RESUMO
The pulp and paper industry is an important contributor to global greenhouse gas emissions1,2. Country-specific strategies are essential for the industry to achieve net-zero emissions by 2050, given its vast heterogeneities across countries3,4. Here we develop a comprehensive bottom-up assessment of net greenhouse gas emissions of the domestic paper-related sectors for 30 major countries from 1961 to 2019-about 3.2% of global anthropogenic greenhouse gas emissions from the same period5-and explore mitigation strategies through 2,160 scenarios covering key factors. Our results show substantial differences across countries in terms of historical emissions evolution trends and structure. All countries can achieve net-zero emissions for their pulp and paper industry by 2050, with a single measure for most developed countries and several measures for most developing countries. Except for energy-efficiency improvement and energy-system decarbonization, tropical developing countries with abundant forest resources should give priority to sustainable forest management, whereas other developing countries should pay more attention to enhancing methane capture rate and reducing recycling. These insights are crucial for developing net-zero strategies tailored to each country and achieving net-zero emissions by 2050 for the pulp and paper industry.
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Agricultura Florestal , Efeito Estufa , Gases de Efeito Estufa , Indústrias , Internacionalidade , Papel , Desenvolvimento Sustentável , Madeira , Efeito Estufa/prevenção & controle , Efeito Estufa/estatística & dados numéricos , Gases de Efeito Estufa/análise , Gases de Efeito Estufa/isolamento & purificação , Indústrias/legislação & jurisprudência , Indústrias/estatística & dados numéricos , Metano/análise , Metano/isolamento & purificação , Reciclagem/estatística & dados numéricos , Reciclagem/tendências , Países Desenvolvidos , Países em Desenvolvimento , Florestas , Agricultura Florestal/métodos , Agricultura Florestal/tendências , Desenvolvimento Sustentável/tendências , Clima TropicalRESUMO
Glucagon-like peptide-1 (GLP-1) and its analogs are widely used for diabetes treatment. The paraventricular nucleus (PVN) is crucial for regulating cardiovascular activity. This study aims to determine the roles of GLP-1 and its receptors (GLP-1R) in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male normotensive rats and spontaneously hypertensive rats (SHR). Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. GLP-1 and GLP-1R expressions were present in the PVN. PVN microinjection of GLP-1R agonist recombinant human GLP-1 (rhGLP-1) or EX-4 increased RSNA and MAP, which were prevented by GLP-1R antagonist exendin 9-39 (EX9-39) or GLP-1R antagonist 1, superoxide scavenger tempol, antioxidant N-acetylcysteine, NADPH oxidase (NOX) inhibitor apocynin, adenylyl cyclase (AC) inhibitor SQ22536 or protein kinase A (PKA) inhibitor H89. PVN microinjection of rhGLP-1 increased superoxide production, NADPH oxidase activity, cAMP level, AC, and PKA activity, which were prevented by SQ22536 or H89. GLP-1 and GLP-1R were upregulated in the PVN of SHR. PVN microinjection of GLP-1 agonist increased RSNA and MAP in both WKY and SHR, but GLP-1 antagonists caused greater effects in reducing RSNA and MAP in SHR than in WKY. The increased superoxide production and NADPH oxidase activity in the PVN of SHR were augmented by GLP-1R agonists but attenuated by GLP-1R antagonists. These results indicate that activation of GLP-1R in the PVN increased sympathetic outflow and blood pressure via cAMP-PKA-mediated NADPH oxidase activation and subsequent superoxide production. GLP-1 and GLP-1R upregulation in the PVN partially contributes to sympathetic overactivity and hypertension.
