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Recognizing binding sites of DNA-binding proteins is a key factor for elucidating transcriptional regulation in organisms. ChIP-exo enables researchers to delineate genome-wide binding landscapes of DNA-binding proteins with near single base-pair resolution. However, the peak calling step hinders ChIP-exo application since the published algorithms tend to generate false-positive and false-negative predictions. Here, we report the development of DEOCSU (DEep-learning Optimized ChIP-exo peak calling SUite), a novel machine learning-based ChIP-exo peak calling suite. DEOCSU entails the deep convolutional neural network model which was trained with curated ChIP-exo peak data to distinguish the visualized data of bona fide peaks from false ones. Performance validation of the trained deep-learning model indicated its high accuracy, high precision and high recall of over 95%. Applying the new suite to both in-house and publicly available ChIP-exo datasets obtained from bacteria, eukaryotes and archaea revealed an accurate prediction of peaks containing canonical motifs, highlighting the versatility and efficiency of DEOCSU. Furthermore, DEOCSU can be executed on a cloud computing platform or the local environment. With visualization software included in the suite, adjustable options such as the threshold of peak probability, and iterable updating of the pre-trained model, DEOCSU can be optimized for users' specific needs.
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Secuenciación de Inmunoprecipitación de Cromatina , Aprendizaje Profundo , Inmunoprecipitación de Cromatina , Proteínas de Unión al ADN/metabolismo , Programas Informáticos , Algoritmos , Sitios de Unión , Análisis de Secuencia de ADNRESUMEN
While global transcription factors (TFs) have been studied extensively in Escherichia coli model strains, conservation and diversity in TF regulation between strains is still unknown. Here we use a combination of ChIP-exo-to define ferric uptake regulator (Fur) binding sites-and differential gene expression-to define the Fur regulon in nine E. coli strains. We then define a pan-regulon consisting of 469 target genes that includes all Fur target genes in all nine strains. The pan-regulon is then divided into the core regulon (target genes found in all the strains, n = 36), the accessory regulon (target found in two to eight strains, n = 158) and the unique regulon (target genes found in one strain, n = 275). Thus, there is a small set of Fur regulated genes common to all nine strains, but a large number of regulatory targets unique to a particular strain. Many of the unique regulatory targets are genes unique to that strain. This first-established pan-regulon reveals a common core of conserved regulatory targets and significant diversity in transcriptional regulation amongst E. coli strains, reflecting diverse niche specification and strain history.
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Proteínas de Escherichia coli , Escherichia coli , Regulón , Proteínas Represoras , Escherichia coli/genética , Escherichia coli/metabolismo , Regulación Bacteriana de la Expresión Génica , Hierro/metabolismo , Regulón/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Factores de TranscripciónRESUMEN
Transcriptomic data is accumulating rapidly; thus, scalable methods for extracting knowledge from this data are critical. Here, we assembled a top-down expression and regulation knowledge base for Escherichia coli. The expression component is a 1035-sample, high-quality RNA-seq compendium consisting of data generated in our lab using a single experimental protocol. The compendium contains diverse growth conditions, including: 9 media; 39 supplements, including antibiotics; 42 heterologous proteins; and 76 gene knockouts. Using this resource, we elucidated global expression patterns. We used machine learning to extract 201 modules that account for 86% of known regulatory interactions, creating the regulatory component. With these modules, we identified two novel regulons and quantified systems-level regulatory responses. We also integrated 1675 curated, publicly-available transcriptomes into the resource. We demonstrated workflows for analyzing new data against this knowledge base via deconstruction of regulation during aerobic transition. This resource illuminates the E. coli transcriptome at scale and provides a blueprint for top-down transcriptomic analysis of non-model organisms.
