Reducing acetylated tau is neuroprotective in brain injury.

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.

Multimodal single-cell/nucleus RNA sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer's disease.

Because disease-associated microglia (DAM) and disease-associated astrocytes (DAA) are involved in the pathophysiology of Alzheimer's disease (AD), we systematically identified molecular networks between DAM and DAA to uncover novel therapeutic targets for AD. Specifically, we develop a network-based methodology that leverages single-cell/nucleus RNA sequencing data from both transgenic mouse models and AD patient brains, as well as drug-target network, metabolite-enzyme associations, the human protein-protein interactome, and large-scale longitudinal patient data. Through this approach, we find both common and unique gene network regulators between DAM (i.e., PAK1, MAPK14, and CSF1R) and DAA (i.e., NFKB1, FOS, and JUN) that are significantly enriched by neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1). We identify shared immune pathways between DAM and DAA, including Th17 cell differentiation and chemokine signaling. Last, integrative metabolite-enzyme network analyses suggest that fatty acids and amino acids may trigger molecular alterations in DAM and DAA. Combining network-based prediction and retrospective case-control observations with 7.2 million individuals, we identify that usage of fluticasone (an approved glucocorticoid receptor agonist) is significantly associated with a reduced incidence of AD (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.83-0.89, P < 1.0 × 10-8). Propensity score-stratified cohort studies reveal that usage of mometasone (a stronger glucocorticoid receptor agonist) is significantly associated with a decreased risk of AD (HR = 0.74, 95% CI 0.68-0.81, P < 1.0 × 10-8) compared to fluticasone after adjusting age, gender, and disease comorbidities. In summary, we present a network-based, multimodal methodology for single-cell/nucleus genomics-informed drug discovery and have identified fluticasone and mometasone as potential treatments in AD.

Exercise as part of survivorship care in metastatic breast cancer: protocol for the randomized EMBody trial.

BACKGROUND: Exercise is associated with improved survival, physical functioning, treatment tolerability, and quality of life in early-stage breast cancer. These same endpoints matter in metastatic breast cancer (MBC). Prior trials in MBC have found exercise to be not feasible or of limited benefit, possibly due to inclusion of patients with heterogeneous disease trajectories. Patients with MBC have variable disease trajectories and supportive care needs; those with indolent MBC have longer life expectancy, lower symptom burden and distinct priorities, and are well-positioned to participate in and benefit from an exercise program. The EMBody trial aims to determine the impact of a multimodal exercise intervention on cardiorespiratory fitness, physical function, body composition, and patient-reported outcomes, specifically in patients with stable, indolent MBC. METHODS: Eligible patients have MBC with no evidence of disease progression on current therapy in the prior 12 months and cannot be receiving cytotoxic chemotherapy. The trial aims to enroll 100 patients, randomized 1:1 to the exercise intervention versus usual care, stratified by baseline function. The virtually-delivered exercise intervention arm achieves moderate intensity exercise with exercise physiologists 3 days/week for 16 weeks. The 60-minute sessions include aerobic, resistance, balance and stretching exercises. The exercise arm receives informational sessions on the role of exercise in cancer and principles of habit and self-efficacy. The primary endpoint is 16 week change in fitness on a ramp treadmill test between the exercise and control arms. Secondary endpoints include change in a physical function, muscle mass assessed by CT scans, and PROs of fatigue and quality of life. Exploratory analysis includes behavioral modifiers of exercise adherence and effectiveness and serologic measures of inflammatory, metabolic, and immune pathway biomarkers. DISCUSSION: The EMBody trial evaluates exercise in a unique patient population with indolent, non-progressive MBC. Patients living with MBC experience similar symptom burden to those undergoing therapy for early-stage disease and the benefits achieved with exercise could be similarly impactful. This trial will contribute evidence to support expansion of exercise recommendations, among other survivorship care efforts, to those living with metastatic disease. CLINICAL TRIAL INFORMATION: NCT05468034. TRIAL REGISTRATION: NCT05468034. Date of registration: 7/12/2022.

