The LXR nuclear receptors are intracellular sensors of cholesterol excess and are activated by various oxysterols. LXRs have been shown to regulate multiple genes of lipid metabolism, including ABCA1 ...(formerly known asABC1). ABCA1 is a lipid pump that effluxes cholesterol and phospholipid out of cells. ABCA1 deficiency causes extremely low high density lipoprotein (HDL) levels, demonstrating the importance of ABCA1 in the formation of HDL. The present work shows that the acetyl-podocarpic dimer (APD) is a potent, selective agonist for both LXRα (NR1H3) and LXRβ (NR1H2). In transient transactivation assays, APD was ∼1000-fold more potent, and yielded ∼6-fold greater maximal stimulation, than the widely used LXR agonist 22-(R)-hydroxycholesterol. APD induced ABCA1mRNA levels, and increased efflux of both cholesterol and phospholipid, from multiple cell types. Gas chromatography-mass spectrometry measurements demonstrated that APD stimulated efflux of endogenous cholesterol, eliminating any possible artifacts of cholesterol labeling. For both mRNA induction and stimulation of cholesterol efflux, APD was found to be more effective than was cholesterol loading. Taken together, these data show that APD is a more effective LXR agonist than endogenous oxysterols. LXR agonists may therefore be useful for the prevention and treatment of atherosclerosis, especially in the context of low HDL levels.
Here, we report the total and differential cross sections for $J/\psi$ photoproduction with the large acceptance GlueX spectrometer for photon beam energies from the threshold at 8.2 GeV up to 11.44 ...GeV and over the full kinematic range of momentum transfer squared, $t$. Such coverage facilitates the extrapolation of the differential cross sections to the forward ($t = 0$) point beyond the physical region. The forward cross section is used by many theoretical models and plays an important role in understanding $J/\psi$ photoproduction and its relation to the $J/\psi$-proton interaction. These measurements of $J/\psi$ photoproduction near threshold are also crucial inputs to theoretical models that are used to study important aspects of the gluon structure of the proton, such as the gluon Generalized Parton Distribution (GPD) of the proton, the mass radius of the proton, and the trace anomaly contribution to the proton mass. We observe possible structures in the total cross section energy dependence and find evidence for contributions beyond gluon exchange in the differential cross section close to threshold, both of which are consistent with contributions from open-charm intermediate states.
Tumor necrosis factor (TNF) related apoptosis inducing ligand (TRAIL) can induce the apoptosis of tumor cells, but leaving its effect on malignant lymphoma largely insignificant, as these tumors may ...develop drug resistance. Chlorambucil (CLB) had definitive treatment efficacy on low-malignant non-Hodgkin lymphoma (NHL), but with unclear efficacy on highly malignant Burkitt lymphoma. A study has been shown that CLB could enhance the sensitivity of chronic lymphatic leukemia cells against TRAIL. This work aims to investigate the effect of CLB combined with TRAIL on in vitro proliferation and apoptosis of Raji cells.
TRAIL (0, 20, 40 and 80 ng/ml) or CLB (0, 2.5 5 and 10 μM) was used to treat Raji cells. Cell counting kit 8 (CCK-8) was used to test proliferation whilst flow cytometry was employed to examine the apoptosis. The effect of TRAIL or CLB treatment on expression of death receptor 4 (DR4) and DR5 was tested. Combined treatment (80 ng/ml TRAIL and 10 μM CLB) was adopted for observing Raji cell proliferation and apoptosis.
Single treatment of TRAIL or CLB has weak effects of inducing apoptosis or inhibiting proliferation. TRAIL concentration has no significant effects on DR4/DR5 expression in Raji cells, whilst CLB treatment elevated those gene expressions. Combined treatment of TRAIL and CLB had more potent effects regarding cell proliferation inhibition or apoptosis induction compared to single treatment.
TRAIL or CLB has weak inhibitor effects on Raji cell proliferation or induction of apoptosis. Via up-regulating DR4 and DR5 expression, CLB has synergistic effects with TRAIL to potentiate the apoptotic induction and proliferation inhibition role.
The EAST tokamak was built to carry out long pulse plasma discharges up to 1000s. To facilitate this, an active divertor pumping (ADP) system was installed under the lower outer (LO) divertor target ...plate (DTP) for plasma density control and impurity exhaust. The ADP system was used in the first EAST divertor physics campaign, and achieved very promising results on neutral gas particle exhaust and recycling control. The system can improve divertor screening for neutrals and reduce the ratio H/(H+D), and appears to be effective at controlling the main chamber hydrogenic recycling. The influence of ADP on lower inner (LI) and LO DTP is observed. Furthermore, we attempt to find an optimized strike point to mitigate DTP heat load during ADP operation. This article reports on these interesting results, in particular, for the lower single null (LSN) plasma configuration.
Antibacterial protein hydrogels are receiving increasing attention in the aspect of bacteria-infected-wound healing. However, bacterial drug resistance and biofilm infections lead to hard healing of ...wounds, thus the construction of biological agents that can overcome these issues is essential. Here, a simple and universal method to construct antibiotic-free protein hydrogel with excellent biocompatibility and superior antibacterial activity against drug-resistant bacteria and biofilms was developed. The green industrial microbicide tetrakis (hydroxymethyl) phosphonium sulfate (THPS) as cross-linking agent can be quickly cross-linked with model protein bovine serum albumin (BSA) to form antibacterial hydrogel through simple mixing without any other initiators, subsequently promoting drug-resistance bacteria-infected wound healing. This simple gelatinization strategy allows at least ten different proteins to form hydrogels (e.g. BSA, human serum albumin (HSA), egg albumin, chymotrypsin, trypsin, lysozyme, transferrin, myohemoglobin, hemoglobin, and phycocyanin) under the same conditions, showing prominent universality. Furthermore, drug-resistance bacteria and biofilm could be efficiently destroyed by the representative BSA hydrogel (B-Hydrogel) with antibacterial activity, overcoming biofilm-induced bacterial resistance. The in vivo study demonstrated that the B-Hydrogel as wound dressing can promote reepithelization to accelerate the healing of methicillin-resistant staphylococcus aureus (MRSA)-infected skin wounds without inducing significant side-effect. This readily accessible antibiotic-free protein-based hydrogel not only opens an avenue to provide a facile, feasible and general gelation strategy, but also exhibits promising application in hospital and community MRSA disinfection and treatment.
