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Caudal epidural blockade is one of the most frequently administered regional anesthesia techniques in children. It is a supplement during general anesthesia and for providing postoperative analgesia in pediatrics for sub-umbilical surgeries, especially for genitourinary surgeries. However, the duration of the analgesic effect is occasionally unsatisfactory. In this review, we discuss the main advantages and disadvantages of different techniques to prolong postoperative analgesia for single-injection caudal blockade in children. A literature search of the keywords “caudal”, “analgesia”, “pediatric”, and “children” was performed using PubMed and Web of Science databases. We highlight that analgesic quality correlates substantially with the local anesthetic's type, dose, the timing relationship between caudal block and surgery, caudal catheterization, and administration of epidural opioids or other adjuvant drugs.

Abstract Background Myocardial injury after noncardiac surgery (MINS) is one of the most common complications associated with postoperative adverse cardiovascular outcomes and mortality. However, MINS often fails to be timely diagnosed due to the absence of clinical symptoms and limited diagnostic methods. The metabolomic analysis might be an efficient way to discover new biomarkers of MINS. Characterizing the metabolomic features of MINS patients may provide new insight into the diagnosis of MINS. Methods In this study, serum samples from 20 matched patients with or without MINS (n = 10 per group) were subjected to untargeted metabolomics analysis to investigate comprehensive metabolic information. Differential metabolites were identified, and the enriched metabolic pathway was determined based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results A comprehensive analysis revealed 124 distinct metabolites, predominantly encompassing lipids, amino acids and other compounds. The observed modifications in metabolic pathways in patients with or without MINS showed significant clustering in cholesterol metabolism, aldosterone synthesis and secretion, primary bile acid biosynthesis, as well as cysteine and methionine metabolism. Four specific metabolites (taurocholic acid, L-pyroglutamic acid, taurochenodeoxycholic acid, and pyridoxamine) exhibited promising potential as biomarkers for prognosticating MINS. Conclusions This study contributes valuable insights into the metabolomic features of MINS and the discovery of potential biomarkers which may help the early diagnosis of MINS. The identified metabolites and altered pathways offer valuable insights into the molecular underpinnings of MINS, paving the way for improved diagnostic approaches and potential intervention strategies.

Abstract Extensive efforts have been dedicated to enhancing the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in cancer cells for the development of effective cancer treatments. However, highly safe and efficient delivery of TRAIL gene remains a significant challenge, especially using cationic polymers. Here, a series of highly branched-linear poly(β-amino ester)s (H-LPAEs) are developed through a unique oligomer branching strategy. H-LPAEs exhibit a more uniform distribution of linear segments and branching units, leading to excellent DNA condensation and favorable physicochemical properties of H-LPAE/DNA polyplexes. In SW1353 and BMSC cells, the optimized H-LPAEs, H-LPAEB4−S5−TMPTA, achieves superior gene transfection efficiency of 58.0% and 33.4%, which were 2.5-fold and 2.0-fold higher than that of the leading commercial gene transfection reagent, Lipofectamine 3000. Excitingly, H-LPAEB4−S5−TMPTA mediated 56.7% and 28.1% cell apoptosis in HepG2 cells and HeLa cells highlighting its potential application in cancer gene therapy. In addition, locally administered H-LPAEB4−S5−TMPTA delivered TRAIL DNA to HepG2 xenograft tumors and inhibited tumor growth in vivo. This study not only proposes a novel strategy for synthesizing poly(β-amino ester)s with a unique branched-linear topology but also identifies a promising candidate for highly efficient TRAIL gene transfection.