A Precision Mixture Risk Model to Identify Adverse Drug Events in Subpopulations Using a Case-Crossover Design.

Despite the success of pharmacovigilance studies in detecting signals of adverse drug events (ADEs) from real-world data, the risks of ADEs in subpopulations warrant increased scrutiny to prevent them in vulnerable individuals. Recently, the case-crossover design has been implemented to leverage large-scale administrative claims data for ADE detection, while controlling both observed confounding effects and short-term fixed unobserved confounding effects. Additionally, as the case-crossover design only includes cases, subpopulations can be conveniently derived. In this manuscript, we propose a precision mixture risk model (PMRM) to identify ADE signals from subpopulations under the case-crossover design. The proposed model is able to identify signals from all ADE-subpopulation-drug combinations, while controlling for false discovery rate (FDR) and confounding effects. We applied the PMRM to an administrative claims data. We identified ADE signals in subpopulations defined by demographic variables, comorbidities, and detailed diagnosis codes. Interestingly, certain drugs were associated with a higher risk of ADE only in subpopulations, while these drugs had a neutral association with ADE in the general population. Additionally, the PMRM could control FDR at a desired level and had a higher probability to detect true ADE signals than the widely used McNemar's test. In conclusion, the PMRM is able to identify subpopulation-specific ADE signals from a tremendous number of ADE-subpopulation-drug combinations, while controlling for both FDR and confounding effects.

The INGENIOUS trial: Impact of pharmacogenetic testing on adverse events in a pragmatic clinical trial.

Adverse drug events (ADEs) account for a significant mortality, morbidity, and cost burden. Pharmacogenetic testing has the potential to reduce ADEs and inefficacy. The objective of this INGENIOUS trial (NCT02297126) analysis was to determine whether conducting and reporting pharmacogenetic panel testing impacts ADE frequency. The trial was a pragmatic, randomized controlled clinical trial, adapted as a propensity matched analysis in individuals (N = 2612) receiving a new prescription for one or more of 26 pharmacogenetic-actionable drugs across a community safety-net and academic health system. The intervention was a pharmacogenetic testing panel for 26 drugs with dosage and selection recommendations returned to the health record. The primary outcome was occurrence of ADEs within 1 year, according to modified Common Terminology Criteria for Adverse Events (CTCAE). In the propensity-matched analysis, 16.1% of individuals experienced any ADE within 1-year. Serious ADEs (CTCAE level ≥ 3) occurred in 3.2% of individuals. When combining all 26 drugs, no significant difference was observed between the pharmacogenetic testing and control arms for any ADE (Odds ratio 0.96, 95% CI: 0.78-1.18), serious ADEs (OR: 0.91, 95% CI: 0.58-1.40), or mortality (OR: 0.60, 95% CI: 0.28-1.21). However, sub-group analyses revealed a reduction in serious ADEs and death in individuals who underwent pharmacogenotyping for aripiprazole and serotonin or serotonin-norepinephrine reuptake inhibitors (OR 0.34, 95% CI: 0.12-0.85). In conclusion, no change in overall ADEs was observed after pharmacogenetic testing. However, limitations incurred during INGENIOUS likely affected the results. Future studies may consider preemptive, rather than reactive, pharmacogenetic panel testing.

Epigenomic features of DNA G-quadruplexes and their roles in regulating rice gene transcription.

A DNA G-quadruplex (G4) is a non-canonical four-stranded nucleic acid structure involved in many biological processes in mammals. The current knowledge on plant DNA G4s, however, is limited; whether and how DNA G4s impact gene expression in plants is still largely unknown. Here, we applied a protocol referred to as BG4-DNA-IP-seq followed by a comprehensive characterization of DNA G4s in rice (Oryza sativa L.); we next integrated dG4s (experimentally detectable G4s) with existing omics data and found that dG4s exhibited differential DNA methylation between transposable element (TE) and non-TE genes. dG4 regions displayed genic-dependent enrichment of epigenomic signatures; finally, we showed that these sites displayed a positive association with expression of DNA G4-containing genes when located at promoters, and a negative association when located in the gene body, suggesting localization-dependent promotional/repressive roles of DNA G4s in regulating gene transcription. This study reveals interrelations between DNA G4s and epigenomic signatures, as well as implicates DNA G4s in modulating gene transcription in rice. Our study provides valuable resources for the functional characterization or bioengineering of some of key DNA G4s in rice.

