Apigenin protects against ischemic stroke by increasing DNA repair.

Background and Objective: Oxidative stress is an important pathological process in ischemic stroke (IS). Apigenin (APG) is a natural product with favorable antioxidative effects, and some studies have already demonstrated the antioxidative mechanism of APG in the treatment of IS. However, the mechanism of APG on DNA damage and repair after IS is not clear. The aim of this study was to investigate the mechanism of APG on DNA repair after IS. Methods: Male Sprague-Dawley rats were used to establish a model of permanent middle cerebral artery occlusion (pMCAO) on one side, and were pre-treated with gavage of APG (30, 60, or 120 mg/kg) for 7 days. One day after pMCAO, the brain tissues were collected. Cerebral infarct volume, brain water content, HE staining and antioxidant index were analyzed to evaluated the brain damage. Molecular Docking, molecular dynamics (MD) simulation, immunohistochemistry, and Western blot were used to explore the potential proteins related to DNA damage repair. Results: APG has a low binding score with DNA repair-related proteins. APG treatment has improved the volume of cerebral infarction and neurological deficits, reduced brain edema, and decreased parthanatos and apoptosis by inhibiting PARP1/AIF pathway. In addition, APG improved the antioxidative capacity through reducing reactive oxygen species and malondialdehyde, and increasing glutathione and superoxide dismutase. Also, APG has reduced DNA damage- and cell death-related proteins such as PARP1, γH2A.X, 53BP1, AIF, cleaved caspase3, Cytochrome c, and increased DNA repair by BRCA1 and RAD51 through homologous recombination repair, and reduced non-homologous end link repair by KU70. Conclusion: APG can improve nerve damage after IS, and these protective effects were realized by reducing oxidative stress and DNA damage, and improving DNA repair.

MetagenomicKG: a knowledge graph for metagenomic applications.

Motivation: The sheer volume and variety of genomic content within microbial communities makes metagenomics a field rich in biomedical knowledge. To traverse these complex communities and their vast unknowns, metagenomic studies often depend on distinct reference databases, such as the Genome Taxonomy Database (GTDB), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and the Bacterial and Viral Bioinformatics Resource Center (BV-BRC), for various analytical purposes. These databases are crucial for genetic and functional annotation of microbial communities. Nevertheless, the inconsistent nomenclature or identifiers of these databases present challenges for effective integration, representation, and utilization. Knowledge graphs (KGs) offer an appropriate solution by organizing biological entities and their interrelations into a cohesive network. The graph structure not only facilitates the unveiling of hidden patterns but also enriches our biological understanding with deeper insights. Despite KGs having shown potential in various biomedical fields, their application in metagenomics remains underexplored. Results: We present MetagenomicKG, a novel knowledge graph specifically tailored for metagenomic analysis. MetagenomicKG integrates taxonomic, functional, and pathogenesis-related information from widely used databases, and further links these with established biomedical knowledge graphs to expand biological connections. Through several use cases, we demonstrate its utility in enabling hypothesis generation regarding the relationships between microbes and diseases, generating sample-specific graph embeddings, and providing robust pathogen prediction. Availability and Implementation: The source code and technical details for constructing the MetagenomicKG and reproducing all analyses are available at Github: https://github.com/KoslickiLab/MetagenomicKG. We also host a Neo4j instance: http://mkg.cse.psu.edu:7474 for accessing and querying this graph.

Predictive cues elicit a liminal confirmation bias in the moral evaluation of real-world images.

Previous research suggested that predictive cues enhance the preference and reduce the response time for congruent targets during bivalent food evaluation, indicating a confirmation bias. Less is known about how prior processing affects subjective moral evaluation. Here, we used three different types of predictive cues to elicit directional vs. non-predictive prior processing and then asked the participants to perform moral evaluations on a continuous scale from -10 ("very immoral") to +10 ("very moral") with a diverse set of real-world images. Our experimental image database balanced the morality of image content and the volatility of the ratings based on the means and standard deviations in a preliminary study. Ratings, response times, and gaze positions were measured to examine the effects of predictive cues on the moral evaluation of real-world images. We found that the moral ratings were in line with the expectations induced by the cues. Compared to the non-predictive condition, the moral evaluation in the directional conditions was more polarized. For neutral images, the predictive cues tilted the evaluations to positive vs. negative, indicating a decisive liminal influence. High-volatility images were impacted more than low-volatility images in ratings as well as response times. Furthermore, the gaze positions during the interval between the predictive cue and the image showed a spatial displacement in line with the cue instruction, indicating a response bias. Together, the results show that predictive cues elicit a liminal confirmation bias in moral image evaluation, much in the same way as in bivalent food evaluation.