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Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipertensão , Núcleo Hipotalâmico Paraventricular , Ratos Endogâmicos SHR , Sistema Nervoso Simpático , Animais , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Masculino , Hipertensão/fisiopatologia , Hipertensão/metabolismo , Ratos , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Ratos Endogâmicos WKY , Ratos Sprague-DawleyRESUMO
Multiple transcript isoforms of genes can be formed by processing and modifying the 5' and 3' ends of RNA. Herein, the aim of this study is to uncover the characteristics of RNA processing modification (RPM) in hepatocellular carcinoma (HCC), and to identify novel biomarkers and potential targets for treatment. Firstly, integrated bioinformatics analysis was carried out to identify risk prognostic RPM regulators (RPMRs). Then, we used these RPMRs to identify subtypes of HCC and explore differences in immune microenvironment and cellular function improvement pathways between the sub-types. Finally, we used the principal component analysis algorithms to estimate RPMscore, which were applied to 5 cohorts. Lower RPMscore among patients correlated with a declined survival rate, increased immune infiltration, and raised expression of immune checkpoints, aligning with the "immunity tidal model theory". The RPMscore exhibited robust, which was validated in multiple datasets. Mechanistically, low RPMscore can create an immunosuppressive microenvironment in HCC by manipulating tumor-associated macrophages. Preclinically, patients with high RPMscore might benefit from immunotherapy. The RPMscore is helpful in clustering HCC patients with distinct prognosis and immunotherapy. Our RPMscore model can help clinicians to select personalized therapy for HCC patients, and RPMscore may act a part in the development of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Microambiente Tumoral , Processamento Pós-Transcricional do RNA , ImunoterapiaRESUMO
Atherosclerosis (AS) is the underlying cause of many severe vascular diseases and is primarily characterized by abnormal lipid metabolism. Paeonol (Pae), a bioactive compound derived from Paeonia Suffruticosa Andr., is recognized for its significant role in reducing lipid accumulation. Our research objective is to explore the link between lipid buildup in foam cells originating from macrophages and the process of ferroptosis, and explore the effect and mechanism of Pae on inhibiting AS by regulating ferroptosis. In our animal model, ApoE-deficient mice, which were provided with a high-fat regimen to provoke atherosclerosis, were administered Pae. The treatment was benchmarked against simvastatin and ferrostatin-1. The results showed that Pae significantly reduced aortic ferroptosis and lipid accumulation in the mice. In vitro experiments further demonstrated that Pae could decrease lipid accumulation in foam cells induced by oxidized low-density lipoprotein (LDL) and challenged with the ferroptosis inducer erastin. Crucially, the protective effect of Pae against lipid accumulation was dependent on the SIRT1/NRF2/GPX4 pathway, as SIRT1 knockdown abolished this effect. Our findings suggest that Pae may offer a novel therapeutic approach for AS by inhibiting lipid accumulation through the suppression of ferroptosis, mediated by the SIRT1/NRF2/GPX4 pathway. Such knowledge has the potential to inform the creation of novel therapeutic strategies aimed at regulating ferroptosis within the context of atherosclerosis.
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Acetofenonas , Aterosclerose , Ferroptose , Animais , Camundongos , Células Espumosas , Fator 2 Relacionado a NF-E2 , Sirtuína 1 , Macrófagos , Aterosclerose/tratamento farmacológico , Transdução de SinaisRESUMO
BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS: This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION: Clinical Trials Registry: NCT04424147.
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Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Azacitidina/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/uso terapêutico , Mepesuccinato de Omacetaxina/uso terapêutico , Leucemia Mieloide Aguda/terapia , Resposta Patológica Completa , Sorafenibe/efeitos adversos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , IdosoRESUMO
Accurate cell classification is the groundwork for downstream analysis of single-cell sequencing data, yet how to identify true marker genes for different cell types still remains a big challenge. Here, we report COSine similarity-based marker Gene identification (COSG) as a cosine similarity-based method for more accurate and scalable marker gene identification. COSG is applicable to single-cell RNA sequencing data, single-cell ATAC sequencing data and spatially resolved transcriptome data. COSG is fast and scalable for ultra-large datasets of million-scale cells. Application on both simulated and real experimental datasets showed that the marker genes or genomic regions identified by COSG have greater cell-type specificity, demonstrating the superior performance of COSG in terms of both accuracy and efficiency as compared with other available methods.
