Recursive splicing (RS) is a splicing mechanism to remove long introns from messenger RNA precursors of long genes. Compared to the hundreds of RS events identified in humans and drosophila, only ten ...RS events have been reported in mice. To further investigate RS in mice, we analyzed RS in the mouse brain, a tissue that is enriched in the expression of long genes. We found that nuclear total RNA sequencing is an efficient approach to investigate RS events. We analyzed 1.15 billion uniquely mapped reads from the nuclear total RNA sequencing data in the mouse cerebral cortex. Unexpectedly, we only identified 20 RS sites, suggesting that RS is a rare event in the mouse brain. We also identified that RS is constitutive between excitatory and inhibitory neurons and between sexes in the mouse cerebral cortex. In addition, we found that the primary sequence context is associated with RS splicing intermediates and distinguishes RS AGGT site from non-RS AGGT sites, indicating the importance of the primary sequence context in RS sites. Moreover, we discovered that cryptic exons may use an RS-like mechanism for splicing. Overall, we provide novel findings about RS in long genes in the mouse brain.
Efforts to manipulate locus-specific histone acetylation to assess their causal role in gene expression and cellular and behavioural phenotypes have been impeded by a lack of experimental tools. The ...Cas9 nuclease has been adapted to target epigenomic modifications, but a detailed description of the parameters of such synthetic epigenome remodellers is still lacking. Here we describe a Cas9-based histone deacetylase (HDAC) and the design principles required to achieve locus-specific histone deacetylation. We assess its range of activity and specificity, and analyse target gene expression in two different cell types to investigate cellular context-dependent effects. Our findings demonstrate that the chromatin environment is an important element to consider when utilizing this synthetic HDAC.
Abstract
Heparan sulfate (HS) is a linear polysaccharide found in almost all animal cells and plays an important role in various biological processes. HS functions mainly via covalently binding to ...core proteins to form HS proteoglycans (HSPGs), which are heterogeneous in the lengths of the HS chain, the modifications on HS and the core proteins. The molecular mechanisms underlying HSPG heterogeneity, although widely studied, are not yet fully defined. The expression profiles of HS biosynthesis enzymes and HSPG core proteins likely contribute to the HSPG heterogeneity, but these expression profiles remain poorly characterized. To investigate the expression profiles of genes encoding HS biosynthesis enzymes and HSPG core proteins, we systematically integrated the publicly available RNA sequencing data in mice. To reveal the spatial expression of these genes, we analyzed their expression in 21 mouse tissues. To reveal the temporal expression of these genes, we analyzed their expression at 17 time points during the mouse forebrain development. To determine the cell-type-specific expression of these genes, we obtained their expression profiles in 23 cell types in the mouse cerebral cortex by integrating single nucleus RNA sequencing data. Our findings demonstrate the spatial, temporal and cell-type-specific expression of genes encoding HS biosynthesis enzymes and HSPG core proteins and represent a valuable resource to the HS research community.
What is known and objective
Propofol and esketamine are routine anaesthetics used in sedation or general anaesthesia for paediatric procedures. Coadministration could reduce the dose of either ...propofol or esketamine required and lower the incidence of drug‐related adverse events. We designed a four‐arm randomized controlled trial in children undergoing diagnostic upper gastrointestinal endoscopy to investigate the dose of propofol with different doses of esketamine inducing appropriate depth of anaesthesia in 50% patients (median effective dose, ED50).
Methods
After getting the approval of the research ethics committee and informed consent, 92 paediatric patients planning for upper gastrointestinal endoscopy were divided into four groups randomly: esketamine 0, 0.25, 0.5 and 1 mg/kg groups (n = 23/group). Propofol doses followed the Dixon and Massey up‐and‐down method with different starting and interval doses between groups. During the first attempt of endoscope insertion, if patients' reactions prevented the insertion, it would be considered as a failure. The awakening time, total propofol doses, as well as the perioperative and post‐procedure adverse events were evaluated and recorded for each patient.
Results and discussion
The ED50 (median, 95% confidence interval) of propofol was significantly greater in esketamine 0 and 0.25 mg/kg groups in comparison with the esketamine 0.5 and 1 mg/kg groups (4.1 3.3–4.9; 3.1 2.5–3.8 mg/kg vs. 1.8 1.1–2.4; 0.8 0.2–1.3 mg/kg, respectively, p < .05). The total doses of propofol in esketamine 0.5 and 1 mg/kg groups were statistically lower than these in esketamine 0 and 0.25 mg/kg group (p < .01). The mean blood pressure was lower in the esketamine 0 mg/kg group than that in 1 mg/kg group after administration and during the procedure (p < .01). The esketamine 1 mg/kg group showed a higher incidence of vomiting and visual disturbances than the other three groups (p < .001).