Abstract Colorectal cancer (CRC) is a major cause of cancer-related deaths in humans, and effective treatments are still needed in clinical practice. Despite significant developments in anticancer drugs and inhibitors, their poor stability, water solubility, and cellular membrane permeability limit their therapeutic efficacy. To address these issues, multifunctional CaCO3 nanoparticles loaded with Curcumin (Cur) and protein deacetylase (HDAC) inhibitor QTX125, and coated with hyaluronic acid (HA) (CaCO3@Cur@QTX125@HA), were prepared through a one-step gas diffusion strategy. Dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) showed that CaCO3@Cur@QTX125@HA nanoparticles have uniform spherical morphology and elemental distribution, with diameters around 450 nm and a Zeta potential of − 8.11 mV. The controlled release of Cur from the nanoparticles was observed over time periods of 48 h. Cellular uptake showed that CaCO3@Cur@QTX125@HA nanoparticles were efficiently taken up by cancer cells and significantly inhibited their growth. Importantly, CaCO3@Cur@QTX125@HA nanoparticles showed specific inhibitory effects on CRC cell growth. Encouragingly, CaCO3@Cur@QTX125@HA nanoparticles successfully internalized into CRC patient-derived organoid (PDO) models and induced apoptosis of tumor cells. The multifunctional CaCO3@Cur@QTX125@HA nanoparticles hold promise for the treatment of CRC.

REV-ERB agonists have shown antifibrotic effects in the heart and other organs. The function of REV-ERB in the cardiac fibroblasts remains unstudied. Here, we characterize the functional difference of REV-ERB in mouse embryonic fibroblasts and cardiac fibroblasts using genetic deletion of REV-ERBα and ß in vitro. We show that REV-ERB α/β double deleted cardiac fibroblasts have reduced viability and proliferation, but increased migration and myofibroblasts activation. Thus, REV-ERB α/β has essential cell-autonomous role in cardiac fibroblasts in maintaining them in a healthy, quiescent state. We also show that existing REV-ERB agonist SR9009 strongly suppresses cardiac fibroblasts activation but in a REV-ERB-independent manner highlighting the need to develop novel REV-ERB agonists for treating cardiac fibrosis.

In this study, the structural and property changes induced in the highly ordered structure of preoriented poly(3-hydroxybutyrate-co-3-hydroxyvalerate) PHBV films containing the β-form during annealing were investigated. The transformation of the β-form was investigated by means of in situ wide-angle X-ray diffraction (WAXD) using synchrotron X-rays. The comparison of PHBV films with the β-form before and after annealing was performed using small-angle X-ray scattering (SAXS), scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The evolution mechanism of β-crystal transformation was elucidated. It was revealed that most of the highly oriented β-form directly transforms into the highly oriented α-form, and there might be two kinds of transformations: (1) The β-crystalline bundles may be transformed one by one rather than one part by one part during annealing before a certain annealing time. (2) The β-crystalline bundles crack or the molecular chains of the β-form are separated from the lateral side after annealing after a certain annealing time. A model to describe the microstructural evolution of the ordered structure during annealing was established based on the results obtained.

Sulfur-based autotrophic denitrification is a novel biological denitrification process characterized by the absence of an organic carbon source, a short reaction time, a high denitrification rate, a low treatment cost, and a small footprint. However, the technique is facing challenges with respect to engineering applications. In this study, a pilot-scale sulfur-based autotrophic denitrification system was established with an optimal hydraulic retention time (HRT) of 0.21 h, which achieved the highest denitrification load of 1158 mg/(L·d) and a denitrification rate of 164 gNO3−-N/(m3·h). Effective backwashing is the basis for the long-term stable and efficient nitrogen removal performance, which recovered its normal nitrogen removal performance within 0.5 h. In addition, the operation cost is merely 0.013 $/t, indicating that the sulfur-based autotrophic denitrification process presents good economic applicability, and the relatively low operation cost will lay a foundation for practical application.