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Análise de Célula Única , Transcriptoma , Perfilação da Expressão Gênica , Análise de Sequência de RNA , Análise de Célula Única/métodos , Sequenciamento do ExomaRESUMO
BACKGROUND: Myelodysplastic neoplasms (MDS) are myeloid neoplasms characterized by disordered differentiation of hematopoietic stem cells and a predisposition to acute myeloid leukemia (AML). The underline pathogenesis remains unclear. METHODS: In this study, the trajectory of differentiation and mechanisms of leukemic transformation were explored through bioinformatics analysis of single-cell RNA-Seq data from hematopoietic stem and progenitor cells (HSPCs) in MDS patients. RESULTS: Among the HSPC clusters, the proportion of common myeloid progenitor (CMP) was the main cell cluster in the patients with excess blasts (EB)/ secondary AML. Cell cycle analysis indicated the CMP of MDS patients were in an active proliferative state. The genes involved in the cell proliferation, such as MAML3 and PLCB1, were up-regulated in MDS CMP. Further validation analysis indicated that the expression levels of MAML3 and PLCB1 in patients with MDS-EB were significantly higher than those without EB. Patients with high expression of PLCB1 had a higher risk of transformation to AML. PLCB1 inhibitor can suppress proliferation, induce cell cycle arrest, and activate apoptosis of leukemic cells in vitro. CONCLUSION: This study revealed the transcriptomic change of HSPCs in MDS patients along the pseudotime and indicated that PLCB1 plays a key role in the transformation of MDS into leukemia.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Transcriptoma , Células-Tronco Hematopoéticas/metabolismo , Síndromes Mielodisplásicas/patologia , Leucemia Mieloide Aguda/genética , Perfilação da Expressão GênicaRESUMO
BACKGROUND: The identification of survival predictors is crucial for early intervention to improve outcome in acute myeloid leukemia (AML). This study aim to identify chest computed tomography (CT)-derived features to predict prognosis for acute myeloid leukemia (AML). METHODS: 952 patients with pathologically-confirmed AML were retrospectively enrolled between 2010 and 2020. CT-derived features (including body composition and subcutaneous fat features), were obtained from the initial chest CT images and were used to build models to predict the prognosis. A CT-derived MSF nomogram was constructed using multivariate Cox regression incorporating CT-based features. The performance of the prediction models was assessed with discrimination, calibration, decision curves and improvements. RESULTS: Three CT-derived features, including myosarcopenia, spleen_CTV, and SF_CTV (MSF) were identified as the independent predictors for prognosis in AML (P < 0.01). A CT-MSF nomogram showed a performance with AUCs of 0.717, 0.794, 0.796 and 0.792 for predicting the 1-, 2-, 3-, and 5-year overall survival (OS) probabilities in the validation cohort, which were significantly higher than the ELN risk model. Moreover, a new MSN stratification system (MSF nomogram plus ELN risk model) could stratify patients into new high, intermediate and low risk group. Patients with high MSN risk may benefit from intensive treatment (P = 0.0011). CONCLUSIONS: In summary, the chest CT-MSF nomogram, integrating myosarcopenia, spleen_CTV, and SF_CTV features, could be used to predict prognosis of AML.
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Leucemia Mieloide Aguda , Nomogramas , Humanos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Área Sob a Curva , Leucemia Mieloide Aguda/diagnóstico por imagemRESUMO
Upgrading to the CHINA 7 standard is crucial for managing air pollution from passenger vehicles in China. Meanwhile, China aims to achieve carbon neutrality by 2060, which necessitates large-scale replacement of gasoline vehicles with electric vehicles in the future. Consequently, the public might view upgrading gasoline vehicles to the CHINA 7 standard as redundant. However, the emission reduction benefits of upgrading standards in the context of uncertain electrification ambitions have not received adequate attention. Here, we show that upgrading standards will compensate for the absence of emissions reductions due to hindered electrification efforts. In the best scenario, China's CO2 emissions can be reduced to 0.047 Gt and NOx to 8.2 × 103 t in 2050. In nonextreme electrification scenarios with CHINA 7 standard, the emission intensity reduction will remain the main driver for emission reductions, outweighing the electrification contribution. In extreme electrification scenarios, upgrading standards will tackle the increased emissions from plug-in hybrid electric vehicles. Our fleet-level results advocate for early standards upgrades to enhance resilience against air pollution risks arising from uncertainties in electrification. Our evidence from China, with one of the most stringent emission standards, can provide a reference point for the world on the upgrading passenger vehicle emission standard issue.
