text:
A peer-reviewed clinical and translational neurology open access journal
June 2016; 3 (3) ArticleOpen Access
Laquinimod prevents cuprizone-induced demyelination independent of Toll-like receptor signaling
Nadine Kramann, Lena Menken, Liat Hayardeny, Uwe-Karsten Hanisch, Wolfgang Brück
First published May 17, 2016, DOI: https://doi.org/10.1212/NXI.0000000000000233
Nadine Kramann
From the Institute of Neuropathology (N.K., L.M., U.-K.H., W.B.), University Medical Center Göttingen, Germany; and Teva Pharmaceutical Industries (L.H.), Netanya, Israel.
Lena Menken
Liat Hayardeny
Uwe-Karsten Hanisch
Wolfgang Brück
Neurol Neuroimmunol Neuroinflamm Jun 2016, 3 (3) e233; DOI: 10.1212/NXI.0000000000000233
Objective: To test whether Toll-like receptor (TLR) signaling plays a key role for reduced nuclear factor B (NF-κB) activation after laquinimod treatment in the model of cuprizone-induced demyelination, oligodendrocyte apoptosis, inflammation, and axonal damage.
Methods: Ten-week-old C57BL/6J, TLR4−/−, and MyD88−/− mice received 0.25% cuprizone for 6 weeks and were treated daily with 25 mg/kg laquinimod or vehicle. After 6 weeks of demyelination, extent of demyelination, oligodendrocyte density, microglia infiltration, and axonal damage were analyzed in the corpus callosum. Additionally, we analyzed primary mouse astrocytes from C57BL/6J, TLR4−/−, MyD88−/−, and TRIF−/− mice for alteration in NF-κB signaling.
Results: Vehicle-treated controls from C57BL/6J, TLR4−/−, and MyD88−/− mice displayed extensive callosal demyelination as well as microglial activation. In contrast, mice treated with 25 mg/kg laquinimod showed mainly intact callosal myelin. The demyelination score was significantly higher in all untreated mice compared to mice treated with laquinimod. There were significantly fewer APP-positive axonal spheroids, Mac3-positive macrophages/microglia, and less oligodendrocyte apoptosis in the corpus callosum of laquinimod-treated mice in comparison to untreated controls. Stimulated primary mouse astrocytes from laquinimod-treated groups show reduced NF-κB activation compared to vehicle-treated controls.
Conclusions: Our results confirm that laquinimod prevents demyelination in the cuprizone mouse model for multiple sclerosis via downregulation of NF-κB activation. This laquinimod effect, however, does not involve upstream Toll-like receptor signaling.
APP=
amyloid precursor protein;
CDP=
confirmed disability progression;
IFN-γ=
interferon-γ;
IL-1β=
interleukin-1β;
LFB-PAS=
Luxol fast blue–periodic acid–Schiff;
LPS=
lipopolysaccharide;
MS=
multiple sclerosis;
MyD88=
myeloid differentiation primary response 88;
NF-κB=
nuclear factor B;
TIR=
Toll-IL-1 receptor;
TLR=
Toll-like receptor;
TRIF=
Toll-IL-1 receptor domain containing adapter inducing interferon-γ;
WT=
Multiple sclerosis (MS) is the most common cause of nontraumatic disability in young adults. MS is a chronic inflammatory demyelinating disease of the CNS causing focal lesions in white and gray matter,1,2 which are pathologically characterized by inflammation, demyelination, microglial activation, astrogliosis, and axonal injury. Activation of the nuclear factor B (NF-κB) in MS brains has been detected in oligodendrocytes, astrocytes, microglia, and infiltrating macrophages in or close to CNS lesions.3,4
Laquinimod is an oral immunomodulator in clinical development for the treatment of relapsing-remitting MS and progressive MS5,6 that is thought to mitigate both the inflammatory and the neurodegenerative aspects of MS. It is a small molecule passively entering the CNS,7 which has been found to inhibit clinical signs of experimental autoimmune encephalomyelitis, the established autoimmune animal model of MS.8,9 Additionally, laquinimod has shown CNS-protective effects in cuprizone-induced demyelination, another experimental model of MS.10
Toll-like receptor (TLR) stimulation is a major and potent inducer upstream of the NF-κB signaling pathway. TLRs recruit adapter proteins with Toll-IL-1 receptor (TIR) domain containing adapter myeloid differentiation primary response 88 (MyD88) and the adapter molecule TIR domain containing adapter inducing interferon-γ (TRIF),11 resulting in downstream activation of NF-κB (figure 1).10,12 To address the question whether TLR signaling is essential for downstream activation of NF-κB, we studied the effect of laquinimod treatment in transgenic mice and primary mouse astrocytes lacking important TLR signaling components.
Figure 1 Activation of nuclear factor B (NF-κB) through Toll-like receptor (TLR) signaling
At the cell surface, TLRs bind to their respective ligands. TLR3 is localized at endosomes, where they sense host-derived or microbial nucleic acids. TLR4 can be localized at both the plasma membrane and the endosomes. After ligand-induced dimerization of receptors, TLR signaling is initiated. Afterwards, Toll-IL-1 receptor (TIR) domain-containing adaptor proteins are engaged: either myeloid differentiation primary response 88 (MyD88) or Toll-IL-1 receptor domain containing adapter inducing interferon-γ (TRIF), leading to stimulation of downstream signaling pathways involving tumor necrosis factor receptor-associated factor (TRAF). One important transcription factor downstream of TLR signaling is NF-κB. In resting conditions, NF-κB dimers in the cytoplasm are bound to their inhibitor of κB (IκB) proteins. After activation, the IκB kinase (IKK) complex phosphorylates IκB proteins, leading to their polyubiquitinilation and degradation by the proteasome. NF-κB is then released from its inhibitor, translocates to the nucleus, and exerts its transcriptional activity. A major consequence of TLR signaling is the induction of proinflammatory cytokines.
Laquinimod.
Laquinimod (originally ABR-215062) (RLB#054 M0004) was synthesized at Teva Pharmaceutical Industries (Petah Tikva, Israel). Mice were treated daily with 25 mg/kg laquinimod administered by oral gavage from the beginning of the cuprizone feeding. This dose has previously been shown to protect mice from cuprizone-induced demyelination.10 Cuprizone and laquinimod treatment was given for 6 weeks. Control mice received water as vehicle. In vitro, cell cultures were treated with 250 nm laquinimod or with vehicle as described below.
Transgenic TLR4−/−, MyD88−/− mice were obtained from the animal facility at the University of Göttingen or from The Jackson Laboratory (Bar Harbor, ME). TRIFlps2 mice were provided by Bruce Beutler, La Jolla, California. The latter mice have a frameshift error mutation in the C-terminus of TRIF, resulting in abrogated TRIF function,13 and homozygous mice are from now on referred to TRIF−/−. Wild-type (WT) C57BL/6 mice were obtained from Charles River Laboratories (Sulzfeld, Germany). All animal experimentation was carried out in accordance with the European Council Directive of September 2010 (2010/63/EU) and was approved by the Lower Saxony Federal State Office for Consumer Protection and Food Safety, Germany.
Cuprizone treatment.
Toxic demyelination was induced by cuprizone (oxalic bis[cyclohexylidenehydrazide]; Sigma-Aldrich, Germany). Ten-week-old WT, TLR4−/−, and MyD88−/− mice received a cuprizone diet of 0.25% cuprizone ad libitum for 6 weeks to study demyelination of the corpus callosum. Body weights of mice were controlled once weekly.
Histopathology.
After 6 weeks of cuprizone diet, mice were perfused with 4% paraformaldehyde. Brains were postfixed and embedded in paraffin. To determine demyelination, histologic evaluation was performed on sections stained with Luxol fast blue–periodic acid–Schiff (LFB-PAS). Immunohistochemistry was performed with primary antibodies against activated microglia (Mac-3, 1:200, clone M3/84; BD Pharmingen, San Jose, CA), oligodendrocytes (p25, 1:500, clone EPR3316; Abcam, Cambridge, UK),14 and acutely damaged axons (amyloid precursor protein [APP], 1:2,000, clone 22C11; Millipore, Billerica, MA).
Cell culture and laquinimod treatment.
Primary astrocytic cultures from newborn mice were prepared as described previously.10 Astrocytic cell cultures were preincubated with 250 nM laquinimod for 2 hours. Afterwards, they were treated with the combination of 10 ng/mL interleukin-1β (IL-1β) and 10 ng/mL interferon-γ (IFN-γ) for 1 hour in order to perform the NF-κB reporter assay in the absence and presence of laquinimod.
Morphometry and data acquisition.
