Miracle-dz/UniFAR-FTUs huggingface dataset:
Baicalin Protects Against 17α-Ethinylestradiol-Induced Cholestasis via the Sirtuin 1/Hepatic Nuclear Receptor-1α/Farnesoid X Receptor Pathway

Estrogen-induced cholestasis (EIC) is characterized by impairment of bile flow and accumulated bile acids (BAs) in the liver, always along with the liver damage. Baicalin is a major flavonoid component of Scutellaria baicalensis, and has been used in the treatment of liver diseases for many years. However, the role of baicalin in EIC remains to be elucidated. In this study, we demonstrated that baicalin showed obvious hepatoprotective effects in EIC rats by reducing serum biomarkers and increasing the bile flow rate, as well as by alleviating liver histology and restoring the abnormal composition of hepatic BAs. In addition, baicalin protected against estrogen-induced liver injury by up-regulation of the expression of hepatic efflux transporters and down-regulation of hepatic uptake transporters. Furthermore, baicalin increased the expression of hepatic BA synthase (CYP27A1) and metabolic enzymes (Bal, Baat, Sult2a1) in EIC rats. We showed that baicalin significantly inhibited hepatic inflammatory responses in EIC rats through reducing elevated levels of TNF-α, IL-1β, IL-6, and NF-κB. Finally, we confirmed that baicalin maintains hepatic BA homeostasis and alleviates inflammation through sirtuin 1 (Sirt1)/hepatic nuclear receptor-1α (HNF-1α)/farnesoid X receptor (FXR) signaling pathway. Thus, baicalin protects against estrogen-induced cholestatic liver injury, and the underlying mechanism involved is related to activation of the Sirt1/HNF-1α/FXR signaling pathway.
A Review of Precision Oncology Knowledgebases for Determining the Clinical Actionability of Genetic Variants

The increased availability of tumor genetic testing and targeted cancer therapies contributes to the advancement of precision medicine in the field of oncology. Precision oncology knowledgebases provide a way of organizing clinically relevant genetic information in a way that is easily accessible for both oncologists and patients, facilitating the genetic-based clinical decision making. Many organizations and companies have built precision oncology knowledgebases, intended for multiple users. In general, these knowledgebases offer information on cancer-related genetic variants as well as their associated diagnostic, prognostic, and therapeutic implications, but they often differ in their information curations, designs, and user experiences. It is advisable that oncologists use multiple knowledgebases during their practice to have them complement each other. In the future, convergence toward common standards and formats is needed to ensure that the comprehensive knowledge across all sources can be unified to bring the oncology community closer to the achievement of the goal of precision oncology.
Bioproduct Potential of Outdoor Cultures of Tolypothrix sp.: Effect of Carbon Dioxide and Metal-Rich Wastewater

Rising CO2 levels, associated climatic instability, freshwater scarcity and diminishing arable land exacerbate the challenge to maintain food security for the fast growing human population. Although coal-fired power plants generate large amounts of CO2 emissions and wastewater, containing environmentally unsafe concentrations of metals, they ensure energy security. Nitrogen (N2)-fixation by cyanobacteria eliminate nitrogen fertilization costs, making them promising candidates for remediation of waste CO2 and metals from macronutrient-poor ash dam water and the biomass is suitable for phycocyanin and biofertilizer product development. Here, the effects of CO2 and metal mixtures on growth, bioproduct and metal removal potential were investigated for the self-flocculating, N2-fixing freshwater cyanobacterium Tolypothrix sp. Tolypothrix sp. was grown outdoors in simulated ash dam wastewater (SADW) in 500 L vertical bag suspension cultures and as biofilms in modified algal-turf scrubbers. The cultivation systems were aerated with air containing either 15% CO2 (v/v) or not. CO2-fertilization resulted in ∼1.25- and 1.45-fold higher biomass productivities and ∼40 and 27% increased phycocyanin and phycoerythrin contents for biofilm and suspension cultures, respectively. CO2 had no effect on removal of Al, As, Cu, Fe, Sr, and Zn, while Mo removal increased by 37% in both systems. In contrast, Ni removal was reduced in biofilm systems, while Se removal increased by 73% in suspension cultures. Based on biomass yields and biochemical data obtained, net present value (NPV) and sensitivities analyses used four bioproduct scenarios: (1) phycocyanin sole product, (2) biofertilizer sole product, (3) 50% phycocyanin and 50% biofertilizer, and (4) 100% phycocyanin and 100% biofertilizer (residual biomass) for power station co-located and not co-located 10 ha facilities over a 20-year period. Economic feasibility for the production of food-grade phycocyanin either as a sole product or with co-production of biofertilizer was demonstrated for CO2-enriched vertical and raceway suspension cultures raised without nitrogen-fertilization and co-location with power stations significantly increased profit margins. Graphical Abstract Framework for an integrated bio-economic model for co-locating cyanobacterial cultivation with coal-fired power station based on a biorefinery approach.
Molecular Basis of Growth Inhibition by Acetate of an Adenylate Cyclase-Deficient Mutant of Corynebacterium glutamicum

