Search

Blood-brain barrier (BBB) disruption plays a critical role in brain injury induced by cerebral ischemia, and preserving BBB integrity during ischemia could alleviate cerebral injury. We examined the role of miR-130a in ischemic BBB disruption by using models of rat middle cerebral artery occlusion and cell oxygen-glucose deprivation. We found that ischemia significantly increased microRNA-130a (miR-130a) level and that miR-130a was predominantly from brain microvascular endothelial cells. Antagomir-130a, an antagonist of miR-130a, could attenuate brain edema, lower BBB permeability, reduce infarct volume, and improve neurologic function. MiR-130a overexpression induced by miR-130a mimic increased monolayer permeability, and intercellular inhibition of miR-130a by a miR-130a inhibitor suppressed oxygen-glucose deprivation-induced increase in monolayer permeability. Moreover, dual luciferase reporter system showed that Homeobox A5 was the direct target of miR-130a. MiR-130a, by inhibiting Homeobox A5 expression, could down-regulate occludin, thereby increasing BBB permeability. Our results suggested that miR-130a might be implicated in ischemia-induced BBB dysfunction and serve as a target for the treatment of ischemic stroke. [ABSTRACT FROM AUTHOR]

Abstract Mesoscale convective systems (MCSs) are the main source of precipitation in the tropics and parts of the mid‐latitudes and are responsible for high‐impact weather worldwide. Studies showed that deficiencies in simulating mid‐latitude MCSs in state‐of‐the‐art climate models can be alleviated by kilometer‐scale models. However, whether these models can also improve tropical MCSs and whether we can find model settings that perform well in both regions is understudied. We take advantage of high‐quality MCS observations collected over the Atmospheric Radiation Measurement (ARM) facilities in the US Southern Great Plains (SGP) and the Amazon basin near Manaus (MAO) to evaluate a perturbed physics ensemble of simulated MCSs with 4 km horizontal grid spacing. A new model evaluation method is developed that enables to distinguish biases stemming from spatiotemporal displacements of MCSs from biases in their reflectivity and cloud shield. Amazon MCSs are similarly well simulated across these evaluation metrics than SGP MCSs despite the challenges anticipated from weaker large‐scale forcing in the tropics. Generally, SGP MCSs are more sensitive to the choice of model microphysics, while Amazon cases are more sensitive to the planetary boundary layer (PBL) scheme. Although our tested model physics combinations had strengths and weaknesses, combinations that performed well for SGP simulations result in worse results in the Amazon basin and vice versa. However, we identified model settings that perform well at both locations, which include the Thompson and Morrison microphysics coupled with the Yonsei University (YSU) PBL scheme and the Thompson scheme coupled with the Mellor‐Yamada‐Janjic PBL scheme.

In the present study, three meteorological events of extreme deep moist convection, characteristic of southeastern South America, are considered to conduct a systematic evaluation of the microphysical parameterizations available in the Weather Research and Forecasting (WRF) model by undertaking a direct comparison between satellite-based simulated and observed microwave radiances. A research radiative transfer model, the Atmospheric Radiative Transfer Simulator (ARTS), is coupled with the WRF model under three different microphysical parameterizations (WSM6, WDM6 and Thompson schemes). Microwave radiometry has shown a promising ability in the characterization of frozen hydrometeors. At high microwave frequencies, however, frozen hydrometeors significantly scatter radiation, and the relationship between radiation and hydrometeor populations becomes very complex. The main difficulty in microwave remote sensing of frozen hydrometeor characterization is correctly characterizing this scattering signal due to the complex and variable nature of the size, composition and shape of frozen hydrometeors. The present study further aims at improving the understanding of frozen hydrometeor optical properties characteristic of deep moist convection events in south-eastern South America. In the present study, bulk optical properties are computed by integrating the single-scattering properties of the Liu (2008) discrete dipole approximation (DDA) single-scattering database across the particle size distributions parameterized by the different WRF schemes in a consistent manner, introducing the equal mass approach. The equal mass approach consists of describing the optical properties of the WRF snow and graupel hydrometeors with the optical properties of habits in the DDA database whose dimensions might be different (D' max) but whose mass is conserved. The performance of the radiative transfer simulations is evaluated by comparing the simulations with the available coincident microwave observations up to 190 GHz (with observations from Tropical Rainfall Measuring Mission's (TRMM) Microwave Imager (TMI), Microwave Humidity Sounder (MHS) and Special Sensor Microwave Imager/Sounder (SSMI/S)) using the χ2 test. Good agreement is obtained with all observations provided special care is taken to represent the scattering properties of the snow and graupel species. [ABSTRACT FROM AUTHOR]

