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Isostatic pressure effects on the elastic and electronic properties of non-doped and Mn 4+ -doped K 2 SiF 6 (KSF) have been investigated by first-principles calculations within density functional theory (DFT). Bulk modulus was obtained by the Murnaghan's equation of states (EOS) using the relationship between volume and pressures at pressures between 0 and 40 GPa, and elastic constants were calculated by the stress-strain relationship giving small distortions at each pressure point. The other elastic parameters such as shear modulus, sound velocity and Debye temperature, which can be obtained from the elastic constants, were also estimated. The influence of external isostatic pressure on the electronic properties, such as crystal field strength 10 Dq and emission energy of 2 E → 4 A 2 transition ( E em ), of KSF:Mn 4+ was also studied. The results suggest that 10 Dq and E em linearly increase and decrease, respectively, with increasing pressure.

Growing interest is being dedicated to smart soft matters because of their potential in controlling bioactives upon exposure to an appropriate stimulus. Herein, structuring of edible liquid oil into oleogels and emulgels as smart thermo-triggered soft vehicles for controllable release of diverse nutrients was developed. Edible liquid oil was trapped inside the crystal network structure of phytosterols and monoglycerides resulting in bicomponent solidlike oleogels. Subsequently, both water-in-oleogel (W/O) emulgels and glycerol-in-oleogel (G/O) emulgels were further fabricated by spatial distribution of the stabilizing interfacial crystals around dispersed droplets as well as the network crystals in the continuous phase. Rheological measurements showed that the gel strength of the oleogel-based emulgels depends on the fraction of the aqueous phase and is greater than that of corresponding oleogels due to a filler effect of dispersed aqueous droplets within the crystal network, offering an additional strategy to tune the structure and rheology. Comparatively, introducing glycerol endowed a higher gel strength for the oleogel-based emulgels than water, particularly at increased filler loads. In addition, these soft matters exhibited interesting thermoresponsive nature, which exhibit the flexibility for programmed release of coencapsulated bioactive components upon exposure to an appropriate thermal triggered switchable. The resulted smart thermo-triggered soft matters have emerging opportunities for application in functional active ingredient delivery by on-demand strategies.

Phytosterols oleogel-based flavor emulsions were successfully fabricated for the first time using natural tea saponin as emulsifier and one-pot ultrasonic technique. The effects of ultrasonic time and power, surfactant concentration, and type of flavor oils (e.g., orange, lemon and peppermint) on the emulsion droplet size were investigated. Submicron emulsions with a dispersed phase made by flavor oil (20 wt%) + phytosterol (4 wt%) were stabilized with 3 wt% saponin were obtained by applying an ultrasonic time of 5 min and ultrasonic power of 280 W. The natural tea saponin emulsions exhibited a superior stability and encapsulation efficiency of phytosterol, compared to traditional emulsifiers. Flavor oil-phytosterol enriched powders were prepared by spray-drying and characterized by SEM, XRD and repose angle. The natural saponin encapsulated oil + phytosterol powders had excellent fluidity, redispersion behavior and low phytosterol crystallinity. It was demonstrated that ultrasound is an effective and suitable technique for fabricating fortified flavor emulsions and microcapsules, which may be used for developing functional lipids-based applications in the food, beverage and cosmetic industries., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We propose and demonstrate a circular-side octagonal microcavity (COM) semiconductor laser with a spatially distributed current injection for manipulating the lasing modes. There are two types of high-quality-factor whispering-gallery (WG) modes with distinct field patterns in a COM: the four-bounced quadrilateral modes and the eight-bounced octagonal modes. By designing two separated p-electrodes, the COM laser is divided into two regions that are pumped independently to select specific modes for lasing. The two types of WG modes lase simultaneously when the two regions are injected with equivalent currents. Degeneracy removal of the quadrilateral modes is observed in both simulation and experiment when the two regions are injected with inequivalent currents. The quadrilateral modes are suppressed when one of the two regions is un-injected or biased with a negative current, and single-octagonal-mode lasing is realized. The results show that the lasing modes can be efficiently manipulated with the spatially distributed current injection considering the distinct field patterns of different WG modes in the microcavities, which can promote the practical application of the microcavity lasers.

In this commentary, we describe the triple threat that parents in recovery face during the COVID-19 pandemic due to the loss of social support. We explore how the absence of human connection during the pandemic can be detrimental to parents in recovery as well as the parent-child relationship. We conclude by proposing strategies to offer critical support for families as this period of social isolation extends and the effects become increasingly apparent., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 American Society of Addiction Medicine.)

Rare-earth vanadates, niobates, and tantalates have shown self-activated and Bi 3+ -activated emissions. Their intrinsic emission has been attributed to self-trapped excitons (STEs), but the detailed information concerning the geometric and electronic structures of the excited states has remained unknown. Regarding the Bi 3+ dopants in these hosts, the luminescence has been attributed to two different mechanisms, i.e ., Bi 3+ ↔ (V/Nb/Ta) 5+ metal-to-metal charge transfer and interconfigurational ( 3 P 0,1 → 1 S 0 ) transition. Here, first-principles calculations using hybrid functionals are employed to resolve these issues. The STEs are shown to be composed of an electron localized on an individual vanadium, niobium, or tantalum ion and a hole localized on a single nearest-neighbor oxygen ion that is not shared by covalent complexes, and the bond length of the (V/Nb/Ta)-O bond with oxygen accommodating the hole is significantly elongated. The Bi 3+ -related emission is identified as the recombination of an exciton with a hole and an electron localized correspondingly at Bi 3+ and (V/Nb/Ta) 5+ ions, while the excitation is dominated by the 6s → 6p transition of Bi 3+ . Furthermore, Bi 3+ has a hole trap level in all of the hosts considered with the trap levels in the vacuum-referred binding energy diagram being nearly flat but has an electron trap level only in rare-earth tantalates. Furthermore, the long-wavelength emission observed in niobates and tantalates is interpreted based on our calculations to be excitons bound to intrinsic defects. The insights gained in this work deepen our understanding of the STEs and form the basis for interpreting similar luminescence phenomena in other ternary closed-shell d 0 transition-metal oxides. The clarification of Bi 3+ -related transitions and the analyses with the vacuum-referred binding energy diagram may find applications for the design and optimization of Bi 3+ -activated phosphors.

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). Here we report the temporal and spatial evolution of various functional neurons during demyelination in a cuprizone (CPZ)-induced mouse model. CPZ did not significantly induce the damage of axons and neurons after 2 wk of feeding. However, after 4-6 wk of CPZ feeding, axons and neurons were markedly reduced in the cortex, posterior thalamic nuclear group, and hippocampus. Simultaneously, the expression of TPH + tryptophan neurons and VGLUT1 + glutamate neurons was obviously decreased, and the expression of TH + dopaminergic neurons was slightly decreased in the tail part of the substantia nigra striatum, whereas the number of ChAT + cholinergic neurons was not significantly different in the brain. In the second week of feeding, CPZ caused a higher level of glutamate secretion and upregulated the expression of EAAT2 on astrocytes, which should contribute to rapid and sufficient glutamate uptake and removal. This finding reveals that astrocyte-driven glutamate reuptake protected the CNS from excitotoxicity by rapid reuptake of glutamate in 4-6 wk of CPZ feeding. At this stage, although NG2 + oligodendroglia progenitor cells (OPCs) were enhanced in the demyelination foci, the myelin sheath was still absent. In conclusion, we comprehensively observed the temporal and spatial evolution of various functional neurons. Our results will assist with understanding how demyelination affects neurons during CPZ-induced demyelination and provide novel information for neuroprotection in myelin regeneration and demyelinating diseases. NEW & NOTEWORTHY Our results further indicate temporal and spatial evolution of various functional neurons during the demyelination in a cuprizone (CPZ)-induced mouse model, which mainly occur 4-6 wk after CPZ feeding. At the same time, the axonal compartment is damaged and, consequently, neuronal death occurs, while glutamate neurons are lost obviously. The astrocyte-mediated glutamate reuptake could protect the neurons from the excitatory effects of glutamate.