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Escherichia coli , Bases del Conocimiento , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Perfilación de la Expresión Génica , Regulación Bacteriana de la Expresión Génica , TranscriptomaRESUMEN
Pathogenic species from the Mycobacterium genus are responsible for a number of adverse health conditions in humans and animals that threaten health security and the economy worldwide. Mycobacteria have up to five specialized secretion systems (ESX-1 to ESX-5) that transport virulence factors across their complex cell envelope to facilitate manipulation of their environment. In pathogenic species, these virulence factors influence the immune system's response and are responsible for membrane disruption and contributing to cell death. While structural details of these secretion systems have been recently described, gaps still remain in the structural understanding of the secretion mechanisms of most substrates. Here, we describe the crystal structure of Mycobacterium tuberculosis ESX-1 secretion-associated substrate EspB bound to its chaperone EspK. We found that EspB interacts with the C-terminal domain of EspK through its helical tip. Furthermore, cryogenic electron microscopy, size exclusion chromatography analysis, and small-angle X-ray scattering experiments show that EspK keeps EspB in its secretion-competent monomeric form and prevents its oligomerization. The structure presented in this study suggests an additional secretion mechanism in ESX-1, analogous to the chaperoning of proline-glutamate (PE)-proline-proline-glutamate (PPE) proteins by EspG, where EspK facilitates the secretion of EspB in Mycobacterium species.
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Proteínas de la Membrana Bacteriana Externa , Proteínas Bacterianas , Mycobacterium tuberculosis , Factores de Virulencia , Humanos , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Glutamatos/metabolismo , Mycobacterium tuberculosis/metabolismo , Prolina/metabolismo , Factores de Virulencia/química , Factores de Virulencia/metabolismo , Muerte Celular , Proteínas de la Membrana Bacteriana Externa/química , Proteínas de la Membrana Bacteriana Externa/metabolismo , Cristalización , Microscopía por CrioelectrónRESUMEN
BACKGROUND AND AIMS: The risk and pathological factors of recurrence after endoscopic resection (ER) for superficial esophageal squamous cell carcinoma (ESCC) are inconsistent across studies. We evaluated this in a systematic review and meta-analysis. METHODS: The data of recurrence in such patients was extracted from all studies. Risk ratios (RRs) were combined using random-effects meta-analysis, to assess pooled recurrence rate and pathological risk factors. Relapse-free survival was combined using the Kaplan-Meier method to estimate the relationship between various pathological factors and recurrence time. RESULTS: We identified 26 studies, with a total of 5100 patients and 321 with recurrences (pooled rate, 6.2%). The risk of recurrence was significantly higher in positive vertical margin (VM) (RR [95% CI]: 4.51 [2.16 - 9.44]), positive horizontal margin (HM) (RR [95% CI]: 2.54 [1.57 - 4.13]), lymphovascular invasion (LVI) (RR [95% CI]: 2.33 [1.75 - 3.11], P < 0.001), lymphatic invasion (LI) (RR [95% CI]: 2.24 [1.24 - 4.06]), and tumor invading submucosa ≤200 µm (SM1) (RR [95% CI]: 1.71 [1.32 - 2.21], compared to muscularis mucosa). Patients with LI (HR 2.47; 95% CI 1.24 - 4.90; P = 0.02) and LVI (HR 2.36; 95% CI 2.22 - 4.59; P = 0.0006) tended to have earlier recurrence after ER. CONCLUSION: The recurrence rate of superficial ESCC after ER is acceptable. Patients with positive margins, LVI, LI and SM1 need to pay significant attention to the risk of recurrence. LI and VI should be evaluate separately. (PROSPERO CRD42023406309).
