Temporal patterns of endophytic microbial heterogeneity across distinct ecological compartments within the Panax ginseng root system following deforestation for cultivation.

Alterations in the microbial community significantly impact the yield and quality of ginseng. Yet, the dynamics of microbial community shifts within the root endophytes of ginseng across varying cultivation periods remain inadequately understood. This study zeroes in on the microbial community variations within the xylem (M), phloem (R), and fibrous roots (X) of ginseng during the fourth (F4) and fifth (F5) years of cultivation, aiming to bridge this research gap. We assessed soil physicochemical properties, enzyme activities, and nine individual saponins, complemented by high-throughput sequencing techniques (16S rDNA and ITS) to determine their profiles. The results showed that cultivation years mainly affected the microbial diversity of endophytic bacteria in ginseng fibrous roots compartment: the ASVs number and α-diversity Chao1 index of bacteria and fungi in F5X compartment with higher cultivation years were significantly higher than those in F4X compartment with lower cultivation years. It is speculated that the changes of fibrous roots bacterial groups may be related to the regulation of amino acid metabolic pathway. Such as D-glutamine and D-glutamate metabolism D-glutamine, cysteine and methionine metabolism regulation. The dominant bacteria in ginseng root are Proteobacteria (relative abundance 52.07-80.35%), Cyanobacteria (1.97-42.52%) and Bacteroidota (1.11-5.08%). Firmicutes (1.28-3.76%). There were two dominant phyla: Ascomycota (60.10-93.71%) and Basidiomycota (2.25-30.57%). Endophytic fungi were more closely related to soil physicochemical properties and enzyme activities. AN, TK, OP, SWC and EC were the main driving factors of endophytic flora of ginseng root. Tetracladium decreased with the increase of cultivation years, and the decrease was more significant in phloem (F4R: 33.36%, F5R: 16.48%). The relative abundance of Bradyrhizobium, Agrobacterium and Bacillus in each ecological niche increased with the increase of cultivation years. The relative abundance of Bradyrhizobium and Agrobacterium in F5X increased by 8.35 and 9.29 times, respectively, and Bacillus in F5M increased by 5.57 times. We found a variety of potential beneficial bacteria and pathogen antagonists related to ginseng biomass and saponins, such as Bradyrhizobium, Agrobacterium, Bacillus and Exophiala, which have good potential for practical application and development.

The anti-fatigue and sleep-aiding effects vary significantly among different recipes containing Ganoderma lucidum extracts.

Aims: This study aims to delve into the anti-fatigue and sleep-aiding effects of various formulations containing Ganoderma lucidum extracts. Materials and methods: PGB [incorporating Ganoderma lucidum extract (GE), broken Ganoderma lucidum spore powder (GB) and Paecilomyces hepiali mycelium (PH)] and GBS [composed of GE, GB, and Ganoderma sinense powder (GS)] were chosen as representative recipes for this study. Mice were treated with these recipes or key components of Ganoderma lucidum for 14 consecutive days. Subsequently, a weight-bearing swimming experiment was conducted to assess the mice's exhaustion time and evaluate the anti-fatigue properties of the recipes. Sleep-aiding effects were analyzed by measuring the sleep latency and duration. Furthermore, levels of blood lactic acid, serum urea nitrogen, hepatic glycogen, muscle glycogen, and malondialdehyde (MDA) were measured in the livers and muscles. Key findings: The anti-fatigue abilities of the tested mice were significantly improved after treatment with PGB and their sleep quality improved as well with GBS treatment. PGB treatment for 14 days could significantly prolong the exhaustion time in weight-bearing swimming (from 10.1 ± 0.5 min to 15.2 ± 1.3 min). Meanwhile, glycogen levels in the livers and muscles were significantly increased, while the levels of serum lactic acid, serum urea nitrogen, and MDA in the livers and muscles were significantly decreased. In contrast, mice treated with GBS for 14 days experienced significant improvements in sleep quality, with shortened sleep latency (from 6.8 ± 0.7 min to 4.2 ± 0.4 min), extended sleep duration (from 88.3 ± 1.4 min to 152.5 ± 9.3 min), and decreased muscle MDA levels. These results indicated that Ganoderma lucidum extracts can be used for anti-fatigue and or aid in sleeping, depending on how they are prepared and administered. Significance: This study provides experimental evidence and theoretical basis for the development of Ganoderma lucidum recipes that are specifically designed to help with anti-fatigue and sleep.