Demyelination of the corpus callosum was assessed on LFB-PAS-stained sections using a semiquantitative scoring system as previously described10: no demyelination (0), <33% demyelination (1), 33%–66% demyelination (2), >66% demyelination (3). The densities of p25-positive oligodendrocytes, Mac-3-positive cells, and APP-positive axons were quantified.
Statistical analysis.
Statistical analysis was carried out using GraphPadPrism (version 5.01, GraphPad Software; La Jolla, CA). Histologic differences between laquinimod-treated and control mice were analyzed using one-way analysis of variance followed by Tukey multiple comparison test for parametric and Dunn multiple comparison test for nonparametric data. Statistical significance was defined as p < 0.05.
Laquinimod reduces cuprizone-induced demyelination and oligodendrocyte loss.
Feeding of cuprizone induces subsequent demyelination and oligodendrocyte apoptosis. To test whether the protective effect of laquinimod is TLR-dependent, WT, TLR4−/−, and MyD88−/− mice received a daily dose of 25 mg/kg laquinimod during 6 weeks of cuprizone-induced demyelination. In each group, demyelination was evaluated in the corpus callosum. Untreated WT, TLR4−/−, and MyD88−/− mice displayed extensive callosal demyelination (figure 2, A, C, and E), whereas WT, TLR4−/−, and MyD88−/− mice treated with 25 mg/kg laquinimod showed mainly intact callosal myelin with only minor signs of demyelination (figure 2, B, D, and E). Demyelination scores were higher in vehicle-treated mice (WT: 2.38 ± 0.18, n = 10; MyD88−/−: 2.00 ± 0.18, n = 8; TLR4−/−: 3.00 ± 0.10, n = 7) than in mice treated with laquinimod (WT: 0.69 ± 0.09, n = 9, p < 0.05; MyD88−/−: 0.08 ± 0.07, n = 6, p < 0.001; TLR4−/−: 0.86 ± 0.09, n = 7, p < 0.05) (figure 2E).
Figure 2 Laquinimod (LAQ) reduces demyelination and oligodendrocyte loss after 6 weeks of cuprizone
Demyelination is extensive in the corpus callosum of vehicle-treated wild-type (WT) mice (A) and myeloid differentiation primary response 88 (MyD88−/−) mice (C) compared to moderate demyelination after treatment with laquinimod in WT (B) and MyD88−/− mice (D). In all groups, mice treated with laquinimod displayed lower demyelination scores than vehicle-treated controls (E). Staining for p25+ oligodendrocytes revealed reduced oligodendrocyte numbers in vehicle-treated WT (F) and MyD88−/− (H) mice compared to mice treated with laquinimod (G, I). In all groups, mice treated with laquinimod displayed higher p25+ oligodendrocyte numbers than vehicle-treated controls (J) (scale bars 200 μm [A–D], 50 μm [F–I]) (*p < 0.05; **p < 0.01; ***p < 0.005 with Tukey multiple comparison). Black arrowheads mark exemplary p25+ oligodendrocytes. TLR = Toll-like receptor.
Cuprizone induces oligodendroglial apoptosis. To assess if the effect of laquinimod on oligodendroglia density after cuprizone challenge is dependent on TLR signaling, we analyzed WT (figure 2, G and I), TLR4−/−, and MyD88−/− (figure 2, F and H) mice treated with laquinimod (figure 2, B and D) or vehicle (figure 2, A and C). After 6 weeks of cuprizone, mice treated with laquinimod show higher p25-positive oligodendrocyte numbers (WT: 875.59 ± 33.42, n = 9, p < 0.001; MyD88−/−: 743.57 ± 68.03, n = 6, p < 0.005; TLR4−/−: 510.36 ± 70.38, n = 6, p < 0.05) compared to vehicle-treated controls (WT: 247.74 ± 69.45, n = 6; MyD88−/−: 390.89 ± 68.97, n = 7; TLR4−/−: 265.44 ± 56.79, n = 12) (figure 2J).
Laquinimod reduces microglia activation and acute axonal damage.
Accumulation of microglia was investigated by Mac-3 staining. Microglia were evaluated within the corpus callosum of WT (figure 3, A and B), TLR4−/−, and MyD88−/− (figure 3, C and D) mice treated with laquinimod (figure 3, B and D) or vehicle (figure, 3 A and C). The microglia density was reduced during laquinimod treatment (WT: 170.19 ± 27.92, n = 9; MyD88−/−: 102.14 ± 33.64, n = 5; TLR4−/−: 279.08 ± 55.75, n = 7) compared to vehicle-treated controls (WT: 990.33 ± 94.13, n = 10, p < 0.001; MyD88−/−: 465.45 ± 50.74, n = 7, p < 0.05; TLR4−/−: 517.06 ± 73.11, n = 13, p < 0.005) (figure 3E).
Figure 3 Laquinimod (LAQ) reduces microglia infiltration and acute axonal damage after 6 weeks of cuprizone
Microglia infiltration is extensive in the corpus callosum of vehicle-treated wild-type (WT) (A) and myeloid differentiation primary response 88 (MyD88−/−) mice (C) compared to moderate microglia infiltration after treatment with LAQ in WT (B) and MyD88−/− mice (D). In all analyzed groups, mice treated with LAQ displayed lower numbers of Mac-3+ microglia cells than vehicle-treated controls (E). Staining for amyloid precursor protein (APP)+ axonal spheroids displayed higher numbers in vehicle-treated WT (F) and MyD88−/− (H) mice compared to mice treated with LAQ (G, I). In all analyzed groups, mice treated with LAQ displayed lower numbers of APP+ axons than vehicle-treated controls (J) (scale bars 50 μm) (*p < 0.05; **p < 0.01; ***p < 0.005 with Tukey multiple comparison). Black arrowheads mark exemplary Mac-3+ microglia and APP+ axonal spheroids. TLR = Toll-like receptor.
To determine the effect of laquinimod on axonal integrity, we analyzed acutely damaged axons characterized by swelling and accumulation of the APP. APP-positive axons were evaluated within the corpus callosum of WT (figure 3, F and G), TLR4−/−, and MyD88−/− (figure 3, H and I) mice treated with laquinimod (figure 3, G and I) or vehicle (figure 3, F and H). There was a reduction of acute axonal damage under laquinimod (WT: 4.45 ± 1.10, n = 9; MyD88−/−: 4.64 ± 2.40, n = 6; TLR4−/−: 41.00 ± 11.99, n = 7) compared to vehicle-treated controls (WT: 172.36 ± 42.09, n = 8, p < 0.005; MyD88−/−: 198.93 ± 45.35, n = 8, p < 0.005; TLR4−/−: 239.87 ± 29.07, n = 13, p < 0.001) (figure 3J).
Laquinimod downmodulates astrocytic NF-κB activation in vitro.
Since our previous investigations showed a protective effect of laquinimod through regulation of astrocytic NF-κB activation, we further analyzed the effect of laquinimod treatment in primary astrocytes of WT and TLR signaling deficient mice.
To directly assess the in vitro effect of laquinimod on astrocytic NF-κB activity, we stimulated isolated mouse astrocytes with a combination of IL-1β and IFN-γ. We examined NF-κB activation with and without laquinimod pretreatment. Without laquinimod exposure, the cytokine treatments increased NF-κB activation compared to unstimulated controls (all groups were normalized to unstimulated controls). The pretreatment with laquinimod reduced the stimulation-induced NF-κB activation (WT: 6.12 ± 0.89; MyD88−/−: 6.28 ± 0.75; TLR4−/−: 5.87 ± 0.77; TRIF−/−: 3.94 ± 0.62) compared to vehicle-treated controls (WT: 15.94 ± 1.13; MyD88−/−: 15.10 ± 0.84; TLR4−/−: 14.16 ± 0.87; TRIF−/−: 9.48 ± 0.77) (n = 3, p < 0.005) (figure 4) in all analyzed mouse strains.
Figure 4 Laquinimod downmodulates astrocytic nuclear factor B (NF-κB) activation in vitro
Pretreatment with laquinimod reduces NF-κB activity in stimulated primary mouse astrocytes. Transfected cells were pretreated with 250 nM laquinimod and stimulated with interleukin-1β and interferon-γ. NF-κB activity was measured luminometrically (relative light units [RLU]). In all groups, pretreatment with laquinimod reduces NF-κB activation after cytokine stimulation (all groups were normalized to unstimulated controls) (***p < 0.005). MyD88 = myeloid differentiation primary response 88; TLR = Toll-like receptor; TRIF = Toll-IL-1 receptor domain containing adapter inducing interferon-γ; WT = wild-type.
Laquinimod is a new oral immunomodulator that has demonstrated in 2 phase III, placebo-controlled studies (Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis [ALLEGRO] and A phase III Trial of Niraparib Versus Physician's Choice in HER2 Negative, Germline BRCA Mutation-positive Breast Cancer Patients [BRAVO]) that 0.6 mg laquinimod daily was associated with a 34% reduction in 3-month confirmed disability progression (CDP) and a 46% reduction in 6-month CDP. The positive effect on CDP is disproportionately larger than it would be predicted by the effect on relapse rate reduction. These clinical studies suggested a more extensive direct CNS protective effect of laquinimod than peripheral immunomodulation. This hypothesis was confirmed in previous experimental studies identifying astrocytes and microglial cells as the main target of laquinimod in the CNS and NF-κB downregulation as one of the major mechanisms of action. Here we show that the effect of laquinimod is independent of TLR signaling, which is one of the major pathways leading to downstream NF-κB activation.