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Oesophageal squamous cell carcinoma (ESCC) is a common malignant tumour of the gastrointestinal tract. Early detection and access to appropriate treatment are crucial for the long-term survival of patients. However, limited diagnostic and monitoring methods are available for identifying early stage ESCC. Endoscopic screening and surgical resection are commonly used to diagnose and treat early ESCC. However, these methods have disadvantages, such as high recurrence, lethality, and mortality rates. Therefore, methods to improve early diagnosis of ESCC and reduce its mortality rate are urgently required. In 1961, Gary et al. proposed a novel liquid biopsy approach for clinical diagnosis. This involved examining exosomes, circulating tumour cells, circulating free DNA, and circulating free RNA in body fluids. The ability of liquid biopsy to obtain samples repeatedly, wide detection range, and fast detection speed make it a feasible option for non-invasive tumour detection. In clinical practice, liquid biopsy technology has gained popularity for early screening, diagnosis, treatment efficacy monitoring, and prognosis assessment. Thus, this is a highly promising examination method. However, there have been no comprehensive reviews on the four factors of liquid biopsy in the context of ESCC. This review aimed to analyse the progress of liquid biopsy research for ESCC, including its classification, components, and potential future applications.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Biopsia Líquida/métodos , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas de Esófago/diagnóstico , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/terapia , Pronóstico , Detección Precoz del Cáncer/métodos , Células Neoplásicas Circulantes/patología , Biomarcadores de Tumor/sangre , ExosomasRESUMEN
The transcriptional regulatory network in prokaryotes controls global gene expression mostly through transcription factors (TFs), which are DNA-binding proteins. Chromatin immunoprecipitation (ChIP) with DNA sequencing methods can identify TF binding sites across the genome, providing a bottom-up, mechanistic understanding of how gene expression is regulated. ChIP provides indispensable evidence toward the goal of acquiring a comprehensive understanding of cellular adaptation and regulation, including condition-specificity. ChIP-derived data's importance and labor-intensiveness motivate its broad dissemination and reuse, which is currently an unmet need in the prokaryotic domain. To fill this gap, we present proChIPdb (prochipdb.org), an information-rich, interactive web database. This website collects public ChIP-seq/-exo data across several prokaryotes and presents them in dashboards that include curated binding sites, nucleotide-resolution genome viewers, and summary plots such as motif enrichment sequence logos. Users can search for TFs of interest or their target genes, download all data, dashboards, and visuals, and follow external links to understand regulons through biological databases and the literature. This initial release of proChIPdb covers diverse organisms, including most major TFs of Escherichia coli, and can be expanded to support regulon discovery across the prokaryotic domain.
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Inmunoprecipitación de Cromatina , Cromatina/genética , Bases de Datos Genéticas , Factores de Transcripción/genética , Sitios de Unión/genética , Cromatina/clasificación , Genoma/genética , Células Procariotas , Unión Proteica/genéticaRESUMEN
INTRODUCTION: ARDS (acute respiratory distress syndrome) is the most severe form of acute hypoxic respiratory failure. Most studies related to ARDS have excluded patients with hematologic diseases, let alone allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Numerous patients experiencing severe hypoxic respiratory failure do not meet the Berlin definition due to the limitations of diagnosis and treatment. A new definition of ARDS, remove some diagnosis restrictions, was proposed in 2023. Based on the 2023 new definition of ARDS, we investigated the clinical features of ARDS in allo-HSCT recipients and reported risk factors for in-hospital mortality in allo-HSCT recipients defined by the Berlin definition and the new definition of ARDS respectively. METHODS: From Jan 2016 to Dec 2020, 135 allo-HSCT recipients identified with the new definition and 87 identified with the Berlin definition at three teaching hospitals were retrospectively included in this study. Variables (demographic information, characteristics of hematologic disease and ARDS episode, laboratory tests and SOFA score) with P < 0.05 in univariate logistic regression analysis were included in multivariate stepwise logistic regression analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported. RESULTS: Under the new definition, SOFA score (OR = 1.351, 95% CI: 1.146-1.593, P < 0.01) were found as an independent risk factor for in-hospital mortality in ARDS after allo-HSCT, while SpO2/FiO2 (OR = 0.984, 95% CI: 0.972-0.996, P < 0.01) was a protective factor. The infusion of peripheral-derived stem cells was found to be a protective factor against in-hospital mortality in post-transplantation ARDS compared with the infusion of bone marrow-derived stem cells (OR = 0.726, 95% CI: 0.164-3.221, P = 0.04). Under the Berlin definition, PaO2/FiO2 (OR = 0.977, 95% CI: 0.961-0.993, P = 0.01, lactate (OR = 7.337, 95% CI: 1.313-40.989, P < 0.01) and AST (OR = 1.165, 95% CI: 1.072-1.265, P < 0.01) were independently associated with in-hospital mortality. CONCLUSION: These prognostic risk factors we found in allo-HSCT recipients may contribute to closer monitoring and ARDS prevention strategies. These findings require confirmation in prospective, large sample size studies.