A smartphone-combined ratiometric fluorescence molecularly imprinted probe based on biomass-derived carbon dots for determination of tyramine in fermented meat products.

A ratiometric fluorescence molecularly imprinted probe employing two distinct emission wavelengths of biomass carbon dots was developed for highly selective and visual quantitative detection of tyramine in fermented meat products. The red emission biomass carbon dots were employed as responsive elements, and the blue ones were utilized as the reference elements. The molecularly imprinted polymers were incorporated in the ratiometric sensing to distinguish and adsorb tyramine. With the linear range of 1-60 µg/L, the ratiometric fluorescence molecularly imprinted probe was successfully applied to detect tyramine in real samples with the satisfactory recoveries of 79.74-112.12% and the detect limitation of 1.3 µg/kg, indicating that this probe has great potential applications for the detection of tyramine in real samples. Moreover, smartphone-based fluorescence signal recognition analysis on hand has been developed for the quantitative analysis of tyramine, providing a portable visual optical analysis terminal for rapid on-site determination of tyramine.

CPADS: a web tool for comprehensive pancancer analysis of drug sensitivity.

Drug therapy is vital in cancer treatment. Accurate analysis of drug sensitivity for specific cancers can guide healthcare professionals in prescribing drugs, leading to improved patient survival and quality of life. However, there is a lack of web-based tools that offer comprehensive visualization and analysis of pancancer drug sensitivity. We gathered cancer drug sensitivity data from publicly available databases (GEO, TCGA and GDSC) and developed a web tool called Comprehensive Pancancer Analysis of Drug Sensitivity (CPADS) using Shiny. CPADS currently includes transcriptomic data from over 29 000 samples, encompassing 44 types of cancer, 288 drugs and more than 9000 gene perturbations. It allows easy execution of various analyses related to cancer drug sensitivity. With its large sample size and diverse drug range, CPADS offers a range of analysis methods, such as differential gene expression, gene correlation, pathway analysis, drug analysis and gene perturbation analysis. Additionally, it provides several visualization approaches. CPADS significantly aids physicians and researchers in exploring primary and secondary drug resistance at both gene and pathway levels. The integration of drug resistance and gene perturbation data also presents novel perspectives for identifying pivotal genes influencing drug resistance. Access CPADS at https://smuonco.shinyapps.io/CPADS/ or https://robinl-lab.com/CPADS.

The reactivation kinetic analysis, molecular docking, and dynamics of oximes against three V-type nerve agents inhibited four human cholinesterases.

Nerve agents pose significant threats to civilian and military populations. The reactivation of acetylcholinesterase (AChE) is critical in treating acute poisoning, but there is still lacking broad-spectrum reactivators, which presents a big challenge. Therefore, insights gained from the reactivation kinetic analysis and molecular docking are essential for understanding the behavior of reactivators towards intoxicated AChE. In this research, we present a systematic determination of the reactivation kinetics of three V agents-inhibited four human ChEs [(AChE and butyrylcholinesterase (BChE)) from either native or recombinant resources, namely, red blood cell (RBC) AChE, rhAChE, hBChE, rhBChE) reactivated by five standard oximes. We unveiled the effect of native and recombinant ChEs on the reactivation kinetics of V agents ex vitro, where the reactivation kinetics characteristic of Vs-inhibited BChE was reported for the first time. In terms of the inhibition type, all of the five oxime reactivators exhibited noncompetitive inhibition. The inhibition potency of these reactivators would not lead to the difference in the reactivation kinetics between native and recombinant ChE. Despite the significant differences between the native and recombinant ChEs observed in the inhibition, aging, and spontaneous reactivation kinetics, the reactivation kinetics of V agent-inhibited ChEs by oximes were less differentiated, which were supported by the ligand docking results. We also found differences in the reactivation efficiency between five reactivators and the phosphorylated enzyme, and molecular dynamic simulations can further explain from the perspectives of conformational stability, hydrogen bonding, binding free energies, and amino acid contributions. By Poisson-Boltzmann surface area (MM-PBSA) calculations, the total binding free energy trends aligned well with the experimental kr2 values.

