ABSTRACT
Objective: The emergence of clinical Klebsiella pneumoniae strains harboring acrAB-tolC genes in the chromosome, along with the presence of two repetitive tandem core structures for bla KPC-2 and bla CTX-M-65 genes on a plasmid, has presented a significant clinical challenge. Methods: In order to study the detailed genetic features of K. pneumoniae strain SC35, both the bacterial chromosome and plasmids were sequenced using Illumina and nanopore platforms. Furthermore, bioinformatics methods were employed to analyze the mobile genetic elements associated with antibiotic resistance genes. Results: K. pneumoniae strain SC35 was found to possess a class A beta-lactamase and demonstrated resistance to all tested antibiotics. This resistance was attributed to the presence of efflux pump genes, specifically acrAB-tolC, on the SC35 chromosome. Additionally, the SC35 plasmid p1 carried the two repetitive tandem core structures for bla KPC-2 and bla CTX-M-65, as well as bla TEM-1 with rmtB, which shared overlapping structures with mobile genetic elements as In413, Tn3, and TnAs3. Through plasmid transfer assays, it was determined that the SC35 plasmid p1 could be successfully transferred with an average conjugation frequency of 6.85 × 10-4. Conclusion: The structure of the SC35 plasmid p1 appears to have evolved in correlation with other plasmids such as pKPC2_130119, pDD01754-2, and F4_plasmid pA. The infectious strain SC35 exhibits no susceptibility to tested antibioticst, thus effective measures should be taken to prevent the spread and epidemic of this strain.
Subject(s)
Anti-Bacterial Agents , Chromosomes, Bacterial , Klebsiella Infections , Klebsiella pneumoniae , Plasmids , beta-Lactamases , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/drug effects , Plasmids/genetics , beta-Lactamases/genetics , Klebsiella Infections/microbiology , Anti-Bacterial Agents/pharmacology , Chromosomes, Bacterial/genetics , Humans , Microbial Sensitivity Tests , Interspersed Repetitive Sequences/genetics , Bacterial Proteins/genetics , Bacterial Proteins/metabolismABSTRACT
Oxidative stress, characterized by an imbalance between oxidative and antioxidant processes, results in excessive accumulation of intracellular reactive oxygen species. Among these responses, the regulation of intracellular hydroxyl radicals (â¢OH) and glutathione (GSH) is vital for physiological processes. Real-time in situ monitoring these two opposing bioactive species and their redox interactions is essential for understanding physiological balance and imbalance. In this study, we developed a dual-site fluorescence chemosensor OG-3, which can independently image both exogenous and endogenous â¢OH and GSH in separate channels both within cells and in vivo, eliminating issues of spatiotemporal inhomogeneous distribution and cross-interference. With its imaging capabilities of monitoring â¢OH-GSH redox, OG-3 elucidated two different pathways for ferroptosis induction: (i) inhibition of system xc- to block cystine uptake (extrinsic pathway) and (ii) GPX4 inactivation, leading to the loss of antioxidant defense (intrinsic pathway). Moreover, we assessed the antiferroptotic function and effects of ferroptosis inhibitors by monitoring â¢OH and GSH fluctuations during ferroptosis. This method provides a reliable platform for identifying potential ferroptosis inhibitors, contributing to our understanding of relevant metabolic and physiological mechanisms. It shows potential for elucidating the regulation of ferroptosis mechanisms and investigating further strategies for therapeutic applications.
