Bacterial pathogens carrying multidrug resistance (MDR) plasmids are a major threat to human health. The acquisition of antibiotic resistance genes (ARGs) in plasmids is often facilitated by mobile ...genetic elements that copy or translocate ARGs between DNA molecules. The agglomeration of mobile elements in plasmids generates resistance islands comprising multiple ARGs. However, whether the emergence of resistance islands is restricted to specific MDR plasmid lineages remains understudied. Here we show that the agglomeration of ARGs in resistance islands is biased towards specific large plasmid lineages. Analyzing 6784 plasmids in 2441 Escherichia, Salmonella, and Klebsiella isolates, we quantify that 84% of the ARGs in MDR plasmids are found in resistance islands. We furthermore observe rapid evolution of ARG combinations in resistance islands. Most regions identified as resistance islands are shared among closely related plasmids but rarely among distantly related plasmids. Our results suggest the presence of barriers for the dissemination of ARGs between plasmid lineages, which are related to plasmid genetic properties, host range and the plasmid evolutionary history. The agglomeration of ARGs in plasmids is attributed to the workings of mobile genetic elements that operate within the framework of existing plasmid lineages.
Extensive studies in various plants show that the anthocyanin biosynthetic process is affected by environmental factors and regulated by many transcription factors through sophisticated regulatory ...networks. However, it remains largely unclear about the roles of microRNA in this process. Here, we demonstrate that miR858a is a positive regulator of anthocyanin biosynthesis in Arabidopsis seedlings. Overexpression of miR858a enhances the accumulation of anthocyanins, whereas the reduced miR858a activity results in low levels of anthocyanins in STTM858 transgenic plants. We found that miR858a inhibits the expression of MYBL2, a key negative regulator of anthocyanin biosynthesis, by translational repression. In addition, ELONGATED HYPOCOTYL 5 (HY5) was shown to directly bind the MYBL2 promoter and represses its expression via specific histone modifications. Interestingly, we found that miR858a exhibits light-responsive expression in an HY5-dependent manner. Together, these results delineate the HY5-MIR858a-MYBL2 loop as a cellular mechanism for modulating anthocyanin biosynthesis, suggesting that integration of transcriptional and posttranscriptional regulation is critical for governing proper anthocyanin accumulation in response to light and other environmental factors.
We report that miR858a positively regulates anthocyanin accumulation in Arabidopsis seedlings. MIR858a and HY5 co-repress the expression of MYBL2, the negative regulator of anthocyanin biosynthesis, in response to changing environmental cues. Our results reveal a molecular mechanism incorporating both transcriptional and posttranscriptional regulations for controlling anthocyanin biosynthesis in plants.
Abstract IR-780 iodide is a near-infrared (NIR) fluorescence dye with higher and more stable fluorescence intensity than clinically applied dye indocyanine green (ICG). Meanwhile, IR-780 can be ...utilized in photothermal therapy with laser irradiation. IR-780 is an important theranostic agent but its lipophilicity limited its application. In this paper, we synthesize multifunctional heparin–folic acid-IR-780 nanoparticles (HF-IR-780 NPs) by self-assembly of the heparin–folic acid conjugate and IR-780 through ultrasonic sound method. The HF-IR-780 NPs exhibit good monodispersity, significant stability, and excellent molecular targeting to folate receptor over-expressing MCF-7 cells. Furthermore, the in vivo biodistribution experiments show that the HF-IR-780 NPs are specifically targeted to the tumor and can be used for tumor imaging. The in vitro cell viability assays and in vivo photothermal therapy experiments indicate that MCF-7 cells or MCF-7 xenograft tumors could be ablated by combining HF-IR-780 NPs with irradiation of an 808 nm laser. The photothermal therapy in vivo with a single-dose treatment has not caused significant adverse effect. The resulted HF-IR-780 NPs are a potential theranostic agent for imaging-guided cancer therapy.
This study aimed to compare the survival rates after lobectomy, segmentectomy, and wedge resection for the eighth edition of the tumor, node, metastasis classification for stage IA non-small cell ...lung cancer (NSCLC).
Patients who underwent lobectomy, segmentectomy, or wedge resection for stage IA NSCLC were identified from the Surveillance, Epidemiology, and End Results database. A Cox regression model and propensity-matched analysis were used. The overall survival (OS) rates and lung cancer-specific survival (LCSS) rates among the three groups were compared by tumor size.