Reduced Retinal Vascular Density and Skeleton Length in Amblyopia.

Purpose: This study aimed to investigate the possible relationship between retinal vascular abnormalities and amblyopia by analyzing vascular structures of fundus images. Methods: In this observational study, retinal fundus images were collected from 36 patients with unilateral amblyopia, 33 patients with bilateral amblyopia, and 36 healthy control volunteers. We developed a customized training algorithm based on U-Net to digitalize the vasculature in the fundus images to quantify vascular density (area and fractal dimension), skeleton length, and number of bifurcation points. For statistical comparisons, this study divided participants into two groups. The amblyopic eyes and the fellow eyes of patients with unilateral amblyopia formed the paired group, while bilateral amblyopic patients and healthy controls formed the independent group. Results: In the paired group, the vascular area (P = 0.007), vascular fractal dimension (P = 0.007), and vascular skeleton length (P = 0.002) of the amblyopic eyes were significantly smaller than those of the fellow eyes. In the independent group, significant decreases in the vascular fractal dimension (P = 0.006) and skeleton length (P = 0.048) were observed in bilateral amblyopia compared to control. The vascular area was also significantly correlated with best-corrected visual acuity in amblyopic eyes. Conclusions: This study demonstrated that retinal vascular density and skeleton length in amblyopic eyes were significantly smaller compared to control, indicating an association between the changes in retinal vascular features and the state of amblyopia. Translational Relevance: Our algorithm presents amblyopic retinal vascular changes that are more biologically interpretable for both clinicians and researchers.

Development of an 18F-labeled azobenzothiazole tracer for α-synuclein aggregates in the brain.

Nuclear imaging of aggregated α-synuclein pathology is an urgent clinical need for Parkinson's disease, yet promising tracers for brain α-synuclein aggregates are still rare. In this work, a class of compact benzothiazole derivatives was synthesized and evaluated for α-synuclein aggregates. Among them, azobenzothiazoles exhibited specific and selective detection of α-synuclein aggregates under physiological conditions. Fluoro-pegylated azobenzothiazole NN-F further demonstrated high-affinity binding to α-synuclein aggregates and efficient 18F-radiolabeling via nucleophilic displacement of a tosyl precursor. [18F]NN-F was stable in plasma in vitro and showed efficient brain uptake with little defluorination in vivo.

Synergistic effects of graphene microgrooves and electrical stimulation on M2 macrophage polarization.

Macrophages play a crucial role in host response and wound healing, with M2 polarization contributing to the reduction of foreign-body reactions induced by the implantation of biomaterials and promoting tissue regeneration. Electrical stimulation (ES) and micropatterned substrates have a significant impact on the macrophage polarization. However, there is currently a lack of well-established cell culture platforms for studying the synergistic effects of these two factors. In this study, we prepared a graphene free-standing substrate with 20 µm microgrooves using capillary forces induced by water evaporation. Subsequently, we established an ES cell culture platform for macrophage cultivation by integrating a self-designed multi-well chamber cell culture device. We observed that graphene microgrooves, in combination with ES, significantly reduce cell spreading area and circularity. Results from immunofluorescence, ELISA, and flow cytometry demonstrate that the synergistic effect of graphene microgrooves and ES effectively promotes macrophage M2 phenotypic polarization. Finally, RNA sequencing results reveal that the synergistic effects of ES and graphene microgrooves inhibit the macrophage actin polymerization and the downstream PI3K signaling pathway, thereby influencing the phenotypic transition. Our results demonstrate the potential of graphene-based microgrooves and ES to synergistically modulate macrophage polarization, offering promising applications in regenerative medicine.

