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Acute and subacute IL-1β administrations differentially modulate neuroimmune and neurotrophic systems: possible implications for neuroprotection and neurodegeneration
Journal of Neuroinflammation volume 10, Article number: 826 (2013)
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In Alzheimer's disease, stroke and brain injuries, activated microglia can release proinflammatory cytokines, such as interleukin (IL)-1β. These cytokines may change astrocyte and neurotrophin functions, which influences neuronal survival and induces apoptosis. However, the interaction between neuroinflammation and neurotrophin functions in different brain conditions is unknown. The present study hypothesized that acute and subacute elevated IL-1β differentially modulates glial and neurotrophin functions, which are related to their role in neuroprotection and neurodegeneration.
Rats were i.c.v. injected with saline or IL-1β for 1 or 8 days and tested in a radial maze. mRNA and protein expressions of glial cell markers, neurotrophins, neurotrophin receptors, β-amyloid precursor protein (APP) and the concentrations of pro- and anti-inflammatory cytokines were measured in the hippocampus.
When compared to controls, memory deficits were found 4 days after IL-1 administrations, however the deficits were attenuated by IL-1 receptor antagonist (RA). Subacute IL-1 administrations increased expressions of APP, microglial active marker CD11b, and p75 neurotrophin receptor, and the concentration of tumor necrosis factor (TNF)-α and IL-1β, but decreased expressions of astrocyte active marker glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and TrK B. By contrast, up-regulations of NGF, BDNF and TrK B expressions were found after acute IL-1 administration, which are associated with the increase in both glial marker expressions and IL-10 concentrations. However, TrK A was down-regulated by acute and up-regulated by subacute IL-1 administrations. Subacute IL-1-induced changes in the glial activities, cytokine concentrations and expressions of BDNF and p75 were reversed by IL-1RA treatment.
These results indicate that acute and subacute IL-1 administrations induce different changes toward neuroprotection after acute IL-1 administrations but neurodegeneration after subacute ones.
In the last two decades, many studies have found that neuroinflammation is causally related to the onset and progress of several neurodegenerative disorders, including Alzheimer's disease (AD). Increased microglial activity and pro-inflammatory cytokine releases may contribute to neuronal dysfunction and death in neurodegenerative diseases [1, 2]. Among many inflammatory triggers and mediators, both experimental and clinical data have suggested IL-1β as the most potent pro-inflammatory cytokine in neurodegeneration. First, a genetic study has shown that the inheritance of a specific IL-1 gene polymorphism is associated with an earlier age of AD onset and increases the risk for AD development by as much as six-fold [3]. Second, IL-1β cultured with cortical neurons has been found to increase mRNA expressions and the concentration of amyloid precursor proteins (APP), neuropathological markers of AD [3, 4]. Third, our team has previously reported that subacute administration of IL-1β to rats can reduce acetylcholine (ACh) release and impair memory [5]. Therefore, IL-1 administration to rodents has been popularly used as a model for studying the interaction between inflammation, brain functions, and memory deficits in neurodegenerative and psychiatric diseases [6, 7].
However, neuroinflammation has two sides; it may be beneficial in promoting homeostasis and neuron survival, but can also result in tissue injury through the over-action of inflammatory mediators. Even though many studies have reported that increased IL-1 release contributes to neurodegeneration in both acute and chronic brain conditions, findings from acute ischemia, stroke and brain injuries show that the release of IL-1 and other pro-inflammatory cytokines, such as TNF-α, may protect neurons [8–12]. However, many studies have demonstrated that blocking IL-1 or reducing inflammation could reduce neuron death and symptoms of disability as well as save patients' lives [13]. This conflict raises important questions: whether and how acute and subacute or chronic IL-1 releases differentially modulate central nervous system (CNS) functions, which may result in opposite effects during different brain conditions. To answer this question, the pro- and anti-inflammatory mechanisms and the neuroprotective system in the brain should be compared in acute and 8-day repeated IL-1-induced models.
It is well known that in different brain diseases, both activated microglia and astrocytes can produce pro-inflammatory, anti-inflammatory and neurotrophic factors. However, microglia may be more involved in the inflammatory response in neuropathological conditions, while astrocytes may have more supporting and maintaining functions, including releasing neurotrophins and anti-inflammatory cytokines. Neurotrophins and their receptors compose a major neuroprotective system in the brain because they stabilize and maintain homeostasis (protection and repair), clean up neurotoxins, regulate neurotransmission and modulate neuronal regenesis and degenesis [14–17]. The most often studied neurotrophins related to neurodegeneration are nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). The highest mRNA levels of these neurotrophins have been found in the hippocampus, which indicates their important roles in neuroendocrine and cognitive behavior [18]. Indeed, our research group previously reported that the down-regulation of NGF mRNA expression is correlated with the reduction of ACh release after IL-administration for 8 days [5].
BDNF also plays a crucial role in cognition, learning, and memory formation by modulating synaptic plasticity and is, therefore, a critical molecule in dementia and neurodegenerative diseases. Two types of neurotrophin receptors have already been found: tyrosine kinases (TrK A, B, C) and low-affinity NGF (p75) receptor [18]. The receptor for NGF is TrK A and the receptor for BNDF is TrK B, while both neurotrophins also combine with p75 receptors. The binding of neurotrophins to their TrK receptors causes signaling events, which promote neuron survival, whereas the activation of the p75 pathway may trigger apoptosis or enhance the selectivity of neurotrophin binding for specific TrKs [19, 20]. Hence, neurotrophins may activate different cellular mechanisms depending on which type of receptors they interact with.
Recently, increasing evidence has suggested that neuroinflammation may trigger neuroprotection or neurodegeneration through the neurotrophic system [21]. Increased and decreased expressions or concentrations of neurotrophins have been reported in acute and chronic neurodegenerative diseases. For example, both IL-1 and NGF concentrations were markedly increased in the frontal cortex within 24 hours of traumatic brain injuries [22], and BDNF was found to be increased in acute spinal cord injury [23–25]. In the brain of AD patients, increased or decreased NGF and BNDF mRNA or protein expressions have been reported [18, 26, 27]. Furthermore, TrK A and TrK B receptors have been shown to be down-regulated in AD brains [18]. However, it is unclear whether and how acute and subacute glial activation and IL-1 released in response to these different conditions are related to changes in neurotrophin systems. The present study hypothesized that acute and 8-day repeated IL-1 administrations differentially modulate the activity of microglia and astrocytes, which may change the inflammatory and neurotrophin systems, thereby providing protective or degenerative effects on brain functions such as memory and Aβ deposition. To demonstrate this hypothesis, the present study evaluated 1) the effects of 1-day (acute) and 8-day (subacute) IL-1 administrations on hippocampus-dependent working memory in rats, and 2) the gene and protein expressions of the microglial active marker CD11b and astrocyte marker glial fibrillary acidic protein (GFAP), APP, neurotrophins and receptors, and their relationship with pro- and anti-inflammatory cytokines in the hippocampus.
Materials and methods
Male Long-Evans rats (250 to 280 g, Charles River, Quebec, Canada) were housed in pairs and maintained under a 12-h light, 12-h dark cycle, room temperature at 21 ± 1°C, with food and water available ad libitum. There were two independent experiments (EXP1 and EXP2). In EXP1, rats were divided into four groups of 10 as: 1) acute saline treatment (1 day); 2) acute IL-1 (1 day); 3) subacute saline (8 days) and 4) subacute IL-1 (8 days). In EXP2, rats were divided into two groups of 10 as: 1) subacute IL-1 (8 days) + saline, and 2) subacute IL-1 (8 days) + IL-1 receptor antagonist (RA). Since we previously showed that IL-1RA alone did not affect rat memory and NGF expression [5], we did not study the effects of IL-1RA in the control group. All procedures were reviewed and approved by the Institutional Animal Care and Use Committee in the University of Prince Edward Island, in accordance with the guidelines of the Canadian Council on Animal Care (06–004, 1001966). The experimental design for EXP1 is presented in Diagram 1. The experimental procedure for EXP2 was the same as the EXP1.
Following habituation for 1 week, animals were anesthetized with ketamine (100 mg/kg) and xylazine (20 mg/kg) and placed in stereotaxic apparatus. For intracerebroventricular (i.c.v.) injections, guide cannulae (24-gauge) were located stereotaxically over the right lateral ventricles (anterior/posterior=1 mm; medial/lateral=1.6 mm; 1 mm depth) as described in detail elsewhere [28]. A dummy cannula was screwed into the guide cannula to maintain patency. The guide cannula protruding from a concentric custom-made Derelin pedestal was secured to the skull with three screws and dental cement. Tetracycline powder was used to treat the wound. Animals were allowed to recover for 10 days.
Behavioral training and testing
Foraging tests were conducted on an eight-arm radial maze, consisting of an octagonal center platform (51 cm in diameter, arm-to-arm) connected to eight equally spaced arms (40 × 13 cm). Ten days after the surgery, rats were food deprived to 90% of their free-feeding weight and the delayed spatial win-shift version of the radial maze task was adapted from Song et al. [28]. Each trial consisted of a training phase and a memory test phase, separated by a delay (from 5 minutes to 50 minutes). Before the training phase, four arms were randomly baited with food pellets (Bioserv, French, NJ, USA). The other arms were blocked. In the training phase, each rat was allowed 5 minutes to retrieve the food from the four open arms. During the memory test phase, all arms were opened and rats were allowed to explore the maze until they had retrieved food located in the four arms that were blocked during training, or until 5 minutes had elapsed. An arm entry was defined as movement along the arm to the food cup. Errors were recorded as rat entries into unbaited arms. Criterion performance during the memory tests was defined as five or fewer arm entries to locate four food pellets. When criterion performance at a 50-minute delay was maintained for two consecutive days, saline or IL-1 was i.c.v.-injected immediately after the training phase. Since our previous two studies demonstrated that saline or IL-1 administration before the training phase did not significantly impair animal learning [5, 28], in the present study injections were only carried out after the training phase for comparing acute and subacute effects. At 45 minutes after the injection, animal error entries were scored at memory test phases. For the acute injection groups, animal behavior was tested only once after saline or IL-1 administration and animals were decapitated on day 2. Controls that received saline injection for 2 days were compared to the group treated with IL-1 for 2 days; the controls that received saline injection for 3 days were compared to the group treated with IL-1 for 3 days, and so on for 8 days.
I.c.v. injections of IL-1β and IL-1RA
Rat recombinant IL-1 and IL-1RA were obtained from R&D system Inc (Minneapolis, USA) and dissolved in sterile, pyrogen-free saline at doses of 15 ng/10 μL/rat for IL-1 and 100 ng/5 μL/rat for IL-1RA [5]. The dose for IL-1β was based on those used in our previous study (5, 10, and 50 ng) and on other studies (10 to 20 ng) [29, 30]. The method for IL-1 and IL-1RA injection was the same as previously described [28]. In brief, rats were gently handled for 2 weeks before the first injection. On the injection day, 10 μL IL-1, IL-1+IL-1RA or saline was drawn into an internal needle that was connected to a micro-injector through a PE 50 polyethylene tube. IL-1, IL-1RA or saline was slowly infused into the brain over a period of 60 s. The injection needle was allowed to remain inside the guide cannula for 1 minute. Rats were returned to their home cages for a 45-minute period before behavioral tests [28].
Determination of cannula locations
After decapitation, brains were rapidly removed and placed on an ice block. The location of the cannula and the injection site was confirmed in the coronal section of the brain under a microscope. The hippocampuses were dissected quickly on ice and then frozen in N2. Animals with injection sites and probes outside of the lateral ventricular were excluded from the data.
Quantitative PCR
In EXP1, mRNA expressions of CD11b, GFAP, NGF, BDNF, TrK A, TrK B, p75 and APP were measured by quantitative PCR in the hippocampus. The primer sequences for these genes and the internal control, β-actin (Sigma, Canada), are listed in Table 1. The total RNA was purified from brain tissues using RNeasy Mini Kit (Qiagen). cDNA was synthesized from 2 μg total RNA using the Ominiscript RT kit (Qiagen). Primer sequences were purchased from Invitrogen (Carlsbad, CA, USA). The real-time PCR reaction solution contained a final volume of 15 μl QuantiTect SYBR Green PCR Mixture providing a 2.5 mM MgCl2, 1pM each of the primers and 0.5 μl cDNA templates. The real-time PCR was optimized to run with conditions of the initial activation at 95°C for 15 minutes, denaturation at 94°C for 15 s, annealing at 55°C for 20 s, and extension at 72°C for 15 s with a single fluorescence measurement and up to 40 cycles. The specificity of the primers was validated by agarose gel electrophoresis and real-time PCR to ascertain that no non-specific products formed prior to the sample analysis. The values were normalized against the internal control, β-actin, since we previously tried GAPDH to compare β-actin expressions in the hippocampus, and did not find a significant difference between these two house-keeping (HK) genes in the IL-1-induced model.
Western blot
The rabbit origin antibodies for CD11 (160 KDa), GFAP (50 KDa), BDNF (14 KDa), TrK A (140 KDa), TrK B (95–145 KDa) and p75 (75 KDa) were purchased from Santa Cruz Biotechnology, USA. The samples were spun down at 5,000 rpm for 5 minutes following hippocampus removal and homogenizing in the Teen buffer. The pellets were lysed in the lysis buffer, and then spun down at 13,000 rpm for 10 minutes. After adding sample buffer and boiling, the supernatant was collected and loaded to SDS PAGE gels. After running the gels, the proteins were transferred to nitrocellulose membranes. The proteins were then blotted with specific primary and secondary antibodies. Proteins on the membranes were detected by enhanced chemiluminescence (ECL) and then developed with image film. The bands were scanned and densitometrically analyzed using an automatic image analysis system (NIH Image 1.61 software). All target proteins were quantified by normalizing them to β-actin re-probed on the same membrane and then calculated as a percentage of the control group.
Measurement of NGF concentration by ELISA kit
β-NGF concentrations were measured in the hippocampus by the ELISA kit, NGF Emaxtm ImmunoAssay System number G7631 (R&D System, Promega, USA) following the instructions provided by the manufacturer. The brain tissues were homogenized with ultrasonication in an extraction buffer (Tris-acetate 20 mM, pH 7.5, NaCl 150 mM, ethylenediamine-tetraacetic acid (EDTA) 1 mM, EGTA 1 mM, sodium-pyrophosphate 2.5 mM, ortovanadate 1 mM, β-glycerolphosphate 1 mM, NaF 100 mM, phenylmethylsulfonyl fluoride (PMSF) 1 mM, leupeptin 1 μg/mL) and centrifuged at 4°C for 20 minutes, 10,000 g, and supernatants were recovered with the solution (EDTA, PMSF). Briefly, 96-well immunoplates were coated with 100 μL per well of polyclonal anti-NGF antibody. After an overnight incubation at 4°C, the plates were washed once with wash buffer (Tris–HCl 20 mM, pH 7.6, NaCl 150 mM, 0.05% Tween® 20) and then blocked for 1 h with the block & sample 1x buffer provided by the manufacturer (200 μL/well). After washing, the samples were incubated in the coated wells (100 μL each) for 6 h at room temperature with shaking. After an additional five washes the immobilized antigen was incubated with an anti-NGF monoclonal antibody overnight at 4°C. The plates were washed again with wash buffer, and then incubated with an anti-rat IgG horseradish peroxidase (HRP) conjugate (100 μL/well) for 2.5 h at room temperature. After another washing, the plates were incubated with a tetramethyl benzidine (TMB)/peroxidase substrate solution for 15 minutes (100 μL/well), provided by the manufacturer). Reactions were then stopped with 100 μL/well 1 N HCl. The colorimetric reaction product was measured at 450 nm using a microplate reader (Dynatech MR 5000, PBI International, USA). NGF concentrations were determined from the regression line for the NGF standard (ranging from 7.8 to 500 pg/mL purified NGF) incubated under similar conditions in each assay. Under these conditions the recovery of NGF in our assay was >90%. The NGF sensitivity of the assay was about 3 pg/g of wet tissue, and cross-reactivity with other related neurotrophic factors (BDNF, neurotrophin-3 and neurotrophin-4) was less than 3%. Data are represented as ng/mL supernatant and all assays were performed in duplicate.
Measurement of cytokine concentrations by Bio-Plex protein array system
TNF-α, IL-1β and IL-10 were measured in the hippocampus as previously described [31]. In brief, a customized 3-plex rat cytokine panel consisting of fluorescent beads for IL-1β, TNF-α and IL-10 (BioRad, CA, USA) was analyzed with a Luminex protein suspension array system (Bioplex 200, Biorad, CA, USA) according to manufacturer's instructions. Due to the large binding surface of the beads, this assay is highly sensitive and has been proven before to work well for detecting cytokines from brain tissues [32]. The results were expressed as pg/mL of brain supernatant.
Data analysis
The behavioral results were analyzed by two-way analysis of variance (ANOVA); duration (acute or subacute) × treatment (saline or IL-1), with repeated measurement for EXP1 and one-way ANOVA for EXP2. Results for mRNA and protein expressions of glial markers, neurotrophins and their receptors and cytokine concentrations were analyzed by two-way (duration × treatment) ANOVA for EXP1 and one-way ANOVA for EXP2. The statistics were expressed by F (=variance of the group means / mean of the within group variances) with the degree freedom. When P was <0.05 on ANOVA, the difference between groups was assessed by Newman-Keuls post hoc test (GB-STAT, Dynamic Microsystems, Inc., USA). Significance was set at P <0.05. Results are expressed as mean ± standard error of the mean (SEM).
Differential effects of acute and subacute IL-1 B administration on working memory
Rats that received saline i.c.v. administration prior to either the memory training or the testing phase of the delayed working memory task were able to find the location of food pellets in specific arms on the maze. These rats were also able to utilize this information after a 50-minute delay to select and enter a subset of four arms that contained food (Figure 1, training A). The i.c.v. administration of IL-1β prior to training had no effect on the time taken or the number of arm choices to find food rewards during the training period. However, two-way ANOVA confirmed that the treatment factor significantly affected the number of error entries during the memory testing from day 5 to day 8 (day 5, F3,26 = 23.96, P <0.001; day 6, F3,26 =14.16, P <0.001; day 7, F3,26 = 21.34, P <0.001; day 8, F3,26 = 22.19, P <0.001). The post hoc test confirmed that IL-1 administrations significantly increased the number of error entries during testing phases on days 5, 6, 7 and 8 when compared to the control group (P <0.01) (Figure 1A). 8 days repeated IL-1-induced memory impairment was reversed by IL-1RA treatment (day 5, F1,18 = 7.53, P <0.05; day 6, F1,18 = 8.61, P <0.01; day 7, F1,18 = 10.32, P <0.01; day 8, F1,18 = 8.74, P <0.01) (Figure 1B).
IL-1β administration-induced changes in CD11b and GFAP expressions
Two-way ANOVA showed that both treatment and duration factors significantly changed gene expressions of the microglial marker CD 11b (treatment: F1,27 = 13.07, P <0.001; duration F1,27 = 7.48, P <0.05). The post hoc revealed that significant up-regulation of CD11b mRNA expression occurred in the group receiving 8 days of repeated IL-1 administration (P <0.01) (Figure 2A). At the protein level, the ANOVA also indicated that the treatment and duration factors had significant effects on CD11b expressions (treatment: F1,27 = 41.5, P <0.0001; duration F1,27 = 5.1, P <0.05) and that the interaction between these two factors was also significant (F1, 27 = 4.95, P <0.05). The post hoc test revealed that IL-1 significantly increased CD11b expression after both acute (P <0.05) and subacute (P <0.0001) administrations, whereas the increase was much greater in the group that received subacute IL-1 injections (P <0.01) (Figure 2B).
With regards to astrocyte activation, two-way ANOVA showed that the treatment factor significantly affected GFAP protein but not mRNA expressions (treatment: F1,27 = 23.46, P <0.001) (Figure 2C). The post hoc test demonstrated that acute IL-1 significantly increased, while 8 days repeated IL-1 decreased GFAP protein expressions (P <0.01) (Figure 2D).
Results from EXP2 demonstrated that IL-1RA treatment for 8 days significantly attenuated subacute IL-1-induced increase in CD11b and decreased GFAP expressions at the protein level (mRNA expressions were not measured); CD11b: F1,18 = 9.91, P <0.01; GFAP: F1,18 = 7.72, P <0.01) (Figure 2E and F).
IL-1β administration-induced changes in the NGF and TrK A system
Two-way ANOVA demonstrated that the factor of treatment significantly changed NGF mRNA expressions and concentrations in the hippocampus (mRNA: F1,38 = 7.2, P <0.01; concentration: F1,27 = 6.57, p<0.05). The post hoc test showed that acute IL-1 administration significantly up-regulated NGF mRNA expressions and increased NGF concentrations (P <0.05) (Figure 3A and B). However, 8 days repeated IL-1β administration did not significantly change NGF mRNA expressions and concentrations (Figure 3B).
With regards to the mRNA expressions of NGF receptor TrK A, the ANOVA indicated that neither of two factors had any significant effect on TrK A gene expressions (Figure 3C). However, at the protein level, the treatment factor significantly changed protein expressions (F1,38 = 24.08, P <0.0001), and the interaction between the treatment and duration was also significant (mRNA F1,33 = 10.34, P <0.01; protein: F1,27 = 9.59, P <0.001). The post hoc test revealed that acute IL-1 administrations markedly down-regulated TrK A protein expressions (P <0.01) (Figure 3D). By contrast, 8 days repeated IL-1 administrations up-regulated this receptor expression (P <0.01) (Figure 3D).
IL-1β administration-induced changes in the BDNF and TrK B system
Two-way ANOVA indicated that the treatment factor significantly changed BDNF gene and protein expressions (mRNA: F1,38 = 8.71, P <0.001; protein: F1,27 = 15.91, P <0.001), and there was a significant interaction between these two factors (mRNA: F1,38 = 13.62, P <0.01; protein: F1,27 = 17.97, P <0.001). The post hoc test indicated that acute IL-1β administration significantly increased BDNF mRNA expressions (P <0.05), while 8 days repeated IL-1 reduced BDNF expressions (P <0.05) (Figure 4A). Protein expressions of BDNF were not significantly changed by acute IL-1 administration, whereas, consistent with the gene results, a significant reduction in BDNF protein levels was found in the group with subacute IL-1 administrations (P <0.05) (Figure 4B). This BDNF reduction induced by 8 days repeated IL-1RA treatment significantly attenuated IL-1-induced decrease in BDNF protein expressions (F1,18 = 13.62, P <0.01) (Figure 4E). The IL-1 factor also affected TrK B expressions significantly at both mRNA and protein levels (mRNA: F1,38 = 8.14, P <0.01; protein: F1,27 = 15.97, P <0.0001) as revealed by two-way ANOVA. The post hoc test revealed a similar pattern of changes in mRNA and protein expressions of BDNF between groups. Thus, gene expressions of TrK B were up-regulated after acute IL-1 administration (P <0.05) (Figure 4C), but markedly down-regulated by 8 days repeated IL-1 administration (P <0.05) (Figure 4C). At the protein level, the increase in TrK B did not reach significance after acute IL-1 treatment, but a significant reduction of TrK B protein level was found after 8 days repeated IL-1 administration (P <0.01) (Figure 4D). One way ANOVA demonstrated that IL-1RA treatment significantly reversed the TrK B expressions at the protein level (F1,18 = 13.75, P <0.01) (Figure 4f).
IL-1β administrations-induced changes in the expressions of p75 receptor and APP
As shown by Figure 4, the gene and protein expressions of p75 receptor were changed significantly by the treatment (mRNA: F1,38 = 25.34, P <0.0001; protein: F1,27 = 20.07, P <0.001), as indicated by two-way ANOVA. The interaction between IL-1/saline treatment and duration was also significant (mRNA: F1,38 = 23.54, P <0.0001; protein: F1,27 = 21.93, P <0.0001). The post hoc test demonstrated that acute and subacute administration of IL-1β exerted opposite effects on p75 receptors at gene and protein levels; acute IL-1 down-regulated mRNA and protein expressions of p75 receptors (P <0.01), while 8 days repeated IL-1 significantly increased both expressions (P <0.01 and 0.05, respectively) (Figure 5A and B). In the IL-1RA treated group, the increased in p75 protein expression was significantly lower when compared to subacute IL-1 group (F1,18 = 7.92, P <0.01) (Figure 5C).
