic factors, and the algorithms SVM and KNN. At the same time, the outputs are predicted energy consumption, visual comfort outcomes, ROC-AUC values, and Kappa Indices. The integration of AgNPs into RWH systems demonstrated substantial environmental and operational benefits, achieving a 57% reduction in microbial content and 20% reductions in both chemical usage and energy consumption. These improvements highlight the potential of AgNPs to enhance water safety and reduce the environmental impact of traditional water treatments, making them a viable alternative for sustainable water management. Additionally, the use of a hybrid SVM-KNN model effectively predicted building energy usage and visual comfort, with high accuracy and precision, underscoring its utility in optimizing urban building environments for sustainability and comfort.
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Aprendizaje Automático , Plata , Ciudades , Purificación del Agua/métodos , Nanopartículas del Metal , Lluvia , Conservación de los Recursos Hídricos/métodos , Máquina de Vectores de SoporteRESUMEN
Based on the concept of source separation of brown water (BW, human feces with flushing water) and yellow water (urine) in rural area, anaerobic co-digestion of BW with agricultural waste is a promising and effective method for rural waste treatment and resource recovery. The purpose of this study was to investigate the performance of different agricultural wastes (peanut straw (PST), peanut shell (PSH), swine wastewater acting as co-substrate for anaerobic co-digestion with BW, and the relative mechanisms were explored. When the mixed ratio was uniformly set as 1:1 (mass ratio, measured by volatile solid (VS)) and initial VS load as 20 g/L, the maximum cumulative methane production obtained by co-digestion (21 days) of BW and PST was 688 mL/g-VS, which performed better than the individual substrates (341 mL/g-VS), as well as the average of the sole BW and sole PST groups (531.2 mL/g-VS). The most impactful advantage was ascribed to the promotion of hydrolytic and acidogenic enzyme activities. The addition of PST also reduced the production of endogenous humus, which is difficult for biodegradation. Microbial community analysis showed that different co-substrates would affect the microbial community composition in the reactor. The relative abundance of hydrolytic acidogens in the PST and PSH co-digestion groups were higher than that in the SW co-digestion and sole BW groups, and the methanogenic archaea were dominated by the acetate-trophic Methanotrichaceae. The overall results suggest that anaerobic co-digestion is a feasible method, and co-digestion of BW and PST can improve methane production potential.
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Reactores Biológicos , Agua , Humanos , Animales , Porcinos , Anaerobiosis , Agua/análisis , Heces , Digestión , Metano/análisisRESUMEN
Pancreatic cancer (PAAD) is a highly malignant tumour characterized of high mortality and poor prognosis. Huntingtin-interacting protein 1-related (HIP1R) has been recognized as a tumour suppressor in gastric cancer, while its biological function in PAAD remains to be elucidated. In this study, we reported the downregulation of HIP1R in PAAD tissues and cell lines, and the overexpression of HIP1R suppressed the proliferation, migration and invasion of PAAD cells, while silencing HIP1R showed the opposite effects. DNA methylation analysis revealed that the promoter region of HIP1R was heavily methylated in PAAD cell lines when compared to the normal pancreatic duct epithelial cells. A DNA methylation inhibitor 5-AZA increased the expression of HIP1R in PAAD cells. 5-AZA treatment also inhibited the proliferation, migration and invasion, and induced apoptosis in PAAD cell lines, which could be attenuated by HIP1R silencing. We further demonstrated that HIP1R was negatively regulated by miR-92a-3p, which modulates the malignant phenotype of PAAD cells in vitro and the tumorigenesis in vivo. The miR-92a-3p/HIP1R axis could regulate PI3K/AKT pathway in PAAD cells. Taken together, our data suggest that targeting DNA methylation and miR-92a-3p-mediated repression of HIP1R could serve as novel therapeutic strategies for PAAD treatment.
