Abstract
MicroRNAs (miRNAs) are noncoding RNAs with 18–26 nucleotides; they pair with target mRNAs to regulate gene expression and produce significant changes in various physiological and ...pathological processes. In recent years, the interaction between miRNAs and their target genes has become one of the mainstream directions for drug development. As a large-scale biological database that mainly provides miRNA–target interactions (MTIs) verified by biological experiments, miRTarBase has undergone five revisions and enhancements. The database has accumulated >2 200 449 verified MTIs from 13 389 manually curated articles and CLIP-seq data. An optimized scoring system is adopted to enhance this update’s critical recognition of MTI-related articles and corresponding disease information. In addition, single-nucleotide polymorphisms and disease-related variants related to the binding efficiency of miRNA and target were characterized in miRNAs and gene 3′ untranslated regions. miRNA expression profiles across extracellular vesicles, blood and different tissues, including exosomal miRNAs and tissue-specific miRNAs, were integrated to explore miRNA functions and biomarkers. For the user interface, we have classified attributes, including RNA expression, specific interaction, protein expression and biological function, for various validation experiments related to the role of miRNA. We also used seed sequence information to evaluate the binding sites of miRNA. In summary, these enhancements render miRTarBase as one of the most research-amicable MTI databases that contain comprehensive and experimentally verified annotations. The newly updated version of miRTarBase is now available at https://miRTarBase.cuhk.edu.cn/.
Effluent organic matter（Ef OM） from municipal wastewater treatment plants potentially has a detrimental effect on both aquatic organisms and humans.This study evaluated the removal and transformation ...of chromophoric dissolved organic matter（CDOM） and fluorescent dissolved organic matter（FDOM） in a full-scale wastewater treatment plant under different seasons.The results showed that bio-treatment was found to be more efficient in removing bulk DOM（in term of dissolved organic carbon,DOC） than CDOM and FDOM,which was contrary to the disinfection process.CDOM and FDOM were selectively removed at various stages during the treatment.Typically,the low molecular weight fractions of CDOM and protein-like FDOM were more efficiently removed during bio-treatment process,whereas the humic-like FDOM exhibited comparable decreases in both bio-treatment and disinfection processes.Overall,the performance of the WWTP was weak in terms of CDOM and FDOM removal,resulting in enrichment of CDOM and FDOM in effluent.Moreover,the total removal of the bulk DOM（P 〈 0.05） and the protein-like FDOM（P 〈 0.05） displayed a significant seasonal variation,with higher removal efficiencies in summer,whereas removal of CDOM and the humic-like FDOM showed little differences between summer and winter.In all,the results provide useful information for understanding the fate and transformation of DOM,illustrating that sub-fractions of DOM could be selectively removed depending on treatment processes and seasonality.
Ubiquitination, a post-translational modification, refers to the covalent attachment of ubiquitin molecules to substrates. This modification plays a critical role in diverse cellular processes such ...as protein degradation. The specificity of ubiquitination for substrates is regulated by E3 ubiquitin ligases. Dysregulation of ubiquitination has been associated with numerous diseases, including cancers. In our study, we first investigated the protein expression patterns of E3 ligases across 12 cancer types. Our findings indicated that E3 ligases tend to be up-regulated and exhibit reduced tissue specificity in tumors. Moreover, the correlation of protein expression between E3 ligases and substrates demonstrated significant changes in cancers, suggesting that E3-substrate specificity alters in tumors compared to normal tissues. By integrating transcriptome, proteome, and ubiquitylome data, we further characterized the E3-substrate regulatory patterns in lung squamous cell carcinoma. Our analysis revealed that the upregulation of the SKP2 E3 ligase leads to excessive degradation of BRCA2, potentially promoting tumor cell proliferation and metastasis. Furthermore, the upregulation of E3 ubiquitin–protein ligase TRIM33 was identified as a biomarker associated with a favorable prognosis by inhibiting the cell cycle. This work exemplifies how leveraging multi-omics data to analyze E3 ligases across various cancers can unveil prognosis biomarkers and facilitate the identification of potential drug targets for cancer therapy.
Background:
Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits both interleukin (IL)-17A and IL-17F, and is a promising drug for patients with moderate-to-severe plaque psoriasis.
...Objectives:
This study aimed to assess the efficacy and safety of bimekizumab in treating patients with psoriasis and to determine the optimal maintenance dosing schedules of bimekizumab.
Methods and design:
Eligible trials were identified from PubMed, Cochrane Controlled Register of Trials, Embase, ClinicalTrials.gov, and Chinese medical databases. Only double-blind, randomized, active comparator, or placebo-controlled trials of bimekizumab treatment on patients with psoriasis were included in this study.