Efficacy and safety of auricular therapy in the treatment of post-stroke constipation: A protocol for systematic review and meta-analysis.

BACKGROUND: Constipation is one of the common gastrointestinal complications after stroke. It not only aggravates the condition of stroke, but also brings huge medical burden to patients, and has a negative impact on the quality of life of patients. Auricular therapy, as a part of Chinese traditional acupuncture and moxibustion, has been found to be effective in the clinical treatment of constipation. However, no systematic review has investigated the efficacy and safety of auricular therapy in the treatment of post-stroke constipation. Therefore, the aim of this systematic review is to assess the effectiveness and safety of auricular therapy for post-stroke constipation. METHODS AND ANALYSIS: Eight electronic databases including PubMed, Cochrane Library/Cochrane Central Register of Controlled Trials, Web of Science, Embase, China National Knowledge Internet, Chinese Biomedical Literature Database, Wanfang, and VIP databases, will be searched for relevant studies published from inception to February 2023. Two reviewers will independently conduct research selection, data extraction, and evaluation of research quality. Only randomized controlled trials (RCTs) that assess the efficacy and safety of auricular therapy for the treatment of post-stroke constipation will be included in this study. We will use the Cochrane risk of bias assessment tool to evaluate the methodological qualities (including bias risk). If possible, a meta-analysis will be performed after screening. RESULTS: This study may provide high-quality evidence for the efficacy and safety of auricular therapy in treating post-stroke constipation. CONCLUSION: The conclusions of our study will provide an evidence to judge whether auricular therapy is an effective and safe intervention for patients with post-stroke constipation. ETHICS AND DISSEMINATION: Ethical approval is not required, as this study was based on a review of published research. This review will be published in a peer-reviewed journal and disseminated electronically and in print. TRIAL REGISTRATION: Registration number: PROSPERO CRD42023402242.

Dilute Povidone-Iodine Solution Soaking Is Ineffective in Improving Outcomes of Necrotizing Fasciitis Caused by Diabetic Foot.

ABSTRACT: Wound soaking is a physical debridement method that helps reduce bacterial colonization and consequently promotes wound healing. Although soaking in povidone-iodine solution was ineffective in reducing bacterial colonization in acute trauma wounds, there is still a lack of evidence supporting the efficacy of this method in treating severe soft tissue infection. This study aimed to explore the effects of wound soaking in 1% dilute povidone-iodine solution on necrotizing fasciitis caused by diabetic foot ulcers. We retrospectively reviewed and finally included 153 patients who were admitted because of diabetic foot ulcers after undergoing fasciotomy for necrotizing infection from January 2018 to December 2021. Results showed no statistical difference in the outcomes between patients in the soaking and nonsoaking groups. End-stage renal disease (P = 0.029) and high serum C-reactive protein level (P = 0.007) were the only independent factors for below-knee amputation in the univariate and multivariate logistic regression analyses. Therefore, soaking diabetic wounds with severe infection in 1% dilute povidone-iodine solution may not reduce the hospital length of stay, risk of below-knee amputation, and readmission rate.

YACHT: an ANI-based statistical test to detect microbial presence/absence in a metagenomic sample.

