Injectable, degradable, and mechanically adaptive hydrogel induced by L-serine and allyl-functionalized chitosan with platelet-rich plasma for treating intrauterine adhesions.

The integration of barrier materials with pharmacological therapy is a promising strategy to treat intrauterine adhesions (IUAs). However, most of these materials are surgically implanted in a fixed shape and incongruence with the natural mechanical properties of the uterus, causing poor adaptability and significant discomfort to the patients. Herein, an injectable, biodegradable, and mechanically adaptive hydrogel loaded with platelet-rich plasma (PRP) is created by L­serine and allyl functionalized chitosan (ACS) to achieve efficient, comfortable, and minimally invasive treatment of IUAs. L­serine induces fast gelation and mechanical reinforcement of the hydrogel, while ACS introduces, imparting a good injectability and complaint yet strong feature to the hydrogel. This design enables the hydrogel to adapt to the complex geometry and match the mechanical properties of the uterine. Moreover, the hydrogel exhibits proper degradability, sustained growth factors (GFs) of PRP release ability, and good biocompatibility. Consequently, the hydrogel shows promising therapeutic efficacy by reducing collagen fiber deposition and facilitating endometrium cell proliferation, thereby restoring the fertility function of the uterus in an IUAs model of rats. Accordingly, the combination of L­serine and ACS-induced hydrogel with such advantages holds great potential for treating IUAs. STATEMENT OF SIGNIFICANCE: This research introduces a breakthrough in the treatment of intrauterine adhesions (IUAs) with an injectable, biodegradable and mechanically adaptive hydrogel using L­serine and allyl functionalized chitosan (ACS). Unlike traditional surgical treatments, this hydrogel uniquely conforms to the uterus's geometry and mechanical properties, offering a minimally invasive, comfortable, and more effective solution. The hydrogel is designed to release growth factors from platelet-rich plasma (PRP) sustainably, promoting tissue regeneration by enhancing collagen fiber deposition and endometrium cell proliferation. Demonstrated efficacy in a rat model of IUAs indicates its great potential to significantly improve fertility restoration treatments. This advancement represents a significant leap in reproductive medicine, promising to transform IUAs treatment with its innovative approach to achieving efficient, comfortable, and minimally invasive therapy.

Nur77 induced by HIF-1α mediates vascular remodeling in hypoxic pulmonary hypertension.

Nur77 is a member of the NR4A subfamily of orphan nuclear receptors that is expressed and has a function within the immune system. This study aimed to investigate the role of Nur77 in hypoxic pulmonary hypertension. SPF male SD rats were exposed in hypobaric chamber simulating 5000 m high altitude for 0, 3, 7, 14, 21 or 28 days. Rat pulmonary artery smooth muscle cells (RPASMCs) were cultured under normoxic conditions (5% CO2-95% ambient air) or hypoxic conditions (5% O2 for 6 h, 12 h, 24 h, 48 h). Hypoxic rats developed pulmonary arterial remodeling and right ventricular hypertrophy with significantly increased pulmonary arterial pressure. The levels of Nur77, HIF-1α and PNCA were upregulated in pulmonary arterial smooth muscle from hypoxic rats. Silencing of either Nur77 or HIF-1α attenuated hypoxia-induced proliferation. Silencing of HIF-1α down-regulated Nur77 protein level, but Nur77 silence did not reduce HIF-1α. Nur77 was not con-immunoprecipitated with HIF-1α. This study demonstrated that Nur77 acted as a downstream regulator of HIF-1α under hypoxia, and plays a critical role in the hypoxia-induced pulmonary vascular remodeling, which is regulated by HIF-1α. Nur77 maybe a novel target of HPH therapy.

Highly confined epsilon-near-zero and surface phonon polaritons in SrTiO3 membranes.