SARS-CoV-2 Infection, Hospitalization, and Death in Vaccinated and Infected Individuals by Age Groups in Indiana, 2021‒2022.

Objectives. To assess the effectiveness of vaccine-induced immunity against new infections, all-cause emergency department (ED) and hospital visits, and mortality in Indiana. Methods. Combining statewide testing and immunization data with patient medical records, we matched individuals who received at least 1 dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines with individuals with previous SARS-CoV-2 infection on index date, age, gender, race/ethnicity, zip code, and clinical diagnoses. We compared the cumulative incidence of infection, all-cause ED visits, hospitalizations, and mortality. Results. We matched 267 847 pairs of individuals. Six months after the index date, the incidence of SARS-CoV-2 infection was significantly higher in vaccine recipients (6.7%) than the previously infected (2.9%). All-cause mortality in the vaccinated, however, was 37% lower than that of the previously infected. The rates of all-cause ED visits and hospitalizations were 24% and 37% lower in the vaccinated than in the previously infected. Conclusions. The significantly lower rates of all-cause ED visits, hospitalizations, and mortality in the vaccinated highlight the real-world benefits of vaccination. The data raise questions about the wisdom of reliance on natural immunity when safe and effective vaccines are available. (Am J Public Health. 2023;113(1):96-104. https://doi.org/10.2105/AJPH.2022.307112).

A comprehensive assessment of statin discontinuation among patients who concurrently initiate statins and CYP3A4-inhibitor drugs; a multistate transition model.

AIMS: The aim of this study was to describe the 1-year direct and indirect transition probabilities to premature discontinuation of statin therapy after concurrently initiating statins and CYP3A4-inhibitor drugs. METHODS: A retrospective new-user cohort study design was used to identify (N = 160 828) patients who concurrently initiated CYP3A4 inhibitors (diltiazem, ketoconazole, clarithromycin, others) and CYP3A4-metabolized statins (statin DDI exposed, n = 104 774) vs. other statins (unexposed to statin DDI, n = 56 054) from the MarketScan commercial claims database (2012-2017). The statin DDI exposed and unexposed groups were matched (2:1) through propensity score matching techniques. We applied a multistate transition model to compare the 1-year transition probabilities involving four distinct states (start, adverse drug events [ADEs], discontinuation of CYP3A4-inhibitor drugs, and discontinuation of statin therapy) between those exposed to statin DDIs vs. those unexposed. Statistically significant differences were assessed by comparing the 95% confidence intervals (CIs) of probabilities. RESULTS: After concurrently starting stains and CYP3A, patients exposed to statin DDIs, vs. unexposed, were significantly less likely to discontinue statin therapy (71.4% [95% CI: 71.1, 71.6] vs. 73.3% [95% CI: 72.9, 73.6]) but more likely to experience an ADE (3.4% [95% CI: 3.3, 3.5] vs. 3.2% [95% CI: 3.1, 3.3]) and discontinue with CYP3A4-inhibitor therapy (21.0% [95% CI: 20.8, 21.3] vs. 19.5% [95% CI: 19.2, 19.8]). ADEs did not change these associations because those exposed to statin DDIs, vs. unexposed, were still less likely to discontinue statin therapy but more likely to discontinue CYP3A4-inhibitor therapy after experiencing an ADE. CONCLUSION: We did not observe any meaningful clinical differences in the probability of premature statin discontinuation between statin users exposed to statin DDIs and those unexposed.

Risk of lymph node metastasis and feasibility of endoscopic submucosal dissection in undifferentiated-type early gastric cancer.