Biomimetic and multifunctional nanocomposites for precision fungi theranostics.

Fungi infection is a serious threat to public health, but an effective antifungal strategy remains a challenge. Herein, a biomimetic nanocomposite with multifunctionalities, including fungi diagnosis, antifungal adhesion, precise fungi elimination, and cytokine sequestration, is constructed for battling Candida albicans (C. albicans) infection. By screening a range of cells, we find that the polarized macrophage cells have the strongest binding tendency toward C. albicans. Thus, their membranes were exfoliated to camouflage UCNPs and then decorated with photosensitizers (methylene blue, MB) and DNA sensing elements. The resulting nanocomposite can tightly bind to fungal surfaces, promote DNA recognition, and squeeze pro-inflammatory cytokines to relieve inflammation. Consequently, this nanocomposite can detect C. albicans with enhanced sensitivity and precisely eliminate fungal cells through photodynamic therapy with minimal phototoxicity because of its switchable fluorescence behavior. The developed nanocomposite with good biocompatibility achieves a satisfactory diagnostic and therapeutic effect in a C. albicans-infected mouse model, which offers a unique approach to fight fungi infection.

Camellia sinensis polysaccharide attenuates inflammatory responses via the ROS-mediated pathway by endocytosis.

Polysaccharide CSTPs extracted from Camellia sinensis tea-leaves possessed unique against oxidative damage by scavenging ROS. Herein, acid tea polysaccharide CSTPs-2 with tightly packed molecular structure was isolated, purified and characterized in this research. Furthermore, the effects of CSTPs-2 on ROS-involved inflammatory responses and its underlying mechanisms were investigated. The results suggest that CSTPs-2 dramatically reduced the inflammatory cytokines overexpression and LPS-stimulated cell damage. CSTPs-2 could trigger the dephosphorylation of downstream AKT/MAPK/NF-κB signaling proteins and inhibit nuclear transfer of p-NF-κB to regulate the synthesis and release of inflammatory mediators in LPS-stimulated cells by ROS scavenging. Importantly, the impact of CSTPs-2 in downregulating pro-inflammatory cytokines and mitigating ROS overproduction is associated with clathrin- or caveolae-mediated endocytosis uptake mechanisms, rather than TLR-4 receptor-mediated endocytosis. This study presents a novel perspective for investigating the cellular uptake mechanism of polysaccharides in the context of anti-inflammatory mechanisms.

Systems Metabolic Engineering for Efficient Violaxanthin Production in Yeast.

Violaxanthin is a plant-derived orange xanthophyll with remarkable antioxidant activity that has wide applications in various industries, such as food, agriculture, and cosmetics. In addition, it is the key precursor of important substances such as abscisic acid and fucoxanthin. Saccharomyces cerevisiae, as a GRAS (generally regarded as safe) chassis, provides a good platform for producing violaxanthin production with a yield of 7.3 mg/g DCW, which is far away from commercialization. Herein, an integrated strategy involving zeaxanthin epoxidase (ZEP) source screening, cytosol redox state engineering, and nicotinamide adenine dinucleotide phosphate (NADPH) regeneration was implemented to enhance violaxanthin production in S. cerevisiae. 58aa-truncated ZEP from Vitis vinifera exhibited optimal efficiency in an efficient zeaxanthin-producing strain. The titer of violaxanthin gradually increased by 17.9-fold (up to 119.2 mg/L, 15.19 mg/g DCW) via cytosol redox state engineering and NADPH supplementation. Furthermore, balancing redox homeostasis considerably improved the zeaxanthin concentration by 139.3% (up to 143.9 mg/L, 22.06 mg/g DCW). Thus, the highest reported titers of violaxanthin and zeaxanthin in S. cerevisiae were eventually achieved. This study not only builds an efficient platform for violaxanthin biosynthesis but also serves as a useful reference for the microbial production of xanthophylls.

