Miracle-dz/UniFAR-FTUs huggingface dataset:
Mapping Mechanistic Pathways of Acute Oral Systemic Toxicity Using Chemical Structure and Bioactivity Measurements

Regulatory agencies around the world have committed to reducing or eliminating animal testing for establishing chemical safety. Adverse outcome pathways can facilitate replacement by providing a mechanistic framework for identifying the appropriate non-animal methods and connecting them to apical adverse outcomes. This study separated 11,992 chemicals with curated rat oral acute toxicity information into clusters of structurally similar compounds. Each cluster was then assigned one or more ToxCast/Tox21 assays by looking for the minimum number of assays required to record at least one positive hit call below cytotoxicity for all acutely toxic chemicals in the cluster. When structural information is used to select assays for testing, none of the chemicals required more than four assays and 98% required two assays or less. Both the structure-based clusters and activity from the associated assays were significantly associated with the GHS toxicity classification of the chemicals, which suggests that a combination of bioactivity and structural information could be as reproducible as traditional in vivo studies. Predictivity is improved when the in vitro assay directly corresponds to the mechanism of toxicity, but many indirect assays showed promise as well. Given the lower cost of in vitro testing, a small assay battery including both general cytotoxicity assays and two or more orthogonal assays targeting the toxicological mechanism could be used to improve performance further. This approach illustrates the promise of combining existing in silico approaches, such as the Collaborative Acute Toxicity Modeling Suite (CATMoS), with structure-based bioactivity information as part of an efficient tiered testing strategy that can reduce or eliminate animal testing for acute oral toxicity.
Polysaccharide-Based Hydrogels for Wound Dressing: Design Considerations and Clinical Applications

Wound management remains a worldwide challenge. It is undeniable that patients with problems such as difficulties in wound healing, metabolic disorder of the wound microenvironment and even severely infected wounds etc. always suffer great pain that affected their quality of lives. The selection of appropriate wound dressings is vital for the healing process. With the advances of technology, hydrogels dressings have been showing great potentials for the treatment of both acute wounds (e.g., burn injuries, hemorrhage, rupturing of internal organs/aorta) and chronic wounds such as diabetic foot and pressure ulcer. Particularly, in the past decade, polysaccharide-based hydrogels which are made up with abundant and reproducible natural materials that are biocompatible and biodegradable present unique features and huge flexibilities for modifications as wound dressings and are widely applicable in clinical practices. They share not only common characteristics of hydrogels such as excellent tissue adhesion, swelling, water absorption, etc., but also other properties (e.g., anti-inflammatory, bactericidal and immune regulation), to accelerate wound re-epithelialization, mimic skin structure and induce skin regeneration. Herein, in this review, we highlighted the importance of tailoring the physicochemical performance and biological functions of polysaccharide-based hydrogel wound dressings. We also summarized and discussed their clinical states of, aiming to provide valuable hints and references for the future development of more intelligent and multifunctional wound dressings of polysaccharide hydrogels.
Cardiovascular Benefits With Favorable Renal, Amputation and Hypoglycemic Outcomes of SGLT-2 Inhibitors in Type 2 Diabetes From the Asian Perspective: A Population-Based Cohort Study and Systematic Review

Objective We assessed the effects of sodium glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) in a large real-world Asian cohort with type 2 diabetes (T2D) and performed a systematic review with integrating the present study findings to provide up-to-date evidence from the Asian perspective. Methods New users of SGLT2is or DPP4is were identified from the Taiwan’s National Health Insurance Research Database and followed until 2018. Primary outcomes were hospitalization for heart failure (HHF) and three-point major adverse cardiovascular event (3P-MACE; namely, myocardial infarction [MI], stroke, or cardiovascular death). Other outcomes included all-cause death, chronic kidney disease (CKD), amputation, and hospitalized hypoglycemia. Subdistribution hazard models were employed to assess treatment-associated clinical outcomes. Results A total of 21,329 SGLT2i and DPP4i propensity-score-matched pairs were analyzed. SGLT2is versus DPP4is showed lower risks of HHF (hazard ratio [95% CI]: 0.52 [0.45–0.59]), 3P-MACE (0.62 [0.55–0.70]), MI (0.63 [0.50–0.79]), stroke (0.60 [0.51–0.70]), all-cause death (0.57 [0.49–0.67]), CKD (0.46 [0.43–0.50]), amputation (0.64 [0.42–0.98]), and hospitalized hypoglycemia (0.54 [0.45–0.64]). Our results were consistent with findings from a systematic review. Conclusion Among Asian patients with T2D, SGLT2is versus DPP4is showed benefits for several clinical outcomes. More research is warranted to explore the heterogeneous treatment effects of SGLT2is and DPP4is by race/ethnicity.
Pyroptosis-Related Inflammasome Pathway: A New Therapeutic Target for Diabetic Cardiomyopathy