Background: Fasudil, a Rho kinase inhibitor, exerts therapeutic effects in a mouse model of Alzheimer's disease (AD), a chronic neurodegenerative disease with progressive loss of memory. However, the mechanisms remain unclear. In addition, the gut microbiota and its metabolites have been implicated in AD. Methods: We examined the effect of fasudil on learning and memory using the Morris water-maze (MWM) test in APPswe/PSEN1dE9 transgenic (APP/PS1) mice (8 months old) treated (i.p.) with fasudil (25 mg/kg/day; ADF) or saline (ADNS) and in age- and gender-matched wild-type (WT) mice. Fecal metagenomics and metabolites were performed to identify novel biomarkers of AD and elucidate the mechanisms of fasudil induced beneficial effects in AD mice. Results: The MWM test showed significant improvement of spatial memory in APP/PS1 mice treated with fasudil as compared to ADNS. The metagenomic analysis revealed the abundance of the dominant phyla in all the three groups, including Bacteroidetes (23.7-44%) and Firmicutes (6.4-26.6%), and the increased relative abundance ratio of Firmicutes / Bacteroidetes in ADNS (59.1%) compared to WT (31.7%). In contrast, the Firmicutes / Bacteroidetes ratio was decreased to the WT level in ADF (32.8%). Lefse analysis of metagenomics identified s_Prevotella_sp_CAG873 as an ADF potential biomarker, while s_Helicobacter_typhlonius and s_Helicobacter_sp_MIT_03-1616 as ADNS potential biomarkers. Metabolite analysis revealed the increment of various metabolites, including glutamate, hypoxanthine, thymine, hexanoyl-CoA, and leukotriene, which were relative to ADNS or ADF microbiota potential biomarkers and mainly involved in the metabolism of nucleotide, lipids and sugars, and the inflammatory pathway. Conclusions: Memory deficit in APP/PS1 mice was correlated with the gut microbiome and metabolite status. Fasudil reversed the abnormal gut microbiota and subsequently regulated the related metabolisms to normal in the AD mice. It is believed that fasudil can be a novel strategy for the treatment of AD via remodeling of the gut microbiota and metabolites. The novel results also provide valuable references for the use of gut microbiota and metabolites as diagnostic biomarkers and/or therapeutic targets in clinical studies of AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yan, Gao, Fang, Zhang, Kumar, Yan, Song, Li, Zhang, Sun, Wang, Zhao, Skaggs, Zhang and Ma.)

In this paper, the density functional theory accompanied with linear combination of atomic orbitals (LCAO) method is applied to study the atomic and electronic structure of the Ti 3+ and Ti 2+ ions substituted for the host Al atom in orthorhombic Pbnm bulk YAlO 3 crystals. The disordered crystalline structure of YAlO 3 was modelled in a large supercell containing 160 atoms, allowing simulation of a substitutional dopant with a concentration of about 3%. In the case of the Ti 2+ -doped YAlO 3 , compensated F -center (oxygen vacancy with two trapped electrons) is inserted close to the Ti to make the unit cell neutral. Changes of the interatomic distances and angles between the chemical bonds in the defect-containing lattices were analyzed and quantified. The positions of various defect levels in the host band gap were determined.

Astrocytes play multifaceted and vital roles in maintaining neurophysiological function of the central nervous system by regulating homeostasis, increasing synaptic plasticity, and sustaining neuroprotective effects. Astrocytes become activated as a result of inflammatory responses during the progression of pathological changes associated with neurodegenerative disorders. Reactive astrocytes (neurotoxic A1 and neuroprotective A2) are triggered during disease progression and pathogenesis due to neuroinflammation and ischemia. However, only a limited body of literature describes morphological and functional changes of astrocytes during the progression of neurodegenerative diseases. The present review investigated the detrimental and beneficial roles of astrocytes in neurodegenerative diseases reported in recent studies, as these cells have promising therapeutic potential and offer new approaches for treatment of neurodegenerative diseases., Competing Interests: None

Eu 3+ (1 mol %)-doped Ca 2 LnSbO 6 (replacing Ln 3+ ; Ln = Lu, Y, Gd, and La) and Ca 2 EuSbO 6 were synthesized and structurally characterized by means of X-ray powder diffraction. The Eu 3+ luminescence spectroscopy of the doped samples and of Ca 2 EuSbO 6 has been carefully investigated upon collection of the excitation/emission spectra and luminescence decay curves of the main excited states. Surprisingly, apart from the dominant red emission from 5 D 0 , all the doped samples show an uncommon blue and green emission contribution from 5 D J ( J = 1, 2, and 3). This is made possible thanks to both multiphonon and cross-relaxation mechanism inefficiencies. However, the emission from 5 D 3 is more efficient and the decay kinetics of the 5 D J ( J = 0, 1, and 2) levels is slower in the case of Y- and Lu-based doped samples. This evidence can find a possible explanation in the crystal chemistry of this family of double perovskites: our structural investigation suggests an uneven distribution of the Eu 3+ dopant ions in Ca 2 YSbO 6 and Ca 2 LuSbO 6 hosts of the general A 2 BB'O 6 formula. The luminescent center is mainly located in the A crystal site, and on average, the Eu-Eu distances are longer than in the case of the Gd- and La-based matrix. These longer distances can further reduce the efficiency of the cross-relaxation mechanism and, consequently, the radiative transitions are more efficient. The slower depopulation of Eu 3+ 5 D 2 and 5 D 1 levels in Ca 2 YSbO 6 and Ca 2 LuSbO 6 hosts is reflected in the longer rise observed in the 5 D 1 and 5 D 0 decay curves, respectively. Finally, in Ca 2 EuSbO 6 , the high Eu 3+ concentration gives rise to an efficient cross-relaxation within the subset of the lanthanide ions so that no emission from 5 D J ( J = 1, 2, and 3) is possible and the 5 D 0 decay kinetics is faster than for the doped samples.

All-optical switch and multiple logic gates have been demonstrated using a hybrid-cavity semiconductor laser composed of a square microcavity and a Fabry-Perot cavity experimentally. In this paper, two-section tri-mode rate equations with optical injection terms are proposed and applied to study all-optical logic gates of NOT, NOR, and NAND operations utilizing the hybrid-cavity laser. Steady-state and dynamical characteristics of all-optical multiple logic gates are simulated, taking into account the influence of mode frequency detuning, gain suppression coefficients, mode Q factor, injection energy, and biasing current. All-optical logic NOT, NOR, and NAND gates up to 20, 15, and 20 Gbit/s are obtained numerically with dynamic extinction ratios of over 20, 20, and 10 dB, respectively, which are potential response speeds of the all-optical logic gates based on the hybrid-cavity semiconductor lasers.