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Trasplante de Células Madre Hematopoyéticas , Mortalidad Hospitalaria , Síndrome de Dificultad Respiratoria , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Masculino , Estudios Retrospectivos , Femenino , Síndrome de Dificultad Respiratoria/mortalidad , Síndrome de Dificultad Respiratoria/terapia , Persona de Mediana Edad , Factores de Riesgo , Adulto , Trasplante Homólogo/efectos adversos , Anciano , Modelos Logísticos , Adulto JovenRESUMEN
Alzheimer's disease (AD) is characterized by cognitive decline stemming from the accumulation of beta-amyloid (Aß) plaques and the propagation of tau pathology through synapses. Exosomes, crucial mediators in neuronal development, maintenance, and intercellular communication, have gained attention in AD research. Yet, the molecular mechanisms involving exosomal miRNAs in AD remain elusive. In this study, we treated APPswe/PSEN1dE9 transgenic (APP/PS1) mice, a model for AD, with either vehicle (ADNS) or fasudil (ADF), while C57BL/6 (control) mice received vehicle (WT). Cognitive function was evaluated using the Y-maze test, and AD pathology was confirmed through immunostaining and western blot analysis of Aß plaques and phosphorylated tau. Exosomal RNAs were extracted, sequenced, and analyzed from each mouse group. Our findings revealed that fasudil treatment improved cognitive function in AD mice, as evidenced by increased spontaneous alternation in the Y-maze test and reduced Aß plaque load and phosphorylated tau protein expression in the hippocampus. Analysis of exosomal miRNAs identified three miRNAs (mmu-let-7i-5p, mmu-miR-19a-3p, mmu-miR-451a) common to both ADNS vs ADF and WT vs ADNS groups. Utilizing miRTarBase software, we predicted and analyzed target genes associated with these miRNAs. Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of miRNA target genes indicated that mmu-miR-19a-3p and mmu-miR-451a are implicated in signal transduction, immune response, cellular communication, and nervous system pathways. Specifically, mmu-miR-19a-3p targeted genes involved in the sphingolipid signaling pathway, such as Pten and Tnf, while mmu-miR-451a targeted Nsmaf, Gnai3, and Akt3. Moreover, mmu-miR-451a targeted Myc in signaling pathways regulating the pluripotency of stem cells. In conclusion, fasudil treatment enhanced cognitive function by modulating exosomal MicroRNAs, particularly mmu-miR-451a and mmu-miR-19a-3p. These miRNAs hold promise as potential biomarkers and therapeutic targets for novel AD treatments.
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A transcription factor (TF) is a sequence-specific DNA-binding protein that modulates the transcription of a set of particular genes, and thus regulates gene expression in the cell. TFs have commonly been predicted by analyzing sequence homology with the DNA-binding domains of TFs already characterized. Thus, TFs that do not show homologies with the reported ones are difficult to predict. Here we report the development of a deep learning-based tool, DeepTFactor, that predicts whether a protein in question is a TF. DeepTFactor uses a convolutional neural network to extract features of a protein. It showed high performance in predicting TFs of both eukaryotic and prokaryotic origins, resulting in F1 scores of 0.8154 and 0.8000, respectively. Analysis of the gradients of prediction score with respect to input suggested that DeepTFactor detects DNA-binding domains and other latent features for TF prediction. DeepTFactor predicted 332 candidate TFs in Escherichia coli K-12 MG1655. Among them, 84 candidate TFs belong to the y-ome, which is a collection of genes that lack experimental evidence of function. We experimentally validated the results of DeepTFactor prediction by further characterizing genome-wide binding sites of three predicted TFs, YqhC, YiaU, and YahB. Furthermore, we made available the list of 4,674,808 TFs predicted from 73,873,012 protein sequences in 48,346 genomes. DeepTFactor will serve as a useful tool for predicting TFs, which is necessary for understanding the regulatory systems of organisms of interest. We provide DeepTFactor as a stand-alone program, available at https://bitbucket.org/kaistsystemsbiology/deeptfactor.