APP gene expressions were shown to be markedly affected by both treatment and duration factors (treatment: F1,38 = 13.02, P <0.01; duration: F1,38 = 10.98, P <0.01). The interaction between these two factors was also significant (F1,38 = 13.13, P <0.001). The post hoc test revealed that there was no significant change in APP mRNA expressions in the group with acute IL-1 administration. When compared to the group repeatedly treated with saline for 8 days, a significantly up-regulation of APP mRNA expressions was found in the hippocampal tissues in the animals with 8 days repeated IL-1 administration (P <0.01) (Figure 6A). On the other hand, the effect of IL-1 on APP protein expressions only approached significance (F1,27 = 4.33, P = 0.051), and the interaction between IL-1 and treatment duration is also only close to significant (F1,27 = 4.23, P = 0.054). However, the post hoc test did not show any significant changes between groups (Figure 6B).
IL-1 administration-induced changes in hippocampal IL-1β, TNF-α and IL-10 concentrations
The effects of the treatment factor on hippocampal IL-1β, TNF-α and IL-10 concentrations were significant (IL-1: F1,31 = 7.28, P <0.01; TNF: F1,31 = 8.64, P <0.01; IL-10: F1,31 = 7.14, P <0.01). The effects of treatment duration on these three cytokines were also significant (IL-1: F1,31 = 6.37, P <0.05; TNF: F1,31 = 9.72, P <0.01; IL-10: F1,31 = 8.52, P <0.01). As shown by Table 2, acute IL-1 administration did not change IL-1β concentrations but significantly increased TNF-α and IL-10 concentrations (P <0.01), while 8 days repeated IL-1 injection significantly increased both IL-1β and TNF-α but reduced IL-10 levels (P <0.05) when compared to the matched saline treatment group (Table 2). IL-1RA treatment significantly reduced IL-1 (F1,18 = 9.36, P <0.01) and TNF-α (F1,18 = 7.81, P <0.01) concentrations; IL-1 (IL-1 group: 4,125.79 ± 513.36, IL-1 + IL-1RA group: 2,082.53 ± 410.21) and TNF-α (IL-1 group: 1376.72 ± 226.81, IL-1 + IL-1RA group: 395.421 ± 52.39).
A summary and comparison of the results are presented in Table 3. According to these results the following several aspects are discussed.
Acute and subacute IL-1 administration differently change glial activities, which may be related to inflammation in the brain
Acute and higher dose (100 ng/rat) i.c.v. administration of IL-1β has been found to activate microglia and astrocytes [33], which is similar to our findings in the present study. However, effects of chronic or subacute and low dose of IL-1 administrations on glial activities, which more accurately mirror the processes in neurodegenerative diseases, were not reported. Interestingly, the present study found that the increase in the protein expression of microglia marker CD11b was significantly greater after 8 days repeated IL-1 injections than after acute injections. Meanwhile, a more pronounced increase in the concentrations of pro-inflammatory cytokines was observed in the 8-day repeated IL-1 group than in the acute IL-1 group. Results from a mouse model of inducible sustained IL-1β overexpression bred with a triple transgenic mouse model of AD support our finding. In this model, greater microglial activation was found, which was also associated with inflammation [34]. On the other hand, changes in anti-inflammatory cytokine IL-10 and neurotrophins induced by acute and 8 days repeated IL-1 administration presented opposite effects. It is known that microglial, endothelial cells and astrocytes can produce anti-inflammatory cytokines, such as IL-10, while astrocytes can also produce neurotrophins [35, 36]. In the present study, the up-regulation of GFAP expression and moderately increased CD11b expression were associated with increased IL-10 concentrations after acute IL-1 administration. However, a decrease in mRNA expressions of GFAP and a severe increase in CD 11b were found after 8 days repeated IL-1 administrations, which was associated with decreased IL-10. This result may indicate that astrocyte activation involves an anti-inflammatory response in acute neuroinflammation. Thus, the findings demonstrated the first part of our hypothesis that acute and subacute IL-1 administrations differentially modulate microglial and astrocyte activities, which may play different roles in acute and chronic neuroinflammation.
With regards to the role of astrocytes in neurodegeneration, there are currently two opposite opinions. Heneka and co-workers found that the reduction in activated microglia and several inflammatory responses in the brain were parallel with the decrease in Aβ1-42-positive amyloid deposits after treatments with the non-steroid anti-inflammatory drug ibuprofen [37]. However, ibuprofen also markedly inhibited reactive astrocytes in this APP transgenic model. These results support the hypothesis that astrocyte-induced inflammation contributes to neurodegenerative changes. However, it has been also reported that chronic ibuprofen administration worsens cognitive functions following traumatic brain injury in rats [38]. On the other hand, some evidence reveals that astrocytes have neuroprotective functions by inhibiting microglial activation and neuroinflammation in AD [39, 40]. The results from the present study in glial cell activities and neurotrophin expression seems to support this later opinion since 8 days repeated IL-1 administration over-stimulated microglia but suppressed astrocyte functions, which resulted in the decrease of anti-inflammatory cytokines and BDNF neurotrophin and receptors.
There is a lack of parallel between CD11b mRNA and protein expressions. Because mRNA expressions are usually earlier than protein expressions, at a certain time point, their expression patterns could be at different stages.
Acute and subacute IL-1 treatments induced opposite changes in the expressions of neurotrophins and their receptors
For the first time, the present study demonstrated that acute IL-1 injection markedly up-regulated mRNA and protein expressions of NGF and BDNF, while 8 days repeated IL-1 injection down-regulated BDNF mRNA and protein expression without significantly changing NGF expression and concentration in the hippocampus. Many studies have provided solid evidence that neurotrophins also act on mature neurons, particularly on injured and degenerated neurons. Studies in animal models of CNS diseases have shown that neurotrophins can reduce neuroinflammation and inhibit or delay neuronal death or degeneration [36, 41]. In addition, increased NGF and BDNF expressions may contribute to the neuroinflammation-induced neuroprotection observed in acute brain injuries and early stages of stroke [21, 42]. Conversely, the deficiency of BDNF or NGF is believed to be a cause or a trigger of neurodegeneration [43, 44]. Thus, NGF and BDNF, or their receptor agonists, have been used to treat AD and other neurodegenerative diseases [12, 45, 46]. Dr O'Banion's team has recently demonstrated that chronic over expression of IL-1 impairs adult hippocampal neurogenesis in the above mentioned mouse model [47]. Our data suggest that IL-1-induced dysfunction of neurotrophic system could be a contributor to the impairment of neurogenesis.
When compared to BDNF, NGF seems less sensitive to 8 days repeated IL-1 administration in the present study. A longer term of IL-1 administration may be needed in the future since we have previously reported that decreased NGF mRNA expressions were found in the hippocampus after IL-1 treatment for 8 days [5] or 10 days (unpublished results).
In AD patients and AD models, a decrease in the BDNF, its receptor, or its precursor form has been reported [48–50]. An increase in the BDNF concentration in the dentate gyrus of the hippocampus during exercise was associated with memory improvement in a neurodegeneration model of mice [51]. In the present study, the BDNF mRNA and protein expressions were up-regulated by acute IL-1 but down-regulated by 8 days repeated IL-1 administrations. Our results suggest that in response to acute brain insult or inflammation, both glial activities and neurotrophic functions are up-regulated, which may exert protection on the brain, while chronic inflammation, which increased microglia but suppressed astrocytes, may damage the neurotrophic system.
The functions of neurotrophin receptors and their relationship with neuroinflammation have also not been fully studied and understood in neurodegeration. As mentioned in the introduction, when neurotrophins combined with TrK receptors, cell survival should be promoted, while the activation of p75 receptors may trigger apoptosis. The present study demonstrated for the first time that acute IL-1 administration increased TrK B but reduced p75 receptor mRNA and protein expressions, which further supports the hypothesis that acute neuroinflammation may provide neuroprotective effects. Thus, our study demonstrated the second part of our hypothesis. However, it should be emphasized that the function of neurotrophin receptors in the brain is very complicated. For example, pro- and matured neurotrophins have been found to trigger different types of receptors [52]. Therefore, p75 receptors not only induce apoptosis but also modulate neurotrophin expressions and functions.
The relationship between neurotrophins and their receptors and between neurotrophic systems and APP
Decreased TrK A receptors have been previously reported in the cortex of AD patients [53]. The present study found up-regulated TrK A protein expressions in the hippocampus associated with increased APP expressions, but decreased TrK A protein expression in the cortex (unpublished data) after subacute IL-1 injections, which may suggest that subacute IL-1 release in the brain could induce similar AD changes in this receptor.
A publication by D'Onofrio et al. [54] reported that in AD11 mice, an anti-NGF model (with no significant change in NGF mRNA expressions), the clusters of mRNAs that underwent the most changes were in the inflammatory category. The study also found that on postnatal day 30, when neurodegeneration and memory decline were undetectable, the mRNA expressions of BDNF were up-regulated, while on day 90, when Aβ deposition and memory decline started, the expressions of p75 and TrK A receptors were up-regulated but BDNF was down-regulated in the hippocampus. Another study has demonstrated that BDNF could inhibit Aβ production in primary neurons [55]. The present study demonstrated that after 8 days repeated IL-1 administration, an increase in the Aβ precursors APP expressions was associated with the decrease in BDNF mRNA and protein expressions and with the up-regulation of p75 and TrKA expressions, which provided strong evidence that IL-1β plays an important role in AD neuropathology.
As p75 receptors are a key ligand for Aβ, dysfunction of this receptor is linked with the neuropathology of AD; p75 can directly bind to Aβ1-42, leading to an increase in the secretion of APP, which produces Aβ and neurotoxicity [56], and conversely Aβ accumulation can stimulate p75 expressions [57]. In AD cortical neurons, the expression of p75 receptors is higher than in healthy controls [53]. In the present study, the increases in p75 mRNA and protein expressions were also accompanied by an increase in APP expressions in the hippocampus, while IL-1RA reversed the increase in p75 and also reversed APP expressions. Importantly, this change was only found after 8 days repeated, but not acute, IL-1 administrations. Thus, our hypothesis was further demonstrated.
The relevance of IL-1β-induced changes to memory impairment in the neurotrophic system
Previously, Hein et al. [58] reported that in the mouse model with sustained hippocampal IL-1 overexpression, both spatial and contextual memory were impaired, which could have resulted from microglial activation and also from other increased inflammatory factors. The present study further explored microglia activation and inflammation-induced neurotrophin dysfunction. It is known that both NGF and BDNF have been found to enhance acetylcholine release [59, 60], while deficiencies in acetylcholine release and BDNF or NGF expressions are related to memory impairment in AD patients, as mentioned in the introduction [5, 49–51]. The results from the present study, in line with neurotrophin changes and inflammatory response, showed memory impairment 4 days after IL-1 administration. The rats treated with acute IL-1 did not show any memory impairment, as previously acute IL-1 administration has been found to enhance conditioned fear memory in rats [61, 62]. The memory enhancement associated with acute IL-1 could be related to the up-regulated NGF, BDNF and TrK B expressions as observed in the present study. In this study, memory impairment was associated with down-regulated BDNF and TrK B and up-regulated TrK A and p75, and greater expression of p75 receptors in cholinergic neurons is believed to be responsible for cholinergic neuronal apoptosis and degeneration [63]. A previous study also reported that injecting IL-1β into the hippocampus could block the up-regulation of BDNF mRNA induced by conditioning memory [64]. The IL-1RA administration in the current study attenuated subacute IL-1-induced changes in BDNF, p75 and APP with significant improvement of memory performance in the radial maze. Therefore, the down-regulation of BDNF and up-regulation of p 75 may contribute to memory deficits in the radial maze after 8 days repeated IL-1 administration.
In summary, the present study demonstrated that acute and subacute IL-1 administration induced different changes in microglial and astrocyte activities, which cause opposite responses in neurotrophin expressions. Increased inflammatory responses, down-regulated BDNF and TrK B expressions, and up-regulated APP and p75 expressions may contribute to memory impairment after subacute or chronic IL-1 administration. However, results obtained from acute IL-1 administration, such as the up-regulation of NGF, BDNF and TrK B, increased anti-inflammatory cytokine IL-10 and down-regulated p75, may explain the neuroprotective functions of acute microglial and astrocyte activation and neuroinflammation in some brain conditions. Future studies should use glial inhibitors and anti-inflammatory mediators to further demonstrate each step of the pathway from glial activation to memory impairment.
- ACh:
Alzheimer's disease
Analysis of variance
Amyloid precursor protein
Brain-derived neurotrophic factor
- CD11b:
a microglial active marker
Ethylenediamine-tetraacetic acid
Enzyme-linked immunosorbent assay
Glial fibrillary acidic protein
Horseradish peroxidase
Nerve growth factor
- p75:
Low-affinity NGF receptor
Polymerase chain reaction
Phenylmethylsulfonyl fluoride
Receptor antagonist
Standard error of the mean
Tetramethyl benzidine
Tumor necrosis factor
- TrK:
Tyrosine kinase.
Block ML, Hong JS: Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 2005, 76:77–98.
Sugama S, Takenouchi T, Cho BP, Joh TH, Hashimoto M, Kitani H: Possible roles of microglial cells for neurotoxicity in clinical neurodegenerative diseases and experimental animal models. Inflamm Allergy Drug Targets 2009, 8:277–284.
Griffin WS, Mrak RE: Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease. J Leukoc Biol 2002, 72:233–238.
Griffin WS, Liu L, Li Y, Mrak RE, Barger SW: Interleukin-1 mediates Alzheimer and Lewy body pathologies. J Neuroinflam 2006, 3:5.
Taepavarapruk P, Song C: Reductions of acetylcholine release and nerve growth factor expression are correlated with memory impairment induced by interleukin-1beta administrations: effects of omega-3 fatty acid EPA treatment. J Neurochem 2010, 112:1054–1064.
Song C: The effect of thymectomy and IL-1 on memory: implications for the relationship between immunity and depression. Brain Behav Immun 2002, 16:557–568.
Patel HC, Ross FM, Heenan LE, Davies RE, Rothwell NJ, Allan SM: Neurodegenerative actions of interleukin-1 in the rat brain are mediated through increases in seizure activity. J Neurosci Res 2006, 83:385–391.
Shin JA, Park EM, Choi JS, Seo SM, Kang JL, Lee KE, Cho S: Ischemic preconditioning-induced neuroprotection is associated with differential expression of IL-1beta and IL-1 receptor antagonist in the ischemic cortex. J Neuroimmunol 2009, 217:14–19.
Tuttolomondo A, Di Raimondo D, di Sciacca R, Pinto A, Licata G: Inflammatory cytokines in acute ischemic stroke. Curr Pharm Des 2008, 14:3574–3589.
Petcu EB, Kocher T, Kuhr A, Buga AM, Klöting I, Herndon JG, Kessler C, Popa-Wagner A: Mild systemic inflammation has a neuroprotective effect after stroke in rats. Curr Neurovasc Res 2008, 5:214–223.
Pickering M, O'Connor JJ: Pro-inflammatory cytokines and their effects in the dentate gyrus. Prog Brain Res 2007, 163:339–354.
Marschinke F, Strömberg I: Dual effects of TNFalpha on nerve fiber formation from ventral mesencephalic organotypic tissue cultures. Brain Res 2008, 1215:30–39.
Brough D, Tyrrell PJ, Allan SM: Regulation of interleukin-1 in acute brain injury. Trends Pharmacol Sci 2011, 32:617–622.
Matarredona ER, Santiago M, Venero JL, Cano J, Machado A: Group II metabotropic glutamate receptor activation protects striatal dopaminergic nerve terminals against MPP+-induced neurotoxicity along with brain-derived NTF induction. J Neurochem 2001, 76:351–360.
Cadete-Leite A, Pereira PA, Madeira MD, Paula-Barbosa MM: Nerve growth factor prevents cell death and induces hypertrophy of basal forebrain cholinergic neurons in rats withdrawn from prolonged ethanol intake. Neuroscience 2003, 119:1055–1069.
Swanson RA, Ying W, Kauppinen TM: Astrocyte influences on ischemic neuronal death. Curr Mol Med 2004, 4:193–205.
Kerschensteiner M, Meinl E, Hohlfeld R: Neuro-immune crosstalk in CNS diseases. Neuroscience 2009, 158:1122–1132.
Dawbarn D, Allen SJ: Neurotrophins and neurodegeneration. Neuropathol Appl Neurobiol 2003, 29:211–230.
Bibel M, Barde YA: Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev 2000, 14:2919–2937.
Bredesen DE, Mehlen P, Rabizadeh S: Apoptosis and dependence receptors: a molecular basis for cellular addiction. Physiol Rev 2004, 84:411–430.
Leibinger M, Müller A, Andreadaki A, Hauk TG, Kirsch M, Fischer D: Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliary neurotrophic factor and leukemia inhibitory factor. J Neurosci 2009, 29:14334–14341.
Wu MD, Hein AM, Moravan MJ, Shaftel SS, Olschowka JA, O'Banion MK, Winter CD, Iannotti F, Pringle AK, Trikkas C, Clough GF, Church MK: A microdialysis method for the recovery of IL-1beta, IL-6 and nerve growth factor from human brain in vivo. J Neurosci Methods 2002, 119:45–50.
Mattson MP, Barger SW, Furukawa K, Bruce AJ, Wyss-Coray T, Mark RJ, Mucke L: Cellular signaling roles of TGF beta, TNF alpha and beta APP in brain injury responses and Alzheimer's disease. Brain Res Brain Res Rev 1997, 23:47–61.
Ikeda O, Murakami M, Ino H, Yamazaki M, Nemoto T, Koda M, Nakayama C, Moriya H: Acute up-regulation of brain-derived neurotrophic factor expression resulting from experimentally induced injury in the rat spinal cord. Acta Neuropathol 2001, 102:239–245.
Hayashida K, Clayton BA, Johnson JE, Eisenach JC: Brain derived nerve growth factor induces spinal noradrenergic fiber sprouting and enhances clonidine analgesia following nerve injury in rats. Pain 2008, 136:348–355.
Hock C, Heese K, Hulette C, Rosenberg C, Otten U: Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 2000, 57:846–851.
Rojo LE, Fernández JA, Maccioni AA, Jimenez JM, Maccioni RB: Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer's disease. Arch Med Res 2008, 39:1–16.
Song C, Phillips AG, Leonard BE, Horrobin DF: Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1beta in rats. Mol Psychiatry 2004, 9:630–638.
Song C, Horrobin DF: Omega-3 fatty acid ethyl-eicosapentaenoic acid but not soybean oil attenuates memory impairment induced by central IL-1beta-administration. J Lipid Res 2004, 45:1112–1121.
Song C, Leonard BE: The comparison of changes in behavior, neurochemistry, endocrine, and immune functions after different routes, doses and durations of administrations of IL-1beta in rats. Pharmacopsychiatry 2006, 39:88–99.
Luchtman DW, Shao D, Song C: Behavior, neurotransmitters and inflammation in three regimens of the MPTP mouse model of Parkinson's disease. Physiol Behav 2009, 98:130–138.
Datta SC, Opp MR: Lipopolysaccharide-induced increases in cytokines in discrete mouse brain regions are detectable using Luminex xMAP((R)) technology. J Neurosci Methods 2008, 75:119–124.
Proescholdt MG, Chakravarty S, Foster JA, Foti SB, Briley EM, Herkenham M: Intracerebroventricular but not intravenous interleukin-1beta induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation. Neuroscience 2002, 112:731–749.
Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, Laferla FM, Olschowka JA, O'Banion MK: Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model. J Neurosci 2013, 33:5053–5064.
Siegel GJ, Chauhan NB: Neurotrophic factors in Alzheimer's and Parkinson's disease brain. Brain Res Brain Res Rev 2000, 33:199–227.
Villoslada P, Genain CP: Role of nerve growth factor and other trophic factors in brain inflammation. Prog Brain Res 2004, 146:403–414.
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, O'Banion K, Klockgether T, Van Leuven F, Landreth GE: Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1–42 levels in APPV717I transgenic mice. Brain 2005, 128:1442–1453.
Browne KD, Iwata A, Putt ME, Smith DH: Chronic ibuprofen administration worsens cognitive outcome following traumatic brain injury in rats. Exp Neurol 2006, 201:301–307.
Sofroniew MV: Reactive astrocytes in neural repair and protection. Neuroscientist 2005, 11:400–407.
Smits HA, van Beelen AJ, de Vos NM, Rijsmus A, van der Bruggen T, Verhoef J, van Muiswinkel FL, Nottet HS: Activation of human macrophages by amyloid-beta is attenuated by astrocytes. J Immunol 2001, 166:6869–6876.
Saragovi HU, Hamel E, Di Polo A: A neurotrophic rationale for the therapy of neurodegenerative disorders. Curr Alzheimer Res 2009, 6:419–423.
Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC: Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. J Immunol 1999, 163:3963–3968.
Arancio O, Chao MV: Neurotrophins, synaptic plasticity and dementia. Curr Opin Neurobiol 2007, 17:325–330.
Bossers K, Meerhoff G, Balesar R, van Dongen JW, Kruse CG, Swaab DF, Verhaagen J: Analysis of gene expression in Parkinson's disease: possible involvement of neurotrophic support and axon guidance in dopaminergic cell death. Brain Pathol 2009, 19:91–107.
Schulte-Herbrüggen O, Jockers-Scherübl MC, Hellweg R: Neurotrophins: from pathophysiology to treatment in Alzheimer's disease. Curr Alzheimer Res 2008, 5:38–44.
Evans JR, Barker RA: Neurotrophic factors as a therapeutic target for Parkinson's disease. Expert Opin Ther Targets 2008, 12:437–447.
Wu MD, Hein AM, Moravan MJ, Shaftel SS, Olschowka JA, O'Banion MK: Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running. Brain Behav Immun 2012, 26:292–300.
Peng S, Wuu J, Mufson EJ, Fahnestock M: Precursor form of brain-derived NTF and mature brain-derived NTF are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem 2005, 93:1412–1421.
Peng S, Garzon DJ, Marchese M, Klein W, Ginsberg SD, Francis BM, Mount HT, Mufson EJ, Salehi A, Fahnestock M: Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer's disease. J Neurosci 2009, 29:9321–9329.
Li G, Peskind ER, Millard SP, Chi P, Sokal I, Yu CE, Bekris LM, Raskind MA, Galasko DR, Montine TJ: Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PLoS One 2009, 4:5424.
Gobbo OL, O'Mara SM: Exercise, but not environmental enrichment, improves learning after kainic acid-induced hippocampal neurodegeneration in association with an increase in brain-derived NTF. Behav Brain Res 2005, 159:21–26.
Volosin M, Song W, Almeida RD, Kaplan DR, Hempstead BL, Friedman WJ: Interaction of survival and death signaling in basal forebrain neurons: roles of neurotrophins and proneurotrophins. J Neurosci 2006, 26:7756–7766.
Ginsberg SD, Che S, Wuu J, Counts SE, Mufson EJ: Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease. J Neurochem 2006, 97:475–487.
D'Onofrio M, Arisi I, Brandi R, Di Mambro A, Felsani A, Capsoni S, Cattaneo A: Early inflammation and immune response mRNAs in the brain of AD11 anti-NGF mice. Neurobiol Aging 2011, 32:1007–1022.
Rohe M, Synowitz M, Glass R, Paul SM, Nykjaer A, Willnow TE: Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. J Neurosci 2009, 29:15472–15478.
Coulson EJ: Does p75 neurotrophin receptor mediate Aβ-induced toxicity in Alzheimer's disease? J Neurochem 2006, 98:654–660.
Chakravarthy B, Gaudet C, Ménard M, Atkinson T, Brown L, Laferla FM, Armato U, Whitfield J: Amyloid-beta peptides stimulate the expression of the p75 NTR neurotrophin receptor in SHSY5Y human neuroblastoma cells and AD transgenic mice. J Alzheimer's Dis 2010, 19:915–925.
Hein AM, Stasko MR, Matousek SB, Scott-McKean JJ, Maier SF, Olschowka JA, Costa AC, O'Banion MK: Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice. Brain Behav Immun 2010, 24:243–253.
Knipper M, da Penha BM, Blöchl A, Breer H, Thoenen H, Lindholm D: Positive feedback between acetylcholine and the neurotrophins nerve growth factor and brain-derived neurotrophic factor in the rat hippocampus. Eur J Neurosci 1994, 6:668–671.
Auld DS, Mennicken F, Day JC, Quirion R: Neurotrophins differentially enhance acetylcholine release, acetylcholine content and choline acetyltransferase activity in basal forebrain neurons. J Neurochem 2001, 77:253–262.
Song C, Phillips AG, Leonard B: Interleukin 1 beta enhances conditioned fear memory in rats: possible involvement of glucocorticoids. Eur J Neurosci 2003, 18:1739–1743.
Yirmiya R, Winocur G, Goshen I: Brain interleukin-1 is involved in spatial memory and passive avoidance conditioning. Neurobiol Learn Mem 2002, 78:379–389.
Coulson EJ, May LM, Sykes AM, Hamlin AS: The role of the p75 neurotrophin receptor in cholinergic dysfunction in Alzheimer's disease. Neuroscientist 2009, 15:317–323.
Barrientos RM, Sprunger DB, Campeau S, Watkins LR, Rudy JW, Maier SF: BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1beta administration. J Neuroimmunol 2004, 2155:119–126.
This study was supported by Canada Institutes for Health Research (CIHR), Canada, Amarin Neuroscience Ltd, Oxford, UK and Chinese National Natural Science Fund.
Additional information
Competing interests
The authors declare that they have no competing interests with respect to the authorship and/or publication of the article.
Authors' contributions
CS obtained the financial support, designed the experiment, trained researchers, analyzed data, prepared figures and tables and wrote the paper, YZ did a part of experiment (70%) and YD did a part of experiment (30%) and analyzed some of the data. All authors read and approved the final manuscript.
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Cite this article
Song, C., Zhang, Y. & Dong, Y. Acute and subacute IL-1β administrations differentially modulate neuroimmune and neurotrophic systems: possible implications for neuroprotection and neurodegeneration. J Neuroinflammation 10, 826 (2013). https://doi.org/10.1186/1742-2094-10-59
DOI: https://doi.org/10.1186/1742-2094-10-59