Copyright of Transformations in Business & Economics is the property of Vilnius University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In the present study, three meteorological events of extreme deep moist convection, characteristic of Southeastern South America (SESA), are considered to conduct a systematic evaluation of the microphysical parameterizations available in the Weather Research and Forecasting (WRF) model by undertaking a direct comparison between satellite-based simulated and observed microwave radiances. A research radiative transfer model, the Atmospheric Radiative Transfer Simulator (ARTS), is coupled with WRF under three different microphysical parameterizations (WSM6, WDM6 and Thompson). Since the main difficulty encountered in the characterization of the microwave scattering signal arises from the complex and variable nature of microphysics properties of frozen hydrometeors, the present study further aims at improving the understanding of their optical properties. The bulk optical properties are computed by integrating the single scattering properties of the Liu (2008) DDA single scattering database across the particle size distributions parametrized by the different WRF schemes in a consistent manner, introducing the equal-mass pproach. The equal mass approach consists in describing the optical properties of the WRF snow and graupel hydrometeors with the optical properties of habits in the DDA database whose dimensions might be different (D'max) but whose mass is conserved. The performance of the radiative transfer simulations is evaluated by comparing the simulations with the available coincident microwave observations up to 190GHz (with observations from TMI, MHS, and SSMI/S) using the Chi-square test. Good greement is obtained with all observations provided special care is taken to represent the scattering properties of the snow and graupel species. [ABSTRACT FROM AUTHOR]

Receptor for activated C kinase 1 (RACK1) is up-regulated in hepatocellular carcinoma (HCC) and has been reported to augment c-Jun N-terminal protein kinase (JNK) activity in HCC SMMC-7721 cells. By contrast, activator protein-1, a downstream JNK transcription factor, has been revealed to mediate the overexpression of RACK1 in melanoma cells. Therefore, the association between RACK1 and JNK activity in HCC cells has yet to be completely elucidated. The present study analyzed the effects of RACK1 or JNK loss of function on the levels of RACK1 protein, JNK activity, cell proliferation and apoptosis induced by tumor necrosis factor-related apoptosis inducing ligand in HCC SMMC-7721 cells. It was found that JNK loss of function exhibited no effect on RACK1 expression, whereas a loss of RACK1 function led to reduced JNK activity in SMMC-7721 cells. RACK1 and JNK loss of function resulted in the impaired oncogenic growth of SMMC-7721 cells. The present data further support a pivotal role of RACK1 in mediating enhanced JNK activity in HCC cells and also indicate that a novel mechanism exists for RACK1 overexpression in HCC SMMC-7721 cells. [ABSTRACT FROM AUTHOR]

A key control point in gene expression is the initiation of protein translation, with a universal stress response being constituted by inhibitory phosphorylation of the eukaryotic initiation factor 2α(eIF2α). In humans, four kinases sense diverse physiological stresses to regulate eIF2α to control cell differentiation, adaptation, and survival. Herewe develop a computational molecular model of eIF2α and one of its kinases, the protein kinase R, to simulate the dynamics of their interaction. Predictions generated by coarse-grained dynamics simulations suggest a novel mode of action. Experimentation substantiates these predictions, identifying a previously unrecognized interface in the protein complex, which is constituted by dynamic residues in both eIF2α and its kinases that are crucial to regulate protein translation. These findings call for a reinterpretation of the current mechanism of action of the eIF2α kinases and demonstrate the value of conducting computational analysis to evaluate protein function. [ABSTRACT FROM AUTHOR]