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Biología Computacional/métodos , Predicción/métodos , Factores de Transcripción/genética , Algoritmos , Sitios de Unión/genética , Secuenciación de Inmunoprecipitación de Cromatina/métodos , ADN/genética , Proteínas de Unión al ADN/genética , Aprendizaje Profundo/tendencias , Genoma/genética , Unión Proteica/genética , Programas InformáticosRESUMEN
Eupatorium lindleyanum DC. (EL) is a traditional Chinese herb known for its phlegm-reducing, cough-relieving and asthma-calming properties. It is widely used for treating cough and bronchitis. However, preliminary experiments have revealed wide variations in the composition of its different medicinal parts (flowers, leaves and stems), and the composition and efficacy of its different medicinal parts remain largely underexplored at present. In this study, non-targeted rapid resolution liquid chromatography coupled with a quadruple time-of-flight mass spectrometry (RRLC-Q-TOF-MS)-based metabolomics approach was developed to investigate the differences in the chemical composition of different medicinal parts of EL. We identified or tentatively identified 9 alkaloids, 11 flavonoids, 14 sesquiterpene lactones, 3 diterpenoids and 24 phenolic acids. In addition, heatmap visualization, quantitative analysis by high-performance liquid chromatography (HPLC-PDA) and ultra-high-performance liquid chromatography-triple quadrupole tandem mass spectrometry (UPLC-MS/MS) showed particularly high levels of sesquiterpene lactones, flavonoids and phenolic acids in the flowers, such as eupalinolide A and B and chlorogenic acid, among others. The leaves also contained some flavonoid sesquiterpene lactones and phenolic acids, while the stems were almost absent. The findings of in vitro activity studies indicated that the flowers exhibited a notable inhibitory effect on the release of the inflammatory factors TNF-α and IL-6, surpassing the anti-inflammatory efficacy observed in the leaves. Conversely, the stems demonstrated negligible anti-inflammatory activity. The variations in anti-inflammatory activity among the flowers, leaves and stems of EL can primarily be attributed to the presence of flavonoids, phenolic acids and sesquiterpene lactones in both the flowers and leaves. Additionally, the flowers contain a higher concentration of these active components compared to the leaves. These compounds mediate their anti-inflammatory effects through distinct biochemical pathways. The results of this study are anticipated to provide a scientific basis for the rational and effective utilization of EL resources.
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Antiinflamatorios , Eupatorium , Espectrometría de Masas en Tándem , Eupatorium/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Hojas de la Planta/química , Animales , Flavonoides/química , Flavonoides/farmacología , Flavonoides/análisis , Metaboloma , Metabolómica/métodos , Ratones , Extractos Vegetales/química , Extractos Vegetales/farmacología , Células RAW 264.7 , Flores/química , Tallos de la Planta/química , Plantas Medicinales/químicaRESUMEN
The Datong Basin was an important arena for population movement and admixture between the Yellow River Valley and Eastern Steppe. In historical materials, the region was often the setting for a tug-of-war between Han farmers and non-Han nomads. The genetic makeup and population history of this Datong population has, however, remained uncertain. In this study, we analysed 289 mitogenomes from Datong individuals. Our primary findings were: (1) population summary statistics analysis revealed a high level of genetic diversity and strong signals of population expansion in the Datong population; (2) inter-population comparisons (PCA and Fst heatmap) exhibited a close clustering between the Datong population and Northern Han, especially northern frontier groups, such as the Inner Mongolia Han, Heilongjiang Han, Liaoning Han and Tianjin Han; (3) phylogeographic analysis of complete mitogenomes revealed the presence of different components in the maternal gene pools of Datong population-the northern East Asian component was dominant (66.44%), whereas the southern East Asians were the second largest component with 31.49%. We also observed a much reduced west Eurasian (2.07%) component; (4) direct comparisons with ancient groups showed closer relationship between Datong and Yellow River farmers than Eastern Steppe nomads. Despite, therefore, centuries of Eastern Steppe nomadic control over the Datong area, Yellow River farmers had a much more significant impact on the Datong population.
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Genoma Mitocondrial , Humanos , Genoma Mitocondrial/genética , Ríos , Filogeografía , Pueblo Asiatico , China , Genética de Población , ADN Mitocondrial/genéticaRESUMEN
BACKGROUND: Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. METHODS: A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. RESULTS: PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. CONCLUSION: This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI.
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Lesión Pulmonar Aguda , Ferroptosis , Sepsis , Animales , Ratones , Antígenos CD59 , Ciclooxigenasa 2 , Lipopolisacáridos/farmacología , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/etiología , Sepsis/complicaciones , Factor de Transcripción Activador 2RESUMEN
Low quantum efficiency and serious photogenerated carrier recombination have been urgent bottleneck problems for photocatalytic materials. Herein, we prepared Nb, Se-codoped ZnIn2S4/NbSe2composites through a facile solvothermal method. The synergetic effect of codoping and cocatalyst was investigated on the photodegradation performance towards tetracycline under visible-light irradiation. By adjusting the final composition, the comprehensive characterization revealed that the optimum degradation efficiency of NS/ZIS-1.6 catalyst arrived at 75% in 70 min, which was 5.8 times higher than that of pure ZnIn2S4. Deep analysis indicated that the enhanced photocatalytic performance could be attributed to higher light absorption, more efficient electron/hole separation, faster charge transport, and lower carrier recombination. This work may offer novel viewpoint for design of high-performance catalysts towards the visible-light-driven photodegradation system.