Multiple sclerosis (MS) is mainly associated with the neuroinflammation and demyelination in the central nervous system (CNS), in which the failure of remyelination results in persistent neurological dysfunction. Fasudil, a typical Rho kinase inhibitor, has been exhibited beneficial effects on several models of neurodegenerative disorders. In this study, we showed that Fasudil promoted the uptake of myelin debris by microglia via cell experiments and through a cuprizone (CPZ)-induced demyelinating model. In vitro, microglia with phagocytic debris exhibited enhanced expression of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), and the conditioned medium promoted the maturation of oligodendrocyte precursor cells (OPCs). Meanwhile, Fasudil upregulated TREM2/DAP12 pathway, which positively regulated the phagocytosis of myelin debris by microglia. Similarly, in vivo, Fasudil intervention enhanced the clearance of myelin debris, upregulated the expression of BDNF and GDNF on microglia, and promoted the formation of Oligo2+/PDGFRα+ OPCs and the maturation of MBP + oligodendrocytes in the brain. Our results showed that Fasudil targeted the phagocytic function of microglia, effectively clearing myelin debris produced during pathological process possibly by upregulating TREM2/DAP12 pathway, accompanied by increased expression of BDNF and GDNF. However, the precise mechanism underlying the effects of Fasudil in promoting phagocytic effects and neurotrophic factors remains to be elucidated., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In this Letter, we design and realize a hybrid-cavity laser with single- or dual-mode lasing states and study the nonlinear states of the laser under external optical feedback (EOF). The laser at a dual-mode state easily and directly enters the chaotic state without periodic oscillation states and display chaos for a much wider range of the EOF magnitude than the laser at a single-mode state. A flat chaotic signal is obtained for the laser at a dual-mode lasing state under a weak EOF benefitting from the low-frequency energy enhancement caused by mode competition between the dual modes.

Bladder cancer (BLCA) is one of the most common urological cancer with increasing cases and deaths every year. In the present study, we aim to construct an immune-related prognostic lncRNA signature (IRPLS) in bladder cancer (BLCA) patients and explore its immunogenomic implications in pan-cancers. First, the immune-related differentially expressed lncRNAs (IRDELs) were identified by 'limma' R package and the score of IRPLS in every patient were evaluated by Cox regression. The dysregulation of IRDELs expression between cancer and para-cancer normal tissues was validated through RT-qPCR. Then, we further explore the biological functions of a novel lncRNA from IRPLS, RP11-89 in BLCA using CCK8 assay, Transwell assay and Apoptosis analysis, which indicated that RP11-89 was able to promote cell proliferation and invasive capacity while inhibits cell apoptosis in BLCA. In addition, we performed bioinformatic methods and RIP to investigate and validate the RP11-89/miR-27a-3p/PPARγ pathway in order to explore the mechanism. Next, CIBERSORT and ESTIMATE algorithm were used to evaluate abundance of tumour-infiltrating immune cells and scores of tumour environment elements in BLCA with different level of IRPLS risk scores. Finally, multiple bioinformatic methods were performed to show us the immune landscape of these four lncRNAs for pan-cancers. In conclusion, this study first constructed an immune-related prognostic lncRNA signature, which consists of RP11-89, PSORS1C3, LINC02672 and MIR100HG and might shed lights on novel targets for individualized immunotherapy for BLCA patients., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Phytosterols are partly removed during oil refining, and the magnitude of phytosterols loss largely depends on the refining conditions applied and the molecular conformation. The aim of this research was to study the effect of deodorization conditions and molecular unsaturation on the esterification of phytosterols during deodorization of corn oil., Results: In the chemical model, free fatty acids (FFAs) were the major provider of acyl groups during the formation of phytosteryl fatty acid esters (PEs) under deodorization conditions. Among the main parameters of the deodorization, temperature played a role in the formation of PEs with a time-dependent manner. In comparison, saturated palmitic acid had a higher capability of esterifying free phytosterols (FPs) to PEs than unsaturated oleic acid and linoleic acid. Moreover, the influence of FFA unsaturation on the degradation of FPs depended on temperature. Besides, the formation of stigmasteryl ester had a competitive advantage over that of sitosteryl ester by quantum chemistry simulation., Conclusion: For laboratory-scale deodorization of corn oil, saturated fatty acids and deodorization process with steam as stripping gas could obviously esterify FPs to PEs. FPs were abundantly enriched in distillate during the deodorization process with nitrogen as stripping gas, whereas FPs and PEs were distilled simultaneously during the deodorization process with steam. © 2020 Society of Chemical Industry., (© 2020 Society of Chemical Industry.)

Background: With the restructuring of primary care into patient-centered medical homes (PCMH), researchers have described role transformations that accompany the formation of core primary care teamlets (eg, primary care provider, registered nurse care manager, licensed practical nurse, medical support assistant). However, few studies offer insight into how primary care teamlets, once established, integrate additional extended team members, and the factors that influence the quality of their integration., Methods: We examine the process of integrating Clinical Pharmacy Specialists (CPS) into primary care teams in the Veterans Health Administration (VHA). We conducted semi-structured interviews with CPS (n = 6) and clinical team members (n = 16) and performed a thematic analysis of interview transcripts., Results: We characterize 2 ways CPS are integrated into primary care teamlets: in consultative roles and collaborative roles. CPS may be limited to consultative roles by team members' misconceptions about their competencies (ie, if CPS are perceived to handle only medication-related issues like refills) and by primary care providers' opinions about distributing responsibilities for patient care. Over time, teams may correct misconceptions and integrate the CPS in a more collaborative role (ie, CPS helps manage disease states with comprehensive medication management)., Conclusions: CPS integrated into collaborative roles may have more opportunities to optimize their contributions to primary care, underscoring the importance of clarifying roles as part of adequately integrating advanced practitioners in interprofessional teams., Competing Interests: Conflict of interest: None., (© Copyright 2021 by the American Board of Family Medicine.)

Functional compositions, physicochemical properties and antioxidant activities of Amaranthus caudatus L. oils (ACO) obtained by different solvents were comparatively investigated. All the resulted ACO were enrich in 75% unsaturated fatty acid and in squalene of about 4 g/100 g. Different solvents showed varying in oil extraction, where acetone results a highest yield of 6.80 g/100 g. ACO extracted by ethanol showed a highest tocopherol (1351.26 mg/kg), polyphenols (211.28 mg/kg) and squalene (42519.13 mg/kg). However, phytosterols in ACO extracted by hexane (27571.20 mg/kg) was higher than that by acetone (19789.91 mg/kg), ethanol (22015.73 mg/kg) and petroleum ether (24763.30 mg/kg). Furthermore, antioxidant activity of ACO was also measured by DPPH, ABTS and FRAP assay. According to principal component and correlation analysis, squalene was correlated with the DPPH scavenging ability, but phytosterols and tocopherols was correlated with the ABTS and ferric reducing ability of the oils, respectively. This study provides a promising excellent source of functional oil for food industries.