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Poluentes Atmosféricos , Poluição do Ar , Emissões de Veículos/prevenção & controle , Emissões de Veículos/análise , Poluentes Atmosféricos/análise , Gasolina , Incerteza , Poluição do Ar/prevenção & controle , Poluição do Ar/análise , China , Veículos AutomotoresRESUMO
INTRODUCTION: This meta-analysis aimed to investigate the effect of SGLT2 inhibitors on the prognosis of patients with heart failure (HF) or at risk of HF across different body mass index (BMI). METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Library for all randomized controlled trials comparing SGLT2 inhibitors with placebo in patients with HF or at risk of HF and extracted relevant data up to April 2023 for meta-analysis. RESULTS: A total of 29,500 patients were enrolled in the selected five studies. The results showed that patients treated with SGLT2 inhibitors had lower HF hospitalization (HHF) or cardiovascular (CV) mortality compared to those taking placebo (hazard ratio [HR] = 0.73, p < 0.001). Patients taking SGLT2 inhibitors also had a lower all-cause mortality rate than those taking placebo (HR = 0.85, p = 0.017). In BMI subgroup analysis, the HHF rate in the experimental group was lower than that in the control group at BMI ≤24.9 kg/m2, 25.0-29.9 kg/m2, and ≥30.0 kg/m2. There was no significant difference in CV mortality between the two groups at BMI ≤24.9 kg/m2 (HR = 0.91, p = 0.331) and 25.0-29.9 kg/m2 (HR = 0.92, p = 0.307). However, when the BMI was ≥30.0 kg/m2, CV mortality with SGLT2 inhibitors was lower than in the control group (HR = 0.79, p = 0.002). When patients had a BMI ≤24.9 kg/m2 (HR = 0.85, p = 0.033) and 25.0-29.9 kg/m2 (HR = 0.83, p = 0.046), the all-cause mortality was lower in the experimental group than in the control group. However, there was no significant difference between the 2 groups in patients with a BMI ≥30.0 kg/m2 (HR = 0.87, p = 0.094). CONCLUSION: SGLT2 inhibitors improve the prognosis in patients with HF or at risk of HF. This effect is affected by BMI.
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Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Índice de Massa Corporal , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Hospitalização , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
BACKGROUND: This study aims to investigate the effect of PD-1/PD-L1 immunotherapy on cardiac-related adverse events in patients with advanced or metastatic lung cancer. METHODS: We conducted a detailed search in PubMed, Web of Science, Cochran, and Embase for articles on the application of immunotherapy for lung cancer and report cardiac-related adverse events with respect to myocardial ischemia, pericardial effusion, myocarditis, and electrophysiology. The dichotomous variables were assessed by relative risk (RR) and 95% confidence intervals (CI). RESULTS: A total of 7132 subjects were included in 12 phase III randomized controlled trials (RCTs). The results showed that under the fixed effects model, the probability of cardiac-related adverse events in pericardial effusion was higher in the experimental group than in the control group (RR 2.30, 95% CI 1.01-5.21, P = 0.05). Under the random effects model, there was no statistical difference between the two groups (RR 2.03, 95% CI 0.81-5.12, P = 0.13). No statistical difference is observed between the experimental group and the control group (under the fixed effects model and the random effects model) for other cardiac-related adverse events, including myocarditis, acute coronary syndrome, myocardial infarction, acute myocardial infarction, myocardial ischemia, unstable angina, ventricular tachycardia, supraventricular tachycardia, tachycardia, bradycardia, atrial flutter, atrial fibrillation, cardiac failure, cardiac arrest, cardiopulmonary failure, acute heart failure, cardiac arrest (all P > 0.05). CONCLUSIONS: PD-1/PD-L1 immunotherapy in advanced or metastatic lung cancer is generally safe for cardiac-related adverse events.
