Protein kinase C-α signals P115RhoGEF phosphorylation and RhoA activation in TNF-α-induced mouse brain microvascular endothelial cell barrier dysfunction

<p>Abstract</p> <p>Background</p> <p>Tumor necrosis factor-<b>α </b>(TNF-<b>α</b>), a proinflammatory cytokine, is capable of activating the small GTPase RhoA, which in turn contributes to endothelial barrier dysfunction. However, the underlying signaling mechanisms remained undefined. Therefore, we aimed to determine the role of protein kinase C (PKC) isozymes in the mechanism of RhoA activation and in signaling TNF-<b>α</b>-induced mouse brain microvascular endothelial cell (BMEC) barrier dysfunction.</p> <p>Methods</p> <p>Bend.3 cells, an immortalized mouse brain endothelial cell line, were exposed to TNF-<b>α </b>(10 ng/mL). RhoA activity was assessed by pull down assay. PKC-<b>α </b>activity was measured using enzyme assasy. BMEC barrier function was measured by transendothelial electrical resistance (TER). p115RhoGEF phosphorylation was detected by autoradiography followed by western blotting. F-actin organization was observed by rhodamine-phalloidin staining. Both pharmacological inhibitors and knockdown approaches were employed to investigate the role of PKC and p115RhoGEF in TNF-<b>α</b>-induced RhoA activation and BMEC permeability.</p> <p>Results</p> <p>We observed that TNF-<b>α </b>induces a rapid phosphorylation of p115RhoGEF, activation of PKC and RhoA in BMECs. Inhibition of conventional PKC by Gö6976 mitigated the TNF-<b>α</b>-induced p115RhoGEF phosphorylation and RhoA activation. Subsequently, we found that these events are regulated by PKC-<b>α </b>rather than PKC-β by using shRNA. In addition, P115-shRNA and n19RhoA (dominant negative mutant of RhoA) transfections had no effect on mediating TNF-<b>α</b>-induced PKC-<b>α </b>activation. These data suggest that PKC-<b>α </b>but not PKC-β acts as an upstream regulator of p115RhoGEF phosphorylation and RhoA activation in response to TNF-<b>α</b>. Moreover, depletion of PKC-<b>α</b>, of p115RhoGEF, and inhibition of RhoA activation also prevented TNF-<b>α</b>-induced stress fiber formation and a decrease in TER.</p> <p>Conclusions</p> <p>Taken together, our results show that PKC-<b>α </b>phosphorylation of p115RhoGEF mediates TNF-<b>α </b>signaling to RhoA, and that this plays a critical role in signaling F-actin rearrangement and barrier dysfunction in BMECs.</p

Tunneling magnetoresistance sensors with different coupled free layers

Large differences of magnetic coercivity (HC), exchange coupling field (HE), and tun- neling magnetoresistance ratio (TMR) in magnetic tunnel junctions with different coupled free layers are discussed. We demonstrate that the magnetization behavior of the free layer is not only dominated by the interfacial barrier layer but also affected largely by the magnetic or non-magnetic coupled free layers. All these parameters are sensitively controlled by the magnetic nanostructure, which can be tuned also by the magnetic annealing process. The optimized sensors exhibit a large field sensitivity of up to 261%/mT in the region of the reversal synthetic ferri- magnet at the pinned layers

Association Between Visceral Adiposity Index and Insulin Resistance: A Cross-Sectional Study Based on US Adults

BackgroundVisceral obesity index (VAI) is an empirical mathematical model used to evaluate the distribution and function of fat. Some studies have shown that VAI may be associated with the development of insulin resistance. In view of the differences in insulin resistance among different ethnic groups, this study attempts to analyze the special relationship between VAI and insulin resistance in American adults.MethodsWe conducted a cross-sectional study through NHANES database. A total of 27309 patients over the age of 18 from the United States took part in the survey. It was divided into two groups: the IR-positive group and the IR-negative group. The association of VAI with IR was evaluated by logistic regression analyses mainly, including univariate analysis, multivariate regression analysis, curve fitting analysis and subgroup analysis.ResultsThe results showed that in the full-adjusted model, there is a strong positive association between VAI level and insulin resistance (OR: 1.28 (1.2~1.37), P&lt;0.001) and there is a threshold effect.ConclusionsThis study suggests that higher VAI levels are associated with insulin resistance. VAI index may be used as a predictor of insulin resistance

New insights into the BiB 3 O 6 melt structure3

The structure of borate melt has long been a fundamental unsolved problem in condensed matter physics, materials chemistry. Here, we use high temperature Raman spectroscopy and first principles calculations to study the structural change before and after the melting of a BiB 3 O 6 crystal to obtain the BiB 3 O 6 melt structure. A transformation of the 4-fold coordinated boron atoms to 3-fold coordinated boron atoms and a destruction of the atomic configuration around the Bi 3+ ions were found when the crystal melted. Considering the growth habit of the BIBO crystal, we proposed a polymer model for the first time to describe the melt structure

Scale Expansion of Community Investigations and Integration of the Effects of Abiotic and Biotic Processes on Maintenance of Species Diversity

Information on the maintenance of diversity patterns from regional to local scales is dispersed among academic fields due to the local focus of community ecology. To better understand these patterns, the study of ecological communities needs to be expanded to larger scales and the various processes affecting them need to be integrated using a suitable quantitative method. We determined a range of communities on a flora-subregional scale in Yunnan province, China (383210.02 km 2 ). A series of species pools were delimited from the regional to plot scales. Plant diversity was evaluated and abiotic and biotic processes identified at each pool level. The species pool effect was calculated using an innovative model, and the contribution of these processes to the maintenance of plant species diversity was determined and integrated: climate had the greatest effect at the flora-subregional scale, with historical and evolutionary processes contributing ∼11%; climate and human disturbance had the greatest effect at the local site pool scale; competition exclusion and stress limitation explained strong filtering at the successional stage pool scale; biotic processes contributed more on the local community scale than on the regional scale. Scale expansion combined with the filtering model approach solves the local problem in community ecology