Developmental Dynamics of the Gut Virome in Tibetan Pigs at High Altitude: A Metagenomic Perspective across Age Groups.

Tibetan pig is a geographically isolated pig breed that inhabits high-altitude areas of the Qinghai-Tibetan plateau. At present, there is limited research on viral diseases in Tibetan pigs. This study provides a novel metagenomic exploration of the gut virome in Tibetan pigs (altitude ≈ 3000 m) across three critical developmental stages, including lactation, nursery, and fattening. The composition of viral communities in the Tibetan pig intestine, with a dominant presence of Microviridae phages observed across all stages of development, in combination with the previous literature, suggest that it may be associated with geographical locations with high altitude. Functional annotation of viral operational taxonomic units (vOTUs) highlights that, among the constantly increasing vOTUs groups, the adaptability of viruses to environmental stressors such as salt and heat indicates an evolutionary response to high-altitude conditions. It shows that the lactation group has more abundant viral auxiliary metabolic genes (vAMGs) than the nursery and fattening groups. During the nursery and fattening stages, this leaves only DNMT1 at a high level. which may be a contributing factor in promoting gut health. The study found that viruses preferentially adopt lytic lifestyles at all three developmental stages. These findings not only elucidate the dynamic interplay between the gut virome and host development, offering novel insights into the virome ecology of Tibetan pigs and their adaptation to high-altitude environments, but also provide a theoretical basis for further studies on pig production and epidemic prevention under extreme environmental conditions.

Urotensin II receptor deficiency ameliorates ligation-induced carotid intimal hyperplasia partially through the RhoA-YAP1 pathway.

Intimal hyperplasia (IH) is a common pathological feature of vascular proliferative diseases, such as atherosclerosis and restenosis after angioplasty. Urotensin II (UII) and its receptor (UTR) are widely expressed in cardiovascular tissues. However, it remains unclear whether the UII/UTR system is involved in IH. Right unilateral common carotid artery ligation was performed and maintained for 21 days to induce IH in UTR knockout (UTR-/-) and wild-type (WT) mice. Histological analysis revealed that compared with WT mice, UTR-deficient mice exhibited a decreased neointimal area, angiostenosis and intima-media ratio. Immunostaining revealed fewer smooth muscle cells (SMCs), endothelial cells and macrophages in the lesions of UTR-/- mice than in those of WT mice. Protein interaction analysis suggested that the UTR may affect cell proliferation by regulating YAP and its downstream target genes. In vitro experiments revealed that UII can promote the proliferation and migration of SMCs, and western blotting also revealed that UII increased the protein expression of RhoA, CTGF, Cyclin D1 and PCNA and downregulated p-YAP protein expression, while these effects could be partly reversed by urantide. To evaluate the translational value of UTRs in IH management, WT mice were also treated with two doses of urantide, a UTR antagonist, to confirm the benefit of UTR blockade in IH progression. A high dose of urantide (600 µg/kg/day), rather than a low dose (60 µg/kg/day), successfully improved ligation-induced IH compared with that in mice receiving vehicle. The results of the present study suggested that the UII/UTR system may regulate IH partly through the RhoA-YAP signaling pathway.

Repeatability of Epithelium Thickness Measured by an AS-OCT in Different Grades of Keratoconus and Compared to AS-OCT/Placido Topography.