Pyroptosis is a highly specific type of inflammatory programmed cell death that is mediated by Gasdermine (GSDM). It is characterized by inflammasome activation, caspase activation, and cell membrane pore formation. Diabetic cardiomyopathy (DCM) is one of the leading diabetic complications and is a critical cause of fatalities in chronic diabetic patients, it is defined as a clinical condition of abnormal myocardial structure and performance in diabetic patients without other cardiac risk factors, such as hypertension, significant valvular disease, etc. There are no specific drugs in treating DCM despite decades of basic and clinical investigations. Although the relationship between DCM and pyroptosis is not well established yet, current studies provided the impetus for us to clarify the significance of pyroptosis in DCM. In this review, we summarize the recent literature addressing the role of pyroptosis and the inflammasome in the development of DCM and summary the potential use of approaches targeting this pathway which may be future anti-DCM strategies.
High-Rate Sulfate Removal Coupled to Elemental Sulfur Production in Mining Process Waters Based on Membrane-Biofilm Technology

It is anticipated that copper mining output will significantly increase over the next 20 years because of the more intensive use of copper in electricity-related technologies such as for transport and clean power generation, leading to a significant increase in the impacts on water resources if stricter regulations and as a result cleaner mining and processing technologies are not implemented. A key concern of discarded copper production process water is sulfate. In this study we aim to transform sulfate into sulfur in real mining process water. For that, we operate a sequential 2-step membrane biofilm reactor (MBfR) system. We coupled a hydrogenotrophic MBfR (H2-MBfR) for sulfate reduction to an oxidizing MBfR (O2-MBfR) for oxidation of sulfide to elemental sulfur. A key process improvement of the H2-MBfR was online pH control, which led to stable high-rate sulfate removal not limited by biomass accumulation and with H2 supply that was on demand. The H2-MBfR easily adapted to increasing sulfate loads, but the O2-MBfR was difficult to adjust to the varying H2-MBfR outputs, requiring better coupling control. The H2-MBfR achieved high average volumetric sulfate reduction performances of 1.7–3.74 g S/m3-d at 92–97% efficiencies, comparable to current high-rate technologies, but without requiring gas recycling and recompression and by minimizing the H2 off-gassing risk. On the other hand, the O2-MBfR reached average volumetric sulfur production rates of 0.7–2.66 g S/m3-d at efficiencies of 48–78%. The O2-MBfR needs further optimization by automatizing the gas feed, evaluating the controlled removal of excess biomass and S0 particles accumulating in the biofilm, and achieving better coupling control between both reactors. Finally, an economic/sustainability evaluation shows that MBfR technology can benefit from the green production of H2 and O2 at operating costs which compare favorably with membrane filtration, without generating residual streams, and with the recovery of valuable elemental sulfur.
Comparative Fecal Microbiota Analysis of Infants With Acute Bronchiolitis Caused or Not Caused by Respiratory Syncytial Virus