Organophosphorus compounds have toxic effects on organisms and the ecosystem. Therefore, it is vital to monitor and control the effluent organophosphorus levels of wastewater treatment plants (WWTPs). This study analyzed the composition and concentration of organophosphorus compounds from the upstream enterprises of a WWTP and conducted ecological risk and toxicity assessments using ECOSAR (ecological structure activity relationship model), T.E.S.T (Toxicity Estimation Software Tool), and risk quotient (RQ) methods. A total of 14 organic phosphorus pollutants were detected in the effluent of the upstream enterprises and WWTP. The concentration of influent total organic phosphorus from the WWTP was 39.5 mg/L, and the effluent total organic phosphorus was merely 0.301 mg/L, indicating that good phosphorus removal was achieved in the WWTP. According to the acute and chronic toxicity analysis, the ECOSAR ecotoxicity assessment showed that 11 kinds of organophosphorus compounds were hazardous to fish, daphnia, and algae in different degrees. Among them, triphenyl phosphine (TPP) had a 96 hr LC50 of 1.00 mg/L for fish and is a substance with high acute toxicity. T.E.S.T evaluates the acute toxicity of each organophosphorus component and the bioconcentration factor (BCF). The evaluation results showed that the LC50 of TPP and octicizer were 0.39 and 0.098 mg/L, respectively, and the concentrations of these two organophosphorus compounds from the effluent of an environmental protection enterprise were as high as 30.4 mg/L and 0.735 mg/L, which exceeded the acute toxicity values and has led to serious hazards to aquatic organisms. The BCF values of each organophosphorus component in the upstream enterprises and the effluent of the WWTP were less than 2000, implying that there was no bioaccumulation effect on aquatic organisms. The developmental toxicity assessment demonstrated that there were nine types of organophosphorus compounds belonging to developmental toxicants, that the presence of developmental toxicants was found in the effluent of each upstream enterprise, and that triethyl phosphate (TEP) was the most common organophosphorus compound. Comparing the RQ of the effluent from various enterprises, it was found that the effluent from the environmental protection enterprise presented the highest degree of environmental hazard, mainly due to the higher toxicity of TEP and octicizer.

The existence, uniqueness, and Carathe´odory’s successive approximation of the fractional neutral stochastic differential equation (FNSDE) in Hilbert space are considered in this paper. First, we give the Carathe´odory’s approximation solution for the FNSDE with variable time delays. We then establish the boundedness and continuity of the mild solution and Carathe´odory’s approximation solution, respectively. We prove that the mean-square error between the exact solution and the approximation solution depends on the supremum of time delay. Next, we give the Carathe´odory’s approximation solution for the general FNSDE without delay. Under uniform Lipschitz condition and linear growth condition, we show that the proof of the convergence of the Carathe´odory approximation represents an alternative to the procedure for establishing the existence and uniqueness of the solution. Furthermore, under the non-Lipschitz condition, which is weaker than Lipschitz one, we establish the existence and uniqueness theorem of the solution for the FNSDE based on the Carathe´odory’s successive approximation. Finally, a simulation is given to demonstrate the effectiveness of the proposed methods.

In addition to its central role in mediating oxidation reduction in fuel metabolism and bioenergetics, nicotinamide adenine dinucleotide (NAD+) has emerged as a vital co-substrate for a number of proteins involved in diverse cellular processes, including sirtuins, poly(ADP-ribose) polymerases and cyclic ADP-ribose synthetases. The connection with aging and age-associated diseases has led to a new wave of research in the cardiovascular field. Here, we review the basics of NAD+ homeostasis, the molecular physiology and new advances in ischemic-reperfusion injury, heart failure, and arrhythmias, all of which are associated with increased risks for sudden cardiac death. Finally, we summarize the progress of NAD+-boosting therapy in human cardiovascular diseases and the challenges for future studies.