MOTIVATION: In metagenomics, the study of environmentally associated microbial communities from their sampled DNA, one of the most fundamental computational tasks is that of determining which genomes from a reference database are present or absent in a given sample metagenome. Existing tools generally return point estimates, with no associated confidence or uncertainty associated with it. This has led to practitioners experiencing difficulty when interpreting the results from these tools, particularly for low-abundance organisms as these often reside in the "noisy tail" of incorrect predictions. Furthermore, few tools account for the fact that reference databases are often incomplete and rarely, if ever, contain exact replicas of genomes present in an environmentally derived metagenome. RESULTS: We present solutions for these issues by introducing the algorithm YACHT: Yes/No Answers to Community membership via Hypothesis Testing. This approach introduces a statistical framework that accounts for sequence divergence between the reference and sample genomes, in terms of ANI, as well as incomplete sequencing depth, thus providing a hypothesis test for determining the presence or absence of a reference genome in a sample. After introducing our approach, we quantify its statistical power and how this changes with varying parameters. Subsequently, we perform extensive experiments using both simulated and real data to confirm the accuracy and scalability of this approach. AVAILABILITY AND IMPLEMENTATION: The source code implementing this approach is available via Conda and at https://github.com/KoslickiLab/YACHT. We also provide the code for reproducing experiments at https://github.com/KoslickiLab/YACHT-reproducibles.

Performance evaluation of a deep learning-based cascaded HRNet model for automatic measurement of X-ray imaging parameters of lumbar sagittal curvature.

PURPOSE: To develop a deep learning-based cascaded HRNet model, in order to automatically measure X-ray imaging parameters of lumbar sagittal curvature and to evaluate its prediction performance. METHODS: A total of 3730 lumbar lateral digital radiography (DR) images were collected from picture archiving and communication system (PACS). Among them, 3150 images were randomly selected as the training dataset and validation dataset, and 580 images as the test dataset. The landmarks of the lumbar curve index (LCI), lumbar lordosis angle (LLA), sacral slope (SS), lumbar lordosis index (LLI), and the posterior edge tangent angle of the vertebral body (PTA) were identified and marked. The measured results of landmarks on the test dataset were compared with the mean values of manual measurement as the reference standard. Percentage of correct key-points (PCK), intra-class correlation coefficient (ICC), Pearson correlation coefficient (r), mean absolute error (MAE), mean square error (MSE), root-mean-square error (RMSE), and Bland-Altman plot were used to evaluate the performance of the cascade HRNet model. RESULTS: The PCK of the cascaded HRNet model was 97.9-100% in the 3 mm distance threshold. The mean differences between the reference standard and the predicted values for LCI, LLA, SS, LLI, and PTA were 0.43 mm, 0.99°, 1.11°, 0.01 mm, and 0.23°, respectively. There were strong correlation and consistency of the five parameters between the cascaded HRNet model and manual measurements (ICC = 0.989-0.999, R = 0.991-0.999, MAE = 0.63-1.65, MSE = 0.61-4.06, RMSE = 0.78-2.01). CONCLUSION: The cascaded HRNet model based on deep learning algorithm could accurately identify the sagittal curvature-related landmarks on lateral lumbar DR images and automatically measure the relevant parameters, which is of great significance in clinical application.

Associations of ITPA gene polymorphisms with outcomes among chronic hepatitis C patients treated with Peg-interferon/ribavirin: A 5-year follow-up study.

To investigate associations between inosine triphosphatase (ITPA) gene polymorphisms and long-term outcomes among chronic hepatitis C (CHC) patients in Northeast China treated with Peg-interferon (IFN)/ribavirin (RBV). CHC patients who received Peg-IFN-2a/RBV treatment during between 2011 and 2013 at 5 hepatitis centers in Northeast China were enrolled. ITPA single nucleotide polymorphisms rs1127354 and rs7270101 from all patients were detected and their associations with 5-year outcomes were analyzed. A total of 635 patients, including 421 infected with hepatitis C virus (HCV) genotype 1 and 214 infected with non-genotype 1 were included. No significant differences were observed in the distribution frequencies of ITPA rs1127354 variants and ITPase activity between patients with HCV genotype 1 and non-genotype 1. In patients who received more than 80% of the planned RBV dose, the 5-year virological response rate and the improvement in liver fibrosis were higher in those with ITPA rs1127354 non-CC with ITPase activity <25% compared with these outcomes in patients with ITPA rs1127354 CC with 100% ITPase activity. Multiple regression analysis revealed that HCV genotype non-1, low baseline HCV ribose nucleic acid (RNA) levels (≤4 × 105 IU/mL), interleukin-28B rs12979860 CC genotype, low baseline liver fibrosis (Fibroscan 0-2), and ITPA rs1127354 non-CC genotype were independent predictors for a high long-term virological response rate, whereas interleukin-28B rs12979860 CC genotype, ITPA rs1127354 non-CC genotype, and low baseline liver fibrosis were independent predictors for improvement of liver fibrosis. ITPA rs1127354 polymorphisms is predictors of long-term outcomes in CHC patients treated with Peg-IFN/RBV.