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This study aimed to determine the impact of current hepatitis B virus (HBV) infection on patients hospitalised with sepsis. This was a retrospective cohort study. Patients from three medical centres in Suzhou from 10 January 2016 to 23 July 2022 participated in this study. Demographic characteristics and clinical characteristics were collected. A total of 945 adult patients with sepsis were included. The median age was 66.0 years, 68.6% were male, 13.1% presented with current HBV infection, and 34.9% of all patients died. In the multivariable-adjusted Cox model, patients with current HBV infection had significantly higher mortality than those without (hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.11-2.02). A subgroup analysis showed that being infected with HBV significantly increased in-hospital mortality in patients younger than 65 years old (HR 1.74, 95% CI 1.16-2.63), whereas no significant impact was observed in patients ≥65 years. The propensity score-matched case-control analysis showed that the rate of septic shock (91.4% vs. 62.1%, P < 0.001) and in-hospital mortality (48.3% vs. 35.3%, P = 0.045) were much higher in the propensity score-matched HBV infection group compared with the control group. In conclusion, current HBV infection was associated with mortality in adults with sepsis.
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Hepatitis B , Sepsis , Adulto , Humanos , Masculino , Anciano , Femenino , Virus de la Hepatitis B , Estudios Retrospectivos , Hepatitis B/complicaciones , Hepatitis B/epidemiología , Antígenos de Superficie de la Hepatitis BRESUMEN
Multiple circular RNAs (circRNAs) were proven to regulate the development of pancreatic cancer. However, the action of circ_0018909 in pancreatic cancer was still unclear. The expression of circ_0018909, microRNA-545-3p (miR-545-3p), and fatty acid synthase (FASN) was measured using quantitative reverse-transcriptase PCR (qRT-PCR). Cell growth, cell cycle arrest, apoptotic cells, metastasis, and epithelial to mesenchymal transition (EMT) were determined using EdU assay, flow cytometry, wound-healing assay, transwell invasion, and western blotting, respectively. The expression of the macrophage markers, including CD80, MCP-1, iNOS, and IL-6 (M1 markers), as well as CD206 and CD163 (M2 markers), was analyzed using qRT-PCR. Circ_0018909 knockdown dramatically depressed cell growth, migration, invasion, EMT, and elevated the number of apoptotic cells in pancreatic cancer cells, and repressed tumor growth in mice. Moreover, we proved that the absence of miR-545-3p rescued the action of circ_0018909 downregulation on cell growth, metastasis, apoptosis, and EMT in pancreatic cancer cells. MiR-545-3p bound to FASN and FASN overexpression hindered the impacts of miR-545-3p on the progression of pancreatic cancer. Besides this, our data demonstrated that circ_0018909 induced polarization from M0 macrophages to M2 macrophages. Circ_0018909 knockdown retarded the development of pancreatic cancer by modulating miR-545-3p to regulate FASN expression.
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MicroARNs , Neoplasias Pancreáticas , Animales , Ratones , Transición Epitelial-Mesenquimal , Ácido Graso Sintasas , Neoplasias Pancreáticas/genética , Proliferación Celular , MicroARNs/genética , Línea Celular Tumoral , Neoplasias PancreáticasRESUMEN
Bacteria regulate gene expression to adapt to changing environments through transcriptional regulatory networks (TRNs). Although extensively studied, no TRN is fully characterized since the identity and activity of all the transcriptional regulators comprising a TRN are not known. Here, we experimentally evaluate 40 uncharacterized proteins in Escherichia coli K-12 MG1655, which were computationally predicted to be transcription factors (TFs). First, we used a multiplexed chromatin immunoprecipitation method combined with lambda exonuclease digestion (multiplexed ChIP-exo) assay to characterize binding sites for these candidate TFs; 34 of them were found to be DNA-binding proteins. We then compared the relative location between binding sites and RNA polymerase (RNAP). We found 48% (283/588) overlap between the TFs and RNAP. Finally, we used these data to infer potential functions for 10 of the 34 TFs with validated DNA binding sites and consensus binding motifs. Taken together, this study: (i) significantly expands the number of confirmed TFs to 276, close to the estimated total of about 280 TFs; (ii) provides putative functions for the newly discovered TFs and (iii) confirms the functions of four representative TFs through mutant phenotypes.