KLF15 has recently emerged as a central regulator of metabolism. Although its connection to oxidative stress has been suspected, there has not been any study to date that directly demonstrates the molecular link. In this study, we sought to determine the role of KLF15 in cardiac oxidative stress. We found that KLF15 deficiency in the heart is associated with increased oxidative stress. Acute deficiency of KLF15 in neonatal rat ventricular myocytes (NRVMs) leads to the defective clearance of reactive oxygen species (ROS) and an exaggerated cell death following a variety of oxidative stresses. Mechanistically, we found that KLF15 deficiency leads to reduced amounts of the rate-limiting NAD+ salvage enzyme NAMPT and to NAD+ deficiency. The resultant SIRT3-dependent hyperacetylation and the inactivation of mitochondrial antioxidants can be rescued by MnSOD mimetics or NAD+ precursors. Collectively, these findings suggest that KLF15 regulates cardiac ROS clearance through the regulation of NAD+ levels. Our findings establish KLF15 as a central coordinator of cardiac metabolism and ROS clearance.

Based on statistical data of the average abundance of microplastics from 37 global freshwater locations up to November 2019, we classified the freshwater bodies according to developments in their local countries and geographic positions. We highlighted the differences and causes of microplastic pollution in the waters of both developed and developing countries and urban and rural areas. The results showed that microplastic pollution was highest in Asia. The pollution in developed countries was significantly lower than in developing countries. The differences in freshwater pollution between urban and rural areas mainly depended on the extent of human activity. The present study found the following phenomena by comprehensively using simple and multiple regression models and a Pearson correlation analysis to solve the impacts of the features, natural factors, and social and economic factors on the distribution of microplastic pollution. The density of microplastics was higher, which promoted the aggregation of microplastics in sediments. Pursuant to that, microplastic pollution was also influenced by the space-time pollution of movable surface sources, such as the soil and air. A population increase and the average gross domestic product (GDP) could also worsen microplastic pollution.

Cultivated land productivity is a basic guarantee of food security. This study extracted the multiple cropping index (MCI) and most active days (MAD, i.e., days when the EVI exceeded a threshold) based on crop growth EVI curves to analyse the changes and potential characteristics of cultivated land productivity in Jiangsu Province during 2001−2017. The results are as follows: (1) The MCI of 83.8% of cultivated land remained unchanged in Jiangsu, the cultivated land with changed MCI (16.2%) was mainly concentrated in the southern and eastern coastal areas of Jiangsu, and the main cropping systems were single and double seasons. (2) The changes in cultivated land productivity were significant and had an obvious spatial distribution. The areas where the productivity of single cropping system changed occupied 67.8% of the total cultivated land of single cropping system, and the decreased areas (46.5%) were concentrated in southern Jiangsu. (3) For double cropping systems, the percentages of the changed productivity areas accounting for cultivated land were 82.7% and 73.3%. The decreased areas were distributed in central Jiangsu. In addition, the productivity of the first crop showed an overall (72%) increasing trend and increased areas (40.8%) of the second crop were found in northern Jiangsu. (4) During 2001−2017, cultivated land productivity greatly improved in Jiangsu. In the areas where productivity increased, the proportions of cultivated land with productivity potential space greater than 20% in single and double cropping systems were greater than 60% and 90%, respectively. In the areas where productivity decreased, greater than 25% and 75% of cultivated land had potential space in greater than 80% of the single and double cropping systems, respectively. This result shows that productivity still has much room for development in Jiangsu. This study provides new insight for studying cultivated land productivity and provides references for guiding agricultural production.