rhFGF-21 accelerates corneal epithelial wound healing through the attenuation of oxidative stress and inflammatory mediators in diabetic mice.

Diabetic keratopathy, commonly associated with a hyperactive inflammatory response, is one of the most common eye complications of diabetes. The peptide hormone fibroblast growth factor-21 (FGF-21) has been demonstrated to have anti-inflammatory and antioxidant properties. However, whether administration of recombinant human (rh) FGF-21 can potentially regulate diabetic keratopathy is still unknown. Therefore, in this work, we investigated the role of rhFGF-21 in the modulation of corneal epithelial wound healing, the inflammation response, and oxidative stress using type 1 diabetic mice and high glucose-treated human corneal epithelial cells. Our experimental results indicated that the application of rhFGF-21 contributed to the enhancement of epithelial wound healing. This treatment also led to advancements in tear production and reduction in corneal edema. Moreover, there was a notable reduction in the levels of proinflammatory cytokines such as TNF-α, IL-6, IL-1ß, MCP-1, IFN-γ, MMP-2, and MMP-9 in both diabetic mouse corneal epithelium and human corneal epithelial cells treated with high glucose. Furthermore, we found rhFGF-21 treatment inhibited reactive oxygen species production and increased levels of anti-inflammatory molecules IL-10 and SOD-1, which suggests that FGF-21 has a protective role in diabetic corneal epithelial healing by increasing the antioxidant capacity and reducing the release of inflammatory mediators and matrix metalloproteinases. Therefore, we propose that administration of FGF-21 may represent a potential treatment for diabetic keratopathy.

Bioconversion of chitin into chitin oligosaccharides using a novel chitinase with high chitin-binding capacity.

Chitin is the second largest renewable biomass resource in nature, it can be enzymatically degraded into high-value chitin oligosaccharides (CHOSs) by chitinases. In this study, a chitinase (ChiC8-1) was purified and biochemically characterized, its structure was analyzed by molecular modeling. ChiC8-1 had a molecular mass of approximately 96 kDa, exhibited its optimal activity at pH 6.0 and 50 °C. The Km and Vmax values of ChiC8-1 towards colloidal chitin were 10.17 mgmL-1 and 13.32 U/mg, respectively. Notably, ChiC8-1 showed high chitin-binding capacity, which may be related to the two chitin binding domains in the N-terminal. Based on the unique properties of ChiC8-1, a modified affinity chromatography method, which combines protein purification with chitin hydrolysis process, was developed to purify ChiC8-1 while hydrolyzing chitin. In this way, 9.36 ± 0.18 g CHOSs powder was directly obtained by hydrolyzing 10 g colloidal chitin with crude enzyme solution. The CHOSs were composed of 14.77-2.83 % GlcNAc and 85.23-97.17 % (GlcNAc)2 at different enzyme-substrate ratio. This process simplifies the tedious purification and separation steps, and may enable its potential application in the field of green production of chitin oligosaccharides.

YACHT: an ANI-based statistical test to detect microbial presence/absence in a metagenomic sample.

