Genome analysis of the mpox (formerly monkeypox) virus and characterization of core/variable regions.

Since smallpox was eradicated in 1980, the monkeypox virus (MPXV) has emerged as the most threatening orthopoxvirus in the world. In this study, we conducted a comprehensive analysis of the currently published complete genome sequences of the monkeypox virus. The core/variable regions were identified through core-pan analysis of MPXV. Besides single-nucleotide polymorphisms, our study also revealed that specific genes, multi-copy genes, repeat sequences, and recombination fragments are primarily distributed in the variable region. This result suggests that variable regions are not only more susceptible to single-base mutations, but also to events such as gene loss or gain, as well as recombination. Taken together, our results demonstrate the genomic characteristics of the core/variable regions of MPXV, and contribute to our understanding of the evolution of MPXV.

H2O2 Photosynthesis from H2O and O2 under Weak Light by Carbon Nitrides with the Piezoelectric Effect.

Driven by the essential need of a green, safe, and low-cost approach to producing H2O2, a highly valuable multifunctional chemical, artificial photosynthesis emerges as a promising avenue. However, current catalyst systems remain challenging, due to the need of high-density sunlight, poor selectivity and activity, or/and unfavorable thermodynamics. Here, we reported that an indirect 2e- water oxidation reaction (WOR) in photocatalytic H2O2 production was unusually activated by C5N2 with piezoelectric effects. Interestingly, under ultrasonication, C5N2 exhibited an overall H2O2 photosynthesis rate of 918.4 µM/h and an exceptionally high solar-to-chemical conversion efficiency of 2.6% after calibration under weak light (0.1 sun). Mechanism studies showed that the piezoelectric effect of carbon nitride overcame the high uphill thermodynamics of *OH intermediate generation, which enabled a new pathway for 2e- WOR, the kinetic limiting step in the overall H2O2 production from H2O and O2. Benefiting from the outstanding sonication-assisted photocatalytic H2O2 generation under weak light, the concept was further successfully adapted to biomedical applications in efficient sono-photochemodynamic therapy for cancer treatment and water purification.

Pentagalloyl Glucose: A Review of Anticancer Properties, Molecular Targets, Mechanisms of Action, Pharmacokinetics, and Safety Profile.

Pentagalloyl glucose (PGG) is a natural hydrolyzable gallotannin abundant in various plants and herbs. It has a broad range of biological activities, specifically anticancer activities, and numerous molecular targets. Despite multiple studies available on the pharmacological action of PGG, the molecular mechanisms underlying the anticancer effects of PGG are unclear. Here, we have critically reviewed the natural sources of PGG, its anticancer properties, and underlying mechanisms of action. We found that multiple natural sources of PGG are available, and the existing production technology is sufficient to produce large quantities of the required product. Three plants (or their parts) with maximum PGG content were Rhus chinensis Mill, Bouea macrophylla seed, and Mangifera indica kernel. PGG acts on multiple molecular targets and signaling pathways associated with the hallmarks of cancer to inhibit growth, angiogenesis, and metastasis of several cancers. Moreover, PGG can enhance the efficacy of chemotherapy and radiotherapy by modulating various cancer-associated pathways. Therefore, PGG can be used for treating different human cancers; nevertheless, the data on the pharmacokinetics and safety profile of PGG are limited, and further studies are essential to define the clinical use of PGG in cancer therapies.

Sanguinarine inhibits melanoma invasion and migration by targeting the FAK/PI3K/AKT/mTOR signalling pathway.