Astrocytes redifferentiate into oligodendrogenesis, raising the possibility that astrocytes may be a potential target in the treatment of adult demyelinated lesion. Upon the basis of the improvement of behavior abnormality and demyelination by ethyl pyruvate (EP) treatment, we further explored whether EP affects the function of astrocytes, especially the transdifferentiation of astrocytes into oligodendrogenesis. The results showed that EP treatment increased the accumulation of astrocytes in myelin sheath and promoted the phagocytosis of myelin debris by astrocytes in vivo and in vitro. At the same time, EP treatment induced astrocytes to upregulate the expression of CNTF and BDNF in the corpus callosum and striatum as well as cultured astrocytes, accompanied by increased expression of nestin, Sox2, and β-catenin and decreased expression of Notch1 by astrocytes. As a result, EP treatment effectively promoted the generation of NG2 + and PDGF-Ra + oligodendrocyte precursor cells (OPCs) that, in part, express astrocyte marker GFAP. Further confirmation was performed by intracerebral injection of primary astrocytes labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE). As expected, NG2 + OPCs expressing CFSE and Sox2 were elevated in the corpus callosum of mice treated with EP following transplantation, revealing that EP can convert astrocytes into myelinating cells. Our results indicate the possibility that EP lead to effective myelin repair in patients suffering from myelination deficit.Graphical Abstract The diagram of EP action for promoting myelin regeneration in CPZ model. EP promoted migration and enrichment of astrocytes to demyelinated tissue and induced astrocytes to express neurotrophic CNTF and BDNF as well as translation factor nestin, Sox2, and β-catenin, which should contribute to astrocytes to differentiate of oligodendrogenesis. At the same time, EP promoted astrocytes to phagocytized myelin debris for removing the harmful substances of myelin regeneration.

Recent studies have shown that Nogo-A and the Nogo-A receptor affect β-amyloid metabolism and the downstream Rho GTP enzyme signaling pathway, which may affect the levels of β-amyloid and tau. Nogo-A may play a key role in the pathogenesis of Alzheimer's disease. However, the underlying molecular mechanisms of Fasudil treatment in Alzheimer's disease are not yet clear. Our results have found that Fasudil treatment for two months substantially ameliorated behavioral deficits, diminished β-amyloid plaque and tau protein pathology, and alleviated neuronal apoptosis in APP/PS1 transgenic mice. More importantly, two well-established markers for synaptic function, growth-associated protein 43 and synaptophysin, were upregulated after Fasudil treatment. Finally, the levels of Nogo-A, Nogo-A receptor complex NgR/p75NTR/LINGO-1 and the downstream Rho/Rho kinase signaling pathway were significantly reduced. These findings suggest that Fasudil exerts its neuroprotective function in Alzheimer's disease by inhibiting the Nogo-A/NgR1/RhoA signaling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2020 Guo et al. Published by IMR Press.)

Assembly of amphiphiles at the interface of two immiscible fluids is of great scientific and technological interest in offering efficient routes to smart vehicles for functional deliveries. Natural Quillaja saponin (QS) has gathered widespread interest within the scientific community as a result of its unique interfacial properties. Herein, spontaneously interface-driven self-assembly (SIDSA) of QS at the oil-water interface was systematically studied by morphology and spectroscopy. It was found to self-assemble into a micrometer-scale network in helical fibers by combined intermolecular π-π stacking and hydrogen bonding among saponins at the liquid-liquid interface. From SIDSA, multilayer films on the surfaces of dispersed droplets were formed and enhanced emulsion stability. Interfacial QS-based films on droplet surfaces were also shown to confine interfacial diffusion processes by serving as transport barriers. Furthermore, they can be exploited to control the release of volatiles from the dispersed liquid phase by regulating the interface film, which is shown by molecular dynamics to occur through a hydrogen-bonded mechanism. These results provide new insight into the interfacial assembly structure that can enable unique controllable release in a broad range of applications in food, beverages, pharmaceuticals, and cosmetics.

We theoretically and numerically study optical modes in regular-polygonal microcavities with non-uniform gain and loss, where high quality (Q) whispering-gallery-like modes typically appear as superscar states. High Q superscar modes can be described by the propagating plane waves in an effective rectangle formed by unfolding the periodic orbits and exhibit regular and predictable spatial field distributions and transverse-mode spectra. With non-uniform gain and loss, anti-Hermitian coupling between the transverse modes with close frequencies occurs according to the mode coupling theory, which results in novel mode properties such as modified mode spectra and field patterns, and the appearance of exceptional points. Numerical simulation results are in good agreement with the theoretical analyses, and such analyses are also suitable for other kinds of high Q microcavities with non-uniform gain and loss. These results will be highly useful for studying non-Hermitian physics in optical microcavities and advancing the practical applications of microcavity devices.

Patients with clear cell renal cell carcinoma (ccRCC) typically face aggressive disease progression when metastasis occurs. Here, we screened and identified differentially expressed genes in three microarray datasets from the Gene Expression Omnibus database. We identified 112 differentially expressed genes with functional enrichment as candidate prognostic biomarkers. Lasso Cox regression suggested 10 significant oncogenic hub genes involved in earlier recurrence and poor prognosis of ccRCC. Receiver operating characteristic curves validated the specificity and sensitivity of the Cox regression penalty used to predict prognosis. The area under the curve indexes of the integrated genes scores were 0.758 and 0.772 for overall and disease-free survival, respectively. The prognostic values of ADAMTS9, C1S, DPYSL3, H2AFX, MINA, PLOD2, RUNX1, SLC19A1, TPX2 , and TRIB3 were validated through an analysis of 10 hub genes in 380 patients with ccRCC from a real-world cohort. The expression levels of were of high prognostic value for predicting metastatic potential. These findings will likely significantly contribute to our understanding of the underlying mechanisms of ccRCC, which will enhance efforts to optimize therapy., Competing Interests: None., (AJTR Copyright © 2020.)

Retraction: Wang J, Sui R-X, Miao Q, et al. Effect of Fasudil on remyelination following cuprizone-induced demyelination. CNS Neuroscience & Therapeutics, 2020;26:76-89. https://doi.org/10.1111/cns.13154. The above article published online on May 23, 2019, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief, Professor Jun Chen, and John Wiley & Sons Ltd. The retraction has been agreed due to major overlap with a previously published article from the same group of authors., (© 2020 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Emerging evidence suggests an association of Alzheimer's Disease (AD) with microglial and astrocytic dysregulation. Recent studies have proposed that activated microglia can transform astrocytes to a neurotoxic A1 phenotype, which has been shown to be involved in the promotion of neuronal damage in several neurodegenerative diseases, including AD. In the present study, we observed an obvious microglial activation and A1-specific astrocyte response in the brain tissue of APP/PS1 Tg mice. Fasudil treatment improved the cognitive deficits of APP/PS1 Tg mice, inhibited microglial activation and promoted their transformation to an anti-inflammatory phenotype, and further shifted astrocytes from an A1 to an A2 phenotype. Our experiments suggest Fasudil exerted these functions by inhibing the expression of TLR4, MyD88, and NF-κB, which are key mediators of inflammation. Using in vitro experiments, we further validated in vivo findings. Our cell experiments indicated that Fasudil induces a shift of inflammatory microglia towards an anti-inflammatory phenotype. LPS-induced microglia-conditioned medium promotes A1 astrocytic polarization, but Fasudil treatment resulted in a direct transformation of A1 astrocytes to A2. To summarize, our results show that Fasudil inhibits the neurotoxic activation of microglia and shifts astrocytes towards a neuroprotective A2 phenotype, representing a promising candidate for AD treatment., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Inflammatory demyelination in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Besides MS disease-modifying therapy, targeting myelin sheath protection/regeneration is currently a hot spot in the treatment of MS. Here, we attempt to explore the therapeutic potential of Bilobalide (BB) for the myelin protection/regeneration in EAE model. The results showed that BB treatment effectively prevented worsening and demyelination of EAE, accompanied by the inhibition of neuroinflammation that should be closely related to T cell tolerance and M2 macrophages/microglia polarization. BB treatment substantially inhibited the infiltration of T cells and macrophages, thereby alleviating the enlargement of neuroinflammation and the apoptosis of oligodendrocytes in CNS. The accurate mechanism of BB action and the feasibility of clinical application in the prevention and treatment of demyelination remain to be further explored.