PURPOSE: To compare agreement of corneal epithelium thickness (ET) between AS-OCT system (RTVue, Optovue) and AS-OCT/Placido topographer (MS-39, CSO) in eyes with different stages of keratoconus (KC), and to assess the repeatability of RTVue AS-OCT. DESIGN: Prospective reliability analysis. METHODS: KC eyes were classified into forme fruste KC (FFKC), mild, moderate, and severe KC. Agreement was evaluated with Bland-Altman plots and 95% limits of agreement (LoA). The repeatability of RTVue was assessed via within-subject standard deviation (Sw), test-retest variability (TRT), coefficient of variation (CoV), and intraclass correlation coefficient (ICC). RESULTS: A total of 119 KC eyes were enrolled, with 21 being FFKC, 26 mild, 39 moderate, and 34 severe. The 95% LoA ranged between -5.9 and 4.8 µm for center epithelium thickness (CET), between -5.7 and 8.2 µm for thinnest epithelium thickness (TET). At 1-mm measuring points, the 95% LoA of superior, inferior, nasal, and temporal were -4.2 to 4.7 µm, -5.2 to 6.0 µm, -7.9 to 10.2 µm, and -11.2 to 6.0 µm. At 3-mm measuring points, the corresponding values were -2.8 to 9.3 µm, -2.0 to 13.0 µm, -4.6 to 9.6 µm, and -6.3 to 9.7 µm, indicating that the 2 instruments were not interchangeable without adjustment. Despite that the repeatability of RTVue measurements in KC patients were acceptable, repeatability decreased gradually with the peripheralization of the measurement points. CONCLUSIONS: The 2 OCT-based devices, RTVue and MS-39, do not provide interchangeable measurements of epithelium thickness in KC patients. Repeatability decreases in cases of more severe KC, emphasizing the importance of grading before clinical examination to avoid diagnostic errors.

The crucial relationship between miRNA-27 and CSE/H2S, and the mechanism of action of GLP-1 in myocardial hypertrophy.

Cardiac hypertrophy is the most prevalent compensatory heart disease that ultimately leads to spontaneous heart failure. Mounting evidence suggests that microRNAs (miRs) and endogenous hydrogen sulfide (H2S) play a crucial role in the regulation of cardiac hypertrophy. In this study, we aimed to investigate whether inhibition of miR-27a could protect against cardiac hypertrophy by modulating H2S signaling. We established a model of cardiac hypertrophy by obtaining hypertrophic tissue from mice subjected to transverse aortic constriction (TAC) and from cells treated with angiotensin-II. Molecular alterations in the myocardium were quantified using quantitative real time PCR (qRT-PCR), Western blotting, and ELISA. Morphological changes were characterized by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Functional myocardial changes were assessed using echocardiography. Our results demonstrated that miR-27a levels were elevated, while H2S levels were reduced in TAC mice and myocardial hypertrophy. Further luciferase and target scan assays confirmed that cystathionine-γ-lyase (CSE) was a direct target of miR-27a and was negatively regulated by it. Notably, enhancement of H2S expression in the heart was observed in mice injected with recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-27a and in cells transfected with a miR-27a inhibitor during cardiac hypertrophy. However, this effect was abolished by co-transfection with CSE siRNA and the miR-27a inhibitor. Conversely, injecting rAAV9-miR-27a yielded opposite results. Interestingly, our findings demonstrated that glucagon-like peptide-1 (GLP-1) agonists could mitigate myocardial damage by down-regulating miR-27a and up-regulating CSE. In summary, our study suggests that inhibition of miR-27a holds therapeutic promise for the treatment of cardiac hypertrophy by increasing H2S levels. Furthermore, our findings unveil a novel mechanism of GLP-1 agonists involving the miR-27a/H2S pathway in the management of cardiac hypertrophy.

Efficient Selective Adsorption of Rubidium and Cesium from Practical Brine Using a Metal-Organic Framework-Based Magnetic Adsorbent.