Results:
Five studies were identified, which included 2473 patients with moderate-to-severe plaque psoriasis. The results indicated that bimekizumab had better efficacy than placebo or active comparator for Psoriasis Area and Severity Index (PASI) 90 risk ratio (RR) = 29.29, 1.52; 95% confidence interval (CI) = 10.30–83.30, 1.06–2.19, PASI 100 (RR = 59.87, 2.06; 95% CI = 15.06–237.99, 1.12–3.79), and Investigator’s Global Assessment scores of 0 or 1 (IGA 0/1) (RR = 21.55, 1.36; 95% CI = 9.25–50.19, 1.02–1.81). Faster onset of clinically meaningful responses was observed with bimekizumab compared with both active comparators (RR = 2.59; 95% CI = 1.32–5.10) and placebo (RR = 40.46; 95% CI = 13.19–124.13), with PASI 75 response observed at week 4 after one dose. Subgroup analysis showed no significant difference in the reduction of PASI scores between 320 mg q4w dosage and q8w dosage (RR = 1.00; 95% CI = 0.96–1.03). Rates of patients with adverse events (AEs) were comparable in the bimekizumab and active comparator groups (RR = 1.13; 95% CI = 1.01–1.26), and oral candidiasis was one of the most common treatment-emergent AEs.
Conclusion:
The results of this meta-analysis suggest that bimekizumab is more efficacious and has a rapid onset of action than active comparators and placebo in the treatment of moderate-to-severe plaque psoriasis. After 16 weeks of initial maintenance treatment, both bimekizumab maintenance dosing schedules (320 mg every 4 and 8 weeks) had similar efficacy.
Objective To investigate the photodynamic antitumor activity and chemical characteristics of pheophorbide A (PPBa) in vitro. Methods Breast cancer cells (MCF-7), lung cancer cells (A549), cervical ...cancer cells (HeLa), and three kinds of hepatoma cells (HepG2, hep3B and sk-Hep1) were planted in 96-well plates. The effects of light and dark toxicity, light intensity, and drug concentration on the phototoxicity of PPBa were investigated by MTT, and the uptake of PPBa was observed by Hoechst staining under a confocal microscope. The production of singlet oxygen was observed by flow cytometry and confocal microscopy with the reactive oxygen species detection kit. The photobleaching of PPBa was investigated by measuring the absorbance by a microplate reader according to the luminescence characteristics of PPBa. Results PPBa showed strong phototoxicity and low dark toxicity to six kinds of cancer cells, and IC50 values to cancer cells were as follows: MCF-7: 1.033 μmol/L, A549: 1.911 μmol/L, HeLa: 2.319 μmol/L, HepG
Defining and identifying causal intervention effects for transmissible infectious disease outcomes is challenging because a treatment – such as a vaccine – given to one individual may affect the ...infection outcomes of others. Epidemiologists have proposed causal estimands to quantify effects of interventions under contagion using a two-person partnership model. These simple conceptual models have helped researchers develop causal estimands relevant to clinical evaluation of vaccine effects. However, many of these partnership models are formulated under structural assumptions that preclude realistic infectious disease transmission dynamics, limiting their conceptual usefulness in defining and identifying causal treatment effects in empirical intervention trials. In this paper, we propose causal intervention effects in two-person partnerships under arbitrary infectious disease transmission dynamics, and give nonparametric identification results showing how effects can be estimated in empirical trials using time-to-infection or binary outcome data. The key insight is that contagion is a causal phenomenon that induces conditional independencies on infection outcomes that can be exploited for the identification of clinically meaningful causal estimands. These new estimands are compared to existing quantities, and results are illustrated using a realistic simulation of an HIV vaccine trial.
Behcet's disease (BD) is a multi-systemic inflammatory vasculitis which may be life-threatening if combined with cardiovascular problems. The aim of the study was to identify potential risk factors ...associated with cardiovascular involvement in BD.
We reviewed the medical databases of a single center. All BD patients identified as fulfilling the 1990 International Study Group criteria or the International Criteria for Behcet's Disease criteria. Cardiovascular involvement, clinical manifestations, laboratory features, and treatments were recorded. The relationship between parameters and cardiovascular involvement was analyzed.
111 BD patients were included: 21 (18.9%) had documented cardiovascular involvement (CV BD group) and 99 (81.1%) had no cardiovascular involvement (non-CV BD group). Compared with non-CV BD, the proportion of males and smokers were significantly increased in CV BD (p = 0.024 and p < 0.001, respectively). Levels of activated partial thromboplastin time (APTT), cardiac troponin I and C-reactive protein were significantly higher (p = 0.001, p = 0.031, and p = 0.034, respectively) in the CV BD group. Cardiovascular involvement was associated with smoking state, the presence of papulopustular lesions, and higher APTT in multivariate analyzed (p = 0.029, p = 0.021, and p = 0.006, respectively). The ROC curve showed that APTT predicts the risk of cardiovascular involvement (p < 0.01) at a cut-off value of 33.15 s with a sensitivity of 57.1% and specificity of 82.2%.