Subject(s)
Ferroptosis , Fluorescent Dyes , Glutathione , Hydroxyl Radical , Oxidation-Reduction , Ferroptosis/drug effects , Glutathione/metabolism , Glutathione/analysis , Humans , Hydroxyl Radical/metabolism , Animals , Fluorescent Dyes/chemistry , Mice , Optical ImagingABSTRACT
During virus-host co-evolution, viruses have developed multiple strategies to dampen IFN response and prevent its antiviral activity in host cells. To date, the interactions between host IFN response and the immune evasion strategies exploited by fish iridoviruses still remain largely uncertain. Here, a potential immune evasion protein candidate of Singapore grouper iridovirus (SGIV), VP82 (encoded by SGIV ORF82) was screened and its roles during viral replication were investigated in detail. Firstly, VP82 overexpression dramatically decreased IFN or ISRE promoter activity and the transcription levels of IFN stimulated genes (ISGs) stimulated by grouper cyclic GMP-AMP synthase (EccGAS)/stimulator of interferon genes (EcSTING), TANK-binding kinase 1 (EcTBK1), IFN regulatory factor 3 (EcIRF3)and EcIRF7. Secondly, Co-IP assays indicated that VP82 interacted with EcIRF3 and EcIRF7, but not EcSTING and EcTBK1, which was consistent with the co-localization between VP82 and EcIRF3 or EcIRF7. Furthermore, VP82 promoted the degradation of EcIRF3 and EcIRF7 in a dose-dependent manner via the autophagy pathway. Finally, VP82 overexpression accelerated SGIV replication, evidenced by the increased transcriptions of viral core genes and viral production. Moreover, the antiviral action of EcIRF3 or EcIRF7 was significantly depressed in VP82 overexpressed cells. Together, VP82 was speculated to exert crucial roles for SGIV replication by inhibiting the IFN response via the degradation of IRF3 and IRF7. Our findings provided new insights into understanding the immune evasion strategies utilized by fish iridovirus through IFN regulation.
Subject(s)
DNA Virus Infections , Fish Diseases , Fish Proteins , Interferon Regulatory Factor-3 , Interferon Regulatory Factor-7 , Ranavirus , Viral Proteins , Animals , Interferon Regulatory Factor-3/genetics , Interferon Regulatory Factor-3/immunology , Interferon Regulatory Factor-3/metabolism , Interferon Regulatory Factor-7/genetics , Interferon Regulatory Factor-7/metabolism , Interferon Regulatory Factor-7/immunology , Fish Proteins/genetics , Fish Proteins/immunology , Fish Proteins/metabolism , Fish Diseases/immunology , Fish Diseases/virology , DNA Virus Infections/immunology , DNA Virus Infections/veterinary , Ranavirus/physiology , Viral Proteins/genetics , Viral Proteins/metabolism , Immunity, Innate/genetics , Interferons/genetics , Interferons/immunology , Interferons/metabolism , Immune Evasion , Bass/immunology , Bass/genetics , Virus Replication , Zebrafish Proteins , Interferon Regulatory FactorsABSTRACT
In females, the pathophysiological mechanism of poor ovarian response (POR) is not fully understood. Considering the expression level of p62 was significantly reduced in the granulosa cells (GCs) of POR patients, this study focused on identifying the role of the selective autophagy receptor p62 in conducting the effect of follicle-stimulating hormone (FSH) on antral follicles (AFs) formation in female mice. The results showed that p62 in GCs was FSH responsive and that its level increased to a peak and then decreased time-dependently either in ovaries or in GCs after gonadotropin induction in vivo. GC-specific deletion of p62 resulted in subfertility, a significantly reduced number of AFs and irregular estrous cycles, which were same as pathophysiological symptom of POR. By conducting mass spectrum analysis, we found the ubiquitination of proteins was decreased, and autophagic flux was blocked in GCs. Specifically, the level of nonubiquitinated Wilms tumor 1 homolog (WT1), a transcription factor and negative controller of GC differentiation, increased steadily. Co-IP results showed that p62 deletion increased the level of ubiquitin-specific peptidase 5 (USP5), which blocked the ubiquitination of WT1. Furthermore, a joint analysis of RNA-seq and the spatial transcriptome sequencing data showed the expression of steroid metabolic genes and FSH receptors pivotal for GCs differentiation decreased unanimously. Accordingly, the accumulation of WT1 in GCs deficient of p62 decreased steroid hormone levels and reduced FSH responsiveness, while the availability of p62 in GCs simultaneously ensured the degradation of WT1 through the ubiquitinâproteasome system and autophagolysosomal system. Therefore, p62 in GCs participates in GC differentiation and AF formation in FSH induction by dynamically controlling the degradation of WT1. The findings of the study contributes to further study the pathology of POR.