BACKGROUND: Whether endoscopic submucosal dissection (ESD) applies to undifferentiated-type early gastric cancer (UEGC) remains controversial. We aimed to analyze the risk factors for lymph node metastasis (LNM) in UEGC and evaluate the feasibility of ESD. METHODS: This study included 346 patients with UEGC who underwent curative gastrectomy between January 2014 and December 2021. Univariate and multivariate analyses of the correlation between clinicopathological features and LNM were conducted, and the risk factors for exceeding the expanded ESD indications were evaluated. RESULTS: The overall LNM rate in UEGC was 19.94%. Among the preoperatively assessable factors, submucosal invasion (odds ratio [OR] = 4.77, 95% confidence interval [CI]: 2.14-10.66) and > 2 cm(OR = 2.49, 95% CI: 1.20-5.15) were independent risk factors for LNM, while postoperative independent risk factors were > 2 cm (OR = 3.35, 95% CI: 1.02-5.40) and lymphovascular invasion(OR = 13.21, 95% CI: 5.18-33.70). Patients who met the expanded indications had a low LNM risk (4.1%). Additionally, tumors located in the cardia (P = 0.03), non-elevated type (P < 0.01) were independent risk factors for exceeding the expanded indications in UEGC. CONCLUSIONS: ESD may be applicable for UEGC meeting the expanded indications, and preoperative evaluation should be cautious when the lesion is non-elevated type or located in the cardia. TRIAL REGISTRATION: Chinese Clinical Trial Registry (12/05/2022 ChiCTR2200059841 ).

Comparison of different risk stratifications for gastric cancer and establishing a simplified risk-scoring model based on the Kyoto classification.

BACKGROUND AND AIM: The study aims to assess the value of different risk stratifications in diagnosing early gastric cancer (GC) and explore risk factors based on Kyoto gastritis classification. METHODS: This study was a single-centered cross-sectional study; all epidemiological data and endoscopic findings were obtained prospectively. To evaluate the proportion of GC in each risk stratification and to compare the diagnostic performance of different methods using the receiver operating characteristic curve, univariable and multivariable analyses were used to explore the correlation between endoscopic findings and GC. RESULTS: A total of 240 subjects were enrolled, and the diagnostic efficacy of the Kyoto Classification Score was similar to Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) stage, and the accuracy was higher than that of the Japanese scoring system and OLGA stage. Moderate atrophy (odds ratio [OR] = 3.52, 95% confidence interval [CI]: 1.52-8.16), severe atrophy (OR = 4.96, 95% CI: 1.75-14.04), map-like redness (OR = 9.89, 95% CI: 1.16-84.15), and xanthelasma (OR = 3.57, 95% CI: 1.15-11.15) were independent risk factors for GC. The simplified Kyoto classification (area under the receiver operating characteristic [AUROC] = 0.76, P = 0.58) based on multivariable analysis demonstrated favorable diagnostic value compared with traditional Kyoto classification score (AUROC = 0.74). CONCLUSIONS: This study confirms the value of the Kyoto classification score and the OLGIM stage in the risk stratification of GC. Simplified Kyoto classification is also promising in risk assessment of GC but still requires validation in the population.

Recent tapering from long-term opioid therapy and odds of opioid-related hospital use.

PURPOSE: The number of patients tapered from long-term opioid therapy (LTOT) has increased in recent years in the United States. Some patients tapered from LTOT report improved quality of life, while others face increased risks of opioid-related hospital use. Research has not yet established how the risk of opioid-related hospital use changes across LTOT dose and subsequent tapering. Our objective was to examine associations between recent tapering from LTOT with odds of opioid-related hospital use. METHODS: Case-crossover design using 2014-2018 health information exchange data from Indiana. We defined opioid-related hospital use as hospitalizations, and emergency department (ED) visits for a drug overdose, opioid abuse, and dependence. We defined tapering as a 15% or greater dose reduction following at least 3 months of continuous opioid therapy of 50 morphine milligram equivalents (MME)/day or more. We used conditional logistic regression to estimate odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Recent tapering from LTOT was associated with increased odds of opioid-related hospital use (OR: 1.50, 95%CI: 1.34-1.63), ED visit (OR: 1.52; 95%CI: 1.35-1.72), and inpatient hospitalization (OR: 1.40; 95%CI: 1.20-1.65). We found no evidence of heterogeneity of the effect of tapering on opioid-related hospital use by gender, age, and race. Recent tapering among patients on a high baseline dose (>300 MME) was associated with increased odds of opioid-related hospital use (OR: 2.95, 95% CI: 2.12-4.11, p < 0.001) compared to patients on a lower baseline doses. CONCLUSIONS: Recent tapering from LTOT is associated with increased odds of opioid-related hospital use.