The cuprizone (CPZ)-induced demyelination is a relatively reproducible animal model and has been extremely useful for identifying the specific cellular and molecular signals that regulate oligodendrocyte survival and efficiency of oligodendrogenesis and remyelination. Here, we reported the temporal and spatial dynamics of astroglial reaction and immune response in CPZ-induced demyelinating model. CPZ did not induce significant microglia and astrocyte reaction after 2 weeks of feeding. After 4-6 weeks of CPZ feeding, microglia and astrocytes were markedly migrated and accumulated in myelin sheath. Simultaneously, the expression of tight junction protein ZO-1 was declined and the infiltration of CD4+IFNγ+ and CD4+IL-17+ T cells was increased in the brain, accompanied by increased production of IFN-γ and IL-17 in the extract of brain. However, the levels of IFN-γ and IL-17 were reduced, while IL-6 and TNF-α were elevated in the supernatant of splenocytes. At the 4th and 6th weeks of feeding, CPZ caused astrocyte activation and upregulated the expression of BDNF, CNTF, and IGF-II, providing a neurotrophic microenvironment in the brain. At this stage, NG2+ and PDGF-Rα+ oligodendroglia progenitor cells were enhanced in the corpus callosum, but the myelin sheath is still severely lost. Therefore, targeting microglia to improve the inflammatory microenvironment should contribute to the remyelination.

Zearalenone (ZEN) is one of the most widely distributed harmful mycotoxins produced by Fusarium species, especially deposited in corn oil. In this study, we systematically tracked the changes of ZEN in the refining of corn oil, and especially during neutralization process. An alkali neutralization process could remove certain amounts of ZEN that was much more than that of others refining steps. In a mimicking condition, ZEN contents decreased continuously and significantly with increasing neutralization temperature. However, when returned to neutral, recoverable ZEN decreased with increasing temperature, which confirmed more degradation of ZEN at high temperature. HPLC-Q/TOF MS and NMR evidence showed that non-reversible hydrolyzate followed decarboxylation was observed in a high-temperature alkali neutralization condition. The results may serve as the scientific basis for the elimination of zearalenone in refined vegetable oils, and provide clues to understanding the oil-safety aspects of elimination of zearalenone., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Multiple sclerosis (MS) is an inflammatory demyelinating disorder in the central nervous system (CNS), in which remyelination failure results in persistent neurologic impairment. Ginkgolide B (GB), a major terpene lactone and active component of Ginkgo biloba, has neuroprotective effects in several models of neurological diseases. Here, our results show, by using an in vivo cuprizone (CPZ)-induced demyelinating model, administration of GB improved behavior abnormalities, promoted myelin generation, and significantly regulated the dynamic balance of microglia and astrocytes by inhibiting the expression of TLR4, NF-κB and iNOS as well as IL-1β and TNF-α, and up-regulating the expression of Arg-1 and neurotrophic factors. GB treatment also induced the generation of oligodendrocyte precursor cells (OPCs). In vitro cell experiments yielded the results similar to those of the in vivo model. The dynamic balance by decreasing microglia-mediated neuroinflammation and promoting astrocyte-derived neurotrophic factors should contribute to endogenous remyelination. Despite GB treatment may represent a novel strategy for promoting myelin recovery, the precise mechanism of GB targeting microglia and astrocytes remains to be further explored., (Copyright © 2020 Yin, He, An, Miao, Sui, Wang, Yu, Xiao and Ma.)

Background: Multiple sclerosis is characterized by demyelination/remyelination, neuroinflammation, and neurodegeneration. Cuprizone (CPZ)-induced toxic demyelination is an experimental animal model commonly used to study demyelination and remyelination in the central nervous system. Fasudil is one of the most thoroughly studied Rho kinase inhibitors., Methods: Following CPZ exposure, the degree of demyelination in the brain of male C57BL/6 mice was assessed by Luxol fast blue, Black Gold II, myelin basic protein immunofluorescent staining, and Western blot. The effect of Fasudil on behavioral change was determined using elevated plus maze test and pole test. The possible mechanisms of Fasudil action were examined by immunohistochemistry, flow cytometry, ELISA, and dot blot., Results: Fasudil improved behavioral abnormalities, inhibited microglia-mediated neuroinflammation, and promoted astrocyte-derived nerve growth factor and ciliary neurotrophic factor, which should contribute to protection and regeneration of oligodendrocytes. In addition, Fasudil inhibited the production of myelin oligodendrocyte glycoprotein antibody and the infiltration of peripheral CD4 + T cells and CD68 + macrophages, which appears to be related to the integrity of the blood-brain barrier., Conclusion: These results provide evidence for the therapeutic potential of Fasudil in CPZ-induced demyelination. However, how Fasudil acts on microglia, astrocytes, and immune cells remains to be further explored., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Polygala tenuifolia Willd. is a traditional Chinese herbal medicine that is widely used in treating nervous system disorders. Triterpene saponins in P. tenuifolia (polygala saponins) have excellent biological activity. As a precursor for the synthesis of presenegin, oleanolic acid (OA) plays an important role in the biosynthesis of polygala saponins. However, the mechanism behind the biosynthesis of polygala saponins remains to be elucidated. In this study, we found that CYP716A249 (GenBank: ASB17946) oxidized the C-28 position of β-amyrin to produce OA. Using quantitative real-time PCR, we observed that CYP716A249 had the highest expression in the roots of 2-year-old P. tenuifolia, which provided a basis for the selection of samples for gene cloning. To identify the function of CYP716A249, the strain R-BE-20 was constructed by expressing β-amyrin synthase in yeast. Then, CYP716A249 was co-expressed with β-amyrin synthase to construct the strain R-BPE-20 by using the lithium acetate method. Finally, we detected β-amyrin and OA by ultra-HPLC-Q Exactive hybrid quadrupole-Orbitrap high-resolution accurate mass spectrometry and GC-MS. The results of this study provide insights into the biosynthesis pathway of polygala saponins.

Phytosterol-based oleogels have been engineered in edible oils for potential applications as sustainable replacements for petrolatum. Oleogels have emerged with a crystal network structure with oil molecules trapped inside. In addition, the viscosity of highly thixotropic oleogels could be tuned by manipulating the concentration of phytosterols and monoglycerides, and the type of surface-active small molecules and bulk vegetable oils. Furthermore, viscous soft matter could also be tunably made with 8-20% oleogelators in olive oil with favourable water vapour occlusive and wettability properties, in addition to having good texture, and outstanding thixotropic and thermal reversibility properties. These properties are quite similar to those of commercial petrolatum. This work demonstrates that the natural phytosterol-oleogels in edible oils can be a novel source of sustainable and green replacements for petrolatum., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Pelvic lymphadenectomy (PLND) is an integral part of curative surgery for high-risk non-muscle invasive and muscle-invasive bladder cancer. The therapeutic value of extended PLND is controversial., Methods: We conducted a comprehensive online search in PubMed, EMBASE, and the Cochrane Library databases for relevant literature directly comparing extended PLND (e-PLND) with non-extended PLND (ne-PLND) from database inception to June 2019. We performed the meta-analysis to evaluate the impact of PLND templates on recurrence-free survival (RFS), disease-specific survival (DSS), overall survival (OS), rates of postoperative major complications, and mortality within 90 days of surgery., Results: A total of 10 studies involving 3979 patients undergoing either e-PLND or ne-PLND were included. The results showed that e-PLND was significantly associated with better RFS (HR 0.74, 95% CI 0.62-0.90, p = 0.002) and DSS (HR 0.66, 95% CI 0.55-0.79, p < 0.001). However, no correlation was found between e-PLND template and a better OS (HR 0.93, 95% CI 0.55-1.58, p = 0.79). Postoperative major complications were similar between e-PLND group and ne-PLND group, as was mortality within 90 days of surgery., Conclusion: e-PLND template is correlated with favorable RFS and DSS outcomes for patients with bladder cancer. e-PLND did not have more postoperative major complications than did ne-PLND.