Background: The role of naturally occurring regulatory T cells (Treg) in the control of the development of systemic lupus erythematosus (SLE) has not been well defined. Therefore, we dissect the phenotypically heterogeneous CD4+FoxP3+ T cells into subpopulations during the dynamic SLE development. Methodlogy/Principal Findings: To evaluate the proliferative and suppressive capacities of different CD4+ T cell subgroups between active SLE patients and healthy donors, we employed CD45RA and CD25 as surface markers and carboxyfluorescein diacetatesuccinimidyl ester (CFSE) dilution assay. In addition, multiplex cytokines expression in active SLE patients was assessed using Luminex assay. Here, we showed a significant increase in the frequency of CD45RA+FoxP3low naive Treg cells (nTreg cells) and CD45RA2FoxP3low (non-Treg) cells in patients with active SLE. In active SLE patients, the increased proportions of CD45RA+FoxP3low nTreg cells were positively correlated with the disease based on SLE disease activity index (SLEDAI) and the status of serum anti-dsDNA antibodies. We found that the surface marker combination of CD25+CD45RA+ can be used to defined CD45RA+FoxP3lownTreg cells for functional assays, wherein nTreg cells from active SLE patients demonstrated defective suppression function. A significant correlation was observed between inflammatory cytokines, such as IL-6, IL-12 and TNFα, and the frequency of nTreg cells. Furthermore, the CD45RA+FoxP3low nTreg cell subset increased when cultured with SLE serum compared to healthy donor serum, suggesting that the elevated inflammatory cytokines of SLE serum may promote nTreg cell proliferation/expansion. Conclusions/Significance: Our results indicate that impaired numbers of functional CD45RA+FoxP3low naive Treg cell and CD45RA-FoxP3low non-suppressive T cell subsets in inflammatory conditions may contribute to SLE development. Therefore, analysis of subsets of FoxP3+ T cells, using a combination of FoxP3, CD25 and CD45RA, rather than whole FoxP3+ T cells, will help us to better understand the pathogenesis of SLE and may lead to the development of new therapeutic strategies. [ABSTRACT FROM AUTHOR]

The Maclura pomifera agglutinin (MPA) recognizes the T-antigen disaccharide Galβ1,3GalNAc mainly through interaction of the α-GalNAc moiety with its primary site, but the interactions of the two flanking subsites A and B with aglycones and substituents other than Gal, respectively, are not well understood. We therefore characterized the specificity of MPA in more detail by glycan microarray analysis and determined the crystal structures of MPA without ligand and in complexes with Galβ1,3GalNAc and p-nitrophenyl α-GalNAc. In both sugar complexes, pairs of ligands created inter-tetramer hydrogen-bond bridging networks. While subsite A showed increased affinity for hydrophobic aglycones, it also accommodated several sugar substituents. Notably, a GalNAc-O-tripeptide, a Tn-antigen mimic, showed lower affinity than these compounds in surface plasmon resonance (SPR) experiments. The glycan array data that showed subsite B accepted compounds in which the O3 position of the GalNAc was substituted with various sugars other than Gal, but substitutions at O6 led to inactivity. Additions to the Gal moiety of the disaccharide also had only small effects on reactivity. These results are all compatible with the features seen in the crystal structures. [ABSTRACT FROM PUBLISHER]