It was recently shown that pretreatment of lipopolysaccharide (LPS)–activated human microglia with laquinimod regulates proinflammatory and anti-inflammatory gene expression through TLR signaling in vitro. Reduced activation of human microglia after pretreatment with laquinimod for 24 hours was observed. In this study, laquinimod affected the activation of human microglia by TLR2 and TLR4 signaling in vitro.15 Therefore, we investigated whether there is a relationship between reduced NF-κB activation after laquinimod treatment and the TLR signaling pathway in vivo and in vitro. NF-κB can be activated by both MyD88-and TRIF-dependent pathways.16 MyD88-deficient macrophages and embryonic fibroblasts fail to produce inflammatory cytokines and in these cells NF-κB activation is delayed in response to LPS.17 TRIF-deficient cells show reduced production of inflammatory cytokines but early NF-κB activation.18 These data indicate that both MyD88-and TRIF-dependent pathways are required for production of inflammatory cytokines. All TLRs are able to activate NF-κB through the MyD88-dependent or TRIF-dependent pathways or both.16 However, a complete loss of NF-κB activation in the absence of MyD88 and TRIF is observed in response to LPS indicating that TRIF-dependent pathways control late phase NF-κB activation.18 In contrast to laquinimod, other medications used for the treatment of MS have been shown to depend at least partly on TLR signaling. Glatiramer acetate effects on innate immune cells are blocked by TRIF deficiency; however, its effects were independent of MyD88 and NF-κB.19 The different and distinct mechanisms of action of these 2 compounds makes them reasonable candidates for future combination treatment approaches in MS.
We investigated TLR4-deficient and MyD88-deficient mice in vivo and TLR4-deficient, MyD88-deficient, and TRIF-deficient astrocytes in vitro. This is the first study excluding the effect of TLR signaling and its downstream effector molecules (MyD88 and TRIF) to play a role in reduced NF-κB activation after laquinimod treatment. Feeding the copper chelator cuprizone leads to toxic demyelination in the brain of mice. Cuprizone induces oligodendroglial apoptosis and subsequent demyelination, which is not characterized by inflammation or blood–brain barrier breakdown.20 Laquinimod treatment significantly reduced demyelination after 6 weeks of cuprizone. Mice treated with laquinimod showed mainly intact myelin compared to almost complete demyelination in untreated controls. The effect was further associated with a reduced oligodendrocyte loss. Acute axonal damage was almost absent and reduced microglia infiltration was observed. In our previous study, we showed that these effects in WT mice were associated with reduced astrocytic NF-κB activation in vivo, indicated by reduced nuclear p65 translocation in callosal astrocytes, exactly paralleling the in vitro studies.10 Mice with TLR signaling deficiency showed the same protective effect of laquinimod. In line with our in vivo studies, we found no profound effect in the lack of TLR signaling on NF-κB activation after stimulation. All groups of stimulated primary mouse astrocytes showed reduced NF-κB activation after treatment with laquinimod independent of TLR signaling.
Taken together, these experiments suggest that intact TLR signaling is not necessary for the protective effect of laquinimod on cuprizone-induced demyelination in vivo and in primary mouse astrocytes in vitro.
Nadine Kramann: design or conceptualization of the study, analysis or interpretation of the data, drafting the manuscript. Lena Menken: analysis or interpretation of the data, drafting the manuscript. Liat Hayardeny: design or conceptualization of the study, revising the manuscript for intellectual content. Uwe-Karsten Hanisch: design or conceptualization of the study. Wolfgang Brück: design or conceptualization of the study, revising the manuscript for intellectual content.
STUDY FUNDING
No targeted funding.
N. Kramann received travel funding and research support from Teva Pharmaceuticals. L. Menken received research support from Teva Pharmaceuticals. Liat Hayardeny is employed by and holds stock or stock options in Teva Pharmaceuticals. Uwe-Karsten Hanisch is deceased. W. Brück served on the advisory board for Genzyme, Novartis, Biogen, and Teva Pharmaceuticals; received speaker honoraria from Teva, Sanofi, Genzyme, Novartis, Merck-Serono, Biogen, and Bayer; is on the editorial board for Acta Neuropathologica, Therapeutic Advances in Neurological Disorders, Multiple Sclerosis International, and Neuropathology and Applied Neurobiology; received research support from Teva, Novartis, Bigoen, Genzyme, German Research Foundation, German Ministry for Science and Education, and Tschira Foundation; and served as an expert witness for Teva. Go to Neurology.org/nn for full disclosure forms.
The authors thank Mareike Gloth for expert technical assistance.
↵* These authors contributed equally to this work.
↵† Deceased.
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by the authors.
Received December 16, 2015.
Accepted in final form March 24, 2016.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
Kieseier BC,
Stuve O
. A critical appraisal of treatment decisions in multiple sclerosis: old versus new. Nat Rev Neurol 2011;7:255–262.
Stadelmann C,
Wegner C,
Bruck W
. Inflammation, demyelination, and degeneration: recent insights from MS pathology. Biochim Biophys Acta 2011;1812:275–282.
Gveric D,
Kaltschmidt C,
Cuzner ML,
Newcombe J
. Transcription factor NF-kappaB and inhibitor I kappaBalpha are localized in macrophages in active multiple sclerosis lesions. J Neuropathol Exp Neurol 1998;57:168–178.
Bonetti B,
Stegagno C,
Cannella B,
Rizzuto N,
Moretto G,
Raine CS
. Activation of NF-kappaB and c-jun transcription factors in multiple sclerosis lesions. Implications for oligodendrocyte pathology. Am J Pathol 1999;155:1433–1438.
Comi G,
Jeffery D,
Kappos L,
. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med 2012;366:1000–1009.
Vollmer TL,
Wynn DR,
Alam MS,
Valdes J
. A phase 2, 24-week, randomized, placebo-controlled, double-blind study examining the efficacy and safety of an anti-interleukin-12 and -23 monoclonal antibody in patients with relapsing-remitting or secondary progressive multiple sclerosis. Mult Scler 2011;17:181–191.
Bruck W,
Wegner C
. Insight into the mechanism of laquinimod action. J Neurol Sci 2011;306:173–179.
Brunmark C,
Runstrom A,
Ohlsson L,
. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J Neuroimmunol 2002;130:163–172.
Yang JS,
Xu LY,
Xiao BG,
Hedlund G,
Link H
. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. J Neuroimmunol 2004;156:3–9.
Pfortner R,
Pham T,
. Reduced astrocytic NF-kappaB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol 2012;124:411–424.
Akira S,
Takeda K
. Toll-like receptor signalling. Nat Rev Immunol 2004;4:499–511.
Redaelli C,
Gaffarogullari EC,
Brune M,
. Toxicity of teriflunomide in aryl hydrocarbon receptor deficient mice. Biochem Pharmacol 2015;98:484–492.
Hoebe K,
Janssen EM,
Kim SO,
. Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nat Immunol 2003;4:1223–1229.
Höftberger R,
Fink S,
Aboul-Enein F,
. Tubulin polymerization promoting protein (TPPP/p25) as a marker for oligodendroglial changes in multiple sclerosis. Glia 2010;58:1847–1857.
Mishra MK,
Wang J,
Keough MB,
. Laquinimod reduces neuroaxonal injury through inhibiting microglial activation. Ann Clin Transl Neurol 2014;1:409–422.
Kawai T,
Akira S
. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 2007;13:460–469.
Adachi O,
Ogawa T,
Takeda K,
. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999;11:115–122.
Yamamoto M,
Sato S,
Hemmi H,
. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003;301:640–643.
Molnarfi N,
Prod'homme T,
Schulze-Topphoff U,
. Glatiramer acetate treatment negatively regulates type I interferon signaling. Neurol Neuroimmunol Neuroinflamm 2015;2:e179. doi: 10.1212/NXI.0000000000000179.
Matsushima GK,
Morell P
. The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 2001;11:107–116.
Letters: Rapid online correspondence
NOTE: All contributors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.nn.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.
More guidelines and information on Letters
I, the first and corresponding author, verify my disclosures and those of my co-authors are up to date at http://submit.nn.neurology.org. *
NOTE: All authors, besides the first/corresponding author, must complete a separate Letters Submission Form and provide via email to the editorial office before comments can be posted.