Ketogenic Diet as a Treatment for Super-Refractory Status Epilepticus in Febrile Infection-Related Epilepsy Syndrome

Background: Febrile infection-related epilepsy syndrome (FIRES) is a fatal epileptic encephalopathy associated with super-refractory status epilepticus (SRSE). Several treatment strategies have been proposed for this condition although the clinical outcomes are poor. Huge efforts from neurointensivists have been focused on identifying the characteristics of FIRES and treatment to reduce the mortality associated with this condition. However, the role of ketogenic diet (KD) in FIRES is not fully understood.Methods: We performed a retrospective review of patients who met the diagnostic criteria of FIRES, SRSE, and were treated with KD between 2015 and 2018 at the Department of Pediatrics, Xiangya Hospital of Central South University. The following data were recorded: demographic features, clinical presentation, anticonvulsant treatment, timing and duration of KD and follow-up information. Electroencephalography recordings were reviewed and analyzed.Results: Seven patients with FIRES were put on KD (5 via enteral route, and 2 via intravenous line) for SRSE in the PICU. The median age was 8. Four patients were male and 3 were female. Although patients underwent treatment with a median of 4 antiepileptic drugs and 2 anesthetic agents, the status epilepticus (SE) persisted for 7–31 days before KD initiation. After KD initiation, all patients achieved ketosis and SE disappeared within an average of 5 days (IQR 3.5), although there were minor side effects. In 6 patients, a unique pattern was identified in the EEG recording at the peak period. After initiation of KD, the number of seizures reduced, the duration of seizure shortened, the background recovered and sleep architecture normalized in the EEG recordings. The early initiation of KD (at the onset of SE) in the acute phase of patients decreased the mRS score in the subsequent period (p = 0.012, r = 0.866).Conclusions: The characteristic EEG pattern in the acute phase promoted timely diagnosis of FIRES. Our data suggest that KD may be a safe and promising therapy for FIRES with SRSE, and that early initiation of KD produces a favorable prognosis. Therefore, KD should be applied earlier in the course of FIRES. Intravenous KD can be an effective alternative route of administration for patients who may not take KD enterally

Preparation of sea buckthorn (Hippophae rhamnoides L.) seed meal peptide by mixed fermentation and its effect on volatile compounds and hypoglycemia

This study employed mixed bacterial strains to ferment seabuckthorn seed meal into peptides, and conducted a comprehensive evaluation of the growth adaptive conditions, molecular weight distribution, volatile compounds, and in vitro hypoglycemic activity required for fermentation. Results showed that when the amount of maltose was 1.1% and MgSO4·7H2O was added at 0.15 g/L, the peptide yield reached 43.85% with a mixed fermentation of Lactobacillus fermentum, Bacillus subtilis, Lactobacillus casei, Lactobacillus rhamnosus, and Lactobacillus acidophilus. Components with a molecular weight below 1 kDa were found to be more effective in inhibiting the activity of α-amylase and α-glucosidase, with the identified sequence being FYLPKM. Finally, SPME/GC–MS results showed that 86 volatile components were detected during the fermentation of seabuckthorn seed meal, including 22 alcohols, 9 acids, 7 ketones, 14 alkanes, 20 esters, and 14 other compounds. With prolonged fermentation time, the content of acids and esters increased significantly

Large T1 contrast enhancement using superparamagnetic nanoparticles in ultra-low field MRI

Superparamagnetic iron oxide nanoparticles (SPIONs) are widely investigated and utilized as magnetic resonance imaging (MRI) contrast and therapy agents due to their large magnetic moments. Local field inhomogeneities caused by these high magnetic moments are used to generate T2 contrast in clinical high-field MRI, resulting in signal loss (darker contrast). Here we present strong T1 contrast enhancement (brighter contrast) from SPIONs (diameters from 11 nm to 22 nm) as observed in the ultra-low field (ULF) MRI at 0.13 mT. We have achieved a high longitudinal relaxivity for 18 nm SPION solutions, r1 = 615 s−1 mM−1, which is two orders of magnitude larger than typical commercial Gd-based T1 contrast agents operating at high fields (1.5 T and 3 T). The significantly enhanced r1 value at ultralow fields is attributed to the coupling of proton spins with SPION magnetic fluctuations (Brownian and Néel) associated with a low frequency peak in the imaginary part of AC susceptibility (χ”). SPION-based T1-weighted ULF MRI has the advantages of enhanced signal, shorter imaging times, and iron-oxidebased nontoxic biocompatible agents. This approach shows promise to become a functional imaging technique, similar to PET, where low spatial resolution is compensated for by important functional information

Adjusting magnetic nanostructures for high-performance magnetic sensors

The magnetic properties of the soft ferromagnetic layer in magnetic tunnel junctions are one of key factors to determine the performance of magnetoresistance sensors. We use a three-step orthogonal annealing procedure to modify the nanostructures of the free layer in the magnetic tunnel junction to control features such as magnetization reversal, coercivity, exchange field, and tunnel magnetoresistance ratio. We present a sensor with an improved sensitivity as high as 3944%/mT. This magnetic sensor only dissipates 200 lW of power while operating under an applied voltage of 1V