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The University Senate encourages all members of the campus community to submit proposals for improving the university. Proposals can be submitted through the senate office to be initially considered by the faculty leaders, who will forward them to the senate steering committee.
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@bridgecrewio ・ Sep 13,2021 ・ 6 min read ・ 985 views ・ Originally posted on bridgecrew.io
No, this isn't another post about the Secure Development Lifecycle. This is a practical post on why and how to address cloud security at each step of the infrastructure development lifecycle, from infrastructure as code in your IDE to running cloud resources.
The idea of addressing cloud security best practices earlier in the development lifecycle is catching on, as cloud security posture management (CSPM) vendors and cloud workload protection platforms (CWPPs) expand their offerings and acquire developer-first companies like ours. We think it's for a good reason.
Whether you call it developer-first security, DevSecOps, or "shift left," this approach provides a solution to two pervasive challenges with DevOps and cloud native methodologies:
Piggy-backing off the increased use of cloud configuration frameworks and infrastructure as code (IaC), the "shift left" approach promises improved efficiency and decreased risk. But as is true with most new and disruptive ideas, it's essential to view it within the context of real cloud environments, real developer workflows, and real business risk.
Misconfigurations indeed become more risky and expensive the further along in the lifecycle they get. However, it's also true that the earlier in the lifecycle you are, the less information is available about what infrastructure will look like and, thus, what misconfigurations may be present.
That's why it's important to address infrastructure security in both runtime and build-time. We would take that a step further and say that depending on the nature of your team, environment and processes, there are nuances between each phase of the development lifecycle that are important to consider.
Keep in mind that developer-first security doesn't preclude "traditional" cloud security methods—namely monitoring running cloud resources for security and compliance misconfigurations.
First of all, unless you've achieved 100% parity between IaC and the cloud (unlikely), runtime scanning is essential for complete coverage. You probably still have teams or parts of your environment—maybe legacy resources—that are still being manually provisioned via legacy systems or directly in your console and so need to be continuously monitored.
Even if you are mostly covered by IaC, humans make mistakes and SREmergencies are bound to happen. We recently wrote about the importance of cloud drift detection to catch manual changes that result in unintentional deltas between code configuration and running cloud resources. Insight into those resources in production is essential to determine those potentially risky gaps.
Runtime scanning also has some advantages. Because it follows the actual states of configurations, it's the only viable way of evaluating configuration changes over time when managing configuration in multiple methods.
Relying solely on build-time findings without attributing them to actual configuration states in runtime could result in configuration clashes. For example, attempting to encrypt a previously unencrypted DB instance could fail to provision a change, or purge current instances and replace them by new empty ones—since some managed DB services, like RDS, do not permit encryption after the fact.
It's also a great way to satisfy compliance audits that require continuous change-control auditing and tracing. By mapping to compliance benchmarks and sections, you can use the scan reports as baseline evidence to meet most industry-specific requirements and audits.
The beauty of IaC is that it allows for preemptive and even proactive monitoring of infrastructure—before it's deployed. CI/CD pipelines are critical in compiling infrastructure and testing that compiled code before it's delivered and deployed. At this phase, IaC is quite representative of how it will be provisioned once it's deployed.
For Terraform code, for example, terraform plan output contains a much higher integrity of detail than it does in its previous stages. Scanning this level of abstraction is important, to see if misconfigurations exist in the core resources about to be provisioned and in its variables and dependent modules.
The other benefit of embedding infrastructure security into the CI/CD pipeline is that it's automated and can be fully customized for your workflow. You can determine what kinds of checks fail builds and surface feedback directly in your CI/CD provider. It's also a collaborative process that your entire team is using to review, reject, and approve changes.
Similarly, for teams who live and die by their version control systems (VCSs), embedding security into pull requests and sanctioned code review processes has many benefits. Depending on what triggers your CI/CD builds, this approach can be used in tandem with—or instead of' scanning via CI/CD.
Your VCS may also afford some unique controls for implementing internal controls. All three major platforms (GitHub, GitLab, and Bitbucket) offer versioning, branching, and embedded code review and authorization controls, that allow developers to test without compromising running production systems and to continue making code changes before merging.
For example, you may want to set up your code review settings to block merges when checks fail, further ensuring that misconfigured IaC doesn't make its way to your master branch.
Regardless of whether you're scanning in CI/CD or your VCS, this level of control promotes collaboration and accessibility to developers. If you can provide fixes, in addition to detection to and from the same stage, your task is that much easier.
One of the major benefits of scanning integrated code before a CI/CD gets triggered is the ability to make changes without waiting for your build to finish. For many of us, waiting for builds to finish is the bane of our existence. Re-running builds that failed due to a security misconfiguration is a huge time suck that can be avoided by shifting security a step left. Pre-commit unit and integration testing is a generally accepted best practice, but pre-commit security testing may not yet be on your list of priorities as an infrastructure developer.
Scanning IaC locally for misconfigurations is the best way to address errors in the safety of your own workspace, without having to waste time failing builds (and delaying your teammates' builds) or tripping the wire on pull request checks.
Raising flags before it even gets to your shared repositories is the epitome of shift-left security, but the onus is on the developer to run the scans and make the changes.
The only thing better than scanning your IaC before committing it is getting in-line feedback wherever you're actually writing code. Because it minimizes context switching (there's no need to run ad hoc scans), it's the cheapest and most foolproof way to identify misconfigurations.
To shift cloud security as far "left" as possible (besides the design and plan phases), embedding guardrails into your IDE is the best way to go. This likely will come in the form of a plugin or extension, such as the Checkov VS Code extension. The Checkov extension makes that scanning process even more seamless, by providing real-time and continuous scanning and in-line fixes as you code. Whether you're taking the feedback and implementing changes in the moment, or you're using IDE suggestions as an educational tool for writing secure infrastructure, there are very few downsides.
With the right balance of passive analysis and actionable feedback, you can become a better security advocate without an outsized amount of effort.
At the end of the day, that's what will move the needle when it comes to making infrastructure security and compliance accessible to developers. Making these tools accessible while enforcing guardrails collectively and at different checkpoints is the true manifestation of shifting security left.
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21st January 1994
On this day, three far-eastern companies bought Automobili Lamborghini. Indonesian Megatech bought 80 percent of the company, whilst MyCom and V'Power bought 10 percent each. However, all three companies were part of the same Indonesian holding company, Sedtco. In 1995, Megatech sold its shares to the other two, leaving MyCom with 40 percent and V'Power with 60 percent. MyCom, a Malaysian company, was controlled by Jeff Yap. V'Power, Indonesian company led by Tommy Suharto, also owned the American exotic marque Vector at this point of time.