In Corynebacterium glutamicum, cyclic adenosine monophosphate (cAMP) serves as an effector of the global transcriptional regulator GlxR. Synthesis of cAMP is catalyzed by the membrane-bound adenylate cyclase CyaB. In this study, we investigated the consequences of decreased intracellular cAMP levels in a ΔcyaB mutant. While no growth defect of the ΔcyaB strain was observed on glucose, fructose, sucrose, or gluconate alone, the addition of acetate to these growth media resulted in a severe growth inhibition, which could be reversed by plasmid-based cyaB expression or by supplementation of the medium with cAMP. The effect was concentration- and pH-dependent, suggesting a link to the uncoupling activity of acetate. In agreement, the ΔcyaB mutant had an increased sensitivity to the protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP). The increased uncoupler sensitivity correlated with a lowered membrane potential of acetate-grown ΔcyaB cells compared to wild-type cells. A reduced membrane potential affects major cellular processes, such as ATP synthesis by F1FO-ATP synthase and numerous transport processes. The impaired membrane potential of the ΔcyaB mutant could be due to a decreased expression of the cytochrome bc1-aa3 supercomplex, which is the major contributor of proton-motive force in C. glutamicum. Expression of the supercomplex genes was previously reported to be activated by GlxR-cAMP. A suppressor mutant of the ΔcyaB strain with improved growth on acetate was isolated, which carried a single mutation in the genome leading to an Ala131Thr exchange in GlxR. Introduction of this point mutation into the original ΔcyaB mutant restored the growth defect on acetate. This supported the importance of GlxR for the phenotype of the ΔcyaB mutant and, more generally, of the cAMP-GlxR system for the control of energy metabolism in C. glutamicum.
Nicotinamide Increases Intracellular NAD+ Content to Enhance Autophagy-Mediated Group A Streptococcal Clearance in Endothelial Cells

Group A streptococcus (GAS) is a versatile pathogen that causes a wide spectrum of diseases in humans. Invading host cells is a known strategy for GAS to avoid antibiotic killing and immune recognition. However, the underlying mechanisms of GAS resistance to intracellular killing need to be explored. Endothelial HMEC-1 cells were infected with GAS, methicillin-resistant Staphylococcus aureus (MRSA) and Salmonella Typhimurium under nicotinamide (NAM)-supplemented conditions. The intracellular NAD+ level and cell viability were respectively measured by NAD+ quantification kit and protease-based cytotoxicity assay. Moreover, the intracellular bacteria were analyzed by colony-forming assay, transmission electron microscopy, and confocal microscopy. We found that supplementation with exogenous nicotinamide during infection significantly inhibited the growth of intracellular GAS in endothelial cells. Moreover, the NAD+ content and NAD+/NADH ratio of GAS-infected endothelial cells were dramatically increased, whereas the cell cytotoxicity was decreased by exogenous nicotinamide treatment. After knockdown of the autophagy-related ATG9A, the intracellular bacterial load was increased in nicotinamide-treated endothelial cells. The results of Western blot and transmission electron microscopy also revealed that cells treated with nicotinamide can increase autophagy-associated LC3 conversion and double-membrane formation during GAS infection. Confocal microscopy images further showed that more GAS-containing vacuoles were colocalized with lysosome under nicotinamide-supplemented conditions than without nicotinamide treatment. In contrast to GAS, supplementation with exogenous nicotinamide did not effectively inhibit the growth of MRSA or S. Typhimurium in endothelial cells. These results indicate that intracellular NAD+ homeostasis is crucial for controlling intracellular GAS infection in endothelial cells. In addition, nicotinamide may be a potential new therapeutic agent to overcome persistent infections of GAS.
An Ecological Perspective on Dolomite Formation in Great Salt Lake, Utah