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Escherichia coli K12/genética , Proteínas de Escherichia coli/metabolismo , Factores de Transcripción/metabolismo , Sitios de Unión , Secuenciación de Inmunoprecipitación de Cromatina , Escherichia coli K12/metabolismo , Factores de Transcripción/fisiologíaRESUMEN
BACKGROUND: Laser photocoagulation is an effective procedure for the treatment of diabetic macular edema (DME). However, the beneficial effects of conventional laser photocoagulation (CLP) are accompanied by the destruction of retinal photoreceptors. Therefore, subthreshold micropulse laser photocoagulation (SMLP) was proposed for DME. OBJECTIVES: This meta-analysis study was performed to evaluate the efficacy and safety of SMLP compared with CLP for the management of DME. METHODS: The PubMed, Embase, Web of Science, Cochrane, SinoMed,
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Diabetes Mellitus , Retinopatía Diabética , Edema Macular , Humanos , Coagulación con Láser/métodos , Agudeza Visual , Rayos Láser , Resultado del TratamientoRESUMEN
The objective of the present study was to develop PTF-loaded solid lipid nanoparticles (PTF-SLNs) and investigate their efficacy in treating lung cancer. The PTF-SLNs were prepared by the thin film hydration method and verified by FTIR and TEM. Their physicochemical properties were characterized by particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE), drug loading (DL), etc. Then, the pharmacodynamic studies of PTF-SLNs were performed on Lewis lung cancer cells and tumor-bearing mice. Finally, the safety studies were assessed by organ index, serum biochemical indicators, and histopathological changes. The PTF-SLNs were characterized by around 50 nm sphere nanoparticles, sustained ideal stability, and controlled drug release effects. The pharmacodynamic evaluation results showed that PTF-SLNs had stronger anti-tumor efficacy than PTF. An in vitro study revealed a more obvious cytotoxicity and apoptosis effect. The IC 50 values of PTF and PTF-SLNs were 67.43 µg/mL and 20.74 µg/mL, respectively. An in vivo study showed that the tumor inhibition rates of 2 g/kg PTF and 0.4 g/kg PTF-SLNs were 59.97% and 64.55%, respectively. The safety preliminary study indicated that PTF-SLNs improve the damage of PTF to normal organs to a certain extent. This study provides a nanoparticle delivery system with phenolic herbal extract to improve anti-tumor efficacy in lung cancer.
Asunto(s)
Neoplasias Pulmonares , Nanopartículas , Ratones , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Lípidos/química , Taninos , Liposomas , Nanopartículas/química , Tamaño de la Partícula , Portadores de Fármacos/químicaRESUMEN
RNA interference (RNAi)-based gene therapy that promotes anabolic bone formation is an effective approach for addressing osteoporosis. However, the selection of target gene and tissue-specific delivery systems has hindered the progression of this strategy. In this study, we identified casein kinase-2 interacting protein-1 encoding gene (Ckip-1), a negative regulator of bone formation, as an effective target of small interfering RNAs (siRNAs) for improving bone mass. Moreover, an impressive (DSS)6-Liposome (Lipos) nanoparticle system that could target the bone formation surface was synthesized to enhance the delivery of Ckip-1 siRNA to osteogenic lineage cells. The in vitro results confirmed that the (DSS)6-Lipos system could efficaciously improve the intracellular delivery of Ckip-1 siRNA without obvious cell toxicity. The in vivo application of the delivery system showed specific accumulation of siRNA in osteogenic cells located around the bone formation surface. Bone-related analysis indicated increased bone mass and improved bone microarchitecture in mice with ovariectomy-induced osteoporosis. Moreover, the biomechanical characteristics of the tibia were enhanced significantly, indicating increased resistance to fragile fracture induced by osteoporosis. Thus, (DSS)6-Lipos-Ckip-1 siRNA-based osteoanabolic therapy may be a promising option for the treatment of osteoporosis.