CONTEXT: Sanguinarine (SAG) is the most abundant constituent of Macleaya cordata (Willd.) R. Br. (Popaceae). SAG has shown antimammary and colorectal metastatic effects in mice in vivo, suggesting its potential for cancer chemotherapy. OBJECTIVE: To determine the antimetastatic effect and underlying molecular mechanisms of SAG on melanoma. MATERIALS AND METHODS: CCK8 assay was used to determine the inhibition of SAG on the proliferation of A375 and A2058 cells. Network pharmacology analysis was applied to construct a compound-target network and select potential therapeutic targets of SAG against melanoma. Molecular docking simulation was conducted for further analysis of the selected targets. In vitro migration/invasion/western blot assay with 1, 1.5, 2 µM SAG and in vivo effect of 2, 4, 8 mg/kg SAG in xenotransplantation model in nude mice. RESULTS: The key targets of SAG treatment for melanoma were mainly enriched in PI3K-AKT pathway, and the binding energy of SAG to PI3K, AKT, and mTOR were -6.33, -6.31, and -6.07 kcal/mol, respectively. SAG treatment inhibited the proliferation, migration, and invasion ability of A375 and A2058 cells (p < 0.05) with IC50 values of 2.378 µM and 2.719 µM, respectively. It also decreased the phosphorylation levels of FAK, PI3K, AKT, mTOR and protein expression levels of MMP2 and ICAM-2. In the nude mouse xenograft model, 2, 4, 8 mg/kg SAG was shown to be effective in inhibiting tumour growth. CONCLUSIONS: Our research offered a theoretical foundation for the clinical antitumor properties of SAG, further suggesting its potential application in the clinic.

A Water-Soluble Fluorescent Probe for the Selective Sensing of Ag+ and its Application in Imaging of Living Cells and Nematodes.

In this study, an imidazole-coumarin based fluorescent probe was developed for the selective and sensitive detection of Ag+ in aqueous solution. Using a combination of Job plot, NMR titrations, and DFT calculations, the binding properties between Ag+ and the probe were deeply investigated, and the results revealed a 1:1 binding stoichiometry between the probe and Ag+ with a binding constant of 1.02 × 106 M-1. The detection limit was found to be 150 nM, which satisfies the requirement for the quantitative detection of Ag+ in real water samples. Moreover, the new probe, Ic, was successfully applied to sense Ag+ in HeLa and HepG2 cells as well as in C. elegans, indicating that it could be a useful tool for the environmental monitoring of Ag+ pollution. These results demonstrated that Ic could serve as a high-efficiency and low-cost fluorescent probe for tracking Ag+ in an aquatic environment and biological organisms.

Inhibition of human catechol-O-methyltransferase-mediated dopamine O-methylation by daphnetin and its Phase II metabolites.

1. Finding and developing inhibitors of catechol-O-methyltransferase (COMT) from natural products is highly recommended. Daphnetin, a naturally occurring catechol from the family thymelaeaceae, has a chemical structure similar to several potent COMT inhibitors reported previously. Here the potential of daphnetin and its Phase II metabolites as inhibitors of COMT was investigated with human liver cytosol (HLC). 2. Daphnetin and its methylated metabolite (8-O-methyldaphnetin) were found to inhibit COMT-mediated dopamine O-methylation in a dose-dependent manner. The IC50 values for daphnetin (0.51∼0.53 µM) and 8-O-methyldaphnetin (22.5∼24.3 µM) were little affected by changes in HLC concentrations. Further kinetic analysis showed the differences in inhibition type and parameters (Ki) between daphnetin (competitive, 0.37 µM) and 8-O-methyldaphnetin (noncompetitive, 25.7 µM). Other metabolites, including glucuronidated and sulfated species, showed negligible inhibition against COMT. By using in vitro-in vivo extrapolation (IV-IVE), a 24.3-fold increase in the exposure of the COMT substrates was predicted when they are co-administrated with daphnetin. 3. With high COMT-inhibiting activity, daphnetin could serve as a lead compound for the design and development of new COMT inhibitors. Also, much attention should be paid to the clinical impact of combination of daphnetin and herbal preparations containing daphnetin with the drugs primarily cleared by COMT.

[In vitro metabolism of daphnetin in rat liver S9 fractions].