What is new and conclusion
In children who accomplished diagnostic paediatric upper gastrointestinal endoscopy under deep sedation/anaesthesia, the total dosage of propofol needed was reduced significantly in esketamine 0.5 and 1 mg/kg groups with a corresponding reduce in propofol‐related hemodynamic changes. However, a higher incidence of esketamine‐related adverse effects was found in esketamine 1 mg/kg group.
This trial aimed to investigate the median effective dose of propofol with different doses of esketamine in children undergoing diagnostic upper gastrointestinal endoscopy. The total dosage of propofol was reduced in esketamine 0.5 and 1 mg/kg groups with a corresponding reduce in propofol‐related hemodynamic changes, while a higher incidence of esketamine‐related adverse effects was found in esketamine 1 mg/kg group.
Alkenylbenzene skeletons represent one of the most widely occurring structural motifs in pharmaceutical drugs, natural products, and advanced materials. The construction of alkenylbenzenes is ...promising through the use of a straightforward oxidative alkenylation protocol, particularly from unactivated alkenes. This is significant because unactivated alkenes are inexpensive raw materials that can be obtained in bulk quantities from petrochemical feedstocks and renewable resources. However, controlling the reactivity and regioselectivity of olefination with unbiased olefins remains a significant challenge, necessitating continuous efforts and potentially having a substantial impact on both organic synthesis and the industry. This review aims to provide an overview of the latest advances in regiocontrol strategies for oxidative alkenylation reactions with unactivated alkenes, which can be categorized into three types: 1) ligand‐promoted/accelerated reactions; 2) prefunctionalized olefins‐facilitated reactions; 3) directing group‐induced reactions.
Ferroptosis is a regulated form of necrotic cell death that involves the accumulation of lipid peroxide (LPO) species in an iron‐ and reactive oxygen species (ROS)‐dependent manner. Previous ...investigations have reported that ferroptosis‐based cancer therapy can overcome the limitations of traditional therapeutics targeting the apoptosis pathway. However, it is still challenging to enhance the antitumor efficacy of ferroptosis due to intrinsic cellular regulation. In this study, a ferroptosis‐inducing agent, i.e., chlorin e6 (Ce6)‐conjugated human serum albumin–iridium oxide (HSA‐Ce6‐IrO2, HCIr) nanoclusters, is developed to achieve sonodynamic therapy (SDT)‐triggered ferroptosis‐like cancer cell death. The sonosensitizing role of both Ce6 and IrO2 within the HCIr nanoclusters exhibits highly efficient 1O2 generation capacity upon ultrasound stimulation, which promotes the accumulation of LPO and subsequently induces ferroptosis. Meanwhile, the HCIr can deplete glutathione (GSH) by accelerating Ir (IV)–Ir (III) transition, which further suppresses the activity of glutathione peroxidase 4 (GPX4) to enhance the ferroptosis efficacy. Through in vitro and in vivo experiments, it is demonstrated that HCIr possesses tremendous capacity to reduce the intracellular GSH content, which enhances SDT‐triggered ferroptosis‐like cancer cell death. Thus, an iridium‐nanoclusters‐based ferroptosis‐inducing agent is developed, providing a promising strategy for inducing ferroptosis‐like cancer cell death.
A bioactive HCIr nanocluster is reported for triggering effective ferroptosis‐like cancer cell death via triggering GPX4 inhibition and concurrent dual sonodynamic effect by iridium oxide nanoclusters and chlorin e6 (Ce6). These HCIr nanoclusters hold a great promise as a ferroptosis‐inducing agent for treating intrinsic apoptotic resistance of tumors, and the findings provide a promising strategy for future studies exploring nanoclusters as anticancer agents.
Zinc oxide nanoparticles were well-known for the enhanced antifouling and antibacterial properties which could be beneficial for membrane processes in desalination. The functionalization of ZnO onto ...graphene oxide nanoplates was targeted for better distribution. Both ZnO and ZnO-GO NPs were synthesized using sol-gel method. The nanoparticles characteristics were checked with XRD, TEM, and FESEM. The nanohybrid membranes were fabricated via wet phase inversion technique and embedded with various percentage of ZnO (1, 2, 3wt%) and ZnO-GO (0.1, 0.3, 0.6wt%) nanoparticles. All the membranes with nanoparticles incorporation exhibited improved membrane properties in comparison with the pristine PSF membrane. The best membrane performance was shown in membrane with 2wt% of ZnO and 0.6wt% of ZnO-GO. These two membranes presented significantly improved performance such as enhanced hydrophilicity, high permeability and porosity, improved humic acid rejection rate as well as good antifouling and antibacterial control. To an extent, the excellent antimicrobial ability of these nanohybrid membranes appeared as appropriate candidate to contribute or overcome bio-fouling issues in applications such as brackish water or seawater desalination. Hence, ZnO and ZnO-GO NPs were superb nanomaterials in the fabrication of PSF-nanohybrid membranes. The use of GO nanoplates allowed reduction of ZnO composition by up to 5 times while showing similar performances.