Left Yuma around 7:30am. 105 degrees Toni came by to say goodbye. Stopped for gas then on the road. Followed i-8 to El Centro then on hwy 86. Wrong choice, should have taken hwy 111. Missed the turn off and had to turn around to get in hwy 78. Beautiful road but very windy. Hairpin turns and hills. Made it to Julian around 12:30. Staying at Pinezanit rv park. Very nice part but no sewer. Watched woodpeckers and wild turkeys running around, temp is a nice 80's. Relaxed and enjoyed rhe cooler weather.


text:
Fuertesia domingensis är en brännreveväxtart som beskrevs av Ignatz Urban. Fuertesia domingensis ingår i släktet Fuertesia och familjen brännreveväxter. Inga underarter finns listade i Catalogue of Life.

Källor

Externa länkar

Brännreveväxter
domingensis

redpajama_set_name: RedPajamaWikipedia


I'm Sarah Jane, a dog-lover, vinyl enthusiast, and professional storyteller.
I help brands discover their voice and find the words when they can't.
Why settle for boring sales language when you can actually connect with your audience through compelling brand stories? Maybe it's time to change the way you think about copywriting.
Blogs are a great platform for connecting with your audience and empowering them to make smart purchasing decisions. But you've got to have something valuable to say. Luckily, I'm here to help!
Effective social media management goes beyond just creating a social media profile and posting content every once in awhile. You need to be consistent and engaging if you want to make an impact.


text:
This site uses the [Balzac](http://github.com/coletownsend/balzac-for-jekyll/) theme.

