Rose-like NiCo2O4 with Atomic-Scale Controllable Oxygen Vacancies for Modulating Sulfur Redox Kinetics in Lithium-Sulfur Batteries.

The long-term stability of Li-S batteries is significantly compromised by the shuttle effect and insulating nature of active substance S, constraining their commercialization. Developing efficient catalysts to mitigate the shuttle effect of lithium polysulfides (LiPSs) is still a challenge. Herein, we designed and synthesized a rose-like cobalt-nickel bimetallic oxide catalyst NiCo2O4-OV enriched with oxygen vacancies (OV) and verified the controllable synthesis of different contents of OV. Introducing the OV proved to be an efficient approach for controlling the electronic structure of the electrocatalyst and managing the absorption/desorption processes on the reactant surface, thereby addressing the challenges posed by the LiPS shuttle effect and sluggish transformation kinetics in Li-S batteries. In addition, we investigated the effect of OV in NiCo2O4 on the adsorption capacity of LiPSs using adsorption experiments and density functional theory (DFT) simulations. With the increase in the level of OV, the binding energy between the two is enhanced, and the adsorption effect is more obvious. NiCo2O4-OV contributes to the decomposition of Li2S and diffusion of Li+ in Li-S batteries, which promotes the kinetic process of the batteries.

Association of epilepsy, anti-epileptic drugs (AEDs), and type 2 diabetes mellitus (T2DM): a population-based cohort retrospective study, impact of AEDs on T2DM-related molecular pathway, and via peroxisome proliferator-activated receptor γ transactivation.

Introduction: A potential association between epilepsy and subsequent type 2 diabetes mellitus (T2DM) has emerged in recent studies. However, the association between epilepsy, anti-epileptic drugs (AEDs), and the risk of T2DM development remains controversial. We aimed to conduct a nationwide, population-based, retrospective, cohort study to evaluate this relationship. Methods: We extracted data from the Taiwan Longitudinal Generation Tracking Database of patients with new-onset epilepsy and compared it with that of a comparison cohort of patients without epilepsy. A Cox proportional hazards regression model was used to analyze the difference in the risk of developing T2DM between the two cohorts. Next-generation RNA sequencing was used to characterize T2DM-related molecularchanges induced by AEDs and the T2DM-associated pathways they alter. The potential of AEDs to induce peroxisome proliferator-activated receptor γ (PPARγ) transactivation was also evaluated. Results: After adjusting for comorbidities and confounding factors, the case group (N = 14,089) had a higher risk for T2DM than the control group (N = 14,089) [adjusted hazards ratio (aHR), 1.27]. Patients with epilepsy not treated with AEDs exhibited a significantly higher risk of T2DM (aHR, 1.70) than non-epileptic controls. In those treated with AEDs, the risk of developing T2DM was significantly lower than in those not treated (all aHR ≤ 0.60). However, an increase in the defined daily dose of phenytoin (PHE), but not of valproate (VPA), increased the risk of T2DM development (aHR, 2.28). Functional enrichment analysis of differentially expressed genes showed that compared to PHE, VPA induced multiple beneficial genes associated with glucose homeostasis. Among AEDs, VPA induced the specific transactivation of PPARγ. Discussion: Our study shows epilepsy increases the risk of T2DM development, however, some AEDs such as VPA might yield a protective effect against it. Thus, screening blood glucose levels in patients with epilepsy is required to explore the specific role and impact of AEDs in the development of T2DM. Future in depth research on the possibility to repurpose VPA for the treatment of T2DM, will offer valuable insight regarding the relationship between epilepsy and T2DM.

Increasing N active sites by in-situ growing conformal C3N4 layer in hierarchical porous carbon-based networks for fast Li+ transfer and polysulfide anchoring in lithium-sulfur batteries.