Bronchiolitis due to respiratory syncytial virus (RSV) or non-RSV agents is a health-menacing lower respiratory tract (LRT) disease of infants. Whereas RSV causes more severe disease than other viral agents may, genus-dominant fecal microbiota profiles have been identified in US hospitalized infants with bronchiolitis. We investigated the fecal microbiota composition of infants admitted to an Italian hospital with acute RSV (25/37 [67.6%]; group I) or non-RSV (12/37 [32.4%]; group II) bronchiolitis, and the relationship of fecal microbiota characteristics with the clinical characteristics of infants. Group I and group II infants differed significantly (24/25 [96.0%] versus 5/12 [41.7%]; P = 0.001) regarding 90% oxygen saturation (SpO2), which is an increased respiratory effort hallmark. Accordingly, impaired feeding in infants from group I was significantly more frequent than in infants from group II (19/25 [76.0%] versus 4/12 [33.3%]; P = 0.04). Conversely, the median (IQR) length of stay was not significantly different between the two groups (seven [3–14] for group I versus five [5–10] for group II; P = 0.11). The 16S ribosomal RNA V3–V4 region amplification of infants’ fecal samples resulted in 299 annotated amplicon sequence variants. Based on alpha- and beta-diversity microbiota downstream analyses, group I and group II infants had similar bacterial communities in their samples. Additionally, comparing infants having <90% SpO2 (n = 29) with infants having ≥90% SpO2 (n = 8) showed that well-known dominant genera (Bacteroides, Bifidobacterium, Escherichia/Shigella, and Enterobacter/Veillonella) were differently, but not significantly (P = 0.44, P = 0.71, P = 0.98, and P = 0.41, respectively) abundant between the two subgroups. Overall, we showed that, regardless of RSV or non-RSV bronchiolitis etiology, no fecal microbiota-composing bacteria could be associated with the severity of acute bronchiolitis in infants. Larger and longitudinally conducted studies will be necessary to confirm these findings.
Reduced Plasma Extracellular Vesicle CD5L Content in Patients With Acute-On-Chronic Liver Failure: Interplay With Specialized Pro-Resolving Lipid Mediators

Acute-on chronic liver failure (ACLF) is a syndrome that develops in patients with acutely decompensated cirrhosis (AD). It is characterized by a systemic hyperinflammatory state, leading to multiple organ failure. Our objective was to analyze macrophage anti-inflammatory protein CD5L in plasma extracellular vesicles (EVs) and assess its as yet unknown relationship with lipid mediators in ACLF. With this aim, EVs were purified by size exclusion chromatography from the plasma of healthy subjects (HS) (n=6) and patients with compensated cirrhosis (CC) (n=6), AD (n=11) and ACLF (n=11), which were defined as positive for CD9, CD5L and CD63 and their size, number, morphology and lipid mediator content were characterized by NTA, EM, and LC-MS/MS, respectively. Additionally, plasma CD5L was quantified by ELISA in 10 HS, 20 CC and 149 AD patients (69 ACLF). Moreover, macrophage CD5L expression and the biosynthesis of specialized lipid mediators (SPMs) were characterized in vitro in primary cells. Our results indicate that circulating EVs were significantly suppressed in cirrhosis, regardless of severity, and showed considerable alterations in CD5L and lipid mediator content as the disease progressed. In AD, levels of EV CD5L correlated best with those of the SPM RvE1. Analysis of total plasma supported these data and showed that, in ACLF, low CD5L levels were associated with circulatory (p<0.001), brain (p<0.008) and respiratory (p<0.05) failure (Mann-Whitney test). Functional studies in macrophages indicated a positive feedback loop between CD5L and RvE1 biosynthesis. In summary, we have determined a significant alteration of circulating EV contents in ACLF, with a loss of anti-inflammatory and pro-resolving molecules involved in the control of acute inflammation in this condition.
Advances and Potentials of Polydopamine Nanosystem in Photothermal-Based Antibacterial Infection Therapies

Bacterial infection remains one of the most dangerous threats to human health due to the increasing cases of bacterial resistance, which is caused by the extensive use of current antibiotics. Photothermal therapy (PTT) is similar to photodynamic therapy (PDT), but PTT can generate heat energy under the excitation of light of specific wavelength, resulting in overheating and damage to target cells or sites. Polydopamine (PDA) has been proved to show plenty of advantages, such as simple preparation, good photothermal conversion effects, high biocompatibility, and easy functionalization and adhesion. Taking these advantages, dopamine is widely used to synthesize the PDA nanosystem with excellent photothermal effects, good biocompatibility, and high drug loading ability, which therefore play more and more important roles for anticancer and antibacterial treatment. PDA nanosystem-mediated PTT has been reported to induce significant tumor inhibition, as well as bacterial killings due to PTT-induced hyperthermia. Moreover, combined with other cancer or bacterial inhibition strategies, PDA nanosystem-mediated PTT can achieve more effective tumor and bacterial inhibitions. In this review, we summarized the progress of preparation methods for the PDA nanosystem, followed by advances of their biological functions and mechanisms for PTT uses, especially in the field of antibacterial treatments. We also provided advances on how to combine PDA nanosystem-mediated PTT with other antibacterial methods for synergistic bacterial killings. Moreover, we further provide some prospects of PDA nanosystem-mediated PTT against intracellular bacteria, which might be helpful to facilitate their future research progress for antibacterial therapy.
The Association Between Thyroid Diseases and Alzheimer’s Disease in a National Health Screening Cohort in Korea