Subject(s)
Follicle Stimulating Hormone , Granulosa Cells , Ovarian Follicle , Sequestosome-1 Protein , Ubiquitination , WT1 Proteins , Animals , Follicle Stimulating Hormone/metabolism , Follicle Stimulating Hormone/pharmacology , Female , WT1 Proteins/metabolism , WT1 Proteins/genetics , Mice , Ovarian Follicle/metabolism , Ovarian Follicle/drug effects , Granulosa Cells/metabolism , Granulosa Cells/drug effects , Sequestosome-1 Protein/metabolism , Sequestosome-1 Protein/genetics , Mice, Inbred C57BL , Autophagy/drug effects , Proteolysis/drug effects , Humans , Mice, KnockoutABSTRACT
BACKGROUND: Osteoarthritis (OA) is a common orthopedic disorder, and its incidence has been increasing among young adults in recent years. The purpose of this study is to investigate the global, regional, and national trends in OA burden and variation among individuals aged 30 to 44 from 1990 to 2019. METHODS: Data on the incidence, prevalence, and years lived with disability (YLDs) related to OA were sourced from the Global Burden of Disease Study 2019 among individuals aged 30 to 44. These measures were stratified by gender, region, country, and socio-demographic index (SDI). Additionally, we analyzed YLDs attributable to risk factors. RESULTS: In 2019, there were a total of 32,971,701 cases of OA among individuals aged 30 to 44 years worldwide, with an additional 7,794,008 new incident cases reported. OA of the knee was the primary contributor to both incidence and prevalence rates over the past three decades. From 1990 to 2019, both males and females in countries with high SDI and high-middle SDI showed upward trends in age-standardized incidence, prevalence, and YLDs rates. In 2019, the United States of America had the highest age-standardized incidence, prevalence, and YLDs rates. Elevated body-mass index (BMI) was found to be the most prevalent risk factor for osteoarthritis-related YLDs. Age-standardized YLDs rates were positively associated with SDI. CONCLUSIONS: OA remains a significant disease burden on individuals aged 30 to 44, with modifiable risk factors such as unhealthy lifestyle and obesity representing key targets for future interventions aimed at reducing the impact of this condition on younger generations.
Subject(s)
Global Burden of Disease , Osteoarthritis , Male , Female , Young Adult , Humans , Global Health , Osteoarthritis/diagnosis , Osteoarthritis/epidemiology , Prevalence , Cost of Illness , Incidence , Quality-Adjusted Life YearsABSTRACT
In a growing follicle, the survival and maturation of the oocyte largely depend on support from somatic cells to facilitate FSH-induced mutual signaling and chemical communication. Although apoptosis and autophagy in somatic cells are involved in the process of FSH-induced follicular development, the underlying mechanisms require substantial study. According to our study, along with FSH-induced antral follicles (AFs) formation, both lysine-specific demethylase 1 (LSD1) protein levels and autophagy increased simultaneously in granulosa cells (GCs) in a time-dependent manner, we therefore evaluated the importance of LSD1 upon facilitating the formation of AFs correlated to autophagy in GCs. Conditional knockout of Lsd1 in GCs resulted in significantly decreased AF number and subfertility in females, accompanied by marked suppression of the autophagy in GCs. On the one hand, depletion of Lsd1 resulted in accumulation of Wilms tumor 1 homolog (WT1), at both the protein and mRNA levels. WT1 prevented the expression of FSH receptor (Fshr) in GCs and thus reduced the responsiveness of the secondary follicles to FSH induction. On the other hand, depletion of LSD1 resulted in suppressed level of autophagy by upregulation of ATG16L2 in GCs. We finally approved that LSD1 contributed to these sequential activities in GCs through its H3K4me2 demethylase activity. Therefore, the importance of LSD1 in GCs is attributable to its roles in both accelerating autophagy and suppressing WT1 expression to ensure the responsiveness of GCs to FSH during AFs formation.