Various challenges remain to be overcome in lithium-sulfur (Li-S) batteries, including the volume expansion and low conductivity of sulfur, the shuttle effect of lithium polysulfides and the sluggish redox reaction in the cell. Herein, we propose a multilayered conductive framework by the in situ growth of a conformal graphene-like C3N4 (GCN) coating on porous CNT@NC networks with carbon nanotubes (CNTs) as the core and N-doped carbon (NC) as the crosslinking shell. The abundant N in the GCN coating increased the surface N concentration of the framework from 14.38% to 18.77%, which enriched the active sites in the frameworks for the adsorption and catalysis conversion of LiPSs and Li2S with a low energy barrier. Furthermore, the scalable frameworks can provide an 85% porosity for a sufficient reaction interface and accommodate the volume expansion of sulfur. The synergistic effect between GCN and the highly conductive hierarchical structure can accelerate the transport of Li+ and electrons as well as the diffusion of electrolyte. Benefitting from the above advantages, the Al-free CNT@NC@GCN electrode exhibits a reversible capacity of 647.6 mAh g-1 after cycling for 450 cycles at 1C with a low capacity fading rate of 0.09% per cycle. This proposed facile strategy creates inspiring insights into the design of novel cathode materials for Li-S batteries.

A Population-Based Cohort Study on the Association of Hyperthyroidism With the Risk of Hyperlipidemia and the Effects of Anti-thyroid Drugs on Hepatic Gene Expression.

There have been no reports on the association of hyperthyroidism with hyperlipidemia in patients undergoing treatment especially in Asia. To determine the association between hyperthyroidism and the risk of hyperlipidemia in patients, we conducted a retrospective cohort study using Longitudinal Health Insurance Database (LHID) from Taiwan, R.O.C. We also evaluate the influence of 6-n-propyl-2-thiouracil (PTU) and methimazole (MMI) on hepatic genes to explain changes in blood lipid levels in a hepatic cell line model. The cohort study involved 13,667 patients with hyperthyroidism, and the corresponding comparison cohort had four times as many patients. Using Kaplan-Meier analysis method, the results showed that, compared to patients without hyperthyroidism, the overall incidence of hyperlipidemia was significantly higher in the hyperthyroidism patients (18.7 vs. 11.8 cases/1,000 persons-years; adjusted HR 1.5; 95% CI, 1.41-1.59). With only PTU or MMI/carbimazole (CBM) treatment, patients with hyperthyroidism showed a 1.78-fold (95% CI, 1.50-2.11) and 1.43-fold (95% CI, 1.27-1.60) higher risk of hyperlipidemia than those without hyperthyroidism, respectively. Additionally, hyperthyroidism patients that received surgery only or surgery with I131 therapy tended to have a higher risk of hyperlipidemia. Although PTU and MMI treatment decreased the expression levels of genes responsible for circulating remnant lipoproteins, they increased the levels of lipogenic gene expression in hepatic cells. Thus, treatment of hyperthyroid patients with anti-thyroid drugs (ATDs), I131, or surgery is likely to induce hyperlipidemia. ATDs downregulate the expression of genes involved in lipoproteins clearance; increases lipogenic genes expression, which may partly contribute to abnormal blood lipid profiles.

Sesamin, a Naturally Occurring Lignan, Inhibits Ligand-Induced Lipogenesis through Interaction with Liver X Receptor Alpha (LXRα) and Pregnane X Receptor (PXR).