Daphnetin is quickly eliminated in rats after dosing, but the mechanism remains unclear. This study was aimed to investigate the in vitro metabolism of daphnetin using rat liver S9 fractions (RLS9). The metabolites formed in RLS9 were identified and the kinetic parameters for different metabolic pathways were determined. HPLC-DAD-MS analysis showed that daphnetin was biotransformed to six metabolites, which were identified as 7 or 8 mono-glucuronide and mono-sulfate, 8-methylate, and 7-suflo-8-methylate. Methylation and glucuronidation of daphnetin exhibited the Michaelis-Menten kinetic characteristics, whereas the substrate inhibition kinetic and the two-site kinetic were observed for 8-sulfate and 7-sulfate formations. Of the 3 conjugation pathways, the intrinsic clearance rate for sulfation was highest, followed by methylation and glucuronidation. By in vitro-in vivo extrapolation of the kinetic data measured in RLS9, the hepatic clearance were estimated to be 54.9 mL·min−1·kg−1 which is comparable to the system clearance (58.5 mL·min−1·kg−1) observed in rats. In conclusions, the liver might be the main site for daphnetin metabolism in rats. Sulfation, methylation and glucuronidation are important pathways of the hepatic metabolism of daphnetin in rats.

Structural modifications at the C-4 position strongly affect the glucuronidation of 6,7-dihydroxycoumarins.

Esculetin (6,7-dihydroxycoumarin) and its C-4 derivatives have multiple pharmacologic activities, but the poor metabolic stability of these catechols has severely restricted their application in the clinic. Glucuronidation plays important roles in catechols elimination, although thus far the effects of structural modifications on the metabolic selectivity and the catalytic efficacy of the human UDP-glucuronosyltransferase (UGT) enzymes remain unclear. This study was aimed at exploring the structure-glucuronidation relationship of esculetin and its C-4 derivatives, including 4-methyl esculetin, 4-phenyl esculetin, and 4-hydroxymethyl esculetin as well as 4-acetic acid esculetin. It was achieved by identifying the main human UGTs responsible for the different reactions and by careful characterization of the reactions kinetics. These catechols, with the exception of 4-acetic acid esculetin, are selectively metabolized to the corresponding 7-O-glucuronides. UGT1A6 and UGT1A9 are the two major UGTs involved in the 7-O-glucuronidation of 4-methyl esculetin and esculetin. UGT1A6 was the major contributor for 7-O-glucuronidation of 4-hydroxymethyl esculetin, and UGT1A9 played a significant role in the 7-O-glucuronidation of 4-phenyl esculetin. The results of the kinetic analyses revealed that the Km values of the compounds, in both UGT1A9 and human liver microsomes, decreased with increasing hydrophobicity of the C-4 substitutions. The outcome of this was that C-4 hydrophobic and hydrophilic groups on 6,7-dihydroxycoumarin exhibited contrasting effects on UGT affinity. All of these findings provide helpful guidance for further structural modification of 6,7-dihydroxycoumarins with improved metabolic stability.

An interpretable machine learning model for predicting 28-day mortality in patients with sepsis-associated liver injury.

Sepsis-Associated Liver Injury (SALI) is an independent risk factor for death from sepsis. The aim of this study was to develop an interpretable machine learning model for early prediction of 28-day mortality in patients with SALI. Data from the Medical Information Mart for Intensive Care (MIMIC-IV, v2.2, MIMIC-III, v1.4) were used in this study. The study cohort from MIMIC-IV was randomized to the training set (0.7) and the internal validation set (0.3), with MIMIC-III (2001 to 2008) as external validation. The features with more than 20% missing values were deleted and the remaining features were multiple interpolated. Lasso-CV that lasso linear model with iterative fitting along a regularization path in which the best model is selected by cross-validation was used to select important features for model development. Eight machine learning models including Random Forest (RF), Logistic Regression, Decision Tree, Extreme Gradient Boost (XGBoost), K Nearest Neighbor, Support Vector Machine, Generalized Linear Models in which the best model is selected by cross-validation (CV_glmnet), and Linear Discriminant Analysis (LDA) were developed. Shapley additive interpretation (SHAP) was used to improve the interpretability of the optimal model. At last, a total of 1043 patients were included, of whom 710 were from MIMIC-IV and 333 from MIMIC-III. Twenty-four clinically relevant parameters were selected for model construction. For the prediction of 28-day mortality of SALI in the internal validation set, the area under the curve (AUC (95% CI)) of RF was 0.79 (95% CI: 0.73-0.86), and which performed the best. Compared with the traditional disease severity scores including Oxford Acute Severity of Illness Score (OASIS), Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score II (SAPS II), Logistic Organ Dysfunction Score (LODS), Systemic Inflammatory Response Syndrome (SIRS), and Acute Physiology Score III (APS III), RF also had the best performance. SHAP analysis found that Urine output, Charlson Comorbidity Index (CCI), minimal Glasgow Coma Scale (GCS_min), blood urea nitrogen (BUN) and admission_age were the five most important features affecting RF model. Therefore, RF has good predictive ability for 28-day mortality prediction in SALI. Urine output, CCI, GCS_min, BUN and age at admission(admission_age) within 24 h after intensive care unit(ICU) admission contribute significantly to model prediction.