In metagenomics, the study of environmentally associated microbial communities from their sampled DNA, one of the most fundamental computational tasks is that of determining which genomes from a reference database are present or absent in a given sample metagenome. While tools exist to answer this question, all existing approaches to date return point estimates, with no associated confidence or uncertainty associated with it. This has led to practitioners experiencing difficulty when interpreting the results from these tools, particularly for low abundance organisms as these often reside in the "noisy tail" of incorrect predictions. Furthermore, no tools to date account for the fact that reference databases are often incomplete and rarely, if ever, contain exact replicas of genomes present in an environmentally derived metagenome. In this work, we present solutions for these issues by introducing the algorithm YACHT: Yes/No Answers to Community membership via Hypothesis Testing. This approach introduces a statistical framework that accounts for sequence divergence between the reference and sample genomes, in terms of average nucleotide identity, as well as incomplete sequencing depth, thus providing a hypothesis test for determining the presence or absence of a reference genome in a sample. After introducing our approach, we quantify its statistical power as well as quantify theoretically how this changes with varying parameters. Subsequently, we perform extensive experiments using both simulated and real data to confirm the accuracy and scalability of this approach. Code implementing this approach, as well as all experiments performed, is available at https://github.com/KoslickiLab/YACHT.

Anti-Allergic Effect of Dietary Polyphenols Curcumin and Epigallocatechin Gallate via Anti-Degranulation in IgE/Antigen-Stimulated Mast Cell Model: A Lipidomics Perspective.

Polyphenol-rich foods exhibit anti-allergic/-inflammatory properties. As major effector cells of allergies, mast cells undergo degranulation after activation and then initiate inflammatory responses. Key immune phenomena could be regulated by the production and metabolism of lipid mediators by mast cells. Here, we analyzed the antiallergic activities of two representative dietary polyphenols, curcumin and epigallocatechin gallate (EGCG), and traced their effects on cellular lipidome rewiring in the progression of degranulation. Both curcumin and EGCG significantly inhibited degranulation as they suppressed the release of ß-hexosaminidase, interleukin-4, and tumor necrosis factor-α from the IgE/antigen-stimulated mast cell model. A comprehensive lipidomics study involving 957 identified lipid species revealed that although the lipidome remodeling patterns (lipid response and composition) of curcumin intervention were considerably similar to those of EGCG, lipid metabolism was more potently disturbed by curcumin. Seventy-eight percent of significant differential lipids upon IgE/antigen stimulation could be regulated by curcumin/EGCG. LPC-O 22:0 was defined as a potential biomarker for its sensitivity to IgE/antigen stimulation and curcumin/EGCG intervention. The key changes in diacylglycerols, fatty acids, and bismonoacylglycerophosphates provided clues that cell signaling disturbances could be associated with curcumin/EGCG intervention. Our work supplies a novel perspective for understanding curcumin/EGCG involvement in antianaphylaxis and helps guide future attempts to use dietary polyphenols.

Total Surface Area of a Through-and-Through Oromandibular Defect Is Associated With Thromboembolic Events for Reconstruction With a Single Fibula Free Flap.

BACKGROUND: Reconstruction of through-and-through composite oromandibular defects (COMDs) has been a challenge to plastic surgeons for decades. When using a free osteoseptocutaneous fibular flap, the skin paddle is restricted by the orientation of the peroneal vessels and the inset of bone segment(s). Although the combination of double flaps for extensive COMDs is viable and reliable, the decision of single- or double-flap reconstruction is still debated, and the risk factors leading to complications and flap failure of single-flap reconstruction are less discussed. AIM AND OBJECTIVES: The aim of this study was to determine objectively predictive factors for postoperative vascular complications in through-and-through COMDs reconstructed with a single fibula flap. METHODS: This was a retrospective cohort study in patients who underwent single free fibular flap reconstruction for through-and-through COMDs in a tertiary medical center from 2011 to 2020. The enrolled patients' characteristics, surgical methods, thromboembolic event, flap outcomes, intensive care unit care, and total hospital length of stay were analyzed. RESULTS: A total of 43 consecutive patients were included in this study. Patients were categorized into a group without thromboembolic events (n = 35) and a group with thromboembolic events (n = 8). The 8 subjects with thromboembolic events were failed to be salvaged. There was no significant difference in age, body mass index, smoking, hypertension, diabetes mellitus, and history of radiotherapy. The length of bony defect (6.70 ± 1.95 vs 9.04 ± 2.96, P = 0.004) and the total surface area (105.99 ± 60.33 vs 169.38 ± 41.21, P = 0.004) were the 2 factors that showed a significant difference between the groups. Total surface area was the only significant factor in univariate logistic regression for thromboembolic event (P = 0.020; odds ratio, 1.02; 95% confidence interval [CI], 1.003-1.033) and also in multivariate logistic regression analysis after adjusting confounding factors (P = 0.033; odds ratio, 1.026; 95% CI, 1.002-1.051).The cutoff level of total surface area in determining thromboembolic event development was 159 cm2 (P = 0.005; sensitivity of 75% and specificity of 82.9%; 95% CI, 0.684-0.952). CONCLUSIONS: Free fibula flap has its advantages and drawbacks on mandible restoration. Because there is a lack of indicators before, a large total surface area may be an objective reference for single-flap reconstruction of through-and-through COMDs due to an elevated risk of thromboembolic event.