Subject(s)
Granulosa Cells , Ovarian Follicle , Female , Autophagy/genetics , Follicle Stimulating Hormone/pharmacology , Granulosa Cells/metabolism , Ovarian Follicle/metabolism , Signal Transduction , Animals , MiceABSTRACT
Enteric CH4 produced from dairy cows contributes to the emission of greenhouse gases from anthropogenic sources. Recent studies have shown that the selection of lower CH4-emitting cows is possible, but doing so would be simpler if performance measures already recorded on farm could be used, instead of measuring gas emissions from individual cows. These performance measures could be used for selection of low emitting cows. The aim of this analysis was to quantify how much of the between-cow variation in CH4 production can be explained by variation in performance measures. A dataset with 3 experiments and a total of 149 lactating dairy cows with repeated measures was used to estimate the between-cow variation (the variation between cow estimates) for performance and gas measures from GreenFeed (C-Lock, Rapid City, SD). The cow estimates were obtained with a linear mixed model with the diet within period effect as a fixed effect and the cow within experiment as a random effect. The cow estimates for CH4 production were first regressed on the performance and gas measures individually, and then performance and CO2 production measures were grouped in 3 subsets for principal component analysis and principal component regression. The variables that explained most of the between-cow variation in CH4 production were DMI (R2 = 0.44), among the performance measures, and CO2 production (R2 = 0.61), among gas measures. Grouping the measures increased the R2 to 0.53 when only performance measures were used, and to 0.66 when CO2 production was added to the significant performance measures. We found the marginal improvement to be insufficient to justify the use of grouped measures rather than an individual measure because the latter simplifies the model and avoids over-fitting. Investigation of other measures that can be explored to increase explanatory power of between-cow variation in CH4 production is briefly discussed. Finally, the use of residual CH4 as a measure for CH4 efficiency could be considered by using either DMI or CO2 production as the sole predicting variables.
Subject(s)
Diet , Lactation , Methane , Methane/biosynthesis , Methane/metabolism , Animals , Cattle , Female , Diet/veterinary , Milk/chemistry , Milk/metabolism , Animal Feed , Carbon Dioxide/analysisABSTRACT
Background: Polyvinyl alcohol/Chitosan hydrogel is often employed as a carrier because it is non-toxic, biodegradable, and has a three-dimensional network structure. Meanwhile, Magnesium-doped nano-hydroxyapatite(Mg-nHA) demonstrated high characterization to promote the osteogenic differentiation of bone marrow derived mesenchymal stem cell(BMSCs). Therefore, in order to develop a porous hydrogel scaffold for the application of bone tissue engineering, an appropriate-type Mg-nHA hydrogel scaffold was developed and evaluated. Methods: A composite hydrogel containing magnesium-doped nano-hydroxyapatite (Mg-nHA/PVA/CS) was developed using a magnetic stirring-ion exchange method and cyclic freeze-thaw method design, with polyvinyl alcohol and chitosan as the main components. Fourier transform infrared spectra (FTIR), electron energy dispersive spectroscopy (EDS), X-ray photoelectron spectrometer (XPS) and scanning electron microscopy (SEM) were employed to analyze the chemical structure, porosity, and elemental composition of each hydrogels. The equilibrium swelling degree, moisture content, pH change, potential for biomineralization, biocompatibility, the osteogenic potential and magnesium ion release rate of the composite hydrogel were also evaluated. Results: SEM analysis revealed a well-defined 3D spatial structure of micropores in the synthesised hydrogel. FTIR analysis showed that doping nanoparticles had little effect on the hydrogel's structure and both the 5% Mg-nHA/PVA/CS and 10% Mg-nHA/PVA/CS groups promoted amide bond formation. EDS observation indicated that the new material exhibited favourable biomineralization ability, with optimal performance seen in the 5% Mg-nHA/PVA/CS group. The composite hydrogel not only displayed favourable water content, enhanced biocompatibility, and porosity (similar to human cancellous bone), but also maintained an equilibrium swelling degree and released magnesium ions that created an alkaline environment around it. Additionally, it facilitated the proliferation of bone marrow mesenchymal stem cells and their osteogenic differentiation. Conclusion: The Mg-nHA/PVA/CS hydrogel demonstrates significant potential for application in the field of bone repair, making it an excellent composite material for bone tissue engineering.