Rubidium (Rb) and cesium (Cs) have important applications in highly technical fields. Salt lakes contain huge reserves of Rb and Cs with industrial significance, which can be utilized after extraction. In this study, a composite magnetic adsorbent (Fe3O4@ZIF-8@AMP, AMP = ammonium phosphomolybdate) was prepared and its adsorption properties for Rb+ and Cs+ were studied in simulated and practical brine. The structure of the adsorbent was characterized by SEM, XRD, N2 adsorption-desorption, FT-IR, and vibrating sample magnetometer (VSM). The adsorbent had good adsorption affinity for Rb+ and Cs+. The Langmuir model and pseudo-second-order dynamics described the adsorbing isotherm and kinetic dates, respectively. The adsorption capacity and adsorption rate of Fe3O4@ZIF-8@AMP were increased by 1.86- and 2.5-fold compared with those of powdered crystal AMP, owing to the large specific surface area and high dispersibility of the adsorbent in the solution. The adsorbent was rapidly separated from the solution within 17 s using an applied magnetic field owing to the good magnetic properties. The composite adsorbent selectively adsorbed Rb+ and Cs+ from the practical brine even in the presence of a large number of coexisting ions. The promising adsorbent can be used to extract Rb+ and Cs+ from aqueous solutions.

Pharmacokinetics, safety, and tolerability of the novel tetrameric gadolinium-based MRI contrast agent gadoquatrane in healthy Chinese and Japanese men: Two randomized dose-escalation studies including concentration-QTc modeling.

PURPOSE: To investigate the pharmacokinetics, safety, and tolerability of the novel tetrameric high-relaxivity gadolinium-based contrast agent gadoquatrane in Japanese (Study 1) and Chinese men (Study 2). PARTICIPANTS AND METHODS: In two similarly designed single-center, randomized, single-blind, placebo-controlled, consecutive-cohort dose-escalation studies, healthy volunteers were randomly assigned to intravenous administration of gadoquatrane (0.01-0.1 mmol gadolinium/kg body weight) or placebo. Study procedures included blood sampling and collection of urine for pharmacokinetic analyses and safety assessments. RESULTS: Twenty-five healthy Japanese men (mean age ± standard deviation: 26±5.9 years) and 23 healthy Chinese men (31±7.6 years old) were evaluated. In both studies, the pharmacokinetic profile of gadoquatrane was characterized by rapid distribution of the drug into the extracellular space and fast renal elimination. Postdose gadolinium concentrations rapidly declined with a geometric mean effective half-life of 1.3-1.4 h. The exposure increased approximately dose-proportionally with dose. The body weight-normalized volume of distribution was constant across dose levels (0.21-0.24 L/kg). Total recovery of gadolinium in urine amounted to 82-95 % (Study 1) and 96-99 % (Study 2) of the dose administered. Only a few mild, transient adverse events were reported, none of which gave rise to any safety concerns. Exploratory drug concentration-QTc modeling indicated no risk of a clinically relevant QT/QTc prolongation at the anticipated diagnostic dose. CONCLUSION: Gadoquatrane was safe and well tolerated at all doses tested. The pharmacokinetic profile was essentially the same as that of other extracellular macrocyclic gadolinium-based contrast agents and was consequentially also similar for Japanese and Chinese participants.

Perfluorooctanoic acid inhibits cell proliferation through mitochondrial damage.

Grown evidence has shown that the liver and reproductive organs were the main target organs of perfluorooctanoic acid (PFOA). Herein, we studied a toxic mechanism of PFOA using HeLa Chang liver epithelial cells. When incubated with PFOA for 24 h or 48 h, cell proliferation was inhibited in a concentration- and time-dependent fashion, but interestingly, the feature of dead cells was not notable. Mitochondrial volume was increased with concentration and time, whereas the mitochondrial membrane potential and produced ATP amounts were significantly reduced. Autophagosome-like vacuoles and contraction of the mitochondrial inner membrane were observed in PFOA-treated cells. The expression of acetyl CoA carboxylase (ACC) and p-ACC proteins rapidly decreased, and that of mitochondrial dynamics-related proteins increased. The expression of solute carrier family 7 genes, ChaC glutathione-specific gamma-glutamylcyclotransferase 1, and 5S ribosomal RNA gene was up-regulated the most in cells exposed to PFOA for 24 h, and the KEGG pathway analysis revealed that PFOA the most affected metabolic pathways and olfactory transduction. More importantly, PPAR alpha, fatty acid binding protein 1, and CYP450 family 1 subfamily A member 1 were identified as the target proteins for binding between PFOA and cells. Taken together, we suggest that disruption of mitochondrial integrity and function may contribute closely to PFOA-induced cell proliferation inhibition.