Recent theoretical studies have suggested that transition metal perovskite oxide membranes can enable surface phonon polaritons in the infrared range with low loss and much stronger subwavelength confinement than bulk crystals. Such modes, however, have not been experimentally observed so far. Here, using a combination of far-field Fourier-transform infrared (FTIR) spectroscopy and near-field synchrotron infrared nanospectroscopy (SINS) imaging, we study the phonon polaritons in a 100 nm thick freestanding crystalline membrane of SrTiO3 transferred on metallic and dielectric substrates. We observe a symmetric-antisymmetric mode splitting giving rise to epsilon-near-zero and Berreman modes as well as highly confined (by a factor of 10) propagating phonon polaritons, both of which result from the deep-subwavelength thickness of the membranes. Theoretical modeling based on the analytical finite-dipole model and numerical finite-difference methods fully corroborate the experimental results. Our work reveals the potential of oxide membranes as a promising platform for infrared photonics and polaritonics.

Quantitative evaluation of the efficacy and safety profiles of two types of targeted inhibitors combined with endocrine therapy in ER+/HER2- metastatic breast cancer.

PURPOSE: The aim of this study was to quantitatively compare the efficacy and safety of CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors for ER+/HER2- metastatic breast cancer. METHODS: A parametric survival function was used to analyze the time course of overall survival (OS) and progression-free survival (PFS). The objective response rate (ORR) and the incidence of any grade and grade 3-4 adverse events were summarized using the random-effects model of a single-arm meta-analysis. RESULTS: This study included 44 arms from 48 publications, with a total sample size of 7881 patients. Our study revealed that CDK4/6 inhibitors had a median OS of 40.7 months, a median PFS of 14.8 months, and an ORR of 40%, whereas PI3K/AKT/mTOR inhibitors had a median OS of 29.8 months, a median PFS of 8.3 months, and an ORR of 20%. Additionally, this study also found that the proportion of patients with visceral metastases and specific endocrine therapy used in combination significantly impact OS and PFS. In terms of adverse events, CDK4/6 inhibitors exhibited a relatively high incidence of hematological adverse events. CONCLUSION: Our study provides solid quantitative evidence for the first-line recommendation of CDK4/6 inhibitors combined with endocrine therapy for ER+/HER2- metastatic breast cancer in clinical guidelines.

Injectable, stable, and biodegradable hydrogel with platelet-rich plasma induced by l-serine and sodium alginate for effective treatment of intrauterine adhesions.

The combination of pharmacological and physical barrier therapy is a highly promising strategy for treating intrauterine adhesions (IUAs), but there lacks a suitable scaffold that integrates good injectability, proper mechanical stability and degradability, excellent biocompatibility, and non-toxic, non-rejection therapeutic agents. To address this, a novel injectable, degradable hydrogel composed of poly(ethylene glycol) diacrylate (PEGDA), sodium alginate (SA), and l-serine, and loaded with platelet-rich plasma (PRP) (referred to as PSL-PRP) is developed for treating IUAs. l-Serine induces rapid gelation within 1 min and enhances the mechanical properties of the hydrogel, while degradable SA provides the hydrogel with strength, toughness, and appropriate degradation capabilities. As a result, the hydrogel exhibits an excellent scaffold for sustained release of growth factors in PRP and serves as an effective physical barrier. In vivo testing using a rat model of IUAs demonstrates that in situ injection of the PSL-PRP hydrogel significantly reduces fibrosis and promotes endometrial regeneration, ultimately leading to fertility restoration. The combined advantages make the PSL-PRP hydrogel very promising in IUAs therapy and in preventing adhesions in other internal tissue wounds.

The Validation and Modification of the Caprini Risk Assessment Model for Evaluating Venous Thromboembolism after Joint Arthroplasty.