Ethyl pyruvate (EP), a simple derivative of the endogenous energy substrate pyruvate, provides strong anti-inflammatory and anti-oxidative properties. but its role in remyelination has not been explored. In this study, EP efficiently improved the behavioural performance and histological demyelination in cuprizone (CPZ)-induced mouse model. In terms of action, EP treatment enhanced microglia migration, increased the phagocytosis of myelin debris by BV2 microglia and primary microglia, induced cell proliferation and subsequent cell death. At the same time, EP induced microglia to exhibit M2 phenotype, representing decreased iNOS/TNF-α and increased Arg-1/IL-10. In addition, EP decreased microglia enrichment in myelin sheath, and declined TLR4/p-NF-kb/p65 and IL-1β and IL-6, inhibiting microglia-mediated neuroinflammation. As a result, EP treatment promoted the generation of oligodendrocyte progenitor cells (OPCs) and the differentiation from maturation to mature oligodendrocytes, which may be related to the up-regulation of Sox2. Given these data, we provided the proof-of-experiment that EP should be beneficial in multiple sclerosis or demyelinating lesions. However, further studies on the possibility to use EP as therapeutic application are warranted., (Copyright © 2019. Published by Elsevier B.V.)

Alzheimer's disease (AD), a chronic, progressive, neurodegenerative disorder, is the most common type of dementia. Beta amyloid (Aβ) peptide aggregation and phosphorylated tau protein accumulation are considered as one of the causes for AD. Our previous studies have demonstrated the neuroprotective effect of the Rho kinase inhibitor fasudil, but the mechanism remains elucidated. In the present study, we examined the effects of fasudil on Aβ 1-42 aggregation and apoptosis and identified the intracellular signaling pathways involved in these actions in primary cultures of mouse hippocampal neurons. The results showed that fasudil increased neurite outgrowth (52.84%), decreased Aβ burden (46.65%), Tau phosphorylation (96.84%), and ROCK-II expression. In addition, fasudil reversed Aβ 1-42 -induced decreased expression of Bcl-2 and increases in caspase-3, cleaved-PARP, phospho-JNK(Thr183/Tyr185), and phospho-ASK1(Ser966). Further, fasudil decreased mitochondrial membrane potential and intracellular calcium overload in the neurons treated with Aβ 1-42 . These results suggest that inhibition of Rho kinase by fasudil reverses Aβ 1-42 -induced neuronal apoptosis via the ASK1/JNK signal pathway, calcium ions, and mitochondrial membrane potential. Fasudil could be a drug of choice for treatment of Alzheimer's disease.

Recent evidence indicates that low-normal thyroid function test results within the reference ranges may be related to increased cardiometabolic risk factors. The current study aimed to evaluate the relationship between thyroid function using thyroid-stimulating hormone (TSH) and free thyroxine (FT4) and cardiometabolic risk factors and the clustering of these risk factors (metabolic syndrome) in euthyroid children and adolescents. A total of 250 euthyroid children and adolescents aged 10-18 years were included using data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2015. In the unadjusted correlation analyses, TSH was positively correlated with glucose (r = 0.172, P = 0.006), hemoglobin A1c (HbA1c) (r = 0.149, P = 0.018), insulin (r = 0.144, P = 0.023), homeostatic model assessment for insulin resistance (HOMA-IR) (r = 0.163, P = 0.010), and triglyceride (TG) (r = 0.155, P = 0.014), whereas FT4 was negatively associated with the waist circumference (WC) standard deviation score (SDS) (r = -0.134, P = 0.035), body mass index (BMI) SDS (r = -0.126, P = 0.046), insulin (r = -0.219, P < 0.001), and HOMA-IR (r = -0.211, P < 0.001). In the multiple linear regression analysis, TSH was positively associated with glucose (β = 1.179, P = 0.021), HbA1c (β = 0.044, P = 0.039), and TG (β = 8.158, P = 0.041) after adjustment for possible confounders. FT4 was negatively associated with serum fasting insulin (β = -5.884, P = 0.017) and HOMA-IR (β = -1.364, P = 0.023) in the multiple linear regression analysis. Boys and girls with elevated glucose levels had a higher adjusted mean TSH level compared to those without elevated glucose levels after controlling for confounding factors in the analysis of covariance (2.16 mIU/L vs 3.88 mIU/L, P = 0.004). Our results suggest that higher TSH and/or lower FT4 levels, even within the reference ranges, may be related to increased cardiometabolic risk factors.

Although several therapies are approved, none promote re-myelination in multiple sclerosis (MS) patients, limiting their ability for sustained recovery. Thus, treatment development in MS has the opportunity to tackle the challenges, including experimental therapies targeting neuroprotection and re-myelination. Here, we provide a novel therapeutic target for Ginkgolide K (GK) that is now becoming a very critical natural compound to treat demyelination and neurodegeneration. GK improves behavioral dysfunction and demyelination in cuprizone (CPZ) model, followed by the migration and enrichment of astrocytes in the corpus callosum. Both in vitro and in vivo experiments demonstrates that GK triggers the upregulation of Nrf2/HO-1 in astrocytes and inhibition of p-NF-kB/p65, which is associated with the outcome of anti-inflammation and anti-oxidation by suppressing the production of IL-6 and TNFα as well as nitric oxide and iNOS in astrocytes. Further findings suggest that IGF/PI3K, but not BDNF, was induced in the corpus callosum after GK treatment, revealing that Nrf2 activation inhibited caspase-3 and apoptosis in O4+ oligodendrocytes possibly through IGF/PI3K signaling molecules. Since the current immunomodulatory therapies for MS have failed to prevent patients from entering the progressive phase of the disease, thus targeting Nrf2 in astrocytes with GK would be an ideal strategy for myelin protection and regeneration., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Two types of mono-ester-functionalized pillar[5]arenes, P1 and P2, bearing different side-chain groups, were synthesized. Their host-guest complexation and self-inclusion properties were studied by 1 H NMR and 2D nuclear overhauser effect spectroscopy (NOESY) NMR measurements. The results showed that the substituents on their phenolic units have a great influence on the self-assembly of both pillar[5]arenes, although they both could form stable pseudo[1]rotaxanes at room temperature. When eight bulky 4-brombutyloxy groups were capped on the cavity, instead of methoxy groups, pseudo[1]rotaxane P1 became less stable and its locked ester group in the inner space of cavity was not as deep as P2, leading to distinctly different host-guest properties between P1 and P2 with 1,6-dibromohexane. Moreover, pillar[5]arene P1 displayed effective molecular recognition toward 1,6-dichlorohexane and 1,2-bromoethane among the guest dihalides. In addition, the self-complex models and stabilities between P1 and P2 were also studied by computational modeling and experimental calculations.