Protodolomite was detected in sediments from Great Salt Lake (GSL), Utah, United States, that have no history of elevated temperature or pressure, conditions that are thought to promote dolomitization of sedimentary carbonates. Protodolomite was abundant in a non-oolitic sediment core from the South Arm (SA) of GSL at < 17% salinity but was rare in an oolitic sediment core collected from the North Arm (NA) of GSL at > 26% salinity. Protodolomite was also abundant in a non-oolitic NA sediment hand sample yet was absent in a nearby oolitic sediment hand sample in locations that likely receive allochthonous nutrients. Protodolomite was not detected in benthic photosynthetic mats from the SA. However, the mats comprised aragonite with halite and minimal calcite; benthic photosynthetic mats do not form in the NA. To begin to identify potential controls on the formation of protodolomite in the SA and NA of GSL, the composition and abundance of 16S rRNA gene transcripts, carbon cycling activities, and porewater geochemistry of the sediment cores were characterized. Transcripts affiliated with a dominant halophilic, heterotrophic sulfate-reducing bacterium were detected in the uppermost sections of the SA core and their abundance was positively correlated with rates of acetate oxidation/assimilation and concentrations of sulfide. Differences in the quality of organic matter between the SA and NA cores, as indicated by carbon to nitrogen ratios, indicate fresh deposition of photosynthetic biomass at the SA sediment core site but not in the NA sediment core site. Sediment grains from the SA core exhibit micrometer-sized euhedral protodolomite crystals that were not detected in the NA core. Collectively, these observations suggest that deposition of photosynthetic biomass drives the development of a sharp, anoxic lens of heterotrophic sulfate reduction. Sulfide, in turn, may promote dehydration of Mg2+-water complexes and primary protodolomite nucleation and growth. The scarcity of dolomite in the NA sediment core may result from constraints imposed by a combination of extreme hypersalinity and depositional environment on phototrophs and sulfate reducers, their activities, and the thermodynamics of protodolomite formation.
Mechanisms of Epithelial Immunity Evasion by Respiratory Bacterial Pathogens

Bacterial lung infections are major healthcare challenges killing millions of people worldwide and resulting in a huge economic burden. Both basic and clinical research have elucidated host mechanisms that contribute to the bacterial clearance where an indispensable role of immune cells has been established. However, the role of respiratory epithelial cells in bacterial clearance has garnered limited attention due to their weak inflammatory or phagocytic ability compared to immune cells such as macrophages and neutrophils. These studies often underappreciate the fact that epithelial cells are the most abundant cells in the lung, not only serving as building blocks but also providing immune protection throughout the lung. Epithelial cells function either independently to eradicate the pathogen or communicate with immune cells to orchestrate pathogen clearance. The epithelial cells have multiple mechanisms that include mucus production, antimicrobial peptide production, muco-ciliary clearance, and phagocytosis, all of which contribute to their direct antibacterial function. Secretion of cytokines to recruit immune cells and potentiate their antimicrobial activities is a pathway by which the epithelium contributes to bacterial clearance. Successful pathogens outsmart epithelial resistance and find a way to replicate in sufficient numbers to establish infections in the airway or lung epithelial surfaces. In this mini-review, we discuss evidences that establish important roles for epithelial host defense against invading respiratory bacterial pathogens and demonstrate how pathogens outsmart these epithelial immune mechanisms to successfully establish infection. Finally, we discuss briefly how to boost epithelial immunity to improve outcomes in bacterial lung infections.
Training the Fetal Immune System Through Maternal Inflammation—A Layered Hygiene Hypothesis

Over the last century, the alarming surge in allergy and autoimmune disease has led to the hypothesis that decreasing exposure to microbes, which has accompanied industrialization and modern life in the Western world, has fundamentally altered the immune response. In its current iteration, the “hygiene hypothesis” suggests that reduced microbial exposures during early life restricts the production and differentiation of immune cells suited for immune regulation. Although it is now well-appreciated that the increase in hypersensitivity disorders represents a “perfect storm” of many contributing factors, we argue here that two important considerations have rarely been explored. First, the window of microbial exposure that impacts immune development is not limited to early childhood, but likely extends into the womb. Second, restricted microbial interactions by an expectant mother will bias the fetal immune system toward hypersensitivity. Here, we extend this discussion to hypothesize that the cell types sensing microbial exposures include fetal hematopoietic stem cells, which drive long-lasting changes to immunity.
Improved Prediction of Aqueous Solubility of Novel Compounds by Going Deeper With Deep Learning