Liver X receptor (LXR) is a nuclear receptor that regulates various biological processes, including de novo lipogenesis, cholesterol metabolism, and inflammation. Selective inhibition of LXR may aid the treatment of nonalcoholic fatty liver disease (NAFLD). Sesamin is a naturally occurring lignan in many dietary plants and has a wide range of beneficial effects on metabolism. The mechanism underlying sesamin action especially on the regulation of LXR remains elusive. Reporter assays, mRNA and protein expression, and in silico modeling were used to identify sesamin as an antagonist of LXRα. Sesamin was applied to the hepatic HepaRG and intestinal LS174T cells and showed that it markedly ameliorated lipid accumulation in the HepaRG cells, by reducing LXRα transactivation, inhibiting the expression of downstream target genes. This effect was associated with the stimulation of AMP-activated protein kinase (AMPK) signaling pathway, followed by decreased T0901317-LXRα-induced expression of SREBP-1c and its downstream target genes. Mechanistically, sesamin reduced the recruitment of SRC-1 but enhanced that of SMILE to the SREBP-1c promoter region under T0901317 treatment. It regulated the transcriptional control exerted by LXRα by influencing its interaction with coregulators and thus decreased mRNA and protein levels of genes downstream of LXRα and reduced lipid accumulation in hepatic cells. Additionally, sesamin reduced valproate- and rifampin-induced LXRα and pregnane X receptor (PXR) transactivation. This was associated with reduced expression of target genes and decreased lipid accumulation. Thus, sesamin is an antagonist of LXRα and PXR and suggests that it may alleviate drug-induced lipogenesis via the suppression of LXRα and PXR signaling.

Ursolic Acid, a Novel Liver X Receptor α (LXRα) Antagonist Inhibiting Ligand-Induced Nonalcoholic Fatty Liver and Drug-Induced Lipogenesis.

Nonalcoholic fatty liver disease (NAFLD) is a very common liver disease, and its incidence has significantly increased worldwide. The liver X receptor α (LXRα) is a multifunctional nuclear receptor that controls lipid homeostasis. Inhibition of LXRα transactivation may be beneficial for NAFLD and hyperlipidemia treatment. Ursolic acid (UA) is a plant triterpenoid with many beneficial effects; however, the mechanism of its action on LXRα remains elusive. We evaluated the effects of UA on T0901317 (T090)-induced LXRα activation and steatosis. UA significantly decreased the LXR response element and sterol regulatory element-binding protein-1c ( SREBP-1c) gene promoter activities, mRNA, protein expression of LXRα target genes, and hepatic cellular lipid content in a T090-induced mouse model. A molecular docking study indicated that UA bound competitively with T090 at the LXRα ligand binding domain. UA stimulated AMP-activated protein kinase (AMPK) phosphorylation in hepatic cells and increased corepressor, small heterodimer partner-interacting leucine zipper protein (SMILE) but decreased coactivator, steroid receptor coactivator-1 (SRC-1) recruitment to the SREBP-1c promoter region. In contrast, UA induced SRC-1 binding but decreased SMILE binding to reverse cholesterol transport-related gene promoters in intestinal cells, increasing lipid excretion from intestinal cells. Additionally, UA reduced valproate-induced LXRα mediated and rifampin-induced pregnane X receptor mediated lipogenesis, offering potential treatments for drug-induced hepatic steatosis. Thus, UA displays liver specificity and can be selectively repressed while RCT stimulation by LXRα is preserved and enhanced. This is a novel therapeutic option to treat NAFLD and may be helpful in developing LXR agonists to prevent atherosclerosis.

Oleanolic Acid Inhibits Liver X Receptor Alpha and Pregnane X Receptor to Attenuate Ligand-Induced Lipogenesis.

Liver X receptor α (LXRα) controls important biological and pathophysiological processes such as lipid homeostasis. Inhibiting LXRα transactivation may beneficial in the treatment of nonalcoholic fatty liver disease (NAFLD), which is one of the main causes of liver diseases and hyperlipidemia. Oleanolic acid (OA) is a naturally occurring triterpenoid found in many plants. It has several beneficial effects on biological pathways; however, the mechanisms underlying its effects on LXRα are unclear. Therefore, we evaluated the effects of OA on T0901317-induced LXRα activation and explored whether OA can attenuate hepatic lipogenesis. The results showed that OA significantly decreased the promoter activities of LXR response element and sterol regulatory element binding protein-1c (SREBP-1c). It also decreased the mRNA and protein expression of LXRα target genes. These resulted in reduced hepatocellular lipid content. Our results also revealed that the overall binding pose of OA is similar to the X-ray pose of T0901317. Furthermore, OA stimulated AMP-activated protein kinase phosphorylation in hepatic cells. Additionally, it increased small heterodimer partner-interacting leucine zipper protein (SMILE) but decreased steroid receptor coactivator-1 (SRC-1) recruitment to the SREBP-1c promoter region. OA also enhanced LXRα-mediated induction of reverse cholesterol transport (RCT)-related gene, ATP-binding cassette transporter (ABC) A1, and ABCG1 expression in intestinal cells. It was found that OA increased the binding of SRC-1 but decreased SMILE recruitment to the ABCG1 gene promoter region. Furthermore, it reduced valproate- and rifampin-induced LXRα- and pregnane X receptor-mediated lipogenesis, respectively, which indicates its potential benefit in treating drug-induced hepatic steatosis. The results also show that OA is liver-specific and can be selectively repressed of lipogenesis. Moreover, it preserves and enhances LXRα-induced RCT stimulation. The results show that OA may be a promising treatment for NAFLD. Additionally, it can be used in the development of LXRα agonists to prevent atherosclerosis.