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•A simple and universal method to build antibiotic-free protein hydrogel was explored.•The obtained B-Hydrogel can eradicate drug-resistant bacteria and biofilms.•The B-Hydrogel can promote the healing of MRSA-infected skin wounds.
Relative metal–ligand complex stability is predicted by evaluating the relationships between physicochemical properties of metal ions and their experimental biotic and abiotic binding constants,
K. ...Linear regression analysis showed that the softness index (
σ
p
) and the covalent index (
χ
2
m
r) were especially useful in model construction for rainbow trout (
Oncorhynchus mykiss), fathead minnows (
Pimephales promelas) and crustaceansaquatic (
Daphnia magna) based on RMSE and
F-ratio criterion (
F
observed/
F
critical of ≥4). The absolute value of the log of the first hydrolysis constant |log
K
OH| correlated best with log
K values for barley (
R
2=0.74,
p=0.02) and earthworm (
R
2=0.82,
p=0.01). In contrast, the ionic index
Z
2/
r explained most of the variability of log
K values for the two clays kaolinite and montmorillonite, while |log
K
OH| was a better predictor of the generic NICA-Donnan parameters for HA and FA (0.67<
R
2<0.80, 0.002<
p<0.01). This implies dissimilarity of the nature of the binding sites on biotic and chemical ligands and the different binding mechanisms between metal and ligands.
Activated (phosphorylated) mitogen-activated protein kinase p38 (MAPK-p38) and interleukin-1 (IL-1) have both been implicated in the hyperphosphorylation of tau, a major component of the ...neurofibrillary tangles in Alzheimer's disease. This, together with findings showing that IL-1 activates MAPK-p38 in vitro and is markedly overexpressed in Alzheimer brain, suggest a role for IL-1-induced MAPK-p38 activation in the genesis of neurofibrillary pathology in Alzheimer's disease. We found frequent colocalization of hyperphosphorylated tau protein (AT8 antibody) and activated MAPK-p38 in neurons and in dystrophic neurites in Alzheimer brain, and frequent association of these structures with activated microglia overexpressing IL-1. Tissue levels of IL-1 mRNA as well as of both phosphorylated and non-phosphorylated isoforms of tau were elevated in these brains. Significant correlations were found between the numbers of AT8- and MAPK-p38-immunoreactive neurons, and between the numbers of activated microglia overexpressing IL-1 and the numbers of both AT8- and MAPK-p38-immunoreactive neurons. Furthermore, rats bearing IL-1-impregnated pellets showed a six- to seven-fold increase in the levels of MAPK-p38 mRNA, compared with rats with vehicle-only pellets (
P<0.0001). These results suggest that microglial activation and IL-1 overexpression are part of a feedback cascade in which MAPK-p38 overexpression and activation leads to tau hyperphosphorylation and neurofibrillary pathology in Alzheimer's disease.
Penetration of antiretroviral drugs into anatomical HIV-1 reservoirs such as the male genital tract and the central nervous system is important. Data on indinavir (IDV) concentrations in seminal ...plasma are lacking and IDV concentrations in cerebrospinal fluid are at best borderline.
Thirteen patients were treated with zidovudine (or stavudine), lamivudine, abacavir, nevirapine and IDV (1000 mg three times daily). When nevirapine led to low IDV concentrations, IDV was changed into the combination IDV/ritonavir (RTV) 800/100 mg twice daily to improve the pharmacokinetic profile of IDV.
A serum pharmacokinetic profile, a semen sample and a cerebrospinal fluid sample were collected at weeks 8, 24, 48 and 72.
Addition of RTV increased the median IDV trough concentration in serum from 65 to 336 ng/ml (P = 0.005). Median IDV concentration in seminal plasma increased from 141 to 1634 ng/ml (P = 0.002) (n = 9) and in cerebrospinal fluid from 39 (n = 12) to 104 (n = 7) ng/ml (P < 0.001). In six patients with samples collected both before and after the addition of RTV, the IDV concentration in seminal plasma increased 8.2 times 95% confidence interval (CI) 5.2-11.6, and in cerebrospinal fluid 2.4 times (95% CI 1.8-3.9).
IDV penetrates well into the male genital tract. The addition of low-dose RTV not only increases IDV concentrations in serum but also in seminal plasma and cerebrospinal fluid, thereby probably improving the potency of the regimen in these anatomical HIV reservoirs. Higher serum trough levels alone can not sufficiently explain the observed increases in seminal plasma and cerebrospinal fluid concentrations. Inhibition of P-glycoprotein-mediated transport by RTV might be an additional mechanism.
Correction to: Molecular Psychiatry advance online publication, 17 February 2015; doi:10.1038/mp.2014.182 Following publication of the above article, the authors noticed that the seventeenth author’s ...name was listed incorrectly. The author’s name should have been listed as AP IJzerman. The publisherregrets the error.
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