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24th June 2006
Concorde Winter Rally - March 2006The Concorde Winter Meeting held in Mauterndorf, Salzburger Land, between the 16th and 24th March 2006, proved to be a very special experience for everyone who attended.
Surrounded by kindred spirits, a dream landscape and loads of snow, there was something for everyone: skiing, hiking, castle tours and culinary delights in
both solid and liquid form. Here are a few images and impressions.
See Also: Concorde Links:
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Holler at the Most Professional & Reliable Towing Service!!!
Our Carrollton tow truck service provides the best roadside assistance to Plano, Richardson, Allen, Frisco, Coppell, Farmers Branch, Irving, Addison, The Colony, Lewisville, Dallas and of course Carrollton! Imagine this. You are already running late for an urgent meeting, or stuck in the traffic while going to the office. You are trying to make up for the lost time and reach where you need to be as early as possible. But, just when you think that things couldn't get any worse, your car breaks down in the middle of the road, leaving you stranded. It's as if the universe is plotting against you all the time!
We all have experienced situations like this at least once in our lifetime. Only the context is different. For some, it is when they are on their way to catch a game, attending a birthday party, or something else that is urgent. But hey, that's why Towing Carrollton was developed, so that we could get you through these exact situations and get you back on the road! If you want a fast responding and reliable tow truck company, then please give us a call!
Unfortunately, there are also some lame wanna be tow truck services in Carrollton as well. You will find most of them charge exorbitant fees to have your vehicle towed.
More importantly, by the time they are done with your vehicle, they will have inflicted more damages to it that it had in the first place, thanks to their unprofessional services. If you really want the best professional towing services in the entire area of the DFW, and at the most affordable prices, then Towing Carrollton is your top trustworthy towing service partner.
There is nothing more frustrating than being left stranded, and unable to reach where you want to be. Compounding your woes is the fear of impending high towing chargers that you will end up paying at the end of this nightmare. But, guess what! The days of worrying about these issues are a thing of the past. Towing Carrollton TX has been started with an explicit purpose and making the lives of Texans easier and better. Whenever your vehicle has broken down in the middle of nowhere, we respond with the same sense of urgency as you feel. In fact, we empathize with the situation that our customers are, and do everything in our power to make your lives easier. That includes coming to the place where your vehicle has broken down in the least possible time. Irrespective of where your car has broken down in and around Carrollton, Texas, we can give you the best ETA in all of the state of Texas.
It is not just the speed that matters. The quality of our Carrollton wrecker services is also unmatched in the industry. We make use of the latest equipment and machinery to help you in emergency situations.
We are the most popular Carrollton towing service for many reasons. One of the most important reasons is that we are licensed, bonded and completely insured. We are the one Carrollton towing company that completely abides by all towing laws. Even if your vehicle is subjected to any smallest of damages because of our service, you need not worry about that.
Why Us?
You could be thinking "If I pick a tow truck service near me, then I will get faster and better service". But, the fact is that you never know when and where your vehicle will break down. Most importantly, limiting yourself to your neighborhood service doesn't guarantee you high quality. So, it is important that you pick a towing service that guarantees uncompromising professionalism, and great experience. A quick search on the internet will give you numerous options to choose from, when you are looking for a towing service. However, the best towing services are easy to distinguish from the mediocre ones. Here's why we should be your trusted partners in emergency situations.
Quality Towing in Carrollton
We use state-of-the-art technology and towing machines to tow your vehicles. This way, we can prevent any sort of damage from happening to your precious vehicle. We will respond to your call, whenever your vehicle breaks down, instantly. Our professionals will be immediately on their way to address your issue.
Customer Response
Of course, we can say anything we want about our services. But, the truth is best heard from the people whom we have actually served. Just a quick search on the internet will show you that we are the most loved and respected towing service in and around Carrollton. Once customers experience our services, they are overwhelmed by the professionalism and quality of our services. That's why, you will find nothing but sweet things to hear from our customers. Trust their word and you will also become part of one big happy family that is Towing Carrollton TX.
Our Carrollton towing service works 24X7, 365 days a year. No matter when your vehicle breaks down, whether it is the wee hours of the morning, or some holiday, we are always ready to serve you. We are committed to making our customers' lives easier and stick to our commitment, irrespective of the time of the day or the day of the week. So, don't worry. Whenever your vehicle breaks down, just give us a call, and we will be on our way, fully equipped to deal with any kind of emergency.
As professionals, we serve all types of clients with a variety of vehicle sizes. So, the simple answer is that the towing option you should opt for depends on the size of your vehicle. If you have a compact vehicle that weighs less than 5,000 pounds, then you will be needing a light duty towing service. However, if your vehicle weighs anywhere in the range of 10 tons to 25 tons, then you will be requiring a medium duty towing service. On the other hand, if its weight exceeds 25 tons, then you will be requiring heavy duty towing service. Call Now!!!