On the origin of shape fluctuations of the cell nucleus.

The nuclear envelope (NE) presents a physical boundary between the cytoplasm and the nucleoplasm, sandwiched in between two highly active systems inside the cell: cytoskeleton and chromatin. NE defines the shape and size of the cell nucleus, which increases during the cell cycle, accommodating for chromosome decondensation followed by genome duplication. In this work, we study nuclear shape fluctuations at short time scales of seconds in human cells. Using spinning disk confocal microscopy, we observe fast fluctuations of the NE, visualized by fluorescently labeled lamin A, and of the chromatin globule surface (CGS) underneath the NE, visualized by fluorescently labeled histone H2B. Our findings reveal that fluctuation amplitudes of both CGS and NE monotonously decrease during the cell cycle, serving as a reliable cell cycle stage indicator. Remarkably, we find that, while CGS and NE typically fluctuate in phase, they do exhibit localized regions of out-of-phase motion, which lead to separation of NE and CGS. To explore the mechanism behind these shape fluctuations, we use biochemical perturbations. We find the shape fluctuations of CGS and NE to be both thermally and actively driven, the latter caused by forces from chromatin and cytoskeleton. Such undulations might affect gene regulation as well as contribute to the anomalously high rates of nuclear transport by, e.g., stirring of molecules next to NE, or increasing flux of molecules through the nuclear pores.

Influence of bovine lactoferrin on the growth of selected probiotic bacteria under aerobic conditions.

Bovine lactoferrin (bLf) is a natural glycoprotein, and it shows broad-spectrum antimicrobial activity. However, reports on the influences of bLf on probiotic bacteria have been mixed. We examined the effects of apo-bLf (between 0.25 and 128 mg/mL) on both aerobic and anaerobic cultures of probiotics. We found that bLf had similar effects on the growth of probiotics under aerobic or anaerobic conditions, and that it actively and significantly (at concentrations of >0.25 mg/mL) retarded the growth rate of Bifidobacterium bifidum (ATCC 29521), B. longum (ATCC 15707), B. lactis (BCRC 17394), B. infantis (ATCC 15697), Lactobacillus reuteri (ATCC 23272), L. rhamnosus (ATCC 53103), and L. coryniformis (ATCC 25602) in a dose-dependent manner. Otherwise, minimal inhibitory concentrations (MICs) were 128 or >128 mg/mL against B. bifidum, B. longum, B. lactis, L. reuteri, and L. rhamnosus (ATCC 53103). With regard to MICs, bLf showed at least four-fold lower inhibitory effect on probiotics than on pathogens. Intriguingly, bLf (>0.25 mg/mL) significantly enhanced the growth of Rhamnosus (ATCC 7469) and L. acidophilus (BCRC 14065) by approximately 40-200 %, during their late periods of growth. Supernatants produced from aerobic but not anaerobic cultures of L. acidophilus reduced the growth of Escherichia coli by about 20 %. Thus, bLf displayed a dose-dependent inhibitory effect on the growth of most probiotic strains under either aerobic or anaerobic conditions. An antibacterial supernatant prepared from the aerobic cultures may have significant practical use.