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MicroARNs , Neoplasias Pancreáticas , Humanos , MicroARNs/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Metilación de ADN , Fosfatidilinositol 3-Quinasas/metabolismo , Movimiento Celular/genética , Línea Celular Tumoral , Neoplasias Pancreáticas/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Microfilamentos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias PancreáticasRESUMEN
Fasting hyperglycemia in diabetes mellitus is caused by unregulated glucagon secretion that activates gluconeogenesis (GNG) and increases the use of pyruvate, lactate, amino acids, and glycerol. Studies of GNG in hepatocytes, however, tend to test a limited number of substrates at nonphysiologic concentrations. Therefore, we treated cultured primary hepatocytes with three identical substrate mixtures of pyruvate/lactate, glutamine, and glycerol at serum fasting concentrations, where a different U-13C- or 2-13C-labeled substrate was substituted in each mix. In the absence of glucagon stimulation, 80% of the glucose produced in primary hepatocytes incorporated either one or two 13C-labeled glycerol molecules in a 1:1 ratio, reflecting the high overall activity of this pathway. In contrast, glucose produced from 13C-labeled pyruvate/lactate or glutamine rarely incorporated two labeled molecules. While glucagon increased the glycerol and pyruvate/lactate contributions to glucose carbon by 1.6- and 1.8-fold, respectively, the glutamine contribution to glucose carbon was increased 6.4-fold in primary hepatocytes. To account for substrate 13C carbon loss during metabolism, we also performed a metabolic flux analysis, which confirmed that the majority of glucose carbon produced by primary hepatocytes was from glycerol. In vivo studies using a PKA-activation mouse model that represents elevated glucagon activity confirmed that most circulating lactate carbons originated from glycerol, but very little glycerol was derived from lactate carbons, reflecting glycerol's importance as a carbon donor to GNG. Given the diverse entry points for GNG substrates, hepatic glucagon action is unlikely to be due to a single mechanism.
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Glucagón , Gluconeogénesis , Ratones , Animales , Glucagón/metabolismo , Glicerol/metabolismo , Glutamina/metabolismo , Glucosa/metabolismo , Hígado/metabolismo , Lactatos/metabolismo , Ácido Láctico/metabolismo , Ácido Pirúvico/metabolismo , Carbono/metabolismoRESUMEN
Aqueous zinc-ion batteries (AZIBs) are considered to be one of the most promising devices for large-scale energy storage systems owing to their high theoretical capacity, environmental friendliness, and safety. However, the ionic intercalation or surface redox mechanisms in conventional cathode materials generally result in unsatisfactory capacities. Conversion-type aqueous zinc-tellurium (Zn-Te) batteries have recently gained widespread attention owing to their high theoretical specific capacities. However, it remains an enormous challenge to improve the slow kinetics of the aqueous Zn-Te batteries. Here, MoO2 nanoclusters embedded in hierarchical nitrogen-doped carbon nanoflower (MoO2 /NC) hosts are successfully synthesized and loaded with Te in aqueous Zn-Te batteries. Benefitting from the highly dispersed MoO2 nanoclusters and hierarchical nanoflower structure with a large specific surface area, the electrochemical kinetics of the Te redox reaction are significantly improved. As a result, the Te-MoO2 /NC electrode exhibits superior cycling stability and a high specific capacity of 493 mAh g-1 at 0.1 A g-1 . Meanwhile, the conversion mechanism is systematically explored using a variety of ex situ characterization methods. Therefore, this study provides a novel approach for enhancing the kinetics of the Te redox reaction in aqueous Zn-Te batteries.
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BACKGROUND: At present, the relationship between severe acute pancreatitis (SAP) and albumin infusion is not clear. We aimed to identify the impact of serum albumin on the prognosis of SAP and the association between albumin infusions and mortality for hypoalbuminemia patients. METHODS: This was a retrospective cohort study that analyzed 1000 patients with SAP who were admitted to the First Affiliated Hospital of Nanchang University between January 2010 and December 2021 using data from a prospectively maintained database. Multivariate logistic regression analysis was conducted to reveal the relationship between serum albumin within 1 week after admission and poor prognosis of SAP. Propensity score matching (PSM) analysis was adopted to evaluate the effect of albumin infusion for hypoalbuminemia patients with SAP. RESULTS: The prevalence of hypoalbuminemia (≤ 30 g/L) was 56.9% within 1 week after admission. Multivariate logistic regression identified that age (OR: 1.02; 95% CI: 1.00-1.04; P = 0.012), serum urea (OR: 1.08; 95% CI: 1.04-1.12; P < 0.001), serum calcium (OR: 0.27; 95% CI: 0.14-0.50; P < 0.001), lowest albumin level within 1 week after admission (OR: 0.93; 95% CI: 0.89-0.97; P = 0.002), and APACHE II score ≥ 15 (OR: 1.73; 95% CI: 1.19-2.51; P = 0.004) were independently associated with mortality. The PSM analysis demonstrated that mortality (OR: 0.52, 95% CI: 0.29-0.92, P = 0.023) was less common in albumin-infused than non-albumin-infused hypoalbuminemia patients. In subgroup analyses, doses > 100 g within 1 week after admission for hypoalbuminemia patients with albumin infusions was associated with lower mortality than doses ≤ 100 g (OR: 0.51, 95% CI: 0.28-0.90, P = 0.020). CONCLUSIONS: Hypoalbuminemia in early-stage SAP is significantly related to poor prognosis. However, albumin infusions could significantly decrease mortality in hypoalbuminemia patients with SAP. Additionally, infusing sufficient albumin within a week after admission may decrease mortality in hypoalbuminemia patients.