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Friday, July 27, 2012
Follow My Book Blog Friday (49)
19 comments:
I've always wanted to read Wuthering Heights, but haven't!! Thanks for stopping by my post, and I really, really love your blog design! It's so cute!ReplyDelete
New follower :D
My FF
This one is showing up a lot today. I have it on my Classics To Read list. Thanks for stopping by My FFReplyDelete
I have never read this one, although I've seen the movie (I know it's not the same!)ReplyDelete
Liza's Feature Friday
I picked that one as well. I remember reading Wuthering Heights for an essay project. Loved it.ReplyDelete
My FF
So glad you enjoyed this one! I haven't read it yet.ReplyDelete
Thanks for stopping by! :)
i haven't read this one yet! i need to go add it to my TBR list right away.ReplyDelete
trish - my ff
Wuthering Heights is AWESOME!ReplyDelete
But I never had to read it for school!!!
I am a new follower!
Please come follow me back
I love Wuthering Heights! But I hate it when the movies portray Heathcliff as some sort of romantic hero when really he's just a spiteful, downright nasty person.ReplyDelete
New follower!
(from destinationbookland.blogspot.com)
My favorite was Into The Wild. Actually made me cry a bit. Hah :)ReplyDelete
New follower!
Andrea @ Literary Getaway
- AnonymousJuly 27, 2012 at 11:31 AM
Confession: I've never read it! It certainly wasn't on our reading lists at school. I've got a copy on my shelf but just haven't got around to it yet.ReplyDelete
I LOVE the style of the copy in the picture. Thanks for stopping by, new follower :)
I know I have to get to it one day, but the size is intimidating, lol. Thanks for stopping by my blog. I love yours, we have the same taste in books =)ReplyDelete
Wuthering Heights is a great choice! Happy Friday! My FFReplyDelete
I read it but in Spanish and it's really good!ReplyDelete
3 Copies? I have 3 copies as well of the Little Prince.
Old follower
Good choice! I have to say I got kind of fed up with the love story because they are kind of whiny :-) Thanks for stopping by!ReplyDelete
Old follower.
Ensconced in YA
This is definitely one of the better classics I read in school. the only one I read 2 times. The more I read it the more I like it too!ReplyDelete
My FF
Ning @ Reading by Kindle Fire
Great pick! I need to read this soon, it's just stupid that I haven't. Lol. Old follower!ReplyDelete
My FF:
I tried reading this one for fun, but couldn't finish it. Glad you enjoyed it! Old follower.ReplyDelete
Thanks for stopping by!
Doodle @ Doodle's Book Blog
Hey! Thanks for stopping by! I still haven't read Wuthering Heights...ReplyDelete
Vanya D. @ YA Story Teller
Wuthering Heights is another book that I really enjoyed but didn't read in school. For some reason we never read the classics that i liked that every other school read.ReplyDelete