BACKGROUND: The Caprini risk assessment model (RAM) is the most commonly used tool for evaluating venous thromboembolism (VTE) risk, a high score for arthroplasty can result in patients being classified as high risk for VTE. Therefore, its value in post-arthroplasty has been subject to debate. METHODS: Retrospective data were collected from patients who underwent arthroplasty between August 2015 and December 2021. The study cohort included 3,807 patients, all of whom underwent a thorough evaluation using Caprini RAM and vascular Doppler ultrasonography preoperatively. RESULTS: A total of 432 individuals (11.35%) developed VTE, while 3,375 did not. Furthermore, 32 (0.84%) presented with symptomatic VTE, while 400 (10.51%) were detected as asymptomatic. Additionally, 368 (9.67%) VTE events occurred during the hospitalization period, and 64 (1.68%) cases were detected during postdischarge follow-up. Statistical analysis revealed significant differences between the VTE and non-VTE groups in terms of ages, blood loss, D-dimer, body mass index >25, visible varicose veins, swollen legs, smoking, history of blood clots, broken hip, percent of female, hypertension, and knee joint arthroplasty (p < 0.05). The Caprini score was found to be significantly higher in the VTE group (10.10 ± 2.23) compared with the non-VTE group (9.35 ± 2.14) (p < 0.001). Furthermore, there was a significant correlation between the incidence of VTE and the Caprini score (r = 0.775, p = 0.003). Patients with a score ≥9 are at a high-risk threshold for postoperative VTE. CONCLUSION: The Caprini RAM shows a significant correlation with the occurrence of VTE. A higher score indicates a greater likelihood of developing VTE. The score ≥9 is at particularly high risk of developing VTE.

Crucial involvement of fast waves and Delta band in the brain network attributes of infantile epileptic spasms syndrome.

Objective: This study aims to describe the characteristics of the brain network attributes in children diagnosed with Infantile Epileptic Spasms Syndrome (IESS) and to determine the influence exerted by adrenocorticotrophic hormone (ACTH) or methylprednisolone (MP) on network attributes. Methods: In this retrospective cohort study, we recruited 19 infants diagnosed with IESS and 10 healthy subjects as the control from the Pediatric Neurology Department at the Third Affiliated Hospital of Zhengzhou University between October 2019 and December 2020. The first thirty-minute processed electroencephalograms (EEGs) were clipped and filtered into EEG frequency bands (2 s each). A comparative assessment was conducted between the IESS group and the controls as well as the pre- and post-treatment in the IESS group. Mutual information values for each EEG channel were collected and compared including characteristic path length (CPL), node degree (ND), clustering coefficient (CC), and betweenness centrality (BC), based on graph theory. Results: Comparing the control group, in the IESS group, there was an increase in CPL of the Delta band, and a decrease in ND and CC of the Delta band during the waking period, contrary to those during the sleeping period (P < 0.05), a decreased in CPL of the fast waves and an increase in ND and CC (P < 0.05) in the sleep-wake cycle, and a decrease in ND and CC of the Theta band in the waking phase. Post-treatment compared with the pre-treatment, during the waking ictal phase, there was a noted decrease in CPL in the Delta band and fast waves, while an increase was observed in ND and CC (P < 0.05). Conclusions: The Delta band and fast waves are crucial components of the network attributes in IESS. Significance: This investigation provides a precise characterization of the brain network in children afflicted with IESS, and lays the groundwork for predicting the prognosis using graph theory.

[Impact of Endometriosis on the Therapeutic Effect of Hysteroscopic Fallopian Tube Catheterization Combined With Laparoscopy in Infertile Patients With Proximal Tubal Obstruction].