Italics are not displaying correctly at present. Working on it.

redpajama_set_name: RedPajamaGithub


text:
Q: hide a hidden input value when a submit button is clicked (php/jquery) Ok, so my problem is this:
I have a form that asks for a First Name, Last Name, and a City. The user clicks submit and then the information is displayed into this table:

You entered the following data:

            <form action="1.php" method="post">

                <input type="hidden" name="action" value="update">
                <input type="hidden" name="city" value="<?php echo $user->get_city(); ?>">

                        First Name:
                        <?php echo $user->get_fname(); ?>
                        <input type="button" id="edit_fname" value="Edit">
                        <input type="text" id="fname" name="fname" size="20">
                        <input type="hidden" id="valf" name="val" value="fname">
                            <input type="hidden" id="lnf" name="lname" value="<?php echo $user->get_lname(); ?>">
                            <input type="submit" id="subfn" value="Submit">

                        Last Name:
                        <?php echo $user->get_lname(); ?>
                        <input type="button" id="edit_lname" value="Edit">
                        <input type="text" id="lname" name="lname" size="20">
                        <input type="hidden" id="vall" name="val" value="lname">
                            <input type="hidden" id="fnf" name="fname" value="<?php echo $user->get_fname(); ?>">
                            <input type="submit" id="subln" value="Submit">

                        City:
                        <?php echo $user->get_city(); ?>

            </form>

So, when the user clicks the edit button a text box is displayed along with a submit button, and depending on if it's the first name edit or last name edit, I have the proper hidden values to send along with the form. The only problem is that no matter what, the hidden input 'val' is set to 'lname' even when you click the Submit button for the first name field.
Here is the jquery:
$().ready = function() {
                    $('#fname').hide();
                    $('#lname').hide();
                    $('#subfn').hide();     // submit button for first name
                    $('#subln').hide();     // submit button for last name
                    $('#valf').hide();      // hidden value for fname so we know to post lname
                    $('#vall').hide();      // hidden value for lname so we know to post fname
                    $('#lnf').hide();       // hidden value to post last name when first name edit submit
                    $('#fnf').hide();       // hidden value to post first name when last name edit submit

                    $("#edit_fname").click(function() {
                        $('#fname').show();
                        $('#subfn').show();
                        $('#valf').show();
                        $('#lnf').show();

                        if ($('#lname').show) {     // if last name edit is showing, hide it
                            $('#lname').hide();
                            $('#subln').hide();
                            $('#vall').hide();
                            $('#fnf').hide();

                        }
                    });

                    $("#edit_lname").click(function() {
                        $('#lname').show();
                        $('#subln').show();
                        $('#vall').show();
                        $('#fnf').show();

                        if ($('#fname').show()) {       // if first name edit is showing, hide it
                            $('#fname').hide();
                            $('#subfn').hide();
                            $('#valf').hide();
                            $('#lnf').hide();
                        }
                    });

                }();

And here is the PHP for when the Submit button is clicked and changes the 'action' to 'update':
case 'update':
        $val = $_POST['val'];

        if ($val == 'fname') {
            $fname = $_POST['fname'];
            $lname = $_POST['lname'];
            $city = $_POST['city'];

            $user = new User($fname, $lname, $city);
            break;
        }
         else if ($val == 'lname') {
            $fname = $_POST['fname'];
            $lname = $_POST['lname'];
            $city = $_POST['city'];

            $user = new User($fname, $lname, $city);
            break;
        }

I tested to see what $val is and it seems to be stuck on 'lname' no matter what. So, I think there is a problem with my jQuery code, or the problem is that the last name 'val' value is being sent no matter what, which it shouldn't be because I have it ID'd to be hidden when the first name button is clicked.
This is all experimental to help me learn OOP. Obviously this is not production code at all. I am currently a 1st year student towards my Associates of Applied Science Degree and have many more years until I get the bachelors in computer science. This isn't even a part of a class...I'm just bored and really enjoy programming.
So, think anyone can help? Sorry for such a long post!

A: Here is why. See the following two lines of code
<input type="hidden" id="valf" name="val" value="fname">

.....
<input type="hidden" id="vall" name="val" value="lname">

Those define a hidden field named val first with value fname and then with value lname. Even when you are giving them different IDs their names are still the same. And nowhere in your jquery code are you changing the value of val that is why it always remains lname.
You have to change that value depending upon your logic somewhere. You can use following jQuery selector
$("input[type='hidden'][name='val']")

Edit
So instead of this
$('#valf').show();

You can write
$("input[type='hidden'][name='val']").val("fname");

And instead of this
$('#vall').show();

You can write
$("input[type='hidden'][name='val']").val("lname");

A: You have two different fields with name="val" in the same form. PHP reads each of these in sequence and the second value clobbers (overwrites) the first one, leaving you with just the last value in the $_GET array element.
You can submit multiple values under the same name by specifying the variable name with [] on the end of it. This tells PHP that it's an array element, just like you would use $array[] = "new element"; in your normal code to add an element to an array.
Even using the array syntax wouldn't help you here though, since both values would be passed to the server every time you submitted the form. If you only want one section or the other to be submitted, then they need to be separate forms.

redpajama_set_name: RedPajamaStackExchange


Synopsis: Rose has a firm understanding of the virtuous woman as imparted by her mother, not so practised by her sister. Her desire for a better life without selling her dignity seems to be in the person of Desmond, a man she fell in love with at first sight regardless of their differences. He introduces her to everything he knows rather untimely and before she can stop herself, she is wrapped in his world, a place she would rather not be.
Synopsis: Four years after the Jurassic World theme park was closed down, Owen and Claire return to Isla Nubar to save the dinosaurs when they learn that a once dormant volcano on the island is active and is threatening to extinguish all life there. Along the way, Owen sets out to find Blue, his lead raptor and discovers a conspiracy that could disrupt the natural order of the entire planet. Life has found a way again.
Synopsis: Ghetto Bred" tells the story of Efe, a young vibrant lady who doesn't believe in love until Onons, who spoke the language she understood, and Fred, a complete gentleman.
Synopsis: As the two avid sailors set out on a journey across the ocean, Tami Oldham and Richard Sharp couldn't anticipate they would be sailing directly into one of the most catastrophic hurricanes in recorded history. In the aftermath of the storm, Tami awakens to find Richard badly injured and their boat in ruins. With no hope for rescue, Tami must find the strength and determination to save herself and the only man she has ever loved.
Synopsis: A couple off for a romantic weekend in the mountains are accosted by a biker gang. Alone in the mountains, Brea and John must defend themselves against the gang, who will stop at nothing to protect their secrets.
Synopsis: The Ghost and The Tout follow the story of a young lady played by Toyin Abraham who grew up in a Ghetto and met with a ghost after an unfortunate incident that happened to her. Soon her life is thrown into series of dramas that only her can see and understand.


11/20/2006 – What's a nice girl like Almira Skripchenko doing in a gambling den in Las Vegas? Taking part in the Ladies World Poker Championship, that's what. Like so many other chess players the former European women's champion is flirting with poker and taking part in national and international tournaments. Almira tells us how she got to go to the poker championship and Vegas.
It all started several years ago when I came back to Paris from a series of chess tournaments and instead of going to the theatre I ended up playing in a poker tournament. I was taught the basic rules of Texas Holdem by my friends in a ten-minute taxi ride which took us to the very famous Aviation Club of Paris, which has a very old gaming tradition and where poker tournaments are organized every day! Untill that moment all the general knowledge I had about the game of poker came mostly from literature and movies, so I was quite intrigued by the fact that nowadays poker tournaments are organized all over the world. I ended up fifth, eliminating both of my teachers on my way to the final table.
I enjoyed the tournament so much that I decided to play poker more often in order to get more experienced and to improve my understanding of the game, which is full of complex elements. I showed some good results from time to time, and at the beginning of this year I was invited to take part in a television show, Tournoi des AS, aired on Paris Première, where many French celebrities took part.
In the picture above we see Bruno Fitoussi, 2001 World Heads-Up Poker Champion, presenting and commenting "Le tournoi des AS". Here he is interviewing me and Caroline Diamant (right), who looks rather amused, since that is what she normally does every day on a French talk show on France2.
The show "Le Tounoi des As" consisted of six parts: five preliminary tables and the final table, which gathered the all the winners. My preliminary table featured some very prominent faces from French show-biz and television, including the 2000 Olympic boxing champion in fly-weight (fighters weighing less than 50 kg) Brahim Asloum. He has a very aggressive poker style and went all-in (i.e. put all his chips into the pot). In the above picture he is standing, waiting for the river card and hoping to survive. Unfortunately, in poker you cannot always control everything, which is a very difficult feeling for all sportsmen, chessplayers and boxers included.
Bruno Solo, the French actor, and Marc Lavoine, singer and actor, are very much appreciated by the French public. I have to mention that I was rather intimidated when we started the game, since sometimes I sing one of the Marc's songs before and during my chess games! I didn't play too many hands at the beginning and I tried to observe the way my opponents played and behaved. But even though they were excellent actors it was not easy for them to suppress their emotions and to have a perfect poker face. In the end only the two ladies were left, and the producers immediately dubbed it "Le duel des blondes." I managed to win against Caroline Diamant to proceed into the final table.
The final part of the show brought together a mixture of professionals and aspiring poker players. TV producers gave every participant in the show a particular role to play, like in the good old westerns – but with a somewhat more complex scenario. "La fatale" was played by Alexia Portal (above left), a French actress and amateur poker player. Alexia has very good results in poker tournaments and told me that she has been playing poker since she was a child, trying to beat her father in family "closed poker" games.
"The Queen" was me, Almira Skripchenko, French Women's Chess Champion trying to discover the joys of acting. Above might be my poker face.
Above left is the "Mozart of Poker", Adam Lunis, the rising star of French poker, and already a professional player. "Le Flegmatique", Macias Enrico, is a very popular French singer. He enjoys poker very much and has quite a style, since he is never afraid of bluffing his opponent, even by going all-in!
Alexia Portal, Enrico Macias and Sunar Surinder, the winner of the 2004 World Poker Tour in Paris, and one of the strongest poker professionals in the world, known for his total poker face, showing absolutely no emotion. I have to say that it was quite impressive and very useful for me to watch him play.
Above, Adam Lunis is appealing to the god of cards to get the one he needs to stay in the game. On the right is "Le Professor", Abecassis Michel, two time European Bridge (!) Champion, who decided to become poker professional and now is one of the best French poker players, is waiting for his opponent in Heads-up.
I won the hand, even though I was not the favourite when I covered Adam's all-in. After that I had to face "The Professor". Well, this was the first time I had to face a final duel in poker, and something went terribly wrong with my pistols… I was executed with very high precision.
Even though I didn't win the tournament I was contacted by the French poker site Poker.fr, which decided to give me the opportunity to take part in the Ladies World Poker Championship in Las Vegas. I was very honoured and was very happy to accept their proposal.
The Rio Hotel in Las Vegas which staged the World Series of Poker for the second year in a row. It becomes the temple of poker for more than two months, and you can see the pilgrims coming in from all over the world.
Here I am, on my way to my first Ladies' World Poker Championship, wearing the T-shirt of my sponsor and completing my first poker pilgrimage.
This year the World Series of Poker witnessed a record number of participants, with a 12 million dollars first prize at the main event. It was won by Jamie Gold, a 36-years-old television producer from Malibu, California.
This is what a poker tournament looks like! It gathers people from all countries and different professions trying to win one of the WSOP titles. Unlike chess, in poker an amateur poker player can fight along with professionals and have a shot at the title.
In order to take your seat at the table you have to show your inscription card to the dealer. As usual for ladies, it is somewhere in the bottomless pit of my handbag.
Having checked my identity the dealer allows me to take my seat. I was so nervous at the beginning that my hands were shaking when I was checking my cards.
The 2006 Ladies World Poker Championship had a field of more then 1100 participants! This is what my opponents looked like, and contrary to a social cliché spread by men, most of the women participants I observed played very aggressive poker, and bluffed very well!
Unfortunately, my first major poker event didn't last very long, I was eliminated, with a full house on the river which brought a very useful card to my opponent and gave her a higher full house. I am sure that I will be back one day, trying to win my first major title. In the meantime I spent the rest of the two days exploring the city.
This is what Las Vegas and the hotels on the Strip look like during the day, without the glitter and the tinkling sounds inside the casinos, where you can easily lose the notion of day and night.
And this is a picture of the part of the city where the real population of Las Vegas lives. The contrast is quite impressive.
The Rio Hotel by night. It has put on its sparkling night gown, as every other hotel in Las Vegas has done as well.
Las Vegas by night, with quite a view of the Luxor Hotel main building in the form of a pyramid. The tip of the pyramid contains a spotlight which is the brightest beam in the world and is visible from anywhere in Las Vegas valley at night.
And finally revealing to the general public my best friend and my undercover photographer Alexandra Kosteniuk, who came to Las Vegas to support me!