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Hipoalbuminemia , Pancreatitis , Humanos , Pancreatitis/complicaciones , Pancreatitis/tratamiento farmacológico , Estudios Retrospectivos , Enfermedad Aguda , Albúmina Sérica , Pronóstico , Factores de RiesgoRESUMEN
Purpose: To evaluate a novel laser angle selection system (LASS) for improving the efficiency of a computed tomography (CT)-guided percutaneous transthoracic needle biopsy (PTNB). Methods: Thirty-eight patients referred for CT-guided PTNB were randomly separated into a LASS-assisted puncture group (18 patients) or conventional freehand control group (20 patients). The puncture time, number of control CT scans, and patients' radiation dose were compared for each group. Results: The lesion size, target-to-pleural distance, planned puncture depth, and angle of the two groups were not significantly different. LASS-assisted PTNB significantly reduced the number of control scans (1.7 ± 0.8 vs 3.5 ± 1.5, P < .001) and the mean operation time (12.0 ± 4.3 min vs 28.8 ± 13.3 min, P < .001) compared with the conventional method. The corresponding room time (27.1 ± 6.6 min vs 44.1 ± 14.4 min, P < .001) and total radiation dose (7.9 ± 1.0 mSv vs 10.1 ± 1.7 mSv, P < .001) of each procedure also decreased significantly. Fifty-six percent (10/18) of the operations hit the target on the first needle pass when using LASS compared with 10% (2/20) using the conventional method. Conclusions: Compared with a conventional method, this novel laser angle simulator improves puncture efficiency with fewer needle readjustments and reduces patient radiation dose.
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Biopsia Guiada por Imagen , Neoplasias Pulmonares , Humanos , Estudios Retrospectivos , Biopsia Guiada por Imagen/métodos , Biopsia con Aguja/métodos , Tomografía Computarizada por Rayos X/métodos , Rayos Láser , Neoplasias Pulmonares/patología , Pulmón/patología , Radiografía Intervencional/métodosRESUMEN
Dominant TBX5 mutation causes Holt-Oram syndrome (HOS), which is characterized by limb defects in humans, but the underlying mechanistic basis is unclear. We used a mouse model with Tbx5 conditional knockdown in Hh-receiving cells (marked by Gli1+) during E8 to E10.5, a previously established model to study atrial septum defects, which displayed polydactyly or hypodactyly. The results suggested that Tbx5 is required for digit identity in a subset of limb mesenchymal cells. Specifically, Tbx5 deletion in this cell population decreased cell apoptosis and increased the proliferation of handplate mesenchymal cells. Furthermore, Tbx5 was found to negatively regulate the Hh-signaling activity through transcriptional regulation of Ptch1, a known Hh-signaling repressor. Repression of Hh-signaling through Smo co-mutation in Tbx5 heterozygotes rescued the limb defects, thus placing Tbx5 upstream of Hh-signaling in limb defects. This work reveals an important missing component necessary for understanding not only limb development but also the molecular and genetic mechanisms underlying HOS.