Identification of miR-20b-5p as an inhibitory regulator in cardiac differentiation via TET2 and DNA hydroxymethylation.

BACKGROUND: Congenital heart disease (CHD) is a prevalent congenital cardiac malformation, which lacks effective early biological diagnosis and intervention. MicroRNAs, as epigenetic regulators of cardiac development, provide potential biomarkers for the diagnosis and treatment of CHD. However, the mechanisms underlying miRNAs-mediated regulation of cardiac development and CHD malformation remain to be further elucidated. This study aimed to explore the function of microRNA-20b-5p (miR-20b-5p) in cardiac development and CHD pathogenesis. METHODS AND RESULTS: miRNA expression profiling identified that miR-20b-5p was significantly downregulated during a 12-day cardiac differentiation of human embryonic stem cells (hESCs), whereas it was markedly upregulated in plasma samples of atrial septal defect (ASD) patients. Our results further revealed that miR-20b-5p suppressed hESCs-derived cardiac differentiation by targeting tet methylcytosine dioxygenase 2 (TET2) and 5-hydroxymethylcytosine, leading to a reduction in key cardiac transcription factors including GATA4, NKX2.5, TBX5, MYH6 and cTnT. Additionally, knockdown of TET2 significantly inhibited cardiac differentiation, which could be partially restored by miR-20b-5p inhibition. CONCLUSIONS: Collectively, this study provides compelling evidence that miR-20b-5p functions as an inhibitory regulator in hESCs-derived cardiac differentiation by targeting TET2, highlighting its potential as a biomarker for ASD.

Structural and functional changes of binocular corneal innervation and ocular surface function after unilateral SMILE and tPRK.

AIMS: To evaluate the bilateral changes in the sub-basal nerve plexus of the cornea and ocular surface function after unilateral small incision lenticule extraction (SMILE) and transepithelial photorefractive keratectomy (tPRK) procedures. METHODS: 34 patients were enrolled in the study and underwent unilateral SMILE (21 of 34 patients) or unilateral tPRK (13 of 34 patients). Complete ophthalmic examinations, tear film function tests and Cochet-Bonnet esthesiometry were conducted to assess the effects of the surgeries on the corneal nerves and tear function. Morphological changes were assessed using in vivo confocal microscopy to evaluate the corneal sub-basal nerve plexus and dendritic cells. ELISA was used to measure the tear neuromediators. Clinical and morphological data at each follow-up point were compared with preoperative baseline values. RESULTS: All patients who underwent unilateral SMILE or tPRK procedures exhibited bilateral corneal nerve degenerative changes, decreased corneal sensitivity, worsening of dry eye symptoms and changes in bilateral tear neuromediators. In the SMILE group, bilateral corneal sensitivity was positively correlated with corneal nerve fibre length and negatively correlated with dendritic cell area. The dry eye severity was negatively correlated with corneal sensitivity. Tear levels of substance P and nerve growth factor were positively correlated with mean dendritic cell area and dry eye severity, but negatively correlated with corneal sensitivity. In the tPRK group, bilateral corneal sensitivity was positively correlated with corneal nerve fibre density. CONCLUSIONS: Unilateral refractive surgery may bilaterally affect the morphology and function of corneal nerves and ocular surface status postoperatively.