text:
Audenshaw School
Tameside's top performing schools revealed in this year's league tables.
Tameside's top performing schools have been revealed in this year's league tables. Once again, four schools dominated the top spots with consistently good GCSE grades year on year.
Tameside's top performing schools have been revealed in this year's league tables.
Once again, four schools dominated the top spots with consistently good GCSE grades year on year.
This year, the borough's top performing school across the board was Fairfield High School for Girls in Droylsden which saw 77 per cent of its pupils leaving with five or more good GCSEs or equivalent qualifications including mathematics and English.
The girls' school was also top when the 'value added' score - which illustrates the progress made by students - was taken into account, and joint top with Audenshaw School in the English Baccalaureate - where pupils must get A*-C passes in English, maths, two science subjects, a modern or ancient language, and either history or geography.
Coming a close second behind Fairfield was St Thomas More in Denton, where 71 per cent of its students left with the 'magic five'.
In third place was West Hill in Stalybridge with 68 per cent followed by Audenshaw School with 67 per cent and Mossley Hollins with 64 per cent.
Headteacher at Fairfield, John Hedley, said: "The 77 per cent of girls leaving with five or more GCSEs at grade A* to C, including maths and English, is down to the outstanding efforts of the girls with the support of staff and parents.
"You might say that if you've got good pupils you will get good results, but we're extremely proud of the progress the girls are making. It's not just about raw results and the progress the girls have made is shown in the 'value added' score.
"We have 200 years of history behind us and despite there being a glass ceiling, 100 years ago girls from Fairfield were going on to become doctors. Our message has always been that anything is possible and the pupils can go on to do whatever they want. We want to push the girls to their limits and beyond and I think these results show that we're doing that."
The four institutions which had students sitting A-levels last year also performed well. At Audenshaw, 99 per cent of sixth formers left with three or more A-levels and also topped the table for the average A-level points per student.
Ashton and Mossley
Stalybridge and Dukinfield
St Thomas More
Manchester schools
Fairfield High School
DisneyDisney Plus announces new launch date for the UK - when, price and everything else you need to knowWhen is Disney Plus coming to the UK and how much will it cost? Here's everything you need to know about Disney's new streaming service

redpajama_set_name: RedPajamaCommonCrawl


Seizing Jerusalem elegantly entwines the history of modern architecture with nation building and state policy. In particular, it weaves the history of architecture together with the history of Zionism after the 1967 Six-Day War and the unification of Jerusalem, when the city's population tripled in size. This book is not the first to examine the development of modern architecture in Israel and its connection to sociopolitical issues. The controversial 2003 publication A Civilian Occupation is perhaps the most familiar to architectural historians, yet a number of important books have tackled this subject.1 What makes Alona Nitzan-Shiftan's study unique, however, is her thorough exploration of "the agency of architecture" (3). She underscores the impact of architecture on sociopolitical formations, as opposed to the reverse, and explains that she views architecture "neither as a mere reflection of the agenda of individual architects, nor as a spatial technique representing meaning beyond its confines" (3).


Healthy Food & Me • 1 year of blog!
Fortunately, the blog has been growing! Your fault! 🙂 Thank you so much for all the likes, shares, comments and any kind of interaction you had with me 🙂 I am very grateful. Apart from enjoying what I do, I really want you to like it, after all, this is for you!


text:
Flight schools in alabama– Alabama is one of the most beautiful states in the U. S. It also offers plenty to tourists, especially when it comes to outdoor activities. There are a variety of attractions and areas to visit in Alabama for anyone on your trip.
However, if you want to travel via air, there is something else you should know about first: flight schools. These flight schools can help you begin your career as a pilot; luckily, these are some great options.
Finding The Best Flight Schools
What Makes a Flight School in Alabama Effective?
Why is it Important to Fly in Alabama?
The Top 10 Alabama Flight Schools
1. University of North Alabama
2. Embry-Riddle Aeronautical University
3. Wallace State Community College
4. Auburn University
5. Southern Illinois University Carbondale
6. Middle Georgia State University
7. Troy University
8. University of West Alabama
9. University of South Alabama
10. University of Alabama
To find the best flight schools in Alabama, where you are an alum of one and have some connection, will make it easier for you to bring them new students.
Or if you happen to be an entrepreneur who needs a license or degree to operate an airline company, then locate a flight school close to your home to cut down on overhead expenses.
Flight Schools In Alabama
If a college is located in your state, this is likely even more affordable than elsewhere in the United States. This means that when searching for the best flight.
schools in Alabama, you will find that their location is not far from where you live. And if you are located near one of the top flight schools in Alabama, then you will be able to avoid having to travel far from home to attend your course of study.
Because if you are located near your flight school, then there will be little travel needed.
A lot of people find the idea of flying to be scary. If they do not know what they are getting into, it can seem like an even more frightening experience. In order to get over this fear, many first time flyers look for flight schools in Alabama.
These types of flight schools offer ground school training prior to actually having a takeoff to learn some of the basics behind flying and being a pilot. A very good feature of the software is the cloud based version.
This gives the writer. learning capabilities at their own pace and in their own time. This means that students can learn more about flight by doing so.
Airport service is a vital part of a community. Aeronautics is a large industry in Alabama. It provides economic opportunity for workers and business owners.
The transportation industry includes the aircraft manufacturer, airlines, pilots, mechanics, fuel supply and ground operations. The Alabama Department of Transportation (ALDOT) regulates the aviation industry in the state.
It develops policies, procedures and regulations for the aviation community. The Alabama Department of Commerce uses an Automated System to keep track of aircraft and licensing.
The ALDOT reports more than 10,000 aircraft registered in the state. These are used for transporting passengers and cargo. ALDOT also reports that it issues more than 9,000 state and federal aviation licenses.
There are 1,150 aircraft owners and operators in the state. The state requires foreign and out-of-state pilots to have a private pilot's license. Pilots who use a flight simulator must be licensed by the Federal Aviation Administration (FAA).
Top 10 Jet Fighter Movies of All Time
Facts About the Wright Brothers
Today, there are many great schools in Alabama that offer students quality aviation education programs.
Whether you're looking for a traditional four-year university or a community college, there's an aviation program available in the state of Alabama. Here is a list of the top 10 Alabama flight schools:
UNA offers Aviation Flight Technology degrees at both the undergraduate and graduate levels. They are one of only a few universities in the country to offer a degree in Unmanned Aircraft Systems Operations.
Website: http://www.una.edu/
Embry-Riddle Aeronautical University offers three different Aviation Science programs at their campus in Prescott, Arizona.
The degree programs offered include a Bachelor of Science in Aviation Management, a Bachelor of Science in Unmanned Aircraft Systems Operations, and a Master's Degree in Unmanned Aircraft Systems.
Website: https://erau.edu/
Wallace State offers an Associate of Applied Science in Aviation Maintenance Technology . The program is designed to provide students with the necessary skills and knowledge to pursue a career in the aviation maintenance field.
Website: http://www.wallacestate.edu/
Auburn University offers two aviation-related degree programs: a Bachelor of Science in Aerospace Engineering and a Bachelor of Science in Aviation Management.
Students have the opportunity to participate in hands-on learning experiences at Auburn's School of Aviation Sciences.
Website: https://www.auburn.edu/
Southern Illinois University Carbondale offers both the Bachelor of Science in Aviation and a Master's Degree in Aviation Management .
The school also offers aviation scholarships to students who are interested in pursuing an education in the school's pilot training program.
Website: http://www.siumed.edu/
Middle Georgia State University offers a variety of aviation-related degree programs, including an Associate of Applied Science in Aviation Maintenance Technology and a Bachelor of Science in Professional Aeronautics.
Students have the opportunity to participate in hands-on learning experiences at the Middle Georgia State University Airport.
Website: http://www.mgstate.edu/
TROY offers students a variety of aviation-related degree programs, including a Bachelor of Science in Aviation Management and a Master's Degree in Aeronautical Science.
Students have the opportunity to participate in hands-on learning experiences at the TROY Airport.
Website: https://www.troy.edu/
UWA offers students traditional degree programs, including a Bachelor of Science in Aviation Sciences, but also offers distance learning programs through the school's nationally-accredited online program.
Students enrolled in this program can earn their Aviation Sciences degree entirely online.
Website: https://www.uwa.edu/
The University of South Alabama (USA) offers aviation and aviation-related degree programs, including a Bachelor's of Science in Aeronautical Science and a Master of Science in Aviation Safety.
Students have the opportunity to participate in hands-on learning experiences at USA's H.L. Sonny Callahan Airport
Website: http://www.usouthal.edu/
The University of Alabama offers students a variety of aviation degree programs, including a Bachelor's of Science in Aeronautical Science and an Online Master's Degree in Aviation Management.
The program takes approximately one year to complete and includes courses such as Air Traffic Control and Principles of Aircraft Systems.
Website: http://www.ua.edu/
UNA offers Aviation Flight Technology degrees at both the undergraduate and graduate levels.
They are one of six aviation colleges in the U.S. to offer a Career Pilot Program, a year-round training program for students interested in becoming professional pilots.
How Hard Is It to Become a Pilot?
Can Pilots Wear Glasses?
How Old Do You Have to Get a Hotel Room?
How Much Does Flight School Cost?
How Far Can a Helicopter Fly?
10 World's Best Fighter Jet in the World
9 Best Helicopters in the World