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TALK RADIO UPDATE….Yes, Michael Savage is a very bad man, and all right thinking people already know that his employment by MSNBC is a both a mystery and an abomination.
Still, even for us bitter, hardened, cynical liberals who swear that nothing about right wing talk radio can surprise us anymore ? well, Savage still manages to surprise us. The Mighty Reason Man has the latest.


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31 Jul 2020
Bolton on course for international golf destination as Government gives green light to Hulton Park plans
Peel L&P's plans to create an international golf destination in Bolton capable of hosting the Ryder Cup and other major tournaments have been given the go ahead by the Government.
Peel L&P's proposals to transform the historic Hulton Park estate were called-in for a decision by the Secretary of State for Housing Communities and Local Government having secured Bolton Council's approval back in 2018.
Following a public inquiry and evidence to demonstrate the scale of the social and economic benefits of the development, amounting to a £1.2 billion boost to the national economy, Rt Hon Robert Jenrick MP has now given the planning application his seal of approval.
Peel L&P has remained committed to its exciting plans to open an iconic worldwide golf destination at Hulton Park in 2025 which also has the potential of hosting the Ryder Cup.
A socio-economic impact study shows that the overall impact of Hulton Park and the Ryder Cup programme would be £1.2 billion, bringing huge benefits to Bolton, Greater Manchester and the North West in terms of skills, participation, health development and tourism as well as securing future major sporting events.
The plans include a luxury hotel, spa and conference centre and an academy which would be easily accessible to help drive sports participation for the local community.
The provision of new homes would also help to meet Bolton's housing needs and provide affordable housing in the area.
Evidence prepared by leading ecologists and heritage experts showed that the proposals would have a positive impact on the site. Transport evidence including a link road to benefit the wider area shows how the site will be highly accessible.
In addition to securing approval from Bolton Council, the project has the support of a wide range of sports and tourism bodies, local universities and business groups.
Richard Knight, Director of Land and Communities for Peel L&P said: "We take great pride in creating projects that can leave a positive legacy. Our plans for Hulton Park can deliver an amazing global sporting destination capable of hosting major tournaments as well as a catalyst for positive change, healthy living, heritage restoration and tourism in Bolton.
"The proposals can also bring much-needed housing to the borough and the development is both respectful to the area's heritage and the environment with original roads and footpaths retained and the creation of new wildlife habitats to enhance biodiversity.
"We're incredibly pleased that the Secretary of State recognises all of these benefits alongside our vision for Hulton Park and this decision allows us to move to the next stage of making the project a reality."
The Hulton Park proposals have been approved subject to a restriction regarding the award of the Ryder Cup. Further announcements will be made in due course.
Notes for Editors
For further information about the Hulton Park project please see the website www.hultonpark.co.uk
Ryder Cup Europe and the PGA European Tour ultimately decide on the host venue for the Ryder Cup in conjunction with host nation Governments and venues.
Plans received Secretary of State approval on 30 July 2020.
National planning and development consultancy Turley provided planning, economics, EIA and design services for the project and acted in an expert witness role during the inquiry.