Population-based discovery and Mendelian randomization analysis identify telmisartan as a candidate medicine for Alzheimer's disease in African Americans.

INTRODUCTION: African Americans (AAs) and European Americans (EAs) differ in Alzheimer's disease (AD) prevalence, risk factors, and symptomatic presentation and AAs are less likely to enroll in AD clinical trials. METHODS: We conducted race-conscious pharmacoepidemiologic studies of 5.62 million older individuals (age ≥60) to investigate the association of telmisartan exposure and AD outcome using Cox analysis, Kaplan-Meier analysis, and log-rank test. We performed Mendelian randomization (MR) analysis of large ethnically diverse genetic data to test likely causal relationships between telmisartan's target and AD. RESULTS: We identified that moderate/high telmisartan exposure was significantly associated with a reduced incidence of AD in the AAs compared to low/no telmisartan exposure (hazard ratio [HR] = 0.77, 95% CI: 0.65-0.91, p-value = 0.0022), but not in the non-Hispanic EAs (HR = 0.97, 95% CI: 0.89-1.05, p-value = 0.4110). Sensitivity and sex-/age-stratified patient subgroup analyses identified that telmisartan's medication possession ratio (MPR) and average hypertension daily dosage were significantly associated with a stronger reduction in the incidence of both AD and dementia in AAs. Using MR analysis from large genome-wide association studies (GWAS) (over 2 million individuals) across AD, hypertension, and diabetes, we further identified AA-specific beneficial effects of telmisartan for AD. DISCUSSION: Randomized controlled trials with ethnically diverse patient cohorts are warranted to establish causality and therapeutic outcomes of telmisartan and AD. HIGHLIGHTS: Telmisartan is associated with lower risk of Alzheimer's disease (AD) in African Americans (AAs). Telmisartan is the only angiotensin II receptor blockers having PPAR-γ agonistic properties with beneficial anti-diabetic and renal function effects, which mitigate AD risk in AAs. Mendelian randomization (MR) analysis demonstrates the specificity of telmisartan's protective mechanism to AAs.

Characterization of functional relationships of R-loops with gene transcription and epigenetic modifications in rice.

We conducted genome-wide identification of R-loops followed by integrative analyses of R-loops with relation to gene expression and epigenetic signatures in the rice genome. We found that the correlation between gene expression levels and profiled R-loop peak levels was dependent on the positions of R-loops within gene structures (hereafter named "genic position"). Both antisense only (ASO)-R-loops and sense/antisense (S/AS)-R-loops sharply peaked around transcription start sites (TSSs), and these peak levels corresponded positively with transcript levels of overlapping genes. In contrast, sense only (SO)-R-loops were generally spread over the coding regions, and their peak levels corresponded inversely to transcript levels of overlapping genes. In addition, integrative analyses of R-loop data with existing RNA-seq, chromatin immunoprecipitation sequencing (ChIP-seq), DNase I hypersensitive sites sequencing (DNase-seq), and whole-genome bisulfite sequencing (WGBS or BS-seq) data revealed interrelationships and intricate connections among R-loops, gene expression, and epigenetic signatures. Experimental validation provided evidence that the demethylation of both DNA and histone marks can influence R-loop peak levels on a genome-wide scale. This is the first study in plants that reveals novel functional aspects of R-loops, their interrelations with epigenetic methylation, and roles in transcriptional regulation.