Subject(s)
Chitosan , Humans , Durapatite , Osteogenesis , Magnesium , Polyvinyl Alcohol , HydrogelsABSTRACT
Earthworms accumulate organic pollutants to form earthworm tissue-bound residues (EBRs); however, the composition and fate of EBRs in soil remain largely unknown. Here, we investigated the fate of tetrabromobisphenol A (TBBPA)-derived EBRs in soil for 250 days using a 14C-radioactive isotope tracer and the geophagous earthworm Metaphire guillelmi. The EBRs of TBBPA in soil were rapidly transformed into nonextractable residues (NERs), mainly in the form of sequestered and ester-linked residues. After 250 days of incubation, 4.9% of the initially applied EBRs were mineralized and 69.3% were released to extractable residues containing TBBPA and its transformation products (TPs, generated mainly via debromination, O-methylation, and skeletal cleavage). Soil microbial activity and autolytic enzymes of earthworms jointly contributed to the release process. In their full-life period, the earthworms overall retained 24.1% TBBPA and its TPs in soil and thus prolonged the persistence of these pollutants. Our study explored, for the first time, the composition and fate of organic pollutant-derived EBRs in soil and indicated that the decomposition of earthworms may release pollutants and cause potential environmental risks of concern, which should be included in both environmental risk assessment and soil remediation using earthworms.
Subject(s)
Environmental Pollutants , Oligochaeta , Polybrominated Biphenyls , Soil Pollutants , Animals , Soil/chemistryABSTRACT
Singapore grouper iridovirus (SGIV), belonging to genus Ranavirus, family Iridoviridae, is a highly pathogenic agent and causes heavy economic losses in the global grouper aquaculture. Recent studies demonstrated that SGIV infection attenuated antiviral immune and inflammatory response induced by poly (I:C) in vitro. However, little was known about the potential functions of the immune regulatory proteins encoded by SGIV. Here, we identified the detailed roles of VP20 and clarified the potential mechanism underlying its immune regulatory function during SGIV infection. Our results showed that VP20 was an IE gene, and partially co-localized with Golgi apparatus and lysosomes in grouper cells. Overexpression of VP20 enhanced SGIV replication, demonstrated by the increase in the transcription levels of viral core genes and the protein synthesis of MCP. Reporter gene assays showed that SGIV VP20 overexpression significantly reduced the IFN promoter activity induced by poly (I:C), grouper stimulator of interferon genes (EcSTING) and TANK-binding kinase 1 (EcTBK1). Consistently, the transcription levels of IFN related genes were significantly decreased in VP20 overexpressing cells compared to those in control cells. Co-IP assay and confocal microscopy observations indicated that VP20 co-localized and interacted with EcTBK1 and EcIRF3, but not EcSTING. In addition, VP20 was able to degrade EcIRF3 and attenuate the antiviral action of EcIRF3, while had no effect on EcTBK1. Together, SGIV VP20 was speculated to promote viral replication through attenuating the IFN response mediated by TBK1-IRF3 in vitro. Our findings provided new insights into the immune regulatory function of SGIV encoded unknown proteins.
Subject(s)
Bass , DNA Virus Infections , Fish Diseases , Iridovirus , Ranavirus , Animals , Interferons , Ranavirus/physiology , Immunity, Innate/genetics , Singapore , Amino Acid Sequence , Fish Proteins/genetics , Sequence AlignmentABSTRACT
Using a prospective, observational cohort study during the post-"dynamic COVID-zero" wave in China, we estimated short-term relative effectiveness against Omicron BA.5 infection of inhaled aerosolized adenovirus type 5-vectored ancestral strain coronavirus disease 2019 (COVID-19) vaccine as a second booster dose approximately 1 year after homologous boosted primary series of inactivated COVID-19 vaccine compared with no second booster. Participants reported nucleic acid or antigen test results weekly until they tested positive or completed predesignated follow-up. After excluding participants infected <14 days after study entry, relative effectiveness among the 6576 participants was 61% in 18- to 59-year-olds and 38% in ≥60-year-olds and was sustained for 12 weeks.
Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , COVID-19/prevention & control , Prospective Studies , Vaccine Efficacy , China/epidemiology , Adenoviridae/geneticsABSTRACT
Inubritanolides C and D (1 and 2), two exo sesquiterpenoid [4 + 2] adducts with unprecedented interconverting conformations of twist-chair and chair, together with two previously undescribed endo [4 + 2] dimers (3 and 4) were discovered from Inula britannica flowers. Dimers 1 and 2 have an undescribed carbon skeleton comprising of eudesmanolide and guaianolide units with the linkage mode of C-11/C-1' and C-13/C-3' via a Diels-Alder cycloaddition reaction. Their structures were elucidated using 1D/2D NMR, X-ray diffraction, ECD, and variable-temperature NMR experiments. Dimer 2 displayed a strong inhibitory effect on breast cancer cells by promoting lipid ROS production, showing its potential as ferroptosis inducer.
Subject(s)
Asteraceae , Ferroptosis , Inula , Sesquiterpenes , Inula/chemistry , Molecular Conformation , Sesquiterpenes/pharmacology , Sesquiterpenes/chemistry , Molecular StructureABSTRACT
Coronary CT angiography (CCTA) is an effective and non-invasive method for coronary artery disease diagnosis. Extracting an accurate coronary artery tree from CCTA image is essential for centerline extraction, plaque detection, and stenosis quantification. In practice, data quality varies. Sometimes, the arteries and veins have similar intensities and locate closely, which may confuse segmentation algorithms, even deep learning based ones, to obtain accurate arteries. However, it is not always feasible to re-scan the patient for better image quality. In this paper, we propose an artery and vein disentanglement network (AVDNet) for robust and accurate segmentation by incorporating the coronary vein into the segmentation task. This is the first work to segment coronary artery and vein at the same time. The AVDNet consists of an image based vessel recognition network (IVRN) and a topology based vessel refinement network (TVRN). IVRN learns to segment the arteries and veins, while TVRN learns to correct the segmentation errors based on topology consistency. We also design a novel inverse distance weighted dice (IDD) loss function to recover more thin vessel branches and preserve the vascular boundaries. Extensive experiments are conducted on a multi-center dataset of 700 patients. Quantitative and qualitative results demonstrate the effectiveness of the proposed method by comparing it with state-of-the-art methods and different variants. Prediction results of the AVDNet on the Automated Segmentation of Coronary Artery Challenge dataset are avaliabel at https://github.com/WennyJJ/Coronary-Artery-Vein-Segmentation for follow-up research.
Subject(s)
Algorithms , Coronary Vessels , Humans , Coronary Vessels/diagnostic imaging , Tomography, X-Ray Computed/methods , Coronary Angiography/methods , Computed Tomography Angiography/methods , Image Processing, Computer-Assisted/methodsABSTRACT
Ion substitution techniques for nanoparticles have become an important neighborhood of biomedical engineering and have led to the development of innovative bioactive materials for health systems. Magnesium-doped nanohydroxyapatite (Mg-nHA) has good bone conductivity, biological activity, flexural strength, and fracture toughness due to particle doping technology, making it an ideal candidate material for biomedical applications. In this Review, we have systematically presented the synthesis methods of Mg-nHA and their application in the field of biomedical science and highlighted the pros and cons of each method. Finally, some future prospects for this important neighborhood are proposed. The purpose of this Review is to provide readers with an understanding of this new field of research on bioactive materials with innovative functions and systematically introduce the latest technologies for obtaining uniform, continuous, and morphologically diverse Mg-nHA.