Background: Unrestrained activation of Th1 and Th17 cells is associated with the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). While inactivation of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, can reduce EAE severity by protecting myelin from demyelination, its effect on immune responses in EAE has not yet been studied., Methods: We investigated the effect of Mdivi-1, a small molecule inhibitor of Drp1, on EAE. Clinical scores, inflammation, demyelination and Drp1 activation in the central nervous system (CNS), and T cell responses in both CNS and periphery were determined., Results: Mdivi-1 effectively suppressed EAE severity by reducing demyelination and cellular infiltration in the CNS. Mdivi-1 treatment decreased the phosphorylation of Drp1 (ser616) on CD4 + T cells, reduced the numbers of Th1 and Th17 cells, and increased Foxp3 + regulatory T cells in the CNS. Moreover, Mdivi-1 treatment effectively inhibited IFN-γ + , IL-17 + , and GM-CSF + CD4 + T cells, while it induced CD4 + Foxp3 + regulatory T cells in splenocytes by flow cytometry., Conclusions: Together, our results demonstrate that Mdivi-1 has therapeutic potential in EAE by modulating the balance between Th1/Th17 and regulatory T cells.

Aim: Multiple sclerosis (MS) is a relapsing-remitting inflammatory demyelinating disease that requires long-term treatment. Although Rho kinase inhibitor Fasudil shows good therapeutic effect in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, certain side effects may limit its clinical use. This study aimed at observing the therapeutic potential of Fasudil-modified encephalitogenic mononuclear cells (MNCs) via nasal delivery in EAE and exploring possible mechanisms of action., Methods: Experimental autoimmune encephalomyelitis was induced with myelin oligodendrocyte glycoprotein 35-55 in C57BL/6 mice, and encephalitogenic MNCs were treated with Fasudil in vitro. Mice received 3 × 10 6  cells/10 μL per nasal cavity on day 3 and 11 postimmunization, respectively., Results: Fasudil-modified MNCs reduced clinical severity of EAE, improved demyelination, and decreased inflammatory cells in spinal cords. Immunohistochemical results indicated that CD4 + T cells and CD68 + macrophages were barely detected in Fasudil-MNCs group. Fasudil-modified MNCs decreased CD4 + IFN-γ + and CD4 + IL-17 + T cells, increased CD4 + IL-10 + T cells, restrained M1 markers CD16/32, CCR7, IL-12, CD8a, enhanced M2 markers CD206, CD200, CD14 in spleen. Fasudil-modified MNCs inhibited the activation of inflammatory signaling p-NF-kB/P38, accompanied by the decrease of COX-2 and the increase of Arg-1 in spinal cord, as well as the reduction of IL-17, TNF-α, IL-6 and the elevation of IL-10 in cultured supernatant of splenocytes. Fasudil-modified MNCs enhanced the levels of neurotrophic factors BDNF and NT-3 in spinal cord., Conclusion: Our results indicate that intranasal delivery of Fasudil-modified MNCs have therapeutic potential in EAE, providing a safe and effective cell therapeutic strategy to MS and/or other related disorders., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Herein, at first, graphene oxide (GO) was prepared by a modified Hummers' method, compounded with borates and then loaded onto a melamine sponge (MS) skeleton by an impregnation-reduction method to obtain a reduced graphene oxide (rGO)-borate compound (rGB)-loaded MS. Then, MS/rGB/silicone rubber (SR) composites were prepared by a vacuum infusion process. Moreover, the microstructures, electrical conductivity, and dielectric properties of the composites were investigated. The results showed that rGO presented a sheet-like structure, compounding with borates produced during the reduction of GO by sodium borohydride. rGB was co-loaded onto the MS skeleton, and a three-dimensional percolation network was successfully constructed in the MS/rGB/SR composite. In addition, there was an efficient synergistic effect between rGO and borates, which significantly improved the dielectric constant of the composites. At the rGO volume fraction of 1.89 vol%, the composite had the volume resistivity of 6.57 × 10 4 Ω cm, the ultra-high dielectric constant of 2.71 × 10 4 with the dielectric loss of 1.36 at 1 kHz, and the relatively low percolation threshold of 0.815 vol%. Furthermore, the composite exhibited high compression sensitivity at low compressive strains., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Multiple sclerosis is a T cell-mediated inflammatory, demyelinating disease of the central nervous system, accompanied by neuronal degeneration. Based on the anti-inflammatory effects of Ginkgolide K (GK), a platelet activating factor antagonist, we explored the possible application of GK in the treatment of MS. The results showed that GK effectively ameliorated the severity of experimental autoimmune encephalomyelitis. The intervention of GK inhibited the infiltration of inflammatory cells and demyelination in the spinal cord. At the same time, the expression of the inflammation-related molecules TLR4, NF-κB, and COX2 in the spinal cord was significantly lower in the GK-treated mice, indicating that GK intervention can inhibit the inflammatory microenvironment of the spinal cord in EAE mice. In mouse spleen lymphocytes, GK increased the proportion of regulatory T cells (Treg) and reduced the proportion of T helper 17 cells (Th17), modifying the imbalance between Th17/Treg cells. Additionally, GK shifted macrophage/microglia polarization from M1 to M2 cell type. Importantly, GK inhibited the expression of chemotactic molecules CCL-2, CCL-3 and CCL-5, thereby limiting the migration of inflammatory cells to the spinal cord. Our results provide the possibility that GK may be a promising naturally small molecule compound for the future treatment of MS., (Copyright © 2019. Published by Elsevier B.V.)

Multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and other neurodegenerative diseases of central nervous system (CNS) disorders are serious human health problems. Rho-kinase (ROCK) is emerging as a potentially important therapeutic target relevant to inflammatory neurodegeneration diseases. This is supported by studies showing the beneficial effects of fasudil, a ROCK inhibitor, in inflammatory neurodegeneration diseases. MS is an autoimmune disease resulting from inflammation and demyelination in the white matter of the CNS. It has been postulated that activation of Rho/ROCK causes neuropathological changes accompanied with related clinical symptoms, which are improved by treatment with ROCK inhibitors. Therefore, inhibition of abnormal activation of the Rho/ROCK signaling pathway appears to be a new mechanism for treating CNS diseases. In this review, we extensively discussed the role of ROCK inhibitors, summarized the efficacy of fasudil in the MS conventional animal model of experimental autoimmune encephalomyelitis (EAE), both in vivo and in vitro, and highlighted the mechanism involved. Overall, the findings collected in this review support the role of the ROCK signaling pathway in neurodegenerative diseases. Hence, ROCK inhibitors such as fasudil can be novel, and efficacious treatment for inflammatory neurodegenerative diseases.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system characterized by oligodendrocyte loss and progressive neurodegeneration. The cuprizone (CPZ)-induced demyelination is widely used to investigate the demyelination/remyelination. Here, we explored the therapeutic effects of Hydroxyfasudil (HF), an active metabolite of Fasudil, in CPZ model. HF improved behavioral abnormality and reduced myelin damage in the corpus callosum. Splenic atrophy and myelin oligodendrocyte glycoprotein (MOG) antibody were observed in CPZ model, which were partially restored and obviously inhibited by HF, therefore reducing pathogenic binding of MOG antibody to oligodendrocytes. HF inhibited the percentages of CD4 + IL-17 + T cells from splenocytes and infiltration of CD4 + T cells and CD68 + macrophages in the brain. HF also declined microglia-mediated neuroinflammation, and promoted the production of astrocyte-derived brain derived neurotrophic factor (BDNF) and regeneration of NG2 + oligodendrocyte precursor cells. These results provide potent evidence for the therapeutic effects of HF in CPZ-induced demyelination., (Copyright © 2019. Published by Elsevier Inc.)