Aqueous solubility is an important physicochemical property of compounds in anti-cancer drug discovery. Artificial intelligence solubility prediction tools have scored impressive performances by employing regression, machine learning, and deep learning methods. The reported performances vary significantly partly because of the different datasets used. Solubility prediction on novel compounds needs to be improved, which may be achieved by going deeper with deep learning. We constructed deeper-net models of ~20-layer modified ResNet convolutional neural network architecture, which were trained and tested with 9,943 compounds encoded by molecular fingerprints. Retrospectively tested by 62 recently-published novel compounds, one deeper-net model outperformed four established tools, shallow-net models, and four human experts. Deeper-net models also outperformed others in predicting the solubility values of a series of novel compounds newly-synthesized for anti-cancer drug discovery. Solubility prediction may be improved by going deeper with deep learning. Our deeper-net models are accessible at http://www.npbdb. net/solubility/index.jsp.
Astragalus polysaccharides alleviates LPS‐induced inflammation via the NF‐κB/MAPK signaling pathway

Early weaning usually causes intestinal disorders, enteritis, and diarrhea in young animals and human infants. Astragalus polysaccharides (APS) possesses anti‐inflammatory activity. To study the anti‐inflammatory mechanisms of APS and its potential effects on intestinal health, we performed an RNA sequencing (RNA‐seq) study in lipopolysaccharide (LPS)‐stimulated porcine intestinal epithelial cells (IPEC‐J2) in vitro. In addition, LPS‐stimulated BALB/c mice were used to study the effects of APS on intestinal inflammation in vivo. The results from the RNA‐seq analysis show that there were 107, 756, and 5 differentially expressed genes in the control versus LPS, LPS versus LPS+APS, and control versus LPS+APS comparison groups, respectively. The results of Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that the mitogen‐activated protein kinase (MAPK) and nuclear factor‐κB (NF‐κB) signaling pathways play significant roles in the regulation of inflammatory factors and chemokine expression by APS. Further verification of the above two pathways by using western blot and immunofluorescence analysis revealed that the gene expression levels of the phosphorylated p38 MAPK, ERK1/2, and NF‐κB p65 were inhibited by APS, while the expression of IκB‐α protein was significantly increased (p < .05), indicating that APS inhibits the production of inflammatory factors and chemokines by the inhibition of activation of the MAPK and NF‐κB inflammatory pathways induced by LPS stimulation. Animal experiments further demonstrated that prefeeding APS in BALB/c mice can alleviate the expression of the jejunal inflammatory factors interleukin 6 (IL‐6), IL‐Iβ, and tumor necrosis factor‐α induced by LPS stimulation and improve jejunal villus morphology.
Two‐Dimensional Boronate Ester Covalent Organic Framework Thin Films with Large Single Crystalline Domains for a Neuromorphic Memory Device

Abstract Despite the recent progress in the synthesis of crystalline boronate ester covalent organic frameworks (BECOFs) in powder and thin‐film through solvothermal method and on‐solid‐surface synthesis, respectively, their applications in electronics, remain less explored due to the challenges in thin‐film processability and device integration associated with the control of film thickness, layer orientation, stability and crystallinity. Moreover, although the crystalline domain sizes of the powder samples can reach micrometer scale (up to ≈1.5 μm), the reported thin‐film samples have so far rather small crystalline domains up to 100 nm. Here we demonstrate a general and efficient synthesis of crystalline two‐dimensional (2D) BECOF films composed of porphyrin macrocycles and phenyl or naphthyl linkers (named as 2D BECOF‐PP or 2D BECOF‐PN) by employing a surfactant‐monolayer‐assisted interfacial synthesis (SMAIS) on the water surface. The achieved 2D BECOF‐PP is featured as free‐standing thin film with large single‐crystalline domains up to ≈60 μm2 and tunable thickness from 6 to 16 nm. A hybrid memory device composed of 2D BECOF‐PP film on silicon nanowire‐based field‐effect transistor is demonstrated as a bio‐inspired system to mimic neuronal synapses, displaying a learning–erasing–forgetting memory process.
Serial evaluation of cardiac biomarker NT-proBNP with speckle tracking echocardiography in a 6-year-old Golden Retriever dog with subaortic stenosis and dilated cardiomyopathy