The non-steroidal anti-inflammatory drug aspirin and its metabolite, sodium salicylate, have profound effects on cellular protein synthesis and cell physiology. However, the underlying mechanism by which they cause these responses remains unclear. We show here that salicylates induce phosphorylation of the a-subunit of eukaryotic translation initiation factor 2 (eIF2α), resulting in the inhibition of mRNA translation in cells. Exposure of cells to acetyl salicylic acid resulted in strong activation of eIF2α stress-activated protein kinase R-like endoplasmic reticulum kinase (PERK). Analysis of fibroblasts with a targeted deletion of the perk gene revealed that PERK is indispensable for triggering the phosphorylation of eIF2α as well as the inhibition of protein synthesis induced by salicylates. Although salicylate treatment did not trigger activation of inositol-requiring enzyme 1, there was an increased expression of the pro-apoptotic transcription factor CHOP-(gadd153), a downstream event to eIF2α phosphorylation known to mediate endoplasmic reticulum stress-mediated responses. Thus, salicylates selectively trigger an endoplasmic reticulum stress-responsive signaling pathway initiated through activation of PERK to induce their cellular effects. [ABSTRACT FROM AUTHOR]

Nonspecific effects triggered by small interfering RNAs (siRNAs) complicate the use of RNA interference (RNAi) to specifically downregulate gene expression. To uncover the basis of these nonspecific activities, we analyzed the effect of chemically synthesized siRNAs on mammalian double-stranded RNA (dsRNA)-activated signaling pathways. siRNAs ranging from 21 to 27 nucleotides (nt) in length activated the interferon system when they lacked 2-nt 3′ overhangs, a characteristic of Dicer products. We show that the recognition of siRNAs is mediated by the RNA helicase RIG-I and that the presence of 3′ overhangs impairs its ability to unwind the dsRNA substrate and activate downstream signaling to the transcription factor IRF-3. These results suggest a structural basis for discrimination between microRNAs that are endogenous Dicer products, and nonself dsRNAs such as by-products of viral replication. These findings will enable the rational design of siRNAs that avoid nonspecific effects or, alternatively, that induce bystander effects to potentially increase the efficacy of siRNA-based treatments of viral infections or cancer. [ABSTRACT FROM AUTHOR]

AIM: To determine whether an antisense RNA corresponding to the human Alu transposable element (Aluas RNA) can protect human lens epithelial cells (HLECs) from methylglyoxal-induced apoptosis. METHODS: Cell counting kit-8 (CCK-8) and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to assess HLEC viability. HLEC viability/death was detected using a Calcein-AM/PI double staining kit; the annexin V-FITC method was used to detect HLEC apoptosis. The cytosolic reactive oxygen species (ROS) levels in HLECs were determined using a reactive species assay kit. The levels of malondialdehyde (MDA) and the antioxidant activities of total-superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) were assessed in HLECs using their respective kits. RT-qPCR and Western blotting were used to measure mRNA and protein expression levels of the genes. RESULTS: Aluas RNA rescued methylglyoxal-induced apoptosis in HLECs and ameliorated both the methylglyoxal-induced decrease in Bcl-2 mRNA and the methylglyoxal-induced increase in Bax mRNA. In addition, Aluas RNA inhibited the methylglyoxal-induced increase in Alu sense RNA expression. Aluas RNA inhibited the production of ROS induced by methylglyoxal, restored T-SOD and GSH-Px activity, and moderated the increase in MDA content after treatment with methylglyoxal. Aluas RNA significantly restored the methylglyoxal-induced down-regulation of Nrf2 gene and antioxidant defense genes, including glutathione peroxidase, heme oxygenase 1, γ-glutamylcysteine synthetase and quinone oxidoreductase 1. Aluas RNA ameliorated methylglyoxal-induced increases of the mRNA and protein expression of Keap1 that is the negative regulator of Nrf2. CONCLUSION: Aluas RNA reduces apoptosis induced by methylglyoxal by enhancing antioxidant defense.

An efficient Cp*Rh(III)-catalyzed direct acylmethylation of 2H-indazoles with sulfoxonium ylides has been realized under air atmosphere via chelation-assisted strategy. This protocol enables a regioselective access to a variety of ortho-acylmethylated 2-phenylindazole derivatives in moderate to good yield, which has the advantages of broad substrate scope, good functional group tolerance, and operational convenience. The H/D exchange experiment reveals that a reversible cleavage of C–H bond might not be the rate-limiting step in this transformation.