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Insuficiência Cardíaca , Neoplasias Pulmonares , Isquemia Miocárdica , Miocardite , Derrame Pericárdico , Humanos , Receptor de Morte Celular Programada 1 , Antígeno B7-H1 , Neoplasias Pulmonares/terapia , Imunoterapia/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Although donepezil is a commonly used drug for treating Alzheimer's disease (AD), the mechanisms by which it affects patients' functional brain activity, and thus modulates clinical symptoms, remain unclear. METHODS: In the present study, we used resting-state functional magnetic resonance imaging (MRI) and regional homogeneity (ReHo) to investigate the effects of donepezil on local brain activity in AD patients. Resting-state functional MRI data were collected from 32 subjects: 16 healthy controls and 16 AD patients. All 16 AD patients underwent 6 months of donepezil treatment and received two MRI scans (pre- and post-intervention). Analysis of covariance and post hoc analyses were used to compare ReHo differences among the healthy controls, pre-intervention AD patients, and post-intervention AD patients. Pearson correlation analysis was used to examine relationships between ReHo values in differential brain regions and clinical symptoms. RESULTS: Compared with healthy controls, post-intervention AD patients had reduced ReHo in the orbital part of the inferior frontal gyrus, and pre-intervention AD patients had reduced ReHo in the orbital part of the right inferior frontal gyrus. Pattern recognition models revealed that pre-intervention ReHo values in abnormal brain regions of AD patients were 76% accurate for predicting the efficacy of donepezil on cognitive function and 65% accurate for predicting its efficacy on depressive symptoms. CONCLUSIONS: These findings deepen our understanding of the brain mechanisms underlying the clinical efficacy of donepezil in AD patients, and provide a novel way to predict its clinical efficacy in such patients.
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Doença de Alzheimer , Humanos , Donepezila/uso terapêutico , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Córtex Pré-Frontal/diagnóstico por imagem , Encéfalo , CogniçãoRESUMO
Atherosclerosis is a chronic inflammatory disease leading to various vascular diseases. Vascular smooth muscle cell (VSMC) senescence promotes atherosclerotic inflammation and the formation of plaque necrosis core, in part through telomere damage mediated by a high-fat diet. Our previous research found that paeonol, a potential anti-inflammatory agent extracted from Cortex Moutan, could significantly improve VSMCs dysfunction. However, the impact of paeonol on the senescence of VSMCs remains unexplored. This study presents the protective effects of paeonol on VSMCs senescence, and its potential activity in inhibiting the progression of atherosclerosis in vivo and in vitro. Sirtuin 1 (SIRT1) is a nuclear deacetylase involved in cell proliferation, senescence, telomere damage, and inflammation. Here, SIRT1 was identified as a potential target of paeonol having anti-senescence and anti-atherosclerosis activity. Mechanistic studies revealed that paeonol binds directly to SIRT1 and then activates the SIRT1/P53/TRF2 pathway to inhibit VSMCs senescence. Our results suggested that SIRT1-mediated VSMCs senescence is a promising druggable target for atherosclerosis, and that pharmacological modulation of the SIRT1/P53/TRF2 signaling pathway by paeonol is of potential benefit for patients with atherosclerosis.
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Acetofenonas , Aterosclerose , Sirtuínas , Humanos , Sirtuína 1 , Músculo Liso Vascular , Proteína Supressora de Tumor p53 , Aterosclerose/tratamento farmacológico , Inflamação , Transdução de SinaisRESUMO
BACKGROUND: Delirium is a common acute mental disorder, and its adverse outcomes often cause distress to both patients and their families. Despite its prevalence in patients treated in emergency departments, delirium is frequently overlooked. AIM: This study aims to systematically evaluated and meta-analysis the prevalence of delirium among emergency patients, providing insights into its prevalence and offering guidance for its management and prevention. STUDY DESIGN: Observational studies on the prevalence of delirium in emergency departments were systematically searched in PubMed, Embase, the Cochrane Library and Medline databases. Relevant English-language studies published up to 18 September 2023 were reviewed, and meta-analysis was conducted using Stata 14.0 software. Quality assessment of included literature was performed using the methodological index for non-randomized studies (MINORS), and publication bias was assessed using Egger's test. RESULTS: Thirteen studies encompassing a total sample size of 33 839 cases were included, with 3082 cases of delirium incidents. The findings revealed a 15% prevalence rate of delirium in emergency departments, with a 95% confidence interval (CI) of (0.10, 0.20) and an overall heterogeneity of 98.37% (p = .000). Among emergency department patients over 65 years of age, the prevalence of delirium was 12%, with a 95% CI of (0.07, 0.19) and a heterogeneity of 94.59%. For patients over 18 years of age, the prevalence was 17%, with a 95% CI of (0.10, 0.25) and a heterogeneity of 98.94%. CONCLUSIONS: This meta-analysis reveals an overall 15% prevalence rate of delirium among patients in emergency departments. RELEVANCE TO CLINICAL PRACTICE: In clinical practice, emergency medical staff should strengthen the screening and management of emergency delirium patients.