ABSTRACT
Left ventricular regional wall thickness (LVRWT) is an independent predictor of morbidity and mortality in cardiovascular diseases (CVDs). To identify specific genetic influences on individual LVRWT, we established a novel deep learning algorithm to calculate 12 LVRWTs accurately in 42,194 individuals from the UK Biobank with cardiac magnetic resonance (CMR) imaging. Genome-wide association studies of CMR-derived 12 LVRWTs identified 72 significant genetic loci associated with at least one LVRWT phenotype (P < 5 × 10-8), which were revealed to actively participate in heart development and contraction pathways. Significant causal relationships were observed between the LVRWT traits and hypertrophic cardiomyopathy (HCM) using genetic correlation and Mendelian randomization analyses (P < 0.01). The polygenic risk score of inferoseptal LVRWT at end systole exhibited a notable association with incident HCM, facilitating the identification of high-risk individuals. The findings yield insights into the genetic determinants of LVRWT phenotypes and shed light on the biological basis for HCM etiology.
Subject(s)
Cardiomyopathy, Hypertrophic , Genome-Wide Association Study , Humans , Cardiomyopathy, Hypertrophic/diagnostic imaging , Cardiomyopathy, Hypertrophic/genetics , Heart , Heart Ventricles/pathology , PhenotypeABSTRACT
BACKGROUND: Late gadolinium enhancement (LGE) cardiac MRI is the method of choice in revealing the presence of myocardial scarring, but its availability remains limited in clinical practice. PURPOSE: To assess myocardial scarring in patients with autoimmune rheumatic diseases (ARDs) using contrast-free cardiac MRI with a radiomics model. STUDY TYPE: Retrospective. POPULATION: One hundred ninety-two patients (mean age, 41 years ± 15, 62 men) with or without ARDs, grouped into a training set of 153 patients and a testing set of 39 patients. FIELD STRENGTH/SEQUENCE: 3.0 T/ cine imaging with a balanced steady-state free precession sequence, T1 mapping with a modified Look-Locker inversion recovery sequence, and LGE imaging with a phase-sensitive inversion recovery gradient echo sequence. ASSESSMENT: LGE assessment was the reference standard for identifying myocardial scarring. Based on motion features extracted from cine images and tissue characterization features extracted from native T1 maps, a fully automated radiomics model with T1, cine MRI, or combined inputs was developed. STATISTICAL TESTS: Logistic regression model was used to detect myocardial scarring using contrast-free cardiac MRI parameters. Receiver operating characteristic curves were analyzed to assess the accuracy, sensitivity, and specificity in detecting myocardial scarring. Sensitivities of the models were further assessed in patients with various myocardial scarring proportions. Z-statistic and dice coefficient were assessed to compare the performance. P-values <0.05 were considered significant. RESULTS: The multivariable regression model exhibited an accuracy of 85.3%, a sensitivity of 93.5%, and a specificity of 50.0%. The radiomics model with T1 and cine MRI input exhibited an accuracy of 75.7%, a sensitivity of 60.9%, and a specificity of 85.5%. Moreover, the radiomics model showed a sensitivity of 90.9% among patients with >25% myocardial scarring. DATA CONCLUSIONS: The proposed radiomics model allowed for the identification of myocardial scarring similar to LGE, but on contrast-free cardiac MRI in patients with ARDs. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 1.
ABSTRACT
Objective: Today, the emergence of Klebsiella pneumoniae with the tmexCD1-toprJ1 gene cassette in patients has presented a significant clinical challenge. Methods: To present the detailed genetic features of the tmexCD1-toprJ1 gene cassette of K. pneumoniae strain F4_plasmid pA, the whole bacterial genome was sequenced by Illumina and nanopore platforms, and mobile genetic elements related to antibiotic resistance genes were analyzed with a series of bioinformatics methods. Results: K. pneumoniae strain F4 was determined to be a class A+C beta-lactamase, and was resistant to routinely used antibiotics, especially tigecycline, because of the oqxAB gene localized on the F4_chromosome and tmexCD1-toprJ1 on F4_plasmid A. After plasmid transfer assays, the F4_plasmid pA or F4_plasmid pB could be recovered with an average conjugation frequencies of 3.42×10-4 or 4.19×10-4. F4_plasmid pA carried tmexCD1-toprJ1 and bla DHA-1 accompanied by genetic intermixing of TnAs1, Tn5393, TnAs3, and In641, while F4_plasmid pB, bearing bla CTX-M-174, had structural overlap of TnAs3 and In641. Conclusions: We suggested that plasmids carrying tmexCD1- toprJ1 might be strongly related to IS26-integrated loop intermediates. This study showed that due to the structural evolution of F4 and related strains, their resistances were so strong that effective antibiotics were virtually unavailable, therefore their spread and prevalence should be strictly controlled.
