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670 nm light mitigates oxygen-induced degeneration in C57BL/6J mouse retina
© Albarracin et al.; licensee BioMed Central Ltd. 2013
Received: 23 November 2012
Accepted: 18 September 2013
Published: 17 October 2013
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© Albarracin et al.; licensee BioMed Central Ltd. 2013
Received: 23 November 2012
Accepted: 18 September 2013
Published: 17 October 2013
Irradiation with light wavelengths from the far red (FR) to the near infrared (NIR) spectrum (600 nm -1000 nm) has been shown to have beneficial effects in several disease models. In this study, we aim to examine whether 670 nm red light pretreatment can provide protection against hyperoxia-induced damage in the C57BL/6J mouse retina. Adult mice (90–110 days) were pretreated with 9 J/cm2 of 670 nm light once daily for 5 consecutive days prior to being placed in hyperoxic environment (75% oxygen). Control groups were exposed to hyperoxia, but received no 670 nm light pretreatment. Retinas were collected after 0, 3, 7, 10 or 14 days of hyperoxia exposure (n = 12/group) and prepared either for histological analysis, or RNA extraction and quantitative polymerase chain reaction (qPCR). Photoreceptor damage and loss were quantified by counting photoreceptors undergoing cell death and measuring photoreceptor layer thickness. Localization of acrolein, and cytochrome c oxidase subunit Va (Cox Va) were identified through immunohistochemistry. Expression of heme oxygenase-1 (Hmox-1), complement component 3 (C3) and fibroblast growth factor 2 (Fgf-2) genes were quantified using qPCR.
The hyperoxia-induced photoreceptor loss was accompanied by reduction of metabolic marker, Cox Va, and increased expression of oxidative stress indicator, acrolein and Hmox-1. Pretreatment with 670 nm red light reduced expression of markers of oxidative stress and C3, and slowed, but did not prevent, photoreceptor loss over the time course of hyperoxia exposure.
The damaging effects of hyperoxia on photoreceptors were ameliorated following pretreatment with 670 nm light in hyperoxic mouse retinas. These results suggest that pretreatment with 670 nm light may provide stability to photoreceptors in conditions of oxidative stress.
Irradiation with light wavelengths from the far red (FR) to the near infrared (NIR) spectrum (600 nm -1000 nm) has been shown to have beneficial effects in mammalian tissues [1–5]. Red light therapies have been used to treat several disease conditions in humans and in animal models for over 30 years including treatment of soft tissue injuries, diabetic wounds, radiation-induced ulcers, inflammatory and neurodegenerative conditions [6–11].
In the last 10 years, there has been an increasing interest in the use of 670 nm red light to manage retinal injuries. Early reports demonstrated the ability of 670 nm red light to attenuate damaging effects of methanol intoxication in rat retinas and laser-induced injury in primate retinas [12, 13