Clarifying the mechanism of apigenin against blood-brain barrier disruption in ischemic stroke using systems pharmacology.

Currently, recombinant tissue plasminogen activator (rtPA) is an effective therapy for ischemic stroke (IS). However, blood-brain barrier (BBB) disruption is a serious side effect of rtPA therapy and may lead to patients' death. The natural polyphenol apigenin has a good therapeutic effect on IS. Apigenin has potential BBB protection, but the mechanism by which it protects the BBB integrity is not clear. In this study, we used network pharmacology, bioinformatics, molecular docking and molecular dynamics simulation to reveal the mechanisms by which apigenin protects the BBB. Among the 146 targets of apigenin for the treatment of IS, 20 proteins were identified as core targets (e.g., MMP-9, TLR4, STAT3). Apigenin protects BBB integrity by inhibiting the activity of MMPs through anti-inflammation and anti-oxidative stress. These mechanisms included JAK/STAT, the toll-like receptor signaling pathway, and Nitrogen metabolism signaling pathways. The findings of this study contribute to a more comprehensive understanding of the mechanism of apigenin in the treatment of BBB disruption and provide ideas for the development of drugs to treat IS.

ARAX: a graph-based modular reasoning tool for translational biomedicine.

MOTIVATION: With the rapidly growing volume of knowledge and data in biomedical databases, improved methods for knowledge-graph-based computational reasoning are needed in order to answer translational questions. Previous efforts to solve such challenging computational reasoning problems have contributed tools and approaches, but progress has been hindered by the lack of an expressive analysis workflow language for translational reasoning and by the lack of a reasoning engine-supporting that language-that federates semantically integrated knowledge-bases. RESULTS: We introduce ARAX, a new reasoning system for translational biomedicine that provides a web browser user interface and an application programming interface (API). ARAX enables users to encode translational biomedical questions and to integrate knowledge across sources to answer the user's query and facilitate exploration of results. For ARAX, we developed new approaches to query planning, knowledge-gathering, reasoning and result ranking and dynamically integrate knowledge providers for answering biomedical questions. To illustrate ARAX's application and utility in specific disease contexts, we present several use-case examples. AVAILABILITY AND IMPLEMENTATION: The source code and technical documentation for building the ARAX server-side software and its built-in knowledge database are freely available online (https://github.com/RTXteam/RTX). We provide a hosted ARAX service with a web browser interface at arax.rtx.ai and a web API endpoint at arax.rtx.ai/api/arax/v1.3/ui/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Pharmacology, Toxicology, and Rational Application of Cinnabar, Realgar, and Their Formulations.