Subject(s)
Klebsiella Infections , Klebsiella pneumoniae , Humans , Klebsiella pneumoniae/genetics , Klebsiella Infections/microbiology , Plasmids/genetics , beta-Lactamases/genetics , Anti-Bacterial Agents/pharmacology , Microbial Sensitivity TestsABSTRACT
Maternal obesity affects the risk of cardiovascular disease and inflammatory response in offspring. However, the impact of maternal obesity on offspring with Kawasaki disease (KD), the leading cause of childhood acquired heart disease, is still an understudied area. This study aimed to elucidate the impact of maternal obesity on offspring in KD-like vasculitis and the underlying mechanisms. Offspring of obese female mice and normal diet dams were randomly divided into two subgroups. The pups were injected intraperitoneally with either Candida albicans water-soluble fraction (CAWS) or phosphate buffered saline (PBS) to establish the obesity (OB)-CAWS group, OB group, wild type (WT)-CAWS group, and WT group. Their weight was monitored during the study. After four weeks, echocardiography was applied to obtain the alternation of cardiac structures. Mouse cytokine panel, Hematoxylin-Eosin (HE) staining, western blot, and real-time qPCR were used to study the pathological changes and protein and RNA expression alternations. Based on the study of pathology, serology and molecular biology, maternal obesity lead to more severe vasculitis and induced altered cardiac structure in the offspring mice and promoted the expression of pro-inflammatory cytokines through activating the NF-κB signaling pathway. Maternal obesity aggravated the inflammatory response of offspring mice in KD-like vasculitis.
Subject(s)
Cardiovascular Diseases , Mucocutaneous Lymph Node Syndrome , Obesity, Maternal , Vasculitis , Animals , Female , Mice , Mice, Obese , Obesity, Maternal/complications , Candida albicansABSTRACT
The direct catalytic asymmetric hydrogenation of pyridines for the synthesis of piperidines remains a challenge. Herein, we report a one-pot asymmetric hydrogenation of pyridines with subsequent N-alkylation using a traceless Brønsted acid activation strategy. Catalyzed by an iridium-BINAP complex, the substrates undergo ketone reduction, cyclization and pyridine hydrogenation in sequence to form indolizidines and quinolizidines. The absolute configuration of the stereocenter of the alcohol is retained and influences the formation of the second stereocenter. Experimental and theoretical mechanistic studies reveal that the chloride anion and certain noncovalent interactions govern the stereoselectivity of the cascade reaction throughout the catalytic process.
ABSTRACT
Ovarian mesenchymal cells (oMCs) constitute a distinct microenvironment that supports folliculogenesis under physiological conditions. Supplementation of exogenous non-ovarian mesenchymal-related cells has been reported to be an efficient approach to improve ovarian functions. However, the development and cellular and molecular characteristics of endogenous oMCs remain largely unexplored. In this study, we surveyed the single-cell transcriptomic landscape to dissect the cellular and molecular changes associated with the aging of oMCs in mice. Our results showed that the oMCs were composed of five ovarian differentiated MC (odMC) populations and one ovarian mesenchymal progenitor (oMP) cell population. These cells could differentiate into various odMCs via an oMP-derived route to construct the ovarian stroma structures. Comparative analysis revealed that ovarian aging was associated with decreased quantity of oMP cells and reduced quality of odMCs. Based on the findings of bioinformatics analysis, we designed different strategies involving supplementation with young oMCs to examine their effects on female fertility and health. Our functional investigations revealed that oMCs supplementation prior to ovarian senescence was the optimal method to improve female fertility and extend the reproductive lifespan of aged females in the long-term.