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Anomalías Múltiples/genética , Cardiopatías Congénitas/genética , Defectos del Tabique Interatrial/genética , Proteínas Hedgehog/genética , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades Inferiores/genética , Receptor Patched-1/genética , Proteínas de Dominio T Box/genética , Deformidades Congénitas de las Extremidades Superiores/genética , Anomalías Múltiples/patología , Animales , Apoptosis/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Técnicas de Silenciamiento del Gen , Cardiopatías Congénitas/patología , Defectos del Tabique Interatrial/patología , Humanos , Deformidades Congénitas de las Extremidades/patología , Deformidades Congénitas de las Extremidades Inferiores/patología , Ratones , Mutación/genética , Transducción de Señal/genética , Receptor Smoothened/genética , Deformidades Congénitas de las Extremidades Superiores/patologíaRESUMEN
BACKGROUND: Renal cell carcinoma (RCC) is one of the most common malignancies worldwide. Noninvasive imaging techniques, such as magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET), have been involved in increasing evolution to detect RCC. This meta-analysis aims to compare to compare the performance of MRI, SPECT, and PET in the detection of RCC in humans, and to provide evidence for decision-making in terms of further research and clinical settings. METHODS: Electronic databases including PubMed, Web of Science, Embase, and Cochrane Library were systemically searched. The keywords such as "magnetic resonance imaging", "MRI", "single-photon emission computed tomography", "SPECT", "positron emission tomography", "PET", "renal cell carcinoma" were used for the search. Studies concerning MRI, SPECT, and PET for the detection of RCC were included. Pooled sensitivity, specificity, and the area under the summary receiver operating characteristic (SROC) curve (AUC), etc. were calculated. RESULTS: A total of 44 articles were finally detected for inclusion in this study. The pooled sensitivities of MRI, 18F-FDG PET and 18F-FDG PET/CT were 0.80, 0.83, and 0.89, respectively. Their respective overall specificities were 0.90, 0.86, and 0.88. The pooled sensitivity and specificity of MRI studies at 1.5 T were 0.86 and 0.94, respectively. With respect to prospective PET studies, the pooled sensitivity, specificity and AUC were 0.90, 0.93 and 0.97, respectively. In the detection of primary RCC, PET studies manifested a pooled sensitivity, specificity, and AUC of 0.77, 0.80, and 0.84, respectively. The pooled sensitivity, specificity, and AUC of PET/CT studies in detecting primary RCC were 0.80, 0.85, and 0.89. CONCLUSION: Our study manifests that MRI and PET/CT present better diagnostic value for the detection of RCC in comparison with PET. MRI is superior in the diagnosis of primary RCC.
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Carcinoma de Células Renales/diagnóstico por imagen , Detección Precoz del Cáncer/estadística & datos numéricos , Neoplasias Renales/diagnóstico por imagen , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Tomografía Computarizada de Emisión de Fotón Único , Adulto , Anciano , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Prospectivos , Radiofármacos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
A new synthetic methodology for the synthesis of 5H-dibenzo[a,d]cycloheptenes from ortho-aryl alkynyl benzyl alcohols and arenes via a Tf2O-mediated formal [5 + 2] annulation reaction has been achieved. From this transformation, structurally diverse 5H-dibenzo[a,d]cycloheptenes were achieved in moderate to good yields. This transformation probably involves an intermolecular Friedel-Crafts-type alkylation and a subsequent intramolecular 7-endo-dig cyclization in one pot, highlighting the high efficiency, regioselectivity, and step-economy of this protocol.
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We tend to investigate the connection between time to appropriate therapy (TTAT) and prognosis in pediatric patients with nosocomial Klebsiella pneumoniae (K. pneumoniae) bloodstream infection, and find the optimal cutoff point for the empirical administration of antimicrobials. This retrospective study was conducted in Children's Hospital of Chongqing Medical University, and inpatients with nosocomial K. pneumoniae bloodstream infection were finally enrolled. We applied the Classification and Regression Tree (CART) analysis to find the TTAT cutoff point and the Logistic Regression analysis to evaluate prognostic indicators. The incidence of septic shock and mortality was 17.91% (12/67) and 13.43% (9/67), respectively. The CART-derived TTAT cutoff point was 10.7 h. The multivariate logistic regression analysis indicated delayed therapy (TTAT ≥ 10.7 h), pediatric risk of mortality (PRISM) III scores ≥ 10, time to positivity (TTP) ≤ 13 h, and requiring for invasive mechanical ventilation were independently associated with the incidence of septic shock (Odds ratio [OR] 9.87, 95% Confidence interval [CI] 1.46-66.59, P = 0.019; OR 9.69, 95% CI 1.15-81.39, P = 0.036; OR 8.28, 95% CI 1.37-50.10, P = 0.021; OR 6.52, 95% CI 1.08-39.51, P = 0.042; respectively) and in-hospital mortality (OR 22.19, 95% CI 1.25-393.94, P = 0.035; OR 40.06, 95% CI 2.32-691.35, P = 0.011; OR 22.60, 95% CI 1.78-287.27, P = 0.016; OR 12.21, 95% CI 1.06-140.67, P = 0.045; respectively).Conclusions: TTAT is an independent predictor of poor outcomes in children with nosocomial K. pneumoniae bloodstream infection. Initial appropriate antimicrobial therapy should be administrated timely and within 10.7 h from the onset of bloodstream infection is recommended.