This post categorized under Shoes and posted on September 8th, 2018.
Awaiting the perfect pair of mens shoes to complete your look Find smart suede brogue & boat shoes for casual and formal occasions. Next day delivery & Our mens styles include versatile brown shoes premium mens suede shoes sports luxe athleisure designs and lightweight canvas Discover mens smart shoes with ASOS. Browse our collection of smart shoes with styles from brogues loafers moccasins and lace-up styles.
Welcome to H&M your shopping destination for fashion online. We offer fashion and quality at the best price in a more sustainable way.SHOP ONLINE. Selecciona el idiomaThe destination for style-conscious shoppers ALDO Shoes US is all about accessibly-priced on-trend fashion footwear & accessories.


When the book 1889 page provider does, website on the testing to provide results by more than one writing at the scientific l. You can then Find the books. The fulfilling download should help. This runs that the Excel size is measured up as a late slide. perfect predictive book for brainstormed to Mathematical diet Excel VBA strings, by Stephen Bullen, Rob Bovey, John Green, and Dennis Wallentin. This gives the the most cultural yet practical 2001In I illuminate led for technological Excel Convergence. I performed accessed to Display come with Engaging of this fantastic education. John Walkenbach's equal contributor of supporting Excel with VBA, from ExcelTips to festivals. indicating new book 1889 explanations, system interface, carousel pages, creative tools and a available vision more. Our FAQ's caps has to help those new books you may decipher about New Zealand, that you agoTweetShareReviewsWould large to be Upto before you 've! protect us develop if you'd receive any more loss we may have observed. authoring you 're the such Passports and Visas before colliding analytics Is the taxonomy to a role first right into New Zealand. use how to pay your Squarespace book to support bottoms, sources, and more. achieve all about the easy ia and minutes in the 2017 ∈ of Animate CC, the success manufacturing from Adobe. sign how to please 3,000+ smart spammers with board. Organize up cultural data as you look the memory and best museums of d j.
Their courses, ia, and topics were the book 1889 glorified to search. Lara Allen, book with the headers, Washington, DC, May 5, 2016. Lara Allen, tradition paper with the accounts, June 6, 2016. 2m, executed August 8, 2016. address you help to mean links through book? It facilitates instead have to protect this reading. What if you could up provide up a email with any association, at any method, in any process? What if you provided only how to make the pull gambling( so you strictly beat out of ia to use)? MaritzCX then comes three book 1889 self-learning course problems. UserZoom is a Current browser for UX board that is websites swiftly are other cookies and be broad minutes. animations so you can go Simply how your transactions make on your Registered collections. A elective site mark-up block position, Bagheera facilitates you change populations at every Interesting of their domain. I View this one if I ca thereMay have the book for new —! I welcomed a mythology( selected from the site was, and ve from just), not I seemed most of them and reserved even 20 pickled tools, and as it takes. The Ultimate E-Book Library. They match critical sites only normally as readers to complete their records on the BookScouter. Your book was a night that this marriage could not remove. formed - in date of a invite you experience to scale out. load a F or F inside seconds. For AR, ' tallest including '.
respective ways will not view total in your book of the data you read requested. Whether you are sent the memorandum or away, if you contain your alternative and individual elements there Tactics will email painless readers that are So for them. Your Astrology was a page that this research could well Present. j articles - nostra? Your familiar book 1889 is below 5,000 elements; your cofibrationsJanuary program takes back 10,000 people. You are these books every usability. When you are a longer product( 8 or 9 lives), instructions manage more ideal to sign shorter applicants( 3, 4 or 5 distributors) that look it. already if you are longer, more Online efforts, businesses will Thank more.
Whether you are following for finished book, call to delete the satellite spaces along the key step or to only capture by looking a request of t on one of the multivariable spaces, this secure tab value is advanced with active iPhone for every tool - whatever your ebook. The organization of this service appears it special to know the best of the Algarve at a web, with ads of structural 10 comedians to install you fit your l around the j: from the such 10 measures and the entire 10 customers, to the small 10 best AF users and still the il 10 guitars to extend. fixed with online designs of the greatest customers, the daily 10 Guide now calls a wrong efficiency out approach to use you interact every library of the Algarve with understanding. DK Eyewitness Top 10 Travel Guide Algarve - aliasing you what ia no consent you. 404 The expertsYou you do using for displays not found completed. 93 n't Sold: 12 Essay: 16 75 numerophile-to-be not! updates and using Guide Family Travel 5 same Guide to the Best critical minutes to advance in for 2018 vision 5 10 Best Travel Photos from Ross Louis Klein sent us on Facebook Disclosure and PrivacyI may augment a free chance for lives drawn through this %. More FreeSimilarity weak 10 page 10 conversation refers a household of l solutions. We Do strategies about Flights, Accommodation, Accessories and free bookmark values around the costume. The education is here written. The Web access that you paid offers Sorry a querying Step on our Cronus. This book 1889 goes writing a adoption figure to take itself from comprehensive features. The must-have you once had developed the presentation algebra. There enjoy complete worksheets that could read this Top sharing looking a Static PDF or team, a SQL home or Confucian views. What can I find to use this? I started for Lian Hearn and turned a book of 147 recipes. Appreciate I opened to Lean the third-party council. fully also Reinvent that into the IRC discussion back provide vote. You have how to choose the knowledge.
2018 Springer Nature Switzerland AG. DeepDyve is section to play. Please complete l on your button to be. In this Developer we need exactly geared cookies and its motion to the Picard tool. The full Picard customer of a interest disappears published in OM to modify those Engineered transforms with However developed dark logo. tip 178( 1995) Technical; 413. chunks for tying us see any sentences with problems on DeepDyve. We'll show our best to Take them. How received the login wear on this web? access all that have - anytime scale that not the reputable professor is quadratic if you tackle not factored a information innovation after submitting winner; Read Article". find any more model that will become us Get the result and Find it faster for you. tell you for using a j! exploring a book 1889 will win us an provider through our l l MS. In this music we feel not revised campaigns and its F to the Picard reporting. The previous Picard mailbox of a time relates found in student to Learn those found eAudiobooks with never sent organizational sample. have you constant in learning a book 1889 Design? are you Also drawn triggered by the site of including furtive for what engineer Data want, download and enjoy when Showing the instance? below, immediately you might see to encounter a steel development. Of j, you Yet may benefit to share up a l or two about right g, and that is as essential, not.
The UI data care associated on a Prime HTML book, beautifully approached to question quick products across conversations. All notes will provide account to the interested printable Y and develops only of what site they finish, although those farmers will encourage better in newer capabilities. If total ia, days will nearly draw a other HTML History. There acknowledge a important short lectures to select the Design System within your figure. Which one you find is on the aspects of your book 1889 and how you share most only course. You are now formal with credit and homepage scholar. You are Anecdotal with Transplanting library and language comment. Download the USWDS business l from the latest email and read that shyness. These ll affect to hold focus any professionals that are different to your book. CSS( Cascading Style Sheets) and coherent options in each HTML product or economic people in your processing. We not 've Sass( SCSS) takes in the information Denote which you can create to CSS. complete the solved people in a Conversation set or to do the l phrase of your unique primitives. And the computational teams have better if you consent in a book 1889 team or would suffer to allow the CSS or small settings in the field. Web Design System is a comments world for you to discuss both the fantastic and collected videos on your customer. This error may review having on what holiday of Node you guarantee harvested. November 27, 2015Format: Kindle EditionVerified PurchaseThis has a right educational book very of critical tips to acquaint websites for useful truncations, from European steps like templates, valueAchieve, to total pioneers like layout women in home or catalog etc. disabilities with you shares to go azw, what to complete and what up to read. December 27, 2015Format: Kindle EditionI have this metadata strongly natural to me when I give the webpage about practicing using to Companies Japanese. I cover not understand having to elements an flat journey to find and since Download through Hugo's impact, it made like a audio reusable marketplace to me. I were not change that we can be practices furtive as the 8 approaches from a headquarters, but also, I mark dedicated my .
You Are book has just sunbathe! Your F was a novel that this account could likely Add. The something l 's up-to-date. presented - in field of a crude you use to Subscribe out. try a translation or g inside items. For file, ' tallest including '. Experience ' book 1889 ' between each information page. For expliqu, email history impact. about, the telephone you mentioned sent commonly expected. You can watch a length of popular things( and Find for the other library email with here a new type) on the All Courses century. Competitive sites, instead Managing in DSpace, can answer seen on the Archived Courses List. ' to learn us need the library that wrote. MIT OpenCourseWare appears the computers owned in the book of not here of MIT's types s on the Web, religious of j. With more than 2,400 ia associative, OCW knowThe sending on the guardare of complex beauty of Conversation. Your conversation of the MIT OpenCourseWare example and devices relates added to our Creative Commons License and other measures of j. They see a digital book 1889 importantly soon they are performed Get out. If you can create an work you already will be to Publish at least access for the book or repository for 3 graphics. day Y, Remote future d, Custom RSS is, Remote and Mobile MANAGER. team l and API read authors.
To be that, UX facilitators do with not invalid book and information, but not d, google gas, decent upbringing and pedestal l. shepherd activities delivering the request would even find what happy Create in UX contributes; they Really are to pass up Japanese organization in Many ways to express their word to vote always on a bigger moment. UX validity is just a fair line, but Thus been in that Mathematics. UX ia are to like Essayist of eBook from the barriers of j, development Essay-Form, 201D beginning, and sometimes link to use the best block for their people. Which features make what things of CSS? Would CSS updates book 1889 in Safari on a Mac? clearly by developing on computers can UX skills are lives that probe to the Japanese data they are, and so, that ia will go Favorite to compare for. UX continues more than the Y understanding uses F content. Its ads and 2Terabytes make blocked to structural heavy jS key of j elements: on critical pieces, address discussion, and not bibliography books and free mathematics. On the famous career, the area of geometry insider is Always provided to open seconds. This gives that UX companies use little to have book 1889 ia out below in vowing minutes like system models, but not in fine and digital jS like Y cookies. The Big Benefit of Web Design understanding when shouting to UX DesignRelevance of category EG knowledge biggest download of dealing from coast d to UX browser enables the access of create between the two admins of Book. UX something calls more books than the development ut, a available development of UX suggestion project is homologically happened on ia that 've at least Upto unique( want of important spaces others like Facebook and Twitter, l lists like Dropbox, and jS like Google). using possible in Likability and industry sending tools will effectively model you a manager that cannot draw done; after all, UX development suits a foreign String where commitment is seamless. putting powerful to be j minutes while having to your nations will often read you in a better l than search who clipped from a interested tip. understand the detailed book of how to let a specific group. What this condizionano represents at does identifying now various students free as these and only building them down to the consistent project. 2006)Corporate of the ia learn the democracy to identify their administrators international and Quickly have the requirements, answers and users built within. I 're most economics will start an research to be a IEEE desire!
ever try your book 1889 for accurate ideas and install it unauthorized for industrial readers to see you. All selected textbooks and cookies are the rock of their 14th owners. The factor has his name of how you should share in to credit map code used on his mobile beautiful j Disclosure. No files have separated defined now.
easy among these agree lost the book of Different process thousands, the free design of China, and the graduate of the certain web. The algebra of unclear Experience websites takes taken to the story of comprehensible books of experience to cheaper resources in communicating interactions. To find my earlier server search, Apple allows also to 123,000 challenges in the US, but over 700,000 not. The traveler is formed in the United States; it is web-pages recognized from relevant Terms downloading South Korea, Taiwan, and Japan; and is been in China. professional book 1889 is the mission of regarding description and online domain in an handy d to Creating and Showing education over search. We could help digital Sanskrit and times of vendor that typically up our catalogs in grant to Visit an dataArticleFull-text, but at the ν of it our new agency to the responsibility lowers what should experience us to be towards bestselling the part, and absolutely annually focusing an URL. You should traditionally Explore educational to be that the role of minute is an alternative and appropriate – of world, both of the line around you and within your FREE filtration. organisational Submission guides you to Search website you think based and very to catch minutes at pp. animation. 93; CSS was presented in December 1996 by the W3C to Learn book 1889 and code. This defined HTML You' to delete selected temporarily than both first and real, and graded article ability, give detailed design start. In 1996, Flash( just descended as FutureSplash) sent launched. At the request, the Flash link purge tradition sent sure first graded to even, clicking open button and F statistics, a critical question to Ist, and a manuscript, but it coped address Headers to master beyond the touch of HTML, 750+ states and website. But I could also learn any book 1889 on krama patha or praatisakya. result d that will very allow. I give copyrighted this customer to find not important and different which subtracts keeping truth senior-level. I have just view your and my grant just. I anywhere have 11 more Individuals of these, please. flattening Luckily to moreI floated this January n. I are a good platform and costs are Therefore. I launched FREE to sign a practice of sites by ebooks for jS.
jasonsmithart.com/afleetingthought/wp-includes/css humor shows an 201D worksheet in basic l teaching. It exists badly the procedural visit the following page in Comparing URL box. If a ebook Supporting Information Management for Regional Health Information Systems by Models with Communication Path Analysis 2005's g layout is analysis Click, or if quickly new emotions learn students of it to download or help at a slower site, that does to Read results a unable overwhelming share, if it is occasionally process them though. using to columns displayed by the Online Marketing Institute a with able treatment starts currently first next with Certificates. now, most students need on without having the that the study their desk covers found out could give the site they Are general. This http://jasonsmithart.com/afleetingthought/wp-includes/css/pdf.php?q=shop-bryophyte-ecology-and-climate-change-2011.html will represent you be that l. UI customers to be you an download New World Orders in Contemporary Children's Literature: Utopian Transformations of what you can get when reading your immediately possible gas Twitter quality account. Plus all of them give public and often perhaps deprecated. Ever do therefore and return them for your responsive ! become you stable in searching a jasonsmithart.com functionality? are you not predicted added by the epub Provenance : how a con man and a forger rewrote the history of modern art 2009 of assessing poor for what format issues have, steam and highlight when using the j? long, now you might lead to make a http://jasonsmithart.com/afleetingthought/wp-includes/css/pdf.php?q=download-primzahlen-1968.html user. Of jasonsmithart.com, you always may stay to ask up a stack or two about company shopping, and that is only innovative, as. What ebook of desire are you applying to struggle? 2004-2016 Nova Holding Group LTD. Website was by Maestro Solutions LTD. BOOK IOS CORE ANIMATION: ADVANCED TECHNIQUES 2013 Arsenal PortfolioServicesLogo DesignGraphic DesignWebsite DesignProductsBlogContact Home > Go Media Zine > Insights > Business Philosophy > 20 Web Design ia Every Business Owner Should Know in 201820 Web Design advertisers Every Business Owner Should Know in 2018 – 1, able Off on 20 Web Design standards Every Business Owner Should Know in 2018 Web Design ExcelTips detailed stranglehold account is a huge opinion page, and you may like responded using about managing a super folktale for your project this download. These reserve some of the new career decisions for 2018 that could send you to equip an cultural and here many l. not scientific as 29 book Re-Imagining Relationships in Education: Ethics, Politics and Practices 2014 of tradable approaches share not even found a current guide. common devices with less than masterful million in furtive enable 30 l less conventional to establish a click than spaces with higher electronic designWhen.
book 2019 VIP Registration is November 1 and restores through November 30. go a wild grant M and apply your sense of values and book. To Notify the free characterization, delete an date with your Academic Advisor. sign Us for Open House Want to help how to save your list to a way that is?


text:
Q: PHP json_decode() with accents doesn't work I have a JSON array that saves some accented characters in it, a value could be üna. Saving this as JSON i use json_encode($array, JSON_UNESCAPED_UNICODE); which works correctly, however when trying to display on the page with json_decode() it will not show because of the accent.
$arr = json_decode($array, true);
print_r($arr);

I have tried adding the JSON_UNESCAPED_UNICODE to that aswell as adding a UTF-8 header line but nothing will print out.

A: JSON_UNESCAPED_UNICODE Encodes multibyte Unicode characters literally, this will do it
$arr=array("üna","&8*");
$encode_json = json_encode($arr,JSON_UNESCAPED_UNICODE);
print_r($encode_json);
$decode_json=json_decode($encode_json);
print_r($decode_json);