A total of 16,819 patients met our criteria. Although the OS rate was better for lobectomy than for wedge resection, no statistical differences in the LCSS rate were identified among the three treatment groups of patients with tumors that were 1.0 cm or smaller. For tumors from 1.1 to 2.0 cm, lobectomy and segmentectomy showed no statistical differences in the LCSS rate, but both conferred better OS and LCSS rates than wedge resection. For tumors from 2.1 to 3.0 cm, the OS and LCSS rates were better for lobectomy than for segmentectomy or wedge resection, but similar for segmentectomy and wedge resection.
Lobectomy, segmentectomy, and wedge resection are comparable oncologic procedures for patients with stage IA NSCLC that is 1.0 cm or smaller. For tumors from 1.1 to 2.0 cm, lobectomy and segmentectomy could lead to equivalent survival rates but showed better survival rates than that observed with wedge resection. For tumors from 2.1 to 3.0 cm, lobectomy is still the standard surgical procedure; for patients who are unsuitable candidates for lobectomy, segmentectomy and wedge resection show similar survival rates.
The purpose of this study was to explore the effect of Semaglutide on intrauterine adhesions and discover new drugs for such adhesions. In this study, the cell model was simulated by TGF-β1-induced ...human endometrial epithelial cells, and the animal model was established through mechanical curettage and inflammatory stimulation. After co-culturing with TGF-β1 with or without different concentrations of Semaglutide for 48 h, cells were collected for RT-qPCR and Western blotting analyses. Three doses were subcutaneously injected into experimental mice once a day for two weeks, while the control group received sterile ddH2O. The serum and uterine tissues of the mice were collected. HE and Masson staining were used for the uterine histomorphological and pathological analyses. RT-qPCR and Western blotting were used for mRNA and protein expression analyses. Serum indicators were detected using ELISA kits. The results showed that Semaglutide significantly reduced the mRNA levels of fibrosis indicators ACTA2, COL1A1, and FN and inflammatory indicators TNF-α, IL-6, and NF-κB in the two models. Semaglutide improved endometrium morphology, increased the number of endometrial glands, and reduced collagen deposition in IUA mice. The results also showed that Semaglutide could inhibit vimentin, E-Cadherin, and N-Cadherin in the two models. In summary, Semaglutide can ameliorate fibrosis and inflammation of intrauterine adhesions as well as inhibit epithelial–mesenchymal transition in IUA models.
Heteroatom-doped graphene attracted tremendous attention because of advanced electrocatalytic properties, for example, for oxygen reduction. However, the role of oxygen atoms as heteroatoms in ...graphene should be explored more deeply. Here, we used statistical Raman spectroscopy for single-layer material analysis and found that the regiochemistry close to vacancy defects plays a decisive role. Accordingly, defects possess a guiding effect on the introduction of oxygen functional groups close to those defect-sites. After the addition of oxo-groups close to vacancy defects, the activity and hydrogen peroxide (H2O2) selectivity of the material on hydrogen peroxide production improved significantly. The selectivity of H2O2 is above 84%, which is higher than the initial oxo-functionalized graphene and electrochemically reduced graphene. The half-wave potential is 0.73 VRHE, which is more positive than the initial oxo-functionalized graphene.
Ovarian cancer ranks seventh in the most common malignant tumors among female disease, which seriously threatens female reproductive health. It is characterized by hidden pathogenesis, missed ...diagnosis, high reoccurrence rate, and poor prognosis. In clinic, the first-line treatment prioritized debulking surgery with paclitaxel-based chemotherapy. The harsh truth is that female patients are prone to relapse due to the dissemination of tumor cells and drug resistance. In these circumstances, the development of new therapy strategies combined with traditional approaches is conductive to improving the quality of treatment. Among numerous drug resources, botanical compounds have unique advantages due to their potentials in multitarget functions, long application history, and wide availability. Previous studies have revealed the therapeutic effects of bioactive plant components in ovarian cancer. These natural ingredients act as part of the initial treatment or an auxiliary option for maintenance therapy, further reducing the tumor and metastatic burden. In this review, we summarized the functions and mechanisms of natural botanical components applied in human ovarian cancer. We focused on the molecular mechanisms of cell apoptosis, autophagy, RNA and DNA lesion, ROS damage, and the multiple-drug resistance. We aim to provide a theoretical reference for in-depth drug research so as to manage ovarian cancer better in clinic.