A pharmacovigilance study of pharmacokinetic drug interactions using a translational informatics discovery approach.

BACKGROUND: While the pharmacokinetic (PK) mechanisms for many drug interactions (DDIs) have been established, pharmacovigilance studies related to these PK DDIs are limited. Using a large surveillance database, a translational informatics approach can systematically screen adverse drug events (ADEs) for many DDIs with known PK mechanisms. METHODS: We collected a set of substrates and inhibitors related to the cytochrome P450 (CYP) isoforms, as recommended by the United States Food and Drug Administration (FDA) and Drug Interactions Flockhart table™. The FDA's Adverse Events Reporting System (FAERS) was used to obtain ADE reports from 2004 to 2018. The substrate and inhibitor information were used to form PK DDI pairs for each of the CYP isoforms and Medical Dictionary for Regulatory Activities (MedDRA) preferred terms used for ADEs in FAERS. A shrinkage observed-to-expected ratio (Ω) analysis was performed to screen for potential PK DDI and ADE associations. RESULTS: We identified 149 CYP substrates and 62 CYP inhibitors from the FDA and Flockhart tables. Using FAERS data, only those DDI-ADE associations were considered that met the disproportionality threshold of Ω > 0 for a CYP substrate when paired with at least two inhibitors. In total, 590 ADEs were associated with 2085 PK DDI pairs and 38 individual substrates, with ADEs overlapping across different CYP substrates. More importantly, we were able to find clinical and experimental evidence for the paclitaxel-clopidogrel interaction associated with peripheral neuropathy in our study. CONCLUSION: In this study, we utilized a translational informatics approach to discover potentially novel CYP-related substrate-inhibitor and ADE associations using FAERS. Future clinical, population-based and experimental studies are needed to confirm our findings.

Exosome in Crosstalk between Inflammation and Angiogenesis: A Potential Therapeutic Strategy for Stroke.

The endothelial dysfunction, associated with inflammation and vascular permeability, remains the key event in the pathogenesis of cerebral ischemic stroke. Angiogenesis is essential for neuroprotection and neural repair following stroke. The neuroinflammatory reaction plays a vital role in stroke, and inhibition of inflammation contributes to establishing an appropriate external environment for angiogenesis. Exosomes are the heterogeneous population of extracellular vesicles which play critical roles in intercellular communication through transmitting various proteins and nucleic acids to nearby and distant recipient cells by body fluids and circulation. Recent reports have shown that exosomal therapy is a valuable and potential treatment strategy for stroke. In this review, we discussed the exosomes in complex interaction mechanisms of angiogenesis and inflammation following stroke as well as the challenges of exosomal studies such as secretion, uptake, modification, and application.

A Combined Experimental and Computational Study on the Adsorption Sites of Zinc-Based MOFs for Efficient Ammonia Capture.

Ammonia (NH3) is a common pollutant mostly derived from pig manure composting under humid conditions, and it is absolutely necessary to develop materials for ammonia removal with high stability and efficiency. To this end, metal-organic frameworks (MOFs) have received special attention because of their high selectivity of harmful gases in the air, resulting from their large surface area and high density of active sites, which can be tailored by appropriate modifications. Herein, two synthetic metal-organic frameworks (MOFs), 2-methylimidazole zinc salt (ZIF-8) and zinc-trimesic acid (ZnBTC), were selected for ammonia removal under humid conditions during composting. The two MOFs, with different organic linkers, exhibit fairly distinctive ammonia absorption behaviors under the same conditions. For the ZnBTC framework, the ammonia intake is 11.37 mmol/g at 298 K, nine times higher than that of the ZIF-8 framework (1.26 mmol/g). In combination with theoretical calculations, powder XRD patterns, FTIR, and BET surface area tests were conducted to reveal the absorption mechanisms of ammonia for the two materials. The adsorption of ammonia on the ZnBTC framework can be attributed to both physical and chemical adsorption. A strong coordination interaction exists between the nitrogen atom from the ammonia molecule and the zinc atom in the ZnBTC framework. In contrast, the absorption of ammonia in the ZIF-8 framework is mainly physical. The weak interaction between the ammonia molecule and the ZIF-8 framework mainly results from the inherent severely steric hindrance, which is related to the coordination mode of the imidazole ligands and the zinc atom of this framework. Therefore, this study provides a method for designing promising MOFs with appropriate organic linkers for the selective capture of ammonia during manure composting.