Objective: To investigate the impact of endometriosis on the therapeutic effect of hysteroscopic fallopian tube catheterization combined with laparoscopy in infertile patients with proximal tubal obstruction. Methods: We conducted a retrospective analysis of patients who underwent hysteroscopic fallopian tube catheterization combined with laparoscopy for infertility caused by proximal fallopian tube obstruction between January 19, 2016 and March 20, 2020 at the Department of Reproductive Endocrinology, West China Second Hospital, Sichuan University. During the operation, hydrotubation was performed to verify whether there was proximal tubal obstruction. Then, the patients were categorized into an endometriosis group and a non-endometriosis group according to whether their proximal tubal obstruction was combined with endometriosis. The baseline data were balanced by propensity score matching and the rate of successful surgical unblocking of proximal tubal obstruction in infertile patients by hysteroscopic fallopian tube catheterization combined with laparoscopy was calculated. Treating cases lost to follow-up in both groups as non-pregnant cases according to the principle of intention-to-treat analysis, we followed up the pregnancy outcomes after surgery. The primary indicators included overall successful surgical unblocking rate, clinical pregnancy rate, and spontaneous pregnancy rate, while the secondary indicators included live birth rate, miscarriage rate, ectopic pregnancy rate, and the mean time to spontaneous pregnancy after surgery. The primary indicators included overall successful surgical unblocking rate, clinical pregnancy rate, and spontaneous conception rate, while the secondary indicators included live birth rate, miscarriage rate, ectopic pregnancy rate, and the mean time to spontaneous pregnancy after surgery. Results: After propensity score matching, 113 cases were included in each of the two groups, with the overall successful surgical unblocking rate being 72.6%. The successful surgical unblocking rate of patients in the endometriosis group was higher than that of the non-endometriosis group, with the difference being statistically significant (78.8% vs. 66.4%, P<0.05). A total of 38 patients were lost after follow-up matching. Postoperative follow-up was performed to date and, through intention-to-treat analysis, the spontaneous conception rate was found to be higher in the endometriosis group than that in the non-endometriosis group (44.2% vs. 30.1%, P<0.05), while the mean time to spontaneous pregnancy after surgery was shorter in the endometriosis group than that in the non-endometriosis group (46 months vs. 53 months, P<0.05). There was no significant difference in clinical pregnancy rate, live birth rate, miscarriage rate, and ectopic pregnancy rate between the endometriosis group and the non-endometriosis group ( P>0.05). Conclusion: When infertility caused by proximal tubal obstruction is combined with endometriosis, performing hysteroscopic fallopian tube catheterization combined with laparoscopy contributes to the improvement of reproduction outcomes.

Neutral ceramidase-active site inhibitor chemotypes and binding modes.

Ceramides impact a diverse array of biological functions and have been implicated in disease pathogenesis. The enzyme neutral ceramidase (nCDase) is a zinc-containing hydrolase and mediates the metabolism of ceramide to sphingosine (Sph), both in cells and in the intestinal lumen. nCDase inhibitors based on substrate mimetics, for example C6-urea ceramide, have limited potency, aqueous solubility, and micelle-free fraction. To identify non-ceramide mimetic nCDase inhibitors, hit compounds from an HTS campaign were evaluated in biochemical, cell based and in silico modeling approaches. A majority of small molecule nCDase inhibitors contained pharmacophores capable of zinc interaction but retained specificity for nCDase over zinc-containing acid and alkaline ceramidases, as well as matrix metalloprotease-3 and histone deacetylase-1. nCDase inhibitors were refined by SAR, were shown to be substrate competitive and were active in cellular assays. nCDase inhibitor compounds were modeled by in silico DOCK screening and by molecular simulation. Modeling data supports zinc interaction and a similar compound binding pose with ceramide. nCDase inhibitors were identified with notably improved activity and solubility in comparison with the reference lipid-mimetic C6-urea ceramide.

The unusual effect of paraffin wax on the thermal decomposition of cyclotetramethylenetetranitramine.