Abstract Background Anxiety and depression have been increasing among Chinese medical students. The psychological well-being of Chinese medical students has become a critical focus of attention for the medical education community. Increasing evidence shows that positive psychology interventions can be effective in the enhancement of psychological well-being, and may help to prevent depressive symptoms in university students. In the present study, we aimed to explore the potential effect of positive psychology education on improving the mental health of Chinese medical students. Methods An 8-week classroom-based positive psychology intervention workshop, which was established as an elective course embedded in the regular school curriculum, was conducted at the School of Medicine, South China University of Technology (SCUT), China. Undergraduate medical students of the institute in year-2 or year-3 of academic study participated in this training course voluntarily. The participants’ self-reported data on the hope scale, life satisfaction scale, subjective happiness scale, and depression and anxiety scale were collected and analyzed at pre-course (n = 61) and post-course (n = 49) times. The investigation was also validated with an independent cohort of students who enrolled in the course in the year following the preliminary study. Results The analyses showed that the psychological well-being of the participants were improved after the intervention. Their mean scores on the hope scale, life satisfaction scale and subjective happiness scale were significantly improved (P

This study examines the regulating effect of Sonic Hedgehog (Shh) on the permeability of the blood-brain barrier (BBB) in cerebral ischemia. By employing permanent middle cerebral artery occlusion (pMCAO) model, we find that Shh significantly decreases brain edema and preserves BBB permeability. Moreover, Shh increases zonula occludens-1 (ZO-1), occludin and angiopiotetin-1 (Ang-1) expression in the ischemic penumbra. Blockage of Shh with cyclopamine abolishes the effects of Shh on brain edema, BBB permeability and ZO-1, occludin, Ang-1 expression. Primary brain microvessel endothelial cells (BMECs) and astrocytes were pre-treated with Shh, cyclopamine, Ang-1-neutralizing antibody, and subjected to oxygen-glucose deprivation (OGD). Results show that the Ang-1 protein level in the culture medium of Shh-treated astrocytes is significantly higher. Shh also increased ZO-1, occludin and Ang-1 expression in BMECs, while cyclopamine and Ang-1-neutralizing antibody inhibited the effects of Shh on the ZO-1 and occludin expression, respectively. This study suggests that, under ischemic insults, Shh triggers Ang-1 production predominantly in astrocytes, and the secreted Ang-1 acts on BMECs, thereby upregulating ZO-1 and occludin to repair the tight junction and ameliorate the brain edema and BBB leakage.

Bladder cancer is associated with high recurrence and mortality rates due to metastasis. The elucidation of metastasis suppressors may offer therapeutic opportunities if their mechanisms of action can be elucidated and tractably exploited. In this study, we investigated the clinical and functional significance of the transcription factor activating transcription factor 3 (ATF3) in bladder cancer metastasis. Gene expression analysis revealed that decreased ATF3 was associated with bladder cancer progression and reduced survival of patients with bladder cancer. Correspondingly, ATF3 overexpression in highly metastatic bladder cancer cells decreased migration in vitro and experimental metastasis in vivo. Conversely, ATF3 silencing increased the migration of bladder cancer cells with limited metastatic capability in the absence of any effect on proliferation. In keeping with their increased motility, metastatic bladder cancer cells had increased numbers of actin filaments. Moreover, ATF3 expression correlated with expression of the actin filament severing protein gelsolin (GSN). Mechanistic studies revealed that ATF3 upregulated GSN, whereas ATF3 silencing reduced GSN levels, concomitant with alterations in the actin cytoskeleton. Weidentified six ATF3 regulatory elements in the first intron of the GSN gene confirmed by chromatin immunoprecipitation analysis. Critically, GSN expression reversed the metastatic capacity of bladder cancer cells with diminished levels of ATF3. Taken together, our results indicate that ATF3 suppresses metastasis of bladder cancer cells, at least in part through the upregulation of GSN-mediated actin remodeling. These findings suggest ATF3 coupled with GSN as prognostic markers for bladder cancer metastasis. [ABSTRACT FROM AUTHOR]