Myelination, which occurs predominantly postnatally and continues throughout life, is important for proper neurologic function of the mammalian central nervous system (CNS). We have previously demonstrated that the combination therapy of fingolimod (FTY720) and transplanted neural stem cells (NSCs) had a significantly enhanced therapeutic effect on the chronic stage of experimental autoimmune encephalomyelitis, an animal model of CNS autoimmunity, compared to using either one of them alone. However, reduced disease severity may be secondary to the immunomodulatory effects of FTY720 and NSCs, while whether this therapy directly affects myelinogenesis remains unknown. To investigate this important question, we used three myelination models under minimal or non-inflammatory microenvironments. Our results showed that FTY720 drives NSCs to differentiate into oligodendrocytes and promotes myelination in an ex vivo brain slice culture model, and in the developing CNS of healthy postnatal mice in vivo . Elevated levels of neurotrophic factors, e.g., brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, were observed in the CNS of the treated infant mice. Further, FTY720 and NSCs efficiently prolonged the survival and improved sensorimotor function of shiverer mice. Together, these data demonstrate a direct effect of FTY720, beyond its known immunomodulatory capacity, in NSC differentiation and myelin development as a novel mechanism underlying its therapeutic effect in demyelinating diseases.

Objectives: To investigate the role of tumor growth velocity in defining tumor progression in metastatic renal cell carcinoma patients treated with the vascular endothelial growth factor tyrosine kinase inhibitor, sorafenib., Methods: A modified calculation for tumor growth velocity was introduced to evaluate the tumor growth velocity, before and after sorafenib withdrawal. Known prognostic factors together with tumor growth velocity before drug withdrawal and tumor growth velocity after drug withdrawal were compared using a χ 2 -test from a contingency table, and partial likelihood test from a Cox regression model for overall survival., Results: A total of 114 patients who reached progressive disease and withdrew from sorafenib were enrolled after a median follow-up period of 107.8 months. Tumor growth velocity before drug withdrawal was 7.347 ± 4.040, and tumor growth velocity after drug withdrawal was 11.647 ± 5.937 (P < 0.001). Higher tumor growth velocity before drug withdrawal was correlated with a higher risk Memorial Sloan Kettering Cancer Center score (P = 0.022), Karnofsky Performance Status <80 (P = 0.028), non-clear cell carcinoma (P = 0.037), higher tumor nucleus grade (P < 0.001) and best treatment response (P < 0.001). Patients with tumor growth velocity before drug withdrawal >5.0 had shorter overall survival (P < 0.001). On multivariate analysis, factors associated with overall survival were high/intermediate Memorial Sloan Kettering Cancer Center risk score (hazard ratio 2.119, P = 0.006), non-clear histological subtype (hazard ratio 1.900, P = 0.031), tumor growth velocity before drug withdrawal ≥5.0 (hazard ratio 2.758, P < 0.001) and progressive disease as best response (hazard ratio 2.069, P = 0.001)., Conclusions: Significantly faster tumor growth can be observed if sorafenib is discontinued in the case of disease progression. Thus, we suggest not to withdraw targeted agents until tumor growth velocity is >5.0., (© 2018 The Japanese Urological Association.)

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system characterized by recurrent and progressive demyelination, neuroinflammation and oligodendrocyte loss. The cuprizone (CPZ) model is characterized by primary and reversible demyelination, accompanied by oligodendrocyte loss and neuroinflammation. In the current study, we explored the efficiency of Bilobalide in the demyelination and remyelination. The results demonstrate that Bilobalide improved behavioral abnormality and promoted remyelination in the corpus callosum by using Luxol Fast Blue, Black Gold II and myelin basic protein (MBP) staining. We for the first time found that CPZ caused the splenic atrophy and induced the formation of myelin oligodendrocyte glycoprotein (MOG) antibody, which was attenuated by Bilobalide. Thus, Bilobalide decreased the loss of O4+ oligodendrocytes possibly through MOG antibody-dependent cell cytotoxicity. Bilobalide also prevented the infiltration of CD4 + T cells, CD68 + macrophages and B220 + B cells within the brain, and reduced the inflammatory microenvironment mediated with Iba1 + iNOS + and Iba1 + NF-kB + microglia after CPZ challenge, accompanied by the inhibition of IL-1β and IL-6 in the brain. These results identify a potent therapeutic efficiency for Bilobalide and highlight clear pleiotropic effects of the compound beyond specific autoantibody and inflammatory microenvironment in CPZ-mediated demyelination., (Copyright © 2018. Published by Elsevier B.V.)

To date, lanthanide-doped upconversion nanoparticles (UCNPs) have been widely reported as a promising CT contrast agent because they have high atomic numbers and big X-ray attenuation coefficient values. However, it is still a challenge to fabricate a simple multimodal imaging probe with improved image quality for early cancer diagnosis in clinical medicine. Herein, ultra-small, uniform and monodisperse β-NaGdF4:Yb,Er,X% Lu (X = 0, 1, 2.5, 4, 6, 7.5) UCNPs were prepared through a solvothermal method with high-level modulation of both the phase and morphology. Meanwhile, a remarkably enhanced red upconversion luminescence (UCL) in the β-NaGdF4:Yb,Er,X% Lu NPs was successfully realized via Lu3+ doping. It is found that as the content of Lu3+ increases from 0 to 7.5 mol%, the UCL intensity of the red emission first increases and then decreases, with the optimum doping content of Lu3+ ions of 2.5 mol%. The red UCL enhancement is ascribed to the change of the Yb-Er interionic distance controlling the Yb-Er energy transfer rate and the distortion of the local environment of Er3+ ions influencing the 4f-4f transition rates of Er3+ ions, which has been further confirmed by the experimental check of the crystallographic phase and by photoluminescence spectroscopy employing Eu3+ as the structural probe, respectively. More importantly, after being modified with the HS-PEG2000-NH2 ligand, the NH2-PEGylated-NaGdF4:Yb,Er,X% Lu NPs exhibited low cytotoxicity, high biocompatibility, and remarkably enhanced contrast performance in in vitro UCL and in vivo CT imaging. On the basis of our findings, the as-obtained functionalized UCNPs could be considered as a promising versatile dual-mode imaging probe for bioimaging, tumor diagnosis, and cancer therapy.

Fasudil, a Rho kinase (ROCK) inhibitor, effectively inhibits disease severity in a mouse model of Alzheimer's disease (AD). However, given its significant limitations, including a relatively narrow safety window and poor oral bioavailability, Fasudil is not suitable for long-term use. Thus, screening for ROCK inhibitor(s) that are more efficient, safer, can be used orally and suitable for long-term use in the treatment of neurodegenerative disorders is required. The main purpose of the present study is to explore whether FSD-C10, a novel ROCK inhibitor, has therapeutic potential in amyloid precursor protein/presenilin-1 transgenic (APP/PS1 Tg) mice, and to determine possible mechanisms of its action. The results showed that FSD-C10 effectively improved learning and memory impairment, accompanied by reduced expression of amyloid-β 1-42 (Aβ 1-42 ), Tau protein phosphorylation (P-tau) and β-site APP-cleaving enzyme in the hippocampus and cortex area of brain. In addition, FSD-C10 administration boosted the expression of synapse-associated proteins, such as postynaptic density protein 95, synaptophsin, α-amino 3-hydroxy-5-methyl-4-isoxa-zolep-propionate receptor and neurotrophic factors, e,g., brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Taken together, our results demonstrate that FSD-C10 has therapeutic potential in the AD mouse model, possibly through inhibiting the formation of Aβ 1-42 and P-tau, and promoting the generation of synapse-associated proteins and neurotrophic factors.