The practical application of paraffin wax (PW) in cyclotetramethylenetetranitramine (HMX)-based polymer-bonded explosive (PBX) requires an understanding of its effect on the thermal decomposition of HMX. In this work, by comparing the thermal decomposition of HMX and a HMX/PW mixture, combined with crystal morphology analysis, molecular dynamics simulation, kinetic analysis, and gas product analysis, the unusual phenomenon and mechanism of the PW effect on the thermal decomposition of HMX were evaluated. During the initial decomposition, PW infiltrates the crystal surface of HMX, reduces the energy barrier for chemical bond dissociation, and induces the decomposition of molecules on HMX crystals, resulting in a lower initial decomposition temperature. PW consumes the active gas produced by HMX with further thermal decomposition and inhibits the dramatic increase of the HMX thermal decomposition rate. In decomposition kinetics, this effect is manifested as PW inhibits transition from an n-order reaction to an autocatalytic reaction.

Inhibitory effect of Porphyromonas gingivalis-derived phosphoethanolamine dihydroceramide on acid ceramidase expression in oral squamous cells.

The maintenance of diminished acid ceramidase (ASAH1) gene expression leading to the accumulation of antiproliferative intracellular ceramides in oral squamous cell carcinoma (OSCC) has emerged as a prospective oral cancer therapeutic regimen. Our published study demonstrated that the key periodontal pathogen Porphyromonas gingivalis downregulates the expression patterns of ASAH1 mRNA in normal epithelial cells in vitro. Therefore, P. gingivalis may also beneficially diminish the expression of ASAH1 in OSCC. Because a uniquely structured P. gingivalis-derived phosphoethanolamine dihydroceramide (PEDHC) inhibits the proliferation of normal human fibroblasts, this study aimed to test the effect of PEDHC on the survival of human oral squamous OECM-1 cells in vitro. We demonstrated that the P. gingivalis dihydroceramide-null (ΔPG1780) strain upregulates the expression of ASAH1 mRNA and promotes aggressive proliferation and migration of OECM-1 cells compared to the parent P. gingivalis-W83 strain. In addition, the intracellular concentration of ceramides was dramatically elevated in OECM-1 cells exposed to PEDHC in vitro. Furthermore, PEDHC inhibited expression patterns of ASAH1 mRNA as well as some genes associated with degradation of the basement membranes and extracellular matrix, for example, MMP-2, ADAM-17 and IL-6, in OECM-1 cells. Altogether, these data indicated that PEDHC produced by P. gingivalis inhibits acid ceramidase expression, promotes intracellular ceramide accumulation and suppresses the survival and migration of OSCC cells in vitro. Further studies are needed to determine molecular mechanisms of PEDHC-mediated inhibitory effect(s) on OSCC using in vivo models of oral cancer.

Physiologically-based pharmacokinetic pharmacodynamic parent-metabolite model of edoxaban to predict drug-drug-disease interactions: M4 contribution.

This study aimed to develop a physiologically-based pharmacokinetic pharmacodynamic (PBPK/PD) parent-metabolite model of edoxaban, an oral anticoagulant with a narrow therapeutic index, and to predict pharmacokinetic (PK)/PD profiles and potential drug-drug-disease interactions (DDDIs) in patients with renal impairment. A whole-body PBPK model with a linear additive PD model of edoxaban and its active metabolite M4 was developed and validated in SimCYP for healthy adults with or without interacting drugs. The model was extrapolated to situations including renal impairment and drug-drug interactions (DDIs). Observed PK and PD data in adults were compared with predicted data. The effect of several model parameters on the PK/PD response of edoxaban and M4 was investigated in sensitivity analysis. The PBPK/PD model successfully predicted PK profiles of edoxaban and M4 as well as anticoagulation PD responses with or without the influence of interacting drugs. For patients with renal impairment, the PBPK model successfully predicted the fold change in each impairment group. Inhibitory DDI and renal impairment had a synergistic effect on the increased exposure of edoxaban and M4, and their downstream anticoagulation PD effect. Sensitivity analysis and DDDI simulation show that renal clearance, intestinal P-glycoprotein activity, and hepatic OATP1B1 activity are the major factors affecting edoxaban-M4 PK profiles and PD responses. Anticoagulation effect induced by M4 cannot be ignored when OATP1B1 is inhibited or downregulated. Our study provides a reasonable approach to adjust the dose of edoxaban in several complicated scenarios especially when M4 cannot be ignored due to decreased OATP1B1 activity.