Efficiency of Protective Interventions on Irinotecan-Induced Diarrhea: A Systematic Review and Meta-Analysis.

BACKGROUND: Irinotecan is widely used in the treatment of various solid tumors, but the adverse effects from it, especially diarrhea, limit its use. Several clinical trials of prophylactic treatment of irinotecan-induced diarrhea (IID) have been ongoing, and some of the data are controversial. This encouraged us to conduct a meta-analysis of the effects of interventions on preventing IID. METHOD: This systematic review was conducted based on the PRISMA statement. We performed literature searches from PubMed, Web of Science, Embase, and Cochrane Library. The number registered in PROSPERO is CRD42022368633. After searching 1034 articles in the database and references, 8 studies were included in this meta-analysis. RESULT: The RR of high-grade diarrhea and all-grade diarrhea were 0.31 (I2 = 51%, 95% CI: 0.14-0.69; P = .004) and .76 (I2 = 65%, 95% CI: 0.62-0.93; P < .008) respectively, thus the use of intervention measures for preventing IID is effective, and the risk reduction of high-grade diarrhea was more significant. Subgroup analysis revealed that the monotherapy group (RR: 0.48, 95% CI: 0.21-1.13, I2 = 0%) and combination therapy group (RR: 0.14, 95% CI: 0.06-0.32, I2 = 0%) in the risk of high-grade diarrhea had no significant heterogeneity within the groups, and traditional herbal medicines (Kampo medicine Hangeshashin-to, PHY906 and hot ironing with Moxa Salt Packet on Tianshu and Shangjuxu) were effective preventive measures (RR:0.20, 95% CI: 0.07-0.60, I2 = 0%). The Jadad scores for traditional herbal medicines studies were 3, and the follow-up duration was only 2 to 6 weeks. CONCLUSION: This systematic review and meta-analysis suggest that preventive treatments significantly reduced the risk of high-grade and all-grade diarrhea, confirming the efficacy in the incidence and severity of IID, among which traditional herbal medicines (baicalin-containing) provided a protective effect in reducing the severity of IID. However, the traditional herbal medicines studies were of low quality. Combined irinotecan therapy can obtain better preventive effects than monotherapy of IID. These would be helpful for the prevention of IID in clinical practice.

Single-cell transcriptome sequencing reveals heterogeneity of gastric cancer: progress and prospects.

Gastric cancer is one of the most serious malignant tumor and threatens the health of people worldwide. Its heterogeneity leaves many clinical problems unsolved. To treat it effectively, we need to explore its heterogeneity. Single-cell transcriptome sequencing, or single-cell RNA sequencing (scRNA-seq), reveals the complex biological composition and molecular characteristics of gastric cancer at the level of individual cells, which provides a new perspective for understanding the heterogeneity of gastric cancer. In this review, we first introduce the current procedure of scRNA-seq, and discuss the advantages and limitations of scRNA-seq. We then elaborate on the research carried out with scRNA-seq in gastric cancer in recent years, and describe how it reveals cell heterogeneity, the tumor microenvironment, oncogenesis and metastasis, as well as drug response in to gastric cancer, to facilitate early diagnosis, individualized therapy, and prognosis evaluation.