Cardiovascular involvement in BD patients was associated with gender, smoking state, the presence of papulopustular lesions, and higher APTT. All patients newly diagnosed with BD should be systematically screened for cardiovascular involvement.
•Behçet's disease (BD) is a rare systemic vasculitis often complicated by cardiovascular diseases.•Cardiovascular involvement in BD patients was associated with male, the history of smoking, the presence of papulopustular lesions, and higher APTT.•Patients newly diagnosed with BD should br screened for cardiovascular involvement.
Abstract The use of digital devices to collect data in mobile health studies introduces a novel application of time series methods, with the constraint of potential data missing at random or missing ...not at random (MNAR). In time-series analysis, testing for stationarity is an important preliminary step to inform appropriate subsequent analyses. The Dickey–Fuller test evaluates the null hypothesis of unit root non-stationarity, under no missing data. Beyond recommendations under data missing completely at random for complete case analysis or last observation carry forward imputation, researchers have not extended unit root non-stationarity testing to more complex missing data mechanisms. Multiple imputation with chained equations, Kalman smoothing imputation, and linear interpolation have also been used for time-series data, however such methods impose constraints on the autocorrelation structure and impact unit root testing. We propose maximum likelihood estimation and multiple imputation using state space model approaches to adapt the augmented Dickey–Fuller test to a context with missing data. We further develop sensitivity analyses to examine the impact of MNAR data. We evaluate the performance of existing and proposed methods across missing mechanisms in extensive simulations and in their application to a multi-year smartphone study of bipolar patients.
The organism Sipunculus nudus L is a good resource for marine peptides because of its rich protein. However, the disadvantage of biological peptides is their short metabolic half-life, therefore, ...structural modification of peptides is necessary. In this research, the enzymatic hydrolysis of Sipunculus nudus L was performed using trypsin and then peptides were isolated and purified from the hydrolysates, four novel tripeptides were identified by LC-MS-MS as Ser-Arg-Pro (SRP, m/z = 358.39), Pro-Arg-Pro (PRP, m/z = 368.43), Arg-Pro-Ala (RPA, m/z = 342.39), and Lue-Pro-Lys (LPK, m/z = 356.46), their ACE inhibitory activity was investigated with IC50 value as following 0.046, 0.42, 0.97, and 6.54 mM, respectively. Because of its highest ACE inhibitory activity, SRP was further selected to modify the chemical structure for a sustained release agent DSPE-PEG-SRP. Compared with 7 h of free SRP, the release of DSPE-PEG-SRP in vitro was approximately 120 h. The ACE inhibition rate of SRP released from the synthetic product and the raw material SRP was almost the same, molecular docking demonstrated that ACE inhibitory activity was attributed to the formation of hydrogen bonds between SRP and ACE active sites. In conclusion, DSPE-PEG-SRP, a novel sustained release agent, has great potential and is expected to be further applied to treat hypertension.
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•Novel tripeptides were identified from Sipunculus nudus L as Ser-Arg-Pro (SRP), Lue-Pro-Lys (LPK), Pro-Arg-Pro (PRP), Arg-Pro-Ala (RPA).•The IC50 value of Ser-Arg-Pro (SRP) was the lowest as 0.046 mM.•A long-acting molecular DSPE-PEG-SRP was achieved with yield 45%.•The release of DSPE-PEG-SRP in vitro was 120 h, whereas that only 7 h of SRP.
Abstract
Circular RNAs (circRNAs), which are single-stranded RNA molecules that have individually formed into a covalently closed continuous loop, act as sponges of microRNAs to regulate ...transcription and translation. CircRNAs are important molecules in the field of cancer diagnosis, as growing evidence suggests that they are closely related to pathological cancer features. Therefore, they have high potential for clinical use as novel cancer biomarkers. In this article, we present our updates to CircNet (version 2.0), into which circRNAs from circAtlas and MiOncoCirc, and novel circRNAs from The Cancer Genome Atlas database have been integrated. In total, 2732 samples from 37 types of cancers were integrated into CircNet 2.0 and analyzed using several of the most reliable circRNA detection algorithms. Furthermore, target miRNAs were predicted from the full-length circRNA sequence using three reliable tools (PITA, miRanda and TargetScan). Additionally, 384 897 experimentally verified miRNA–target interactions from miRTarBase were integrated into our database to facilitate the construction of high-quality circRNA–miRNA–gene regulatory networks. These improvements, along with the user-friendly interactive web interface for data presentation, search, and visualization, showcase the updated CircNet database as a powerful, experimentally validated resource, for providing strong data support in the biomedical fields. CircNet 2.0 is currently accessible at https://awi.cuhk.edu.cn/∼CircNet.
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