Materials and Methods: A search was performed for the literature on cinnabar and realgar in PubMed, the Chinese Pharmacopeia, Google, and other sources. The search included studies using single herbs, traditional formulations, or novel dosage forms. Results: Cinnabar and cinnabar formulas exhibit good efficacy for sedation, sleep improvement, anxiety alleviation, and brain protection. However, previous studies on neurotransmitters have reached different conclusions, and detailed pharmacological mechanisms are lacking. Realgar and its formulas exert promising antitumor activity through regulation of cell cycle arrest, intrinsic and extrinsic apoptosis, induction of differentiation, autophagy, metabolic reprogramming, matrix metalloproteinase-9 (MMP-9) signaling, and reactive oxygen species (ROS) generation. In addition, realgar can be used to treat a variety of refractory diseases by regulating immunity and exerting antibacterial, antiviral, and other effects. However, the existing pharmacological research on the use of realgar for epidemic prevention is insufficient, and animal experiments and research at the cellular level are lacking. Inappropriate applications of cinnabar and realgar can cause toxicity, including neurotoxicity, liver toxicity, kidney toxicity, and genotoxicity. The toxicological mechanism is complex, and molecular-level research is limited. For clinical applications, theory and clinical experience must be combined to guide scientific and rational drug use and to achieve reduced toxicity and increased efficacy through the use of modern preparation methods or combined drugs. Notably, when cinnabar and realgar are used to treat targeted diseases, these agents have a bidirectional effect of "treatment" and "toxicity" on the central nervous system in pathological and normal states. The pharmacological and toxicological mechanisms need to be elucidated in greater detail in the future. Overall, systematic research is needed to provide a basis for better promotion of the rational use of cinnabar and realgar in the clinic. Conclusion: Mineral medicines are multicomponent, multiactivity, and multitargeted substances. The pharmacology and mechanisms of the toxicity and action of realgar and cinnabar are extremely complex. A number of Chinese medicinal preparations of realgar and cinnabar have demonstrated unique efficacy in the treatment of refractory diseases.

RTX-KG2: a system for building a semantically standardized knowledge graph for translational biomedicine.

BACKGROUND: Biomedical translational science is increasingly using computational reasoning on repositories of structured knowledge (such as UMLS, SemMedDB, ChEMBL, Reactome, DrugBank, and SMPDB in order to facilitate discovery of new therapeutic targets and modalities. The NCATS Biomedical Data Translator project is working to federate autonomous reasoning agents and knowledge providers within a distributed system for answering translational questions. Within that project and the broader field, there is a need for a framework that can efficiently and reproducibly build an integrated, standards-compliant, and comprehensive biomedical knowledge graph that can be downloaded in standard serialized form or queried via a public application programming interface (API). RESULTS: To create a knowledge provider system within the Translator project, we have developed RTX-KG2, an open-source software system for building-and hosting a web API for querying-a biomedical knowledge graph that uses an Extract-Transform-Load approach to integrate 70 knowledge sources (including the aforementioned core six sources) into a knowledge graph with provenance information including (where available) citations. The semantic layer and schema for RTX-KG2 follow the standard Biolink model to maximize interoperability. RTX-KG2 is currently being used by multiple Translator reasoning agents, both in its downloadable form and via its SmartAPI-registered interface. Serializations of RTX-KG2 are available for download in both the pre-canonicalized form and in canonicalized form (in which synonyms are merged). The current canonicalized version (KG2.7.3) of RTX-KG2 contains 6.4M nodes and 39.3M edges with a hierarchy of 77 relationship types from Biolink. CONCLUSION: RTX-KG2 is the first knowledge graph that integrates UMLS, SemMedDB, ChEMBL, DrugBank, Reactome, SMPDB, and 64 additional knowledge sources within a knowledge graph that conforms to the Biolink standard for its semantic layer and schema. RTX-KG2 is publicly available for querying via its API at arax.rtx.ai/api/rtxkg2/v1.2/openapi.json . The code to build RTX-KG2 is publicly available at github:RTXteam/RTX-KG2 .

Pharmacological mechanism and therapeutic efficacy of Icariside II in the treatment of acute ischemic stroke: a systematic review and network pharmacological analysis.