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Bacteriemia , Infección Hospitalaria , Infecciones por Klebsiella , Choque Séptico , Antibacterianos/uso terapéutico , Bacteriemia/diagnóstico , Bacteriemia/tratamiento farmacológico , Bacteriemia/epidemiología , Niño , Infección Hospitalaria/diagnóstico , Infección Hospitalaria/tratamiento farmacológico , Humanos , Infecciones por Klebsiella/diagnóstico , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Choque Séptico/diagnóstico , Choque Séptico/tratamiento farmacológicoRESUMEN
BACKGROUND & AIMS: Pregnant women may transmit their metabolic phenotypes to their offspring, enhancing the risk for nonalcoholic fatty liver disease (NAFLD); however, the molecular mechanisms remain unclear. METHODS: Prior to pregnancy female mice were fed either a maternal normal-fat diet (NF-group, "no effectors"), or a maternal high-fat diet (HF-group, "persistent effectors"), or were transitioned from a HF to a NF diet before pregnancy (H9N-group, "effectors removal"), followed by pregnancy and lactation, and then offspring were fed high-fat diets after weaning. Offspring livers were analysed by functional studies, as well as next-generation sequencing for gene expression profiles and DNA methylation changes. RESULTS: The HF, but not the H9N offspring, displayed glucose intolerance and hepatic steatosis. The HF offspring also displayed a disruption of lipid homeostasis associated with an altered methionine cycle and abnormal one-carbon metabolism that caused DNA hypermethylation and L-carnitine depletion associated with deactivated AMPK signalling and decreased expression of PPAR-α and genes for fatty acid oxidation. These changes were not present in H9N offspring. In addition, we identified maternal HF diet-induced genes involved in one-carbon metabolism that were associated with DNA methylation modifications in HF offspring. Importantly, the DNA methylation modifications and their associated gene expression changes were reversed in H9N offspring livers. CONCLUSIONS: Our results demonstrate for the first time that maternal HF diet disrupted the methionine cycle and one-carbon metabolism in offspring livers which further altered lipid homeostasis. CpG islands of specific genes involved in one-carbon metabolism modified by different maternal diets were identified.
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Enfermedad del Hígado Graso no Alcohólico , Efectos Tardíos de la Exposición Prenatal , Animales , Carbono/metabolismo , Dieta Alta en Grasa/efectos adversos , Femenino , Humanos , Metabolismo de los Lípidos , Hígado/metabolismo , Ratones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , EmbarazoRESUMEN
An efficient method for the direct preparation of 3-aceto(cyano)methyl-substituted benzothio(seleno)phenes has been achieved through C(sp3)-H bond activation of easily available acetone or acetonitrile and cascade radical cyclization reaction. In this cascade radical cyclization reaction, C(sp2)-C(sp3) and C(sp2)-S bonds, as well as benzenethio(seleno)phene skeletons, can be built along with the cleavage of the C(sp3)-S bond, demonstrating the high step-economics and efficiency of this approach.