•Various percentages of minimal-size ZnO and ZnO-GO for PSF membrane enhancement•5 times reduction of ZnO usage with the introduction of GO nanosheets as support•ZnO-GO composite is more hydrophilic compared to other GO-nanohybrid.•ZnO-GO membrane exhibits excellent antifouling and antibacterial properties.
Kallmann syndrome (KS) is a congenital disorder characterized by idiopathic hypogonadotropic hypogonadism and olfactory dysfunction. KS is linked to variants in >34 genes, which are scattered across ...the human genome and show disparate biological functions. Although the genetic basis of KS is well studied, the mechanisms by which disruptions of these diverse genes cause the same outcome of KS are not fully understood. Here we show that disruptions of KS-linked genes affect the same biological processes, indicating convergent molecular mechanisms underlying KS. We carried out machine learning-based predictions and found that KS-linked mutations in heparan sulfate 6-O-sulfotransferase 1 (HS6ST1) are likely loss-of-function mutations. We next disrupted Hs6st1 and another KS-linked gene, fibroblast growth factor receptor 1 (Fgfr1), in mouse neuronal cells and measured transcriptome changes using RNA sequencing. We found that disruptions of Hs6st1 and Fgfr1 altered genes in the same biological processes, including the upregulation of genes in extracellular pathways and the downregulation of genes in chromatin pathways. Moreover, we performed genomics and bioinformatics analyses and found that Hs6st1 and Fgfr1 regulate gene transcription likely via the transcription factor Sox9/Sox10 and the chromatin regulator Chd7, which are also associated with KS. Together, our results demonstrate how different KS-linked genes work coordinately in a convergent signaling pathway to regulate the same biological processes, thus providing new insights into KS.
The forecast of electricity consumption plays an essential role in marketing management. In this study, a random forest (RF) model coupled with ensemble empirical mode decomposition (EEMD) named ...EEMD-RF is presented for forecasting the daily electricity consumption of general enterprises. The candidate data is first decomposed into several intrinsic mode functions (IMFs) by the EEMD. Through fast Fourier transformation, the features in each IMF are extracted in the time-frequency domain, then simulated and predicted by the RF model. Finally, the results of each IMF are integrated into the overall trend of the daily electricity consumption for those enterprises. The proposed method was applied to two enterprises located in the Jiangsu High-Tech Zone, and the period of collected data was from January 1, 2015 to May 3, 2016. To show the applicability and superiority of the EEMD-RF approach, two basic models (a back-propagation neural network (BPNN) and least squares support vector regression (LSSVM) and five model experiments (EEMD-BPNN, EEMD-LSSVM, RF, BPNN and LSSVM) were selected for comparison. Among these approaches, the proposed model exhibited the best forecast performance in terms of mean absolute error, mean absolute percentage error, and root-mean-square error.
•A random forest model coupled with ensemble empirical mode decomposition (EEMD-RF) is proposed.•The EEMD is applied for extracting complex features of different modes.•The RF is applied for modeling the changes of different modes.•The EEMD-RF has high accuracy in enterprise electricity consumption forecasting.
Safe and effective strategies are urgently needed to fight against the life-threatening diseases of various cancers. However, traditional therapeutic modalities, such as radiotherapy, chemotherapy ...and surgery, exhibit suboptimal efficacy for malignant tumors owing to the serious side effects, drug resistance and even relapse. Phototherapies, including photodynamic therapy (PDT) and photothermal therapy (PTT), are emerging therapeutic strategies for localized tumor inhibition, which can produce a large amount of reactive oxygen species (ROS) or elevate the temperature to initiate cell death by non-invasive irradiation. In consideration of the poor bioavailability of phototherapy agents (PTAs), lots of drug delivery systems have been developed to enhance the tumor targeted delivery. Nevertheless, the carriers of drug delivery systems inevitably bring biosafety concerns on account of their metabolism, degradation, and accumulation. Of note, carrier-free nanomedicine attracts great attention for clinical translation with synergistic antitumor effect, which is characterized by high drug loading, simplified synthetic method and good biocompatibility. In this review, the latest advances of phototherapy with various carrier-free nanomedicines are summarized, which may provide a new paradigm for the future development of nanomedicine and tumor precision therapy.
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