Adaptable graphitic C6N6-based copper single-atom catalyst for intelligent biosensing.

Self-adaptability is highly envisioned for artificial devices such as robots with chemical noses. For this goal, seeking catalysts with multiple and modulable reaction pathways is promising but generally hampered by inconsistent reaction conditions and negative internal interferences. Herein, we report an adaptable graphitic C6N6-based copper single-atom catalyst. It drives the basic oxidation of peroxidase substrates by a bound copper-oxo pathway, and undertakes a second gain reaction triggered by light via a free hydroxyl radical pathway. Such multiformity of reactive oxygen-related intermediates for the same oxidation reaction makes the reaction conditions capable to be the same. Moreover, the unique topological structure of CuSAC6N6 along with the specialized donor-π-acceptor linker promotes intramolecular charge separation and migration, thus inhibiting negative interferences of the above two reaction pathways. As a result, a sound basic activity and a superb gain of up to 3.6 times under household lights are observed, superior to that of the controls, including peroxidase-like catalysts, photocatalysts, or their mixtures. CuSAC6N6 is further applied to a glucose biosensor, which can intelligently switch sensitivity and linear detection range in vitro.

Activation of xanthine oxidase by 1,4-naphthoquinones: A novel potential research topic for diet management and risk assessment.

Oral intake of 1,4-naphthoquinones could be a potential risk factor for hyperuricemia and gout via activation of xanthine oxidase (XO). Herein, 1,4-naphthoquinones derived from food and food-borne pollutants were selected to investigate the structure and activity relationship (SAR) and the relative mechanism for activating XO in liver S9 fractions from humans (HLS9) and rats (RLS9). The SAR analysis showed that introduction of electron-donating substituents on the benzene ring or electron-withdrawing substituents on the quinone ring improved the XO-activating effect of 1,4-naphthoquinones. Different activation potential and kinetics behaviors were observed for activating XO by 1,4-naphthoquinones in HLS9/RLS9. Molecular docking simulation and density functional theory calculations showed a good correlation between -LogEC50 and docking free energy or HOMO-LUMO energy gap. The risk of exposure to the 1,4-naphthoquinones was evaluated and discussed. Our findings are helpful to guide diet management in clinic and avoid adverse events attributable to exposure to food-derived 1,4-naphthoquinones.

A comparative investigation of catalytic mechanism and domain between catechol-O-methyltransferase isoforms by isomeric shikonin and alkannin.

The differences in catalytic mechanism and domain between the soluble (S-COMT) and membrane-bound catechol-O-methyltransferase (MB-COMT) are poorly documented due to the unavailable crystal structure of MB-COMT. Considering the enzymatic nature of S-COMT and MB-COMT, the challenge could be solvable by probing the interactions between the enzymes with the ligands with minor differences in structures. Herein, isomeric shikonin and alkannin bearing a R/S -OH group in side chain at the C2 position were used for domain profiling of COMTs. Human and rat liver-derived COMTs showed the differences in inhibitory response (human's IC50 and Ki values for S-COMT < rat's, 5.80-19.56 vs. 19.56-37.47 µM; human's IC50 and Ki values for MB-COMT > rat's) and mechanism (uncompetition vs. noncompetition) towards the two isomers. The inhibition of the two isomers against human and rat S-COMTs was stronger than those for MB-COMTs (S-COMT's IC50 and Ki values < MB-COMT's, 5.80-37.47 vs. 40.01-111.8 µM). Additionally, the inhibition response of alkannin was higher than those of shikonin in no matter human and rat COMTs. Molecular docking stimulation was used for analysis. The inhibitory effects observed in in vitro and in silico tests were confirmed in vivo. These findings would facilitate further COMT-associated basic and applied research.

Characterization of hepatic and intestinal glucuronidation of magnolol: application of the relative activity factor approach to decipher the contributions of multiple UDP-glucuronosyltransferase isoforms.