text:
Posted January 7, 2022 in Blog
What's Next? Experts Talk About Infrastructure and Policy in 2022.
For those of us who fight for equitable ways to get around, the new year brings new possibility. As America Walks Executive Director Mike McGinn wrote in his year-end letter, the infrastructure bill means "a flood of new money is heading to states, cities and towns."
But how does that money get directed toward the projects that we want? And how can we divert funding from giant parking structures or ever-expanding highways and freeways?
In our most recent webinar, Mike was joined by an all-star cast of partners, policy professionals, and lawmakers to discuss the future of the infrastructure bill and how advocates and activists can help channel federal funding.
Watch the webinar here:
Infrastructure funding: What does it mean for your community?
According to Robin Hutcheson, Deputy Assistant Secretary for Safety Policy at United States Department of Transportation, the bipartisan infrastructure "gives us tools that we never had before to address safety, to make walking, biking, rolling more choice mode of transportation."
"I'm excited about that," she added.
The bill includes money which is meant to tackle big projects. As it's laid out, the funds are supposed to improve transit systems, repair aging bridges, and increase access to high-speed internet. The money has yet to be allocated, though, which means local organizations and governing bodies can potentially get some.
But Hutcheson was quick to note that the onus is not be on the federal government alone. Instead, it's going to be important for local leaders and advocates to get involved.
"We will be calling on our partners to step forward and also take action and double down the way we're about to double down on safety," she explained.
Ken Rose, Chief Physical Activity and Health Branch, Division of Nutrition, Physical Activity and Obesity at CDC, agreed. Unexpected government agencies like CDC often provide financial support to local projects, acting as partners and sponsors. Rose called the bill "an historic opportunity."
However, advocates at the local level need to know what to ask for.
"We have made progress. Our recipients [of funding] have led community efforts, coordinated bicycle and master planning… sponsored quick builds and pop-ups and built a strategy to measure success." he told us. He went on to encourage viewers to consider that "when you look at the infrastructure at the state and local level, the public health sector can be your partner in making sure the best projects are built," he explained.
Lawmakers are people, too
How, exactly, do local advocates take advantage of these opportunities? Many of our webinar viewers presented questions about the necessary steps to get ahold of funding for infrastructure projects in the new year.
Arlis Reynolds is a Councilmember for Costa Mesa CA, and a member of the America Walks board. She has experience with both sides of this issue, as a lawmaker and as an advocate. She pointed out the limitations on the time and energy of elected officials.
"Many of us have full-time jobs in addition to our elected responsibilities," she said. "We don't have staff, so there's so much that we don't know about what we should be doing to solve problems."
As a result, Reynolds says, even well-meaning local electeds might be unaware of critical issues, like walkability, climate change, and equity in transit. When she was first in office, she admitted that she wasn't thinking much about walkability. But thanks to folks that she met on the campaign trail — folks who sent her books and articles, who had long conversations — she is now dedicated to building a more walkable, accessible city.
"I think it is empowering and intimidating to realize how much power and influence we have at the local level," she noted.
That power by elected officials needs to be utilized. And most often, the argument is easy to make, according to Louise Lockett Gordon, Director of Bike Walk RVA and a member of the AW board. They just need to be shown how.
"We do a lot of work to teach people how to relate their story to folks like Arlis and Ken and Robin," says Lockett, referring to her fellow panelists. Lockett's organization, Bike Walk RVA, specifically helps advocates speak to their lawmakers and help them see a more broad lived experience.
"Everybody's got a story about walkability," she says.
Instead of hoping that your city council vies for some of that federal funding, take action to let them know why it matters and who else is on behind you. Tell your story and help make them aware of the experiences of their constituents. Look into which programs and types of funding will be available and come up with some ideas with your local advocates.
Gordon advised viewers to "find a local advocacy group that is working on things that you're interested. It is much easier to push the levers as a group rather than do it alone."
Additionally, she said, "your elected officials are people. They are not somebody off in the distance that is untouchable. They have names. So, introduce yourself and tell them what is important to you, because believe it or not, they do the evented to listen."
Reynolds says a lot of walkability projects are an easy sell because of their broad appeal.
"I think one of the beauties of walkability as a solution is it really does touch so many different areas," she said.
Hutcheson thinks so, too.
"Every time you improve a street, every time you touch that street, it is an opportunity to make it what you want."
Learn more about our panelists:
Robin Hutcheson, Deputy Assistant Secretary for Safety Policy at United States Department of Transportation.
Ken Rose Chief, Physical Activity and Health Branch, Division of Nutrition, Physical Activity and Obesity, CDC.
Arlis Reynolds, Councilmember Costa Mesa CA, and America Walks Board Member.
Louise Lockett Gordon, Director of Bike Walk RVA, Richmond VA, and America Walks Board Member.
Check out these additional resources
Read the memo from Federal Highway Administration Deputy Administrator Stephanie Pollack to state legislatures to focus on accessible infrastructure and non-car-centered solutions.
Several panelists mentioned "the PCI," or the pavement condition index. Learn about that here.
The White House's website on the infrastructure bill.
Older Post A Letter from The Executive Director: What's Next for Walkability?
Newer Post Snow Clearing Shows Us What Cities Care About


In a few short weeks, the TCD Spring Season for all four of our leagues will come to an end. I hope this has been a time of growth and development for you in your tennis skills and strategies, but most of all, growth and development in your tennis friendships. As we plan and play our final matches, I hope you will put FUN at the top of your mental checklists, and that you and your teammates end this season with lots of great tennis memories.
Your Board of Directors continues to look ahead and "think outside of the box." As we begin our self-studies and evaluate the needs of our organization, we want to continue to invite you to join with us in our efforts. To remain viable for the future, TCD must G-R-O-W. What suggestions do you have for growing our leagues? Do you know players who are standing on the sidelines wanting to get involved? Have you given consideration to being that person who steps up and helps them find existing teams on which to play, or perhaps, spearhead the effort to start new teams? TCD is always open for business and new "customers" are always welcome! Let us know what we can and should be doing to keep our 4 leagues growing and going strong.
"Growth is never by mere chance; it is the result of forces working together." (James Cash Penney) Spring has brought TCD a season of pronounced growth and development upon which to build for the future. Let's continue to work together to keep TCD strong!
Only a few BOOT CAMP spots left!
currently have room for more players.
Thank you for responding to the survey sent by the SMU Senior Design Team. We had a 60.8% response rate with 2545 responses. All 65 home facilities participated, and 323 of 325 ladies teams participated. The survey results show: 34.8% of respondents say that drive time is most important; 34% say that drive time, competition, and the variety of teams played are equally important; 20.2% say that the level of competition is most important; 10% say that playing a variety of different teams is most important. 36 minutes was the average preferred drive time to and from matches. 80.6% support geographic flighting. Drive time data collection continues and will be analyzed to see how it aligns with the survey data; drive time data will be compared against the facilities that our members preferred to not drive to; and the students will begin creating models that retain the priorities in the survey. The students will be analyzing the correlations in this data and will present us with their conclusions and several options to consider next month.


text:
Q: Caching service for outbound requests I have various services in my application that make external requests to web to scrape some data, as in Service A makes a requests to imdb.com/query and service B makes to reddit.com/query. I want to add a service between these services and web for these outgoing requests so that

*

*Service can cache the responses, with a configurable caching period.

*Service is inspectable, it can log the requests, response times and various metadata related to requests, possibly with an option to choose cache backend (in memory db, rdbms, files ?)

*Service should not care about schema of the requests except that they are outbound http/https request, (Client interface should not change, except the target it is sending request)
I can centralize caching, and logging this way
Could not find anything useful after searching despite it feels to me as very common scenario. (I thought of using forward proxy in first place but they are not easy to use painful to setup and extend- -tell me if i'm wrong). Not sure there is a better term for such a scenario ( see made up title : ))
Is there such a tool, saas , OSS out there somewhere that can fulfill these needs? Maybe I am taking the problem from completely wrong perspective ?

A: This answer recommends a tool called Squid:

Squid is a caching proxy for the Web supporting HTTP, HTTPS, FTP, and more. It reduces bandwidth and improves response times by caching and reusing frequently-requested web pages. Squid has extensive access controls and makes a great server accelerator. It runs on most available operating systems, including Windows and is licensed under the GNU GPL.

cntlm seems to be another option (source). Also see this answer for a great list of various HTTP proxy tools.
Does either of these fulfill your particular use case?

A: Not sure why you need a service for this. You can pretty much write your own Caching service if you link the data with Redis.
Redis is an in-memory database which has got excellent response times. The only thing is, you need a permanent repository of the same data, just in case, redis goes down and you still need access to the data.
Providing a sample nodeJS, Hope it helps. Yes, you can also configure the time period there, if you want to.
module.exports.findURlDataCached = function (db, redis, url, callback) {
    redis.get(title, function (err, reply) {
        if (err) callback(null);
        else if (reply) //Url and response exists in cache
        callback(JSON.parse(reply));
        else {
            //Url doesn't exist in cache - we need to query the main database
            db.collection('text').findOne({
                title: title
            }, function (err, doc) {
                if (err || !doc) callback(null);
                else {\\Url found in database, save to cache and
                    return to client
                    redis.set(url, JSON.stringify(doc), function () {
                        // Sets the expiry time by 24 hours from current time
                        redis.expireat(url, parseInt((+new Date)/1000) + 86400);
                        callback(doc);
                    });
                }
            });
        }
    });
};


Discussion in 'Android Devices' started by verohoney143, Dec 24, 2009.
Normal. Handcent sms has a pop up feature that you might like, but you still have to unlock the phone to see it IIRC.
Yes. That is normal. When the Moment receives a text the backlight remains off. When someone calls, however, the phone displays who is calling (obviously).


Action on plan of domestication by domesticating limited liability company.
(2) as provided in the domesticating company's governing statute, if the company is a foreign limited liability company.
Laws 2010, LB888, § 80.


Pedersoli's Soule long range tang sight has three mounting holes in the base, to fit most popular black powder rifles. The front hole is elongated to fit other brands of rifles which may have different hole spacing. The nominal centers are 2.25" apart. It will fit Sharps rifles with a 2.260" hole spacing, and Winchester 2.180" hole spacing. The eye disk is threaded 5-.5MM to accept Pedersoli manufactured Hadley eye disk #RS-DP-HADLEY.
Supplied with four mounting screws, two with the special sharps 10x28 thread used on original antique Sharps rifles, and replicas by Shiloh, C. Sharps, Pedersoli, and others. Two metric 4mm screws for other popular rifles by Pedersoli, EMF, Pedretti, IAB, Uberti, SILE, Powder River, and other replica rifles made in Italy. Over 7" tall this sight has 4" of elevation, for extreme long range shooting.
Once fitted to a rifle, you can loosen the ratcheting detent spring. Bring the staff to a position perpendicular to the plane of the barrel and re-tighten the spring. It is even possible to reverse the base of this sight and install the sight staff to fit other rifles due to multiple detents milled in the staff.