Network-based prediction of drug-target interactions using an arbitrary-order proximity embedded deep forest.

MOTIVATION: Systematic identification of molecular targets among known drugs plays an essential role in drug repurposing and understanding of their unexpected side effects. Computational approaches for prediction of drug-target interactions (DTIs) are highly desired in comparison to traditional experimental assays. Furthermore, recent advances of multiomics technologies and systems biology approaches have generated large-scale heterogeneous, biological networks, which offer unexpected opportunities for network-based identification of new molecular targets among known drugs. RESULTS: In this study, we present a network-based computational framework, termed AOPEDF, an arbitrary-order proximity embedded deep forest approach, for prediction of DTIs. AOPEDF learns a low-dimensional vector representation of features that preserve arbitrary-order proximity from a highly integrated, heterogeneous biological network connecting drugs, targets (proteins) and diseases. In total, we construct a heterogeneous network by uniquely integrating 15 networks covering chemical, genomic, phenotypic and network profiles among drugs, proteins/targets and diseases. Then, we build a cascade deep forest classifier to infer new DTIs. Via systematic performance evaluation, AOPEDF achieves high accuracy in identifying molecular targets among known drugs on two external validation sets collected from DrugCentral [area under the receiver operating characteristic curve (AUROC) = 0.868] and ChEMBL (AUROC = 0.768) databases, outperforming several state-of-the-art methods. In a case study, we showcase that multiple molecular targets predicted by AOPEDF are associated with mechanism-of-action of substance abuse disorder for several marketed drugs (such as aripiprazole, risperidone and haloperidol). AVAILABILITY AND IMPLEMENTATION: Source code and data can be downloaded from https://github.com/ChengF-Lab/AOPEDF.

Toward an understanding of the detection and function of R-loops in plants.

Although lagging behind studies in humans and other mammals, studies of R-loops in plants have recently entered an exciting stage in which the roles of R-loops in gene expression, genome stability, epigenomic signatures, and plant development and stress responses are being elucidated. Here, we review the strengths and weaknesses of existing methodologies, which were largely developed for R-loop studies in mammals, and then discuss the potential challenges of applying these methodologies to R-loop studies in plants. We then focus on recent advances in the functional characterization of R-loops in Arabidopsis thaliana and rice. Recent studies in plants indicate that there are coordinated relationships between R-loops and gene expression, and between R-loops and epigenomic signatures that depend, in part, on the types of R-loops involved. Finally, we discuss the emerging roles of R-loops in plants and directions for future research.

A Novel Perioperative Multidose Methadone-Based Multimodal Analgesic Strategy in Children Achieved Safe and Low Analgesic Blood Methadone Levels Enabling Opioid-Sparing Sustained Analgesia With Minimal Adverse Effects.