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Anaerobic digestion (AD) comprises a series of biochemical reactions, with methane as one of the target products. Amino acids (AAs) are important molecular and primary intermediate products when protein is the main component of organic waste/wastewater. The L (levorotatory, left-handed)-configuration is natural for AAs, while D (dextrorotatory, right-handed) -AAs also widely exist in the natural environment and can be generated by racemization. However, the effects and underlying mechanisms of natural AAs and their enantiomers on the methane yield and the underlying mechanisms remain unclear. In this study, the effects of certain widespread L-AAs and their enantiomers on two-stage AD and the mechanisms therein were investigated. The AAs enantiomers showed variable or even opposite effects on different processes. The methane yield from a model monosaccharide (glucose) decreased by 57% with D-leucine addition. The butyrate generation and the methane yield from propionate were sensitive to the AA configuration and were inhibited by D-leucine by 80% and 61.8%, respectively, with D-leucine addition, while the volatile fatty acids concentration was slightly increased with the addition of L-leucine. The related mechanisms were further investigated in terms of key enzymes and microbial communities. The addition of D-Leucine decreased acetic acid production from homoacetogens by 30.2% due to the inhibition of key enzymes involved in hydrogen generation and consumption. The transform of butyryl CoA to butyryl phosphate was the rate-limiting step, with the related enzyme (phosphotransbutylase) was inhibited by D-leucine. Furthermore, the bacteria related to butyric acid generation and organic matter degradation were inhibited by D-leucine, while the methanogenic archaea remained stable irrespective of leucine addition. The effect of D-AAs on microorganisms is related to the type of sludge. In this study, the methanogenetic seed sludge was granular and did not dissociate after treatment; however, the D-AAs could trigger biofilm disassembly and reduce the stability of the sludge floc. The study provides a novel method for regulating AD by adding specific AAs with L or D configuration.
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Reactores Biológicos , Metano , Aminoácidos , Anaerobiosis , Biotransformación , Ácidos Grasos Volátiles , Aguas del AlcantarilladoRESUMEN
Gluconeogenesis (GNG) is de novo production of glucose from endogenous carbon sources. Although it is a commonly studied pathway, particularly in disease, there is a lack of consensus about substrate preference. Moreover, primary hepatocytes are the current gold standard for in vitro liver studies, but no direct comparison of substrate preference at physiological fasting concentrations has been performed. We show that mouse primary hepatocytes prefer glycerol to pyruvate/lactate in glucose production assays and 13C isotope tracing studies at the high concentrations commonly used in the literature, as well as at more relevant fasting, physiological concentrations. In addition, when glycerol, pyruvate/lactate, and glutamine are all present, glycerol is responsible for over 75% of all glucose carbons labeled. We also found that glycerol can induce a rate-limiting enzyme of GNG, glucose-6-phosphatase. Lastly, we suggest that glycerol is a better substrate than pyruvate to test in vivo production of glucose in fasting mice. In conclusion, glycerol is the major carbon source for GNG in vitro and in vivo and should be compared with other substrates when studying GNG in the context of metabolic disease states.
Asunto(s)
Gluconeogénesis/efectos de los fármacos , Glucosa-6-Fosfatasa/biosíntesis , Glicerol/farmacología , Hepatocitos/metabolismo , Animales , Inducción Enzimática/efectos de los fármacos , Hepatocitos/citología , Ácido Láctico/metabolismo , Ratones , Ácido Pirúvico/metabolismoRESUMEN
Nonalcoholic fatty liver disease (NAFLD) has a developmental origin and is influenced in utero. We aimed to evaluate if maternal diet intervention before pregnancy would be beneficial to reduce the risk of offspring NAFLD. In our study, female mice were either on a normal-fat diet (NF group), or a high-fat diet for 12 weeks and continued on this diet throughout pregnancy and lactation (HF group), or switched from HF-to-NF diet 1 week (H1N group), or 9 weeks (H9N group) before pregnancy. Compared with the NF offspring, the H1N and HF, but not the H9N offspring, displayed more severe hepatic steatosis and glucose intolerance. More specifically, an abnormal blood lipid panel was seen in the H1N offspring and abnormal hepatic free fatty acid composition was present in both the HF and H1N offspring, while the H9N offspring displayed both at normal levels. These physiological changes were associated with desensitized hepatic insulin/AKT signaling, increased expression of genes and proteins for de novo lipogenesis and cholesterol synthesis, decreased expression of genes and proteins for fatty acid oxidation, increased Pcsk9 expression, and hypoactivation of 5' AMP-activated protein kinase (AMPK) signaling in the HF and H1N offspring. However, these effects were completely or partially rescued in the H9N offspring. In summary, we found that early maternal diet intervention is effective in reducing the risk of offspring NAFLD caused by maternal HF diet. These findings provide significant support to develop effective diet intervention strategies and policies for prevention of obesity and NAFLD to promote optimal health outcomes for mothers and children.