Emergent chirality in a polar meron to skyrmion phase transition.

Polar skyrmions are predicted to emerge from the interplay of elastic, electrostatic and gradient energies, in contrast to the key role of the anti-symmetric Dzyalozhinskii-Moriya interaction in magnetic skyrmions. Here, we explore the reversible transition from a skyrmion state (topological charge of -1) to a two-dimensional, tetratic lattice of merons (with topological charge of -1/2) upon varying the temperature and elastic boundary conditions in [(PbTiO3)16/(SrTiO3)16]8 membranes. This topological phase transition is accompanied by a change in chirality, from zero-net chirality (in meronic phase) to net-handedness (in skyrmionic phase). We show how scanning electron diffraction provides a robust measure of the local polarization simultaneously with the strain state at sub-nm resolution, while also directly mapping the chirality of each skyrmion. Using this, we demonstrate strain as a crucial order parameter to drive isotropic-to-anisotropic structural transitions of chiral polar skyrmions to non-chiral merons, validated with X-ray reciprocal space mapping and phase-field simulations.

Size-Induced Ferroelectricity in Antiferroelectric Oxide Membranes.

Despite extensive studies on size effects in ferroelectrics, how structures and properties evolve in antiferroelectrics with reduced dimensions still remains elusive. Given the enormous potential of utilizing antiferroelectrics for high-energy-density storage applications, understanding their size effects will provide key information for optimizing device performances at small scales. Here, the fundamental intrinsic size dependence of antiferroelectricity in lead-free NaNbO3 membranes is investigated. Via a wide range of experimental and theoretical approaches, an intriguing antiferroelectric-to-ferroelectric transition upon reducing membrane thickness is probed. This size effect leads to a ferroelectric single-phase below 40 nm, as well as a mixed-phase state with ferroelectric and antiferroelectric orders coexisting above this critical thickness. Furthermore, it is shown that the antiferroelectric and ferroelectric orders are electrically switchable. First-principle calculations further reveal that the observed transition is driven by the structural distortion arising from the membrane surface. This work provides direct experimental evidence for intrinsic size-driven scaling in antiferroelectrics and demonstrates enormous potential of utilizing size effects to drive emergent properties in environmentally benign lead-free oxides with the membrane platform.

Corrigendum: Different frequency bands in various regions of the brain play different roles in the onset and wake-sleep stages of infantile spasms.

[This corrects the article DOI: 10.3389/fped.2022.878099.].

A mechanically robust and stable estradiol-loaded PHEMA-based hydrogel barrier for intrauterine adhesion treatment.

Estrogen combined with physical barrier therapy may be a prospective method to repair a damaged endometrium and prevent postsurgical re-adhesion in the treatment of intrauterine adhesions (IUAs), but there lacks a suitable scaffold with good biocompatibility, appropriate mechanical properties, and drug-releasing kinetics. Herein, a mechanically robust and stable barrier based on the poly(hydroxyethyl methacrylate) (PHEMA) hydrogel combined with estradiol-loaded mesoporous silica is designed. The network is formed by covalent bonds and noncovalent coordination bonds, which endow the hydrogel with superior mechanical properties to most reported PHEMA-based hydrogels. Meanwhile, the covalent bonds impart excellent stability to the hydrogel, which maintains its structure and mechanical properties in a simulated uterine fluid for 30 days. The excellent mechanical properties and stability are comparable to those of a typical barrier material intrauterine device (IUD), enabling the hydrogel to be retained in the uterus and removed intact like an IUD. In vitro and in vivo experiments show that the hydrogel possesses good biocompatibility similar to pure PHEMA hydrogels. In addition, the hydrogel releases estradiol continuously and stably, and exhibits a good therapeutic effect in promoting the proliferation of endometrial cells and inhibiting the progression of fibrosis. Therefore, the combinational advantages make the present hydrogel very promising in IUA treatment.