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On Saturday, I bought a new grill in preparation for my annual party on Wednesday. I was tired of the using the old charcoal grill that I inherited with my apartment. It was pain clean out the old ashes, a pain to light the charcoal even with a chimney starter, a pain to grill just at the right time. So I got the cheapest gas grill I could find. Yesterday, I tried it out because I had never cooked with a gas grill. I couldn't get the gas cylinder screwed in. I think I had it cross-threaded. It wouldn't light. Then, it wouldn't unscrew. I think I may have been turning it the wrong direction since the directions said turn counter-clockwise to undo which is wrong. Finally, part of the burner broke off with the regulator. With a better grip, I was able to get it unscrewed. But now the cheapo grill was broken. I sent an email to the company and would like to get a refund but I don't expect much from $20 grill.
Today, I bought a new grill. I got a [Weber Baby Q](http://www.weber.com/bbq/pub/grill/2007/q/Q100.aspx) which is a well-reviewed portable. It was expensive enough that there were cheap standup grills for the same price. I wanted the portable since I can see taking it camping. It was much easier to setup unlike the cheap one which had to be assembled; three screws vs eleven. The cylinder screwed in perfectly. I did have to remove the cylinder holder since I had a 16.4 oz bottle and it takes longer, thinner 14.1 oz bottles. The flame lit easily; I could fine the starter button unlike the cheap one. The construction is solid. I didn't worry about it falling off the little table. And the food was yummy.


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The Dec. 11 lecture at Seattle's Museum of Flight features retired Boeing engineer Bob Bogash presenting the story of Kelly Johnson, one of the most influential aeronautical engineers in aviation history. The program profiles the Lockheed manager and engineer who was involved in the design of dozens of aircraft, including the Model 10 Electra, P-38 Lightning, P-80 Shooting Star, F-104 Starfighter, SR-71 Blackbird and the Constellation airliner. Johnson was also instrumental in the operation of Lockheed's legendary division of advanced projects, the Skunkworks, where he helped develop the U-2 and Blackbird spy planes.
The program is at 2 p.m. in the William M. Allen Theater, and is free with admission to the museum.
Visitors to the museum can see many examples of Johnson's designs, including the Blackbird, Lightning, Starfighter and Constellation. Johnson's personal corporate aircraft, the Lockheed Jetstar prototype, can be seen at the Museum's Restoration Center at Paine Field in Everett.
For more information: MuseumOfFlight.org


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ProjectionsbyJayne Jaudon Ferrer
From A New Mother's Prayers (Pocket Books, 1989 and 1996, and Loyola Press, 2004).
Used here with the author's permission.
Jayne Jaudon Ferrer is the author of four books of poetry and a nonfiction books about games. A public relations specialist and freelance journalist, Ferrer speaks frequently at chuches, schools, and writing-related events. Her work has appeared in hundreds of publications, ranging from Boca Raton Magazine to Christian Parenting Today, and she is the founder and editor of YourDailyPoem.com. Originally from Florida, Jayne now lives in Greenville, South Carolina. The mother of three sons, she enjoys reading, music, old movies, and good conversation. Learn more about Jayne at www.jaynejaudonferrer.com.


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Smart card problems with Dell Latitude and Vista
October 9, 2007 Dell, Drivers, Security, Smart card, Windows Vista 2 Comments
I only have my domain administrator account on a smart card to improve security in my domain, but this is not working as one can expect in Vista. Sometimes, especially when I wake the computer from sleep but also at other times, the credential tile for smart card authentication vanishes as the Smart card service stop working somehow. The only solution to this issue is to reboot the computer unfortunately. After becoming sick and tired of the problem I called Dell from which I got a beta driver. This driver seems to be somewhat more stable but not 100 percent stable. SP1 makes no difference either.


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Speaker Nancy Pelosi (D-CA) announced Thursday she is creating a special House committee to oversee the Trump administration handling of the historic $2 trillion relief package and its ongoing response to the coronavirus pandemic.
"The committee will be empowered to examine all aspects of the federal response to coronavirus and to assure that the taxpayers' dollars are being wisely and efficiently spent to save lives, deliver relief, and benefit our economy," Pelosi said on a conference call with reporters Thursday morning. "The panel will root out waste, fraud and abuse; it will protect against price-gauging, profiteering and political favoritism. We need transparency and accountability."
Pelosi has tapped Rep. Jim Clyburn (D-SC), the House Majority Whip, to lead the "House Select Committee on the Coronavirus Crisis." The bipartisan panel would be tasked to ensure "are spent carefully and effectively" and will investigate how the private sector is spending its government funds.
"We face a deadly virus and a battered economy with millions of Americans suddenly out of work," Pelosi said. "Congress has taken an important step in leading this crisis by passing three bills with over $2 trillion in emergency relief. We need to ensure those dollars are spent carefully and effectively."
The House last week overwhelmingly passed the $2 trillion relief package, dubbed the CARES Act to address the detrimental impact from the coronavirus pandemic. President Trump shortly after the House passage signed the stimulus package into law that includes a one-time payments to many Americans based on their level of income, as well as providing $387 billions in small business loans, $100 billion for hospitals, $200 billion for other "domestic priorities," including child care and assistance for seniors, $250 billions in unemployment insurance benefits and $500 billion in loans for distressed companies.
Pelosi compared the special committee to the one that was chaired by then-U.S. Senator Harry Truman during World War II, saying the eventual president "immediately recognized the urgency of oversight and accountability and making sure the money did what it was supposed to do."
"Where there's money, there's also frequently mischief," Pelsoi said. "We want to just make sure that the funds that are put out there are done so with the conditions that we had in the legislation, that there will be implementation of the bill expeditiously and any way that we can be helpful with having more transparency to get that done."
She also told reporters that the panel will have subpoena power and will be focused on "the here and now," as opposed to an investigation into the past.
"It would have subpoena power that's for sure. It's no use having a committee unless you have subpoena power," she said. "And we would hope that there would be cooperation because this is not a kind of an investigation of the administration it's about the whole response."
House Homeland Security Committee Chairman Rep. Bennie Thompson (D-MS) introduced legislation Wednesday to create an independent commission modeled after the 9/11 commission that will be tasked in producing a "full and complete accounting of the nation's preparedness and response" to the coronavirus. House Intelligence Committee Chairman Adam Schiff (D-CA) was the first Democratic lawmaker to express drafting legislation to create a "nonpartisan commission" to scrutinize the Trump administration's response and handling of the Coronavirus pandemic.
The House is currently in recess and slated to reconvene on April 20.
- Fed FOMC November Meeting: Live Updates
- House Republicans To Choose New Speaker Nominee: Live Update
- Second Republican President Debate: Live Update