BACKGROUND AND OBJECTIVE: Epimedii has long been used as a traditional medicine in Asia for the treatment of various common diseases, including Alzheimer's disease, cancer, erectile dysfunction, and stroke. Studies have reported the ameliorative effects of Icariside II (ICS II), a major metabolite of Epimedii, on acute ischemic stroke (AIS) in animal models. Based on network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we conducted a systematic review to evaluate the effects and neuroprotective mechanisms of ICS II on AIS. METHODS: First, we have searched 6 databases using studies with ICS II treatment on AIS animal models to explore the efficacy of ICS II on AIS in preclinical studies. The literature retrieval time ended on March 8, 2022 (Systematic Review Registration ID: CRD42022306291). There were no restrictions on the language of the search strategy. Systematic review follows the Patient, Intervention, Comparison and Outcome (PICO) methodology and framework. SYCLE's RoB tool was used to evaluate the the risk of bias. In network pharmacology, AIS-related genes were identified and the target-pathway network was constructed. Then, these targets were used in the enrichments of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology (GO). Molecular docking and MD simulation were finally employed between ICS II and the potential target genes. RESULTS: Twelve publications were included describing outcomes of 1993 animals. The literature details, animal strains, induction models, doses administered, duration of administration, and outcome measures were extracted from the 12 included studies. ICS II has a good protective effect against AIS. Most of the studies in this systematic review had the appropriate methodological quality, but some did not clearly state the controlling for bias of potential study. Network pharmacology identified 246 targets with SRC, CTNNB1, HSP90AA1, MAPK1, and RELA as the core target proteins. Besides, 215 potential pathways of ICS II were identified, such as PI3K-Akt, MAPK, and cGMP-PKG signaling pathway. GO enrichment analysis showed that ICS II was significantly enriched in subsequent regulation such as MAPK cascade. Molecular docking and MD simulations showed that ICS II can closely bind with important targets. CONCLUSIONS: ICS II is a promising drug in the treatment of AIS. However, this systematic review reveals key knowledge gaps (i.e., the protective role of ICS II in women) that ICS II must address before it can be used for the treatment of human AIS. Our study shows that ICS II plays a protective role in AIS through multi-target and multi-pathway characteristics, providing ideas for the development of drugs for the treatment of AIS.

Regulation of the Assembled Structure of a Flexible Porphyrin Derivative Containing Tetra Isophthalic Acids by Coronene or Different Pyridines.

Based on previous research, a new coassembly formed by a porphyrin derivative (IPETPP), which contains a flexible substituent of m-phthalic acid, is observed with coronene (COR) molecules at a higher concentration. Besides, a fresh IPETPP self-assembly formed at a lower concentration and another new coassembly with COR molecules are obtained. Moreover, the addition of a series of bipyridines alters the diamond arrangement of IPETPP, which enhances the stability of the two-component structures. It is unprecedented that bipyridine derivatives break intermolecular hydrogen bonds containing m-phthalic acid substituents. All the coassemblies are investigated by scanning tunneling microscopy on a highly oriented pyrolytic graphite. Combined with density functional theory, the formation mechanism of the assembled structures is revealed. These results would contribute to understanding the interfacial crystal behaviors and probably provide an efficient pathway to regulate the binary structures.

Accuracy of the Application of 3-Dimensional Printing Models in Orbital Blowout Fractures-A Preliminary Study.

BACKGROUND: Application of 3-dimensional (3D) printing technology has grown in the medical field over the past 2 decades. In managing orbital blowout fractures, 3D printed models can be used as intraoperative navigators and could shorten the operational time by facilitating prebending or shaping of the mesh preoperatively. However, a comparison of the accuracy of computed tomography (CT) images and printed 3D models is lacking. MATERIAL AND METHODS: This is a single-center retrospective study. Patients with unilateral orbital blowout fracture and signed up for customized 3D printing model were included. Reference points for the 2D distance were defined (intersupraorbital notch distance, transverse horizontal, sagittal vertical, and anteroposterior axes for orbital cavity) and measured directly on 3D printing models and on corresponding CT images. The difference and correlation analysis were conducted. RESULTS: In total, 9 patients were reviewed from June 2017 to December 2020. The mean difference in the intersupraorbital notch measurement between the 2 modules was -0.14 mm (P = 0.67). The mean difference in the distance measured from the modules in the horizontal, vertical, and anteroposterior axes of the traumatic orbits was 0.06 mm (P = 0.85), -0.23 mm (P = 0.47), and 0.51 mm (P = 0.32), whereas that of the unaffected orbits was 0.16 mm (P = 0.44), 0.34 mm (P = 0.24), and 0.1 mm (P = 0.88), respectively. Although 2D parameter differences (<1 mm) between 3D printing models and CT images were discovered, they were not statistically significant. CONCLUSIONS: Three-dimensional printing models showed high identity and correlation to CT image. Therefore, personalized models might be a reliable tool of virtual surgery or as a guide in realistic surgical scenarios for orbital blowout fractures.