BACKGROUND: Intraoperative methadone, a long-acting opioid, is increasingly used for postoperative analgesia, although the optimal methadone dosing strategy in children is still unknown. The use of a single large dose of intraoperative methadone is controversial due to inconsistent reductions in total opioid use in children and adverse effects. We recently demonstrated that small, repeated doses of methadone intraoperatively and postoperatively provided sustained analgesia and reduced opioid use without respiratory depression. The aim of this study was to characterize pharmacokinetics, efficacy, and safety of a multiple small-dose methadone strategy. METHODS: Adolescents undergoing posterior spinal fusion (PSF) for idiopathic scoliosis or pectus excavatum (PE) repair received methadone intraoperatively (0.1 mg/kg, maximum 5 mg) and postoperatively every 12 hours for 3-5 doses in a multimodal analgesic protocol. Blood samples were collected up to 72 hours postoperatively and analyzed for R-methadone and S-methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP) metabolites, and alpha-1 acid glycoprotein (AAG), the primary methadone-binding protein. Peak and trough concentrations of enantiomers, total methadone, and AAG levels were correlated with clinical outcomes including pain scores, postoperative nausea and vomiting (PONV), respiratory depression, and QT interval prolongation. RESULTS: The study population included 38 children (10.8-17.9 years): 25 PSF and 13 PE patients. Median total methadone peak plasma concentration was 24.7 (interquartile range [IQR], 19.2-40.8) ng/mL and the median trough was 4.09 (IQR, 2.74-6.4) ng/mL. AAG concentration almost doubled at 48 hours after surgery (median = 193.9, IQR = 86.3-279.5 µg/mL) from intraoperative levels (median = 87.4, IQR = 70.6-115.8 µg/mL; P < .001), and change of AAG from intraoperative period to 48 hours postoperatively correlated with R-EDDP (P < .001) levels, S-EDDP (P < .001) levels, and pain scores (P = .008). Median opioid usage was minimal, 0.66 (IQR, 0.59-0.75) mg/kg morphine equivalents/d. No respiratory depression (95% Wilson binomial confidence, 0-0.09) or clinically significant QT prolongation (median = 9, IQR = -10 to 28 milliseconds) occurred. PONV occurred in 12 patients and was correlated with morphine equivalent dose (P = .005). CONCLUSIONS: Novel multiple small perioperative methadone doses resulted in safe and lower blood methadone levels, <100 ng/mL, a threshold previously associated with respiratory depression. This methadone dosing in a multimodal regimen resulted in lower blood methadone analgesia concentrations than the historically described minimum analgesic concentrations of methadone from an era before multimodal postoperative analgesia without postoperative respiratory depression and prolonged corrected QT (QTc). Larger studies are needed to further study the safety and efficacy of this methadone dosing strategy.

Nanoparticles prepared from pterostilbene reduce blood glucose and improve diabetes complications.

BACKGROUND: Diabetes complications are the leading cause of mortality in diabetic patients. The common complications are decline in antioxidant capacity and the onset of micro-inflammation syndrome. At present, glucose-responsive nanoparticles are widely used, as they can release insulin-loaded ultrafine particles intelligently and effectively reduce blood sugar. However, the toxicology of this method has not been fully elucidated. The plant extracts of pterostilbene (PTE) have a wide range of biological applications, such as antioxidation and inflammatory response improvement. Therefore, we have proposed new ideas for the cross application of plant extracts and biomaterials, especially as part of a hypoglycaemic nano-drug delivery system. RESULTS: Based on the PTE, we successfully synthesised poly(3-acrylamidophenyl boric acid-b-pterostilbene) (p[AAPBA-b-PTE]) nanoparticles (NPs). The NPs were round in shape and ranged between 150 and 250 nm in size. The NPs possessed good pH and glucose sensitivity. The entrapment efficiency (EE) of insulin-loaded NPs was approximately 56%, and the drug loading (LC) capacity was approximately 13%. The highest release of insulin was 70%, and the highest release of PTE was 85%. Meanwhile, the insulin could undergo self-regulation according to changes in the glucose concentration, thus achieving an effective, sustained release. Both in vivo and in vitro experiments showed that the NPs were safe and nontoxic. Under normal physiological conditions, NPs were completely degraded within 40 days. Fourteen days after mice were injected with p(AAPBA-b-PTE) NPs, there were no obvious abnormalities in the heart, liver, spleen, lung, or kidney. Moreover, NPs effectively reduced blood glucose, improved antioxidant capacity and reversed micro-inflammation in mice. CONCLUSIONS: p(AAPBA-b-PTE) NPs were successfully prepared using PTE as raw material and effectively reduced blood glucose, improved antioxidant capacity and reduced the inflammatory response. This novel preparation can enable new combinations of plant extracts and biomaterials to adiministered through NPs or other dosage forms in order to regulate and treat diseases.