A 6-year-old 37.5-kg Golden Retriever dog was presented with intermittent coughing and cardiac murmur. The dog was diagnosed with subaortic stenosis (SAS) and dilated cardiomyopathy (DCM). The serum N-terminal pro B-type natriuretic peptide (NT-proBNP) concentration, conventional echocardiography, and two-dimensional speckle tracking echocardiography (2D-STE) were serially evaluated for 6 months. At admission, the dog showed a significant increase in the serum NT-proBNP concentration and severe reduction in the 2D-STE strain values. During the monitoring period, the 2D-STE was capable of detecting segmental dyskinesia in apical region, even though the concentration of NT-proBNP in serum was decreased. In addition, longitudinal deformations most sensitively indicated the myocardial damage, while radial and circumferential deformations accurately indicated myocardial contractility. This is the first case report of a dog with SAS and DCM, which demonstrated and compared serial changes of NT-proBNP and 2D-STE with disease progression. In this case, the combined use of NT-proBNP with 2D-STE showed excellent diagnostic and prognostic utility in investigating myocardial injury.
Digital Single-operator Cholangioscopy (DSOC) Improves Interobserver Agreement (IOA) and Accuracy for Evaluation of Indeterminate Biliary Strictures

Background: Visual characteristics seen during digital single-operator cholangioscopy (DSOC) have not been validated. The aim of this 2-phase study was to define terminology by consensus for the visual diagnosis of biliary lesions to develop a model for optimization of the diagnostic performance of DSOC. Materials and Methods: In phase 1 (criteria identification), video-cholangioscopy clips were reviewed by 12 expert biliary endoscopists, who were blinded to the final diagnosis. Visual criteria were consolidated into the following categories: (1) stricture, (2) lesion, (3) mucosal features, (4) papillary projections, (5) ulceration, (6) abnormal vessels, (7) scarring, (8) pronounced pit pattern. During the second phase (validation), 14 expert endoscopists reviewed DSOC (SpyGlass DS, Boston Scientific) clips using the 8 criteria to assess interobserver agreement (IOA) rate. Results: In phase 1, consensus for visual findings were categorized into 8 criteria titled the “Monaco Classification. ” The frequency of criteria were: (1) presence of stricture—75%, (2) presence of lesion type—55%, (3) mucosal features—55%, (4) papillary projections—45%, (5) ulceration—42.5%, (6) abnormal vessels—10%, (7) scarring—40%, and (8) pronounced pit pattern—10%. The accuracy on final diagnosis based on visual impression alone was 70%. In phase 2, the IOA rate using Monaco Classification criteria ranged from slight to fair. The presumptive diagnosis IOA was fair (κ=0.31, SE=0.02), and overall diagnostic accuracy was 70%. Conclusions: The Monaco classification identifies 8 visual criteria for biliary lesions on single-operator digital cholangioscopy. Using the criteria, the IOA and diagnostic accuracy rate of DSOC is improved compared with prior studies.
Alcohol consumption and sick leave: a meta-analysis

Abstract Several factors are involved in the risk of sick leave and it seems that alcohol consumption is a factor in this regard. We seek a meta-analysis of sick leave with regards to alcohol consumption. Until November 2018 scientific databases were searched using keywords, after screening for studies, 21 studies were eligible for including in the meta-analysis. The main result and the results of the subgroups were analyzed based on the random effects method. The pooled risk ratio (RR) was calculated for the results and confidence intervals (CI) were also shown. Result showed that alcohol consumption is a risk factor for sick leave with RR = 1.07 and (CI) = 1.01–1.13 (p = 0.012). In men, the results are equal to RR = 1.11 and CI = 1.01–1.22 (p = 0.030) and in women, the results are equal to RR = 1.10 and CI = 1.03–1.18 (p = 0.006). The results showed a very low bias. Based on the evidence, it can be concluded that alcohol consumption increases the risk of sick leave in working population. Hence, measuring health and conducting prevention and treatment programs can be beneficial in reducing the burden of alcohol.