Magnolol is a food additive that is often found in mints and gums. Human exposure to this compound can reach a high dose; thus, characterization of magnolol disposition in humans is very important. Previous studies indicated that magnolol can undergo extensive glucuronidation in humans in vivo. In this study, in vitro assays were used to characterize the glucuronidation pathway in human liver and intestine. Assays with recombinant human UDP-glucuronosyltransferase enzymes (UGTs) revealed that multiple UGT isoforms were involved in magnolol glucuronidation, including UGT1A1, -1A3, -1A7, -1A8, -1A9, -1A10, and -2B7. Magnolol glucuronidation by human liver microsomes (HLM), human intestine microsomes (HIM), and most recombinant UGTs exhibited strong substrate inhibition kinetics. The degree of substrate inhibition was relatively low in the case of UGT1A10, whereas the reaction catalyzed by UGT1A9 followed biphasic kinetics. Chemical inhibition studies and the relative activity factor (RAF) approach were used to identify the individual UGTs that played important roles in magnolol glucuronidation in HLM and HIM. The results indicate that UGT2B7 is mainly responsible for the reaction in HLM, whereas UGT2B7 and UGT1A10 are significant contributors in HIM. In summary, the current study clarifies the glucuronidation pathway of magnolol and demonstrates that the RAF approach can be used as an efficient method for deciphering the roles of individual UGTs in a given glucuronidation pathway in the native tissue that is catalyzed by multiple isoforms with variable and atypical kinetics.

Potent and selective inhibition of magnolol on catalytic activities of UGT1A7 and 1A9.

1. Human exposure to magnolol can reach a high dose in daily life. Our previous studies indicated that magnolol showed high affinities to several UDP-glucuronosyltransferases (UGTs) This study was designed to examine the in vitro inhibitory effects of magnolol on UGTs, and further to evaluate the possibility of the in vivo inhibition that might happen. 2. Assays with recombinant UGTs and human liver microsomes (HLM) indicated that magnolol (10 µM) can selectively inhibit activities of UGT1A9 and extra-hepatic UGT1A7. Inhibition of magnolol on UGT1A7 followed competitive inhibition mechanism, while the inhibition on UGT1A9 obeyed either competitive or mixed inhibition mechanism, depending on substrates. The K(i) values for UGT1A7 and 1A9 are all in nanomolar ranges, lower than possible magnolol concentrations in human gut lumen and blood, indicating the in vivo inhibition on these two enzymes would likely occur. 3. In conclusion, UGT1A7 and 1A9 can be strongly inhibited by magnolol, raising the alarm for safe application of magnolol and traditional Chinese medicines containing magnolol. Additionally, given that UGT1A7 is an extra-hepatic enzyme, magnolol can serve as a selective UGT1A9 inhibitor that will act as a new useful tool in future hepatic glucuronidation phenotyping.

Investigation of UDP-glucuronosyltransferases (UGTs) inhibitory properties of carvacrol.

UDP-glucuronosyltransferases (UGTs), the most important phase II drug metabolizing enzymes (DMEs), could metabolize many drugs and various endogenous substances including bilirubin, steroid hormones, thyroid hormones, bile acids and fat-soluble vitamins. Evaluation of the inhibitory effects of compounds on UGTs is clinically important because inhibition of UGT isoforms could not only result in serious drug-drug interactions (DDIs), but also induce metabolic disorders of endogenous substances. The aim of the present study was to investigate the inhibitory effects of carvacrol on major UGT isoforms. The results showed that carvacrol could inhibit the activity of UGT1A9 with negligible effects on other UGT isoforms. When 4-methylumbelliferone (4-MU) was used as a nonspecific probe substrate and recombinant UGT enzymes were utilized as an enzyme resource, the inhibition of UGT1A9 was best fit to the competitive type and the inhibition kinetic parameter (K(i)) was calculated to be 5.7 µM. Furthermore, another specific probe substrate, propofol, was employed to determine the inhibitory kinetics of UGT1A9, and the results demonstrated that the inhibitory type was noncompetitive. The inhibition kinetic parameter (K(i)) was determined to be 25.0 µM. Because this substrate-dependent inhibition of UGT1A9 might confuse the in vitro-in vivo extrapolation, these in vitro inhibition kinetic parameters should be interpreted with special caution.