Objectives Thyroid dysfunction is linked to an increased risk of cognitive impairment. However, studies on the relationships between thyroid diseases and Alzheimer’s disease (AD) have reported conflicting results. We investigated the associations between several thyroid diseases and AD in a nested case-control study. Methods A total of 1,977 participants with AD were identified by claims data from 2002-2015 among a random sample of half a million people in the Korean National Health Insurance database. We recruited 16,473 age- and sex-matched (1:4 ratio) control participants and applied conditional logistic regression to estimate the relationships between thyroid diseases and AD, with adjustments for potential confounders, such as basic demographics, lifestyle factors, and various medical conditions or comorbidities. Results The prevalence rates of hypothyroidism (odds ratio [OR]=1.14, 95% confidence interval [CI]=1.00-1.30), thyroiditis (OR=1.22, 95% CI=1.05-1.40), and hyperthyroidism (OR=1.13, 95% CI=1.01-1.28) were significantly higher in participants with AD than in control participants after adjustment for confounders. Conclusion In this large national sample, we found significant relationships between several thyroid diseases and AD. Despite of the need for further investigation, these findings could better support to appreciate the pathophysiology of AD.
Case Report: Usefulness of Drip Infusion Cholangiography With Computed Tomography for the Diagnosis of Biloma in a Dog

Bilomas are encapsulated collections of bile outside or inside the biliary tract within the abdominal cavity. For diagnostic and therapeutic approaches, it is important to identify the origin of bile leaks from the biliary tract. This case report describes the usefulness of drip infusion cholangiography with computed tomography (DIC-CT) for detecting the site of bile leakage in a dog with biloma. A 10-year-old, castrated male Pomeranian dog was referred to our department for gastrointestinal signs. Abdominal ultrasonography detected gallbladder mucocele without evidence of defect on the wall and well-defined anechoic localized fluid accumulation around the right division of the liver. On the other hand, there was only a small amount of ascites in the abdominal cavity. The accumulated fluid collected through abdominocentesis had a bilirubin concentration of 11.4 mg/dl, which was more than twice as high as that in serum (0.4 mg/dl), but had absence of pyogenic bacteria. The DIC-CT with meglumine iotroxate showed two well-defined large fluid collections: one between right medial and lateral lobe and the other between the right lateral lobe and caudate process of caudate lobe. Three-dimensional DIC-CT views that the former was enhanced by the contrast agent and that it communicated with an intrahepatic bile duct of the right lateral lobe. Moreover, the DIC-CT images confirmed communication with each fluid collections. After 6 days of hospitalization, a decrease in the amount of accumulated fluid was confirmed, after which cholecystectomy was performed. The dog was discharged from the hospital without complications. No signs of bile leakage were observed on follow-up imaging on postoperative day 10. According to authors knowledge, this has been the first report to show that DIC-CT can be useful for determining the origin of bile leakage in dogs with bilomas.
Genome-Wide Analysis of the GW2-Like Genes in Gossypium and Functional Characterization of the Seed Size Effect of GhGW2-2D