Alkaline ceramidase catalyzes the hydrolysis of ceramides via a catalytic mechanism shared by Zn2+-dependent amidases.

Human alkaline ceramidase 3 (ACER3) is one of three alkaline ceramidases (ACERs) that catalyze the conversion of ceramide to sphingosine. ACERs are members of the CREST superfamily of integral-membrane hydrolases. All CREST members conserve a set of three Histidine, one Aspartate, and one Serine residue. Although the structure of ACER3 was recently reported, catalytic roles for these residues have not been biochemically tested. Here, we use ACER3 as a prototype enzyme to gain insight into this unique class of enzymes. Recombinant ACER3 was expressed in yeast mutant cells that lack endogenous ceramidase activity, and microsomes were used for biochemical characterization. Six-point mutants of the conserved CREST motif were developed that form a Zn-binding active site based on a recent crystal structure of human ACER3. Five point mutants completely lost their activity, with the exception of S77A, which showed a 600-fold decrease compared with the wild-type enzyme. The activity of S77C mutant was pH sensitive, with neutral pH partially recovering ACER3 activity. This suggested a role for S77 in stabilizing the oxyanion of the transition state. Together, these data indicate that ACER3 is a Zn2+-dependent amidase that catalyzes hydrolysis of ceramides via a similar mechanism to other soluble Zn-based amidases. Consistent with this notion, ACER3 was specifically inhibited by trichostatin A, a strong zinc chelator.

Different Frequency Bands in Various Regions of the Brain Play Different Roles in the Onset and Wake-Sleep Stages of Infantile Spasms.

Objective: The study aimed to identify the signatures of brain networks using electroencephalogram (EEG) in patients with infantile spasms (IS). Methods: Scalp EEGs of subjects with IS were prospectively collected in the first year of life (n = 8; age range 4-8 months; 3 males, 5 females). Ten minutes of ictal and interictal EEGs were clipped and filtered into different EEG frequency bands. The values of each pair of EEG channels were directly compared between ictal with interictal onsets and the sleep-wake phase to calculate IS brain network attributes: characteristic path length (CPL), node degree (ND), clustering coefficient (CC), and betweenness centrality (BC). Results: CPL, ND, and CC of the fast waves decreased while BC increased. CPL and BC of the slow waves decreased, while ND and CC increased during the IS ictal onset (P < 0.05). CPL of the alpha decreased, and BC increased during the waking time (P < 0.05). Conclusion: The transmission capability of the fast waves, the local connectivity, and the defense capability of the slow waves during the IS ictal onset were enhanced. The alpha band played the most important role in both the global and local networks during the waking time. These may represent the brain network signatures of IS.

Manifold Roles of Ceramide Metabolism in Non-Alcoholic Fatty Liver Disease and Liver Cancer.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder manifested in hepatic fat accumulation (hepatic steatosis) in the absence of heavy alcohol use. NAFLD consists of four major stages ranging from simple steatosis or non-alcoholic fatty liver (NAFL) to more advanced stages, non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. NFLAD may further advance to hepatocellular carcinoma (HCC). Primary causes of NAFLD are obesity and obesity-associated insulin resistance (IR). As a result of the obesity pandemic, NAFLD has become one of the most common liver disorders worldwide and both the incidence and mortality rate of HCC that develops from NAFLD are increasing steadily. As treatment options are not available for advanced NAFLD, a better understanding of the molecular mechanisms for NAFLD development and progression is urgently needed. Emerging evidence suggests that dysregulation of the metabolism of sphingolipids contributes to development and progression of NAFLD and NAFLD-associated HCC. The present chapter summarizes roles of bioactive sphingolipids, ceramides, sphingosine, and sphingosine-1-phosphate (S1P) and their metabolizing enzymes in NAFLD and HCC.