Polymeric carbon nitride-based materials: Rising stars in bioimaging.

Polymeric carbon nitrides (CN), due to their unique physicochemical properties, versatile surface functionalization, ultra-high surface area, and good biocompatibility, have attracted considerable interest in diverse biomedical applications, such as biosensors, drug delivery, bioimaging, and theranostics. In this review, the recent advances in bioimaging of CN-based nanomaterials are summarized according to the imaging modalities, including optical (fluorescence and Raman) imaging, magnetic resonance imaging (MRI), photoacoustic imaging (PAI), computed tomography (CT), and multimodal imaging. The pros and cons of CN bioimaging are comprehensively analyzed and compared with those in previous reports. In the end, the prospects and challenges of their future bioimaging applications are outlooked.

Adverse event profiles of adjuvant treatment with opicapone in Parkinson's disease: A systematic review and meta-analysis.

Background: Opicapone, a novel third-generation catechol-O-methyltransferase inhibitor, has demonstrated efficacy in Parkinson's Disease (PD) patients with end-of-dose motor fluctuations. Objective: This study aimed to compare the short-term (<6 months) and long-term (≥6 months) tolerability of opicapone adjuvant treatment in PD patients. Method: Electronic databases including PubMed, Embase, Web of Science and Cochrane library were searched for randomized controlled trials (RCTs) and observational studies. The end points included any treatment-related adverse events (TEAEs), serious TEAEs (SAEs) and treatment discontinuation. A random-effects model was used to generate overall incidences of TEAE. Results: Three RCTs, three RCT extension studies and three open-label studies involving 2177 PD patients were evaluated. In the short-term studies, there were reports of TEAEs with an incidence of ≥5% in individuals treated with opicapone 50 mg, including dyskinesia (14.1%), elevated blood creatine phosphokinase levels (8.0%) and urinary tract infection (6.0%). Any TEAEs, SAEs and treatment discontinuation all occurred at rates of 62.9%, 4.8% and 9.3%, respectively. TEAEs with opicapone 50 mg that were reported by more than 5% of patients in long-term studies included dyskinesia (16.1%), dry mouth (12.1%), medication effect decreased (12.1%), PD exacerbated (7.8%), blood creatine phosphokinase level raised (7.4%), nausea (6.1%) and insomnia (5.1%). The incidence of any TEAEs, SAEs and treatment discontinuation were, correspondingly, 73.2%, 8.7% and 8.4%. Conclusion: These studies demonstrated that opicapone was generally well-tolerated and had a low risk of adverse events, suggesting that it could be a valuable therapeutic choice for people with PD.

ANI analysis of poxvirus genomes reveals its potential application to viral species rank demarcation.

Average nucleotide identity (ANI) is a prominent approach for rapidly classifying archaea and bacteria by recruiting both whole genomic sequences and draft assemblies. To evaluate the feasibility of ANI in virus taxon demarcation, 685 poxviruses were assessed. Prior to the analysis, the fragment length and threshold of the ANI value were optimized as 200 bp and 98 per cent, respectively. After ANI analysis and network visualization, the resulting sixty-one species (ANI species rank) were clustered and largely consistent with the groupings found in National Center for Biotechnology Information Virus [within the International Committee on Taxonomy of Viruses (ICTV) Master Species List]. The species identities of thirty-four other poxviruses (excluded by the ICTV Master Species List) were also identified. Subsequent phylogenetic analysis and Guanine-Cytosine (GC) content comparison done were found to support the ANI analysis. Finally, the BLAST identity of concatenated sequences from previously identified core genes showed 91.8 per cent congruence with ANI analysis at the species rank, thus showing potential as a marker gene for poxviruses classification. Collectively, our results reveal that the ANI analysis may serve as a novel and efficient method for poxviruses demarcation.