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The antibiotic resistance crisis continues to threaten human health. Better predictions of the evolution of antibiotic resistance genes could contribute to the design of more sustainable treatment strategies. However, comprehensive prediction of antibiotic resistance gene evolution via laboratory approaches remains challenging. By combining site-specific integration and high-throughput sequencing, we quantified relative growth under the respective selection of cefotaxime or ceftazidime selection in â¼23,000 Escherichia coli MG1655 strains that each carried a unique, single-copy variant of the extended-spectrum ß-lactamase gene blaCTX-M-14 at the chromosomal att HK022 site. Significant synergistic pleiotropy was observed within four subgenic regions, suggesting key regions for the evolution of resistance to both antibiotics. Moreover, we propose PEARP and PEARR, two deep-learning models with strong clinical correlations, for the prospective and retrospective prediction of blaCTX-M-14 evolution, respectively. Single to quintuple mutations of blaCTX-M-14 predicted to confer resistance by PEARP were significantly enriched among the clinical isolates harboring blaCTX-M-14 variants, and the PEARR scores matched the minimal inhibitory concentrations obtained for the 31 intermediates in all hypothetical trajectories. Altogether, we conclude that the measurement of local fitness landscape enables prediction of the evolutionary trajectories of antibiotic resistance genes, which could be useful for a broad range of clinical applications, from resistance prediction to designing novel treatment strategies.
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Infecções por Escherichia coli , beta-Lactamases , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Resistência Microbiana a Medicamentos , Escherichia coli/genética , Infecções por Escherichia coli/tratamento farmacológico , Humanos , Estudos Prospectivos , Estudos Retrospectivos , beta-Lactamases/genéticaRESUMO
BACKGROUND & AIMS: The screening yield and related cost of a risk-adapted screening approach compared with established screening strategies in population-based colorectal cancer (CRC) screening are not clear. METHODS: We randomly allocated 19,373 participants into 1 of the 3 screening arms in a 1:2:2 ratio: (1) one-time colonoscopy (n = 3883); (2) annual fecal immunochemical test (FIT) (n = 7793); (3) annual risk-adapted screening (n = 7697), in which, based on the risk-stratification score, high-risk participants were referred for colonoscopy and low-risk ones were referred for FIT. Three consecutive screening rounds were conducted for both the FIT and the risk-adapted screening arms. Follow-up to trace the health outcome for all the participants was conducted over the 3-year study period. The detection rate of advanced colorectal neoplasia (CRC and advanced precancerous lesions) was the main outcome. The trial was registered in the Chinese Clinical Trial Registry (number: ChiCTR1800015506). RESULTS: In the colonoscopy, FIT, and risk-adapted screening arms over 3 screening rounds, the participation rates were 42.4%, 99.3%, and 89.2%, respectively; the detection rates for advanced neoplasm (intention-to-treat analysis) were 2.76%, 2.17%, and 2.35%, respectively, with an odds ratio (OR)colonoscopy vs FIT of 1.27 (95% confidence interval [CI]: 0.99-1.63; P = .056), an ORcolonoscopy vsrisk-adapted screening of 1.17 (95% CI, 0.91-1.49; P = .218), and an ORrisk-adapted screeningvs FIT of 1.09 (95% CI, 0.88-1.35; P = .438); the numbers of colonoscopies needed to detect 1 advanced neoplasm were 15.4, 7.8, and 10.2, respectively; the costs for detecting 1 advanced neoplasm from a government perspective using package payment format were 6928 Chinese Yuan (CNY) ($1004), 5821 CNY ($844), and 6694 CNY ($970), respectively. CONCLUSIONS: The risk-adapted approach is a feasible and cost-favorable strategy for population-based CRC screening and therefore could complement the well-established one-time colonoscopy and annual repeated FIT screening strategies. (Chinese Clinical Trial Registry; ChiCTR1800015506).