Cardiac troponin I (cTnI) is an efficient and specific biomarker for the accurate diagnosis of acute myocardial infarction (AMI), one of the diseases with the highest mortality worldwide. Due to the ...short course and high fatality of this disease, a rapid, accurate and portable device for quantitative detection is urgently needed for early diagnosis and treatment. In this work, we designed a handheld device based on a dual-gate ion-sensitive field-effect transistor (ISFET) for early and accurate warning of AMI through cTnI detection. A one-step enzyme-linked immunosorbent assay strategy was proposed for use in this device to recognize trace cTnI in serum, converting the cTnI concentration to a drain-source current generated by an ultrasensitive ISFET. This portable device exhibited an ultrahigh sensitivity of 132 pA pg−1·mL−1, a wide linear range from 1 to 1000 pg/mL that enabled coverage far exceeding the threshold level (280 pg/mL), and a low detection limit of 0.3 pg/mL for the cTnI assay, which was much lower than the current diagnostic cut-off for a healthy control level for AMI (40 pg/mL). In addition, this handheld device showed satisfactory selectivity and reliable results in the analysis of real serum within 20 min, indicating its potential applications in early screening and diagnosis for the clinical evaluation of AMI.
•A cTnI handheld testing device was constructed based on a dual-gate ISFET.•A one-step electrical enzyme-linked immunosorbent strategy was designed for the fast and ultrasensitive response of cTnI.•This portable device enables to achieve accurate detection of cTnI in real serum within 20 min.
The targeted delivery of nanoparticles to solid tumors is one of the most important and challenging problems in cancer nanomedicine, but the detailed delivery mechanisms and design principles are ...still not well understood. Here we report quantitative tumor uptake studies for a class of elongated gold nanocrystals (called nanorods) that are covalently conjugated to tumor-targeting peptides. A major advantage in using gold as a “tracer” is that the accumulated gold in tumors and other organs can be quantitatively determined by elemental mass spectrometry (gold is not a natural element found in animals). Thus, colloidal gold nanorods are stabilized with a layer of polyethylene glycols (PEGs) and are conjugated to three different ligands: (i) a single-chain variable fragment (ScFv) peptide that recognizes the epidermal growth factor receptor (EGFR); (ii) an amino terminal fragment (ATF) peptide that recognizes the urokinase plasminogen activator receptor (uPAR); and (iii) a cyclic RGD peptide that recognizes the avβ3 integrin receptor. Quantitative pharmacokinetic and biodistribution data show that these targeting ligands only marginally improve the total gold accumulation in xenograft tumor models in comparison with nontargeted controls, but their use could greatly alter the intracellular and extracellular nanoparticle distributions. When the gold nanorods are administered via intravenous injection, we also find that active molecular targeting of the tumor microenvironments (e.g., fibroblasts, macrophages, and vasculatures) does not significantly influence the tumor nanoparticle uptake. These results suggest that for photothermal cancer therapy, the preferred route of gold nanorod administration is intratumoral injection instead of intravenous injection.
Runt-related transcription factor 1 (RUNX1) plays the roles of an oncogene and an anti-oncogene in epithelial tumours, and abnormally elevated RUNX1 has been suggested to contribute to the ...carcinogenesis of colorectal cancer (CRC). However, the mechanism remains unclear.
The expression of RUNX1 in CRC and normal tissues was detected by real-time quantitative PCR and Western blotting. The effect of RUNX1 on CRC migration and invasion was conducted by functional experiments in vitro and in vivo. Chromatin Immunoprecipitation assay verified the direct regulation of RUNX1 on the promoter of the KIT, which leads to the activation of Wnt/β-catenin signaling.
RUNX1 expression is upregulated in CRC tissues. Upregulated RUNX1 promotes cell metastasis and epithelial to mesenchymal transition (EMT) of CRC both in vitro and in vivo. Furthermore, RUNX1 can activate Wnt/β-catenin signalling in CRC cells by directly interacting with β-catenin and targeting the promoter and enhancer regions of KIT to promote KIT transcription. These observations demonstrate that RUNX1 upregulation is a common event in CRC specimens and is closely correlated with cancer metastasis and that RUNX1 promotes EMT of CRC cells by activating Wnt/β-catenin signalling. Moreover, RUNX1 is regulated by Wnt/β-catenin.
Our findings first demonstrate that RUNX1 promotes CRC metastasis by activating the Wnt/β-catenin signalling pathway and EMT.
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