Gliomas are the most common and aggressive primary tumors in the central nervous system. Recently, Max interactor-1 (MXI1), an antagonist of c-Myc that is involved in brain tumor progression, has been reported to be deregulated in a variety of tumors including glioma. However, the mechanism of MXI1 deregulation in gliomas remains unclear. In this study, we show that the relative expression level of MXI1 is markedly down-regulated in glioma cell lines. Using integrated bioinformatic analysis and experimental confirmation, we identified several miRNAs by screening a panel of predicted miRNAs that may regulate the MXI1 3'UTR. The strongest inhibitory miRNA, miR-155, can attenuate the activity of a luciferase reporter gene that is fused with the MXI1 3'UTR and decrease the expression levels of MXI1 mRNA and protein in U87 glioma cells. The potential role of miR-155 in promoting glioma cell proliferation by targeting MXI1 was confirmed in various glioma cell lines by rescue experiments using MTT assays, EdU incorporation assay, and cell counting experiments. In addition, we determined that the level of MXI1 mRNA was inversely correlated with the expression of miR-155 in 18 sets of glioblastoma multiforme specimens. These findings reveal for the first time that the targeting of MXI1 by miR-155 may result in a reduction in MXI1 expression and promote glioma cell proliferation; this result suggests a novel function of miR-155 in targeting MXI1 in glioma-genesis.

Animal microRNA (miRNA) target prediction is still a challenge, although many prediction programs have been exploited. MiRNAs exert their function through partially binding the messenger RNAs (mRNAs; likely at 3' untranslated regions [3'UTRs]), which makes it possible to detect the miRNA-mRNA interactions in vitro by co-transfection of miRNA and a luciferase reporter gene containing the target mRNA fragment into mammalian cells under a dual-luciferase assay system. Here, we constructed a human miRNA expression library and used a dual-luciferase assay system to perform large-scale screens of interactions between miRNAs and the 3'UTRs of seven genes, which included more than 3,000 interactions with triplicate experiments for each interaction. The screening results showed that the 3'UTR of one gene can be targeted by multiple miRNAs. Among the prediction algorithms, a Bayesian phylogenetic miRNA target identification algorithm and a support vector machine (SVM) presented a relatively better performance (27% for EIMMo and 24.7% for miRDB) against the average precision (17.3%) of the nine prediction programs used here. Additionally, we noticed that a relatively high conservation level was shown at the miRNA 3' end targeted regions, as well as the 5' end (seed region) binding sites.

BACKGROUND: MicroRNAs (miRNAs) are ubiquitous non-coding RNAs that regulate gene expression at the post-transcriptional level. An increasing number of studies has revealed that viruses can also encode miRNAs, which are proposed to be involved in viral replication and persistence, cell-mediated antiviral immune response, angiogenesis, and cell cycle regulation. Singapore grouper iridovirus (SGIV) is a pathogenic iridovirus that has severely affected grouper aquaculture in China and Southeast Asia. Comprehensive knowledge about the related miRNAs during SGIV infection is helpful for understanding the infection and the pathogenic mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether SGIV encoded miRNAs during infection, a small RNA library derived from SGIV-infected grouper (GP) cells was constructed and sequenced by Illumina/Solexa deep-sequencing technology. We recovered 6,802,977 usable reads, of which 34,400 represented small RNA sequences encoded by SGIV. Sixteen novel SGIV-encoded miRNAs were identified by a computational pipeline, including a miRNA that shared a similar sequence to herpesvirus miRNA HSV2-miR-H4-5p, which suggests miRNAs are conserved in far related viruses. Generally, these 16 miRNAs are dispersed throughout the SGIV genome, whereas three are located within the ORF057L region. Some SGIV-encoded miRNAs showed marked sequence and length heterogeneity at their 3' and/or 5' end that could modulate their functions. Expression levels and potential biological activities of these viral miRNAs were examined by stem-loop quantitative RT-PCR and luciferase reporter assay, respectively, and 11 of these viral miRNAs were present and functional in SGIV-infected GP cells. CONCLUSIONS: Our study provided a genome-wide view of miRNA production for iridoviruses and identified 16 novel viral miRNAs. To the best of our knowledge, this is the first experimental demonstration of miRNAs encoded by aquatic animal viruses. The results provide a useful resource for further in-depth studies on SGIV infection and iridovirus pathogenesis.

BACKGROUND: Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available. METHODS: Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLUPP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload-induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity. RESULTS: Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload-induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes. CONCLUSIONS: ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics. [ABSTRACT FROM AUTHOR]