Cotton is one of the most economically important crops worldwide. Seed size is a vital trait for plants connected with yield and germination. GW2 encodes a RING_Ubox E3 ubiquitin ligase that controls seed development by affecting cell growth. Here, are few reports on GW2-like genes in cotton, and the function of GW2 in cotton is poorly understood. In the present study, a genome-wide analysis identified 6 and 3 GW2-like genes in each of the two cultivated tetraploids (Gossypium hirsutum and G. barbadense) and each of their diploid ancestral species (G. arboreum, G. raimondii), respectively. GhGW2-2D has the same functional domain and high sequence similarity with AtDA2 in Arabidopsis. Overexpression of GhGW2-2D in Arabidopsis significantly reduced seed and seedling size, suggesting GhGW2-2D is a potential target for regulating cotton seed size. These results provided information on the genetic and molecular basis of GW2-like genes in cotton, thus establishing a foundation for functional studies of cotton seeds.
Effect Modification of Hyperuricemia, Cardiovascular Risk, and Age on Chronic Kidney Disease in China: A Cross-Sectional Study Based on the China Health and Nutrition Survey Cohort

Introduction The question of whether the increased burden of chronic kidney disease (CKD) is caused by the interaction of hyperuricemia and cardiovascular disease (CVD) risk factors or is accelerated by aging remains unresolved. The purpose of this study is to better understand the effect modification of hyperuricemia, cardiovascular risk, and age on CKD among the Chinese population. Methods This cross-sectional study of 8243 participants was derived from the China Health and Nutrition Survey (CHNS) in 2009. Inclusion criteria included age ≥18 years, non-pregnancy, and no history of high-protein diet prior to blood test. Demographics, comorbidities, health-related behaviors, and serum biomarkers were collected. Interaction association of hyperuricemia, CVD risk and age with CKD were analyzed using Logistic regression. Results CKD was detected in 359 (27.2%, 95% CI 24.8∼29.7%) of 1321 participants with hyperuricemia and 680 (9.8%, 95% CI 9.1∼10.5%) of 6,922 participants without hyperuricemia, and these patterns remained significant after controlling for age, gender, and Framingham risk score (adjusted odds ratio [aOR] 3.82, 95% CI 3.20∼4.57). We found a negative multiplicative interaction between hyperuricemia and CVD risk on CKD. The aOR in low-CVD risk groups was 5.51 (95% CI 4.03∼7.52), followed by medium-CVD risk groups (aOR: 3.64, 95% CI 2.61∼5.09) and high-CVD risk groups (aOR: 2.89, 95% CI 2.12∼3.96). CVD risk was less associated with CKD in hyperuricemia group (aOR: 0.92, 95% CI 0.68∼1.22) than in non-hyperuricemia group (aOR: 1.43, 95% CI 1.21∼1.70). Furthermore, hyperuricemia and age had a significant additive effect on CKD, with a synergy index of 2.26 (95% CI 1.45∼3.52). Coexisting with older age and hyperuricemia, the likelihood of developing CKD was higher than the sum of the two alone. Conclusion The link between hyperuricemia and CKD begins at a young age and becomes stronger in the low CVD risk group. For young adults, early detection of hyperuricemia, routine CVD risk assessment, and timely intervention of modifiable factors are warranted.
AN APPROACH FOR VERIFICATION AND VALIDAT ION OF THE ENVIRONMENTAL DESIGN SPACE

As part of the efforts to better assess the effect of aviation on the environment, the need for an improved understanding of noise, emissions, and fuel burn interdependencies has been recognized. A suite of analysis tools has been developed by the FAA, in conjunction with NASA and Transport Canada to inform environmental policy making and help shape the future of air transportation. As part of this suite, the Environmental Design Space (EDS) is tasked with the evaluation of the impact of new technologies on vehicle performance through simulation-based analysis of engines and airframes. To ensure the credibility of the EDS model, the assumptions, methodologies, and results must be reviewed through a formal, repeatable, and transparent assessment. This paper outlines the challenges faced, and the approach taken, in the assessment of the EDS model. The development process is divided into three distinct phases. The calibration process demonstrates the ability of the EDS model to reproduce representative aircraft. Using only public domain data, a combination of input parameters is established to approximate existing engines and airframes. The sensitivity analysis explores the relationship between model inputs and outputs while aiding the verification of physical trends. A methodology for variable screening and subsequent determination of input settings is established. Finally, the trade space exploration allows for the determination of a fleet of aircraft that represents the technology space through Pareto-front identification and selection. In each phase, error and uncertainty are quantified and propagated to communicate the probabilistic results of EDS to the other tools within the suite. Future work will focus on the details of implementing the approach for development and assessment.