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Neoplasias Colorretais , Detecção Precoce de Câncer , Humanos , Colonoscopia , Neoplasias Colorretais/diagnóstico , Fatores de Risco , Programas de Rastreamento , Sangue Oculto , FezesRESUMO
Mitophagy is the lysosome-dependent degradation of damaged and dysfunctional mitochondria, which is closely associated with H2O2-related redox imbalance and pathological processes. However, development of fast-responding and highly sensitive reversible fluorescent probes for monitoring of mitochondrial H2O2 dynamics is still lacking. Herein, we report a reversible fluorescent probe (M-HP) that enables real-time imaging of H2O2-related redox imbalance. In vitro studies demonstrated that M-HP had a rapid response and high sensitivity to the H2O2/GSH redox cycle, with a detection limit of 17 nM for H2O2. M-HP was applied to imaging of H2O2 fluctuation in living cells with excellent reversibility and mitochondrial targeting. M-HP reveals an increase in mitochondrial H2O2 under lipopolysaccharide stimulation and a decrease in H2O2 following the combined treatment with rapamycin. This suggests that the level of oxidative stress is significantly suppressed after the enhancement of mitophagy. The rationally designed M-HP offers a powerful tool for understanding redox imbalance during mitophagy.
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Corantes Fluorescentes , Mitofagia , Peróxido de Hidrogênio , Terapia Combinada , OxirreduçãoRESUMO
Fluorescent probes have emerged as powerful tools for the detection of different analytes by virtue of structural tenability. However, the requirement of an excitation source largely hinders their applicability in point-of-care detection, as well as causing autofluorescence interference in complex samples. Herein, based on bioluminescence resonance energy transfer (BRET), we developed a reaction-based ratiometric bioluminescent platform, which allows the excitation-free detection of analytes. The platform has a modular design consisting of a NanoLuc-HaloTag fusion as an energy donor, to which a synthetic fluorescent probe is bioorthogonally labeled as recognition moiety and energy acceptor. Once activated by the target, the fluorescent probe can be excited by NanoLuc to generate a remarkable BRET signal, resulting in obvious color changes of luminescence, which can be easily recorded and quantitatively analyzed by a smartphone. As a proof of concept, a fluorescent probe for HOCl was synthesized to construct the bioluminescent system. Results demonstrated the system showed a constant blue/red emission ratio which is independent to the signal intensity, allowing the quantification of HOCl concentration with high sensitivity (limit of detection (LOD) = 13 nM) and accuracy. Given the universality, this reaction-based bioluminescent platform holds great potential for point-of-care and quantitative detection of reactive species.
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Corantes Fluorescentes , Smartphone , Corantes Fluorescentes/química , Sistemas Automatizados de Assistência Junto ao Leito , Transferência de Energia , Testes ImunológicosRESUMO
Metal nanoparticles have attracted considerable scientific and technological interest in recent years, most related explorations and reports are focused on transition and noble metals. However, the synthesis and application of light metal nanoparticles represented by Mg have not been fully exploited, limited by their ultrahigh reactivity in air and preparation in harsh conditions. In this work, a simple and effective one-step organic solvent-assisted ball-milling process is developed to synthesize Mg and Li nanoparticles, which permits the formation of MgH2 in a hydrogen atmosphere in a one-step reaction process at ambient temperature. Further studies suggest that acetone chemisorbs on defects/surfaces of Mg during ball milling leading to the formation of a metastable magnesium complex, which significantly alters the physical and chemical characteristics of Mg grains. The formation of metastable complexes provides an attractive strategy to produce light metal nanoparticles and inspires the authors to study the interaction of organic solvents with light metals.
RESUMO
DNA repeats are abundant in eukaryotic genomes and have been proved to play a vital role in genome evolution and regulation. A large number of approaches have been proposed to identify various repeats in the genome. Some de novo repeat identification tools can efficiently generate sequence repetitive scores based on k-mer counting for repeat detection. However, we noticed that these tools can still be improved in terms of repetitive score calculation, sensitivity to segmental duplications and detection specificity. Therefore, here, we present a new computational approach named Repeat Locator (RepLoc), which is based on weighted k-mer coverage to quantify the genome sequence repetitiveness and locate the repetitive sequences. According to the repetitiveness map of the human genome generated by RepLoc, we found that there may be relationships between sequence repetitiveness and genome structures. A comprehensive benchmark shows that RepLoc is a more efficient k-mer counting based tool for de novo repeat detection. The RepLoc software is freely available at http://bis.zju.edu.cn/reploc.