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Completion Date: 27 Jun 2005
Client - Salford PCT and LA
Nature of Work -
The Whole Systems Partnership have been asked to undertake, in partnership with local stakeholders, the development of a comprehensive commissioning model for Early Intervention in Psychosis services. It is planning to undertake this work by appraising both national and local policy and stakeholder expectations and then building a model that will be shared and developed in a workshop environment. As well as developing a future model of service the work will identify implementation proposals to ensure progress is made toward realising this model within a reasonable period of time.WSP Lead - Peter Lacey
If no WSP Lead is displayed then please contact email@example.com in the first instance


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*Collaborative post.
Our skin is one of our most prized possessions. We have our skin every day, so taking care of it should be one of the most important things since we can't just go and get new skin. I neglected my skin for years in my youth and I paid dearly for it. Now that I am older and wiser, I now know how important the skin is and why everyone should have a good skincare routine. Our diet and lifestyle affect the skin, which is why we have to really pay attention to what we eat and drink, and how we live day-to-day.
Once you hit the thirties, your skin would likely change. You will usually have to change your skincare products and routine to nourish your new skin. This is where the anti-ageing products come in usually. However, you could include beauty foods to help you nourish your skin from the inside out. Here are some beauty foods for anti-ageing –
Soya-based foods
These help aid skin regeneration while slowing down the ageing process. Some of my favourite soya-based foods are soya milk and soya yoghurt.
Antioxidant rich foods are great for keeping the skin looking youthful and nourished. Some of them are sweet potatoes, mangoes, tomatoes and peppers.
Vitamin A-rich foods
Orange fruit and vegetables are amazing for the skin. They are great for helping clear out acne and other skin conditions.
Drink water
This tip can't be overemphasised. Drinking a couple of glasses of water would do wonders for your skin and health. If you are like me, you may struggle to drink the required amount of water daily, but it's strongly advised that you do. Hydrating foods like cucumber, watermelon and celery are great for the skin as well.
Our skin is super important and caring for it every day should be non-negotiable. Many of us spend a small fortune on skincare products but fail to pay attention to our diet and lifestyle. If we eat right and live right, we may not need that many products to keep our skin glowing.
What do you think of these beauty foods for anti-ageing? Do you eat any on a regular basis? Also, do check out these gry 77777 za darmo online games.


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Quinto Nonas Maji. Luna . The Third Day of May. The Night of the Moon.
|Hierosólymis Invéntio Sacrosánctæ Crucis Domínicæ, sub Constantíno Imperatóre.
|At Jerusalem, in the time of Emperor Constantine, the finding of the holy Cross of our Lord.
|Romæ, via Nomentána, pássio sanctórum Mártyrum Alexándri Papæ Primi, Evéntii et Theodúli Presbyterórum. Ex his Alexánder, sub Hadriáno Príncipe et Aureliáno Júdice, post víncula, cárceres, equúleum, úngulas et ignes, punctis crebérrimis per tota membra confóssus ac perémptus est; Evéntius vero et Theodúlus, post longos cárceres, ígnibus examináti, ad últimum decolláti sunt.
|At Rome, on the Via Nomentana, the holy martyrs Pope Alexander and the priests Eventius and Theodulus. Alexander was bound, imprisoned, racked, lacerated with hooks, burned, and had all his limbs pierced with pointed instruments, and finally met death, under Emperor Hadrian and the judge Aurelian. Eventius and Theodulus after a long imprisonment were exposed to flames and then beheaded.
|Nárniæ sancti Juvenáli, Epíscopi et Confessóris.
|At Narni, St. Juvenal, bishop and confessor.
|Apud montem Senárium, in Etrúria, natális sanctórum Sostenǽi et Ugucciónis Confessórum, e septem Fundatóribus Ordinis Servórum beátæ Maríæ Vírginis; qui, cælitus admóniti, eádem die et hora, salutatiónem Angélicam recitántes, e vita migrárunt. Ipsórum autem ac Sociórum festum prídie Idus Februárii celebrátur.
|On Mount Senario in Etruria, Saints Sosteneo and Ugoccio, confessors, of the seven founders of the Order of Servites of the Blessed Virgin Mary. Responding to a voice from heaven, they departed this life on the same day and at the same hour, while reciting the angelical salutation. Their feast is observed with the rest of their companions on the 12th day of February.
|Constantinópoli sanctórum Mártyrum Alexándri mílitis, et Antonínæ Vírginis. Hæc, in persecutióne Maximiáni, sub Prǽside Festo, ad lupánar damnáta, et ab Alexándro, qui pro ipsa ibi remánserat, mutátis véstibus clam edúcta, cum eo póstmodum jussa est torquéri; et ambo simul in ignem, præcísis mánibus, pro Christo sunt injécti, atque ita, egrégio perácto certámine, coronántur.
|At Constantinople, the holy martyrs Alexander, soldier, and Antonina, virgin. In the persecution of Maximian, under the governor Festus, Antonina, having been condemned to remain in a place of debauchery, was delivered by Alexander, who secretly exchanged garments with her, and took her place. They were tortured together, both had their hands cut off, were cast into the fire, and received their crowns at the end of their heroic combat for the faith.
|In Thebáide sanctórum Mártyrum Timóthei et Mauræ cónjugis, quos Ariánus Præféctus, post multa torménta, cruci jussit affígi; in qua, per novem dies cum vivi pependíssent ac se ipsos in fide roborássent, martyrium consummárunt.
|In Thebais, the holy martyrs Timothy and his wife Maura. The Prefect Arian caused them to be tortured, and then fastened to crosses, on which they remained alive for nine days, encouraging each other to persevere in the faith, until they completed their martyrdom.
|Aphrodísiæ, in Cária, sanctórum Mártyrum Diodóri et Rhodopiáni, qui, in persecutióne Diocletiáni Imperatóris, a cívibus suis lapidáti sunt.
|At Aphrodisia in Caria, the holy martyrs Diodorus and Rodopian, who were stoned to death by their fellow citizens, in the persecution of Diocletian.
|Et álibi aliórum plurimórum sanctórum Mártyrum et Confessórum, atque sanctárum Vírginum.
R. Deo grátias.
|And elsewhere in divers places, many other holy martyrs, confessors, and holy virgins.
R. Thanks be to God.
|May III.
|The Invention or Discovery of the Holy Cross
|St. Alexander, Pope and Martyr
All Civilians Subject To Persecution-What Is Driving The Uncontrolled Violence In The CAR?
NIGERIA: Abducted School Girls Forced To Marry Radical Islamic Captors
Amazing Video Of Chinese Believers Getting 1st Bibles
Three Egyptian Cousins Go to Libya; None Comes Back Alive
A Minor Gang Raped in Pakistan
The Stench of Death, Abomination & Devastation Coming From The Middle East & Africa
Snapshots From Daily Life In Nigeria: Rape, Kidnapping, Torture & Precision Executions
The World In Labor But Aborted In Syria
Should We Pray for the Persecuted?
Today—take some time to Pray for Christians who are Persecuted. They are desperate for your prayers.
Christian Pastor Among 30 Prisoners Badly Beaten in Evin Prison Raid
British Pakistani Christian Association chairman attends Number 10 Easter reception
Nigerian Christians: 'Our Blood Will Speak about Christ'
Christian Pastor Among 30 Prisoners Badly Beaten in Evin Prison Raid


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A group of pro-gas drilling landowners from upstate New York filed a lawsuit Friday against Gov. Andrew Cuomo, seeking to compel the state to complete its review of high-volume hydraulic fracturing.
A de facto moratorium on high-volume hydraulic fracturing, or fracking, has been in effect since the state Department of Environmental Conservation began a review of the practice in 2008. And the state Department of Health has been conducting its own health review of fracking since the fall of 2012. Whether the state will grant fracking permits depends on the outcome of both reviews.
The Joint Landowners Coalition of New York, which represents over 70,000 people spread over 14 counties, said in its lawsuit that Mr. Cuomo has overstepped his authority by becoming involved with both fracking reviews conducted by the DEC and DOH. Mr. Cuomo's involvement has been politically motivated, the complaint said.
"The major reasoning behind this is that we have been at the process for over a half decade," Scott Kurkoski, an attorney for the coalition. The governor has delayed both reviews because "he is worried about how people will react to this issue."
Mr. Cuomo's office didn't immediately respond to a request for comment.
The DOH and its Commissioner Nirav Shah along with the DEC and its commissioner Joseph Martens were also named in the complaint. A DEC spokeswoman said the department didn't comment on pending legislation. A spokesman with the DOH didn't immediately return a requests for comment.
As an alternative to compelling the state to complete its fracking review, the landowners are asking for a hearing and jury trial that would require Mr. Shah and Mr. Martens to testify. The petitioners are also seeking to subpoena all records related to the fracking review from the DEC and DOH and the governor's office under that alternative scenario.


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On Oct. 20, Toronto family lawyer Nathalie Boutet will share her expertise on "The Neuroscience of Conflict" with LLM students at Osgoode Hall Law School.
Boutet, a pioneer in the field of Neuro Family Law — the integration of the science of the brain and the psychology of negotiation into law — will speak to students in The Theory and Practice of Dispute Resolution course from 1:30 – 3 p.m. Only those registered in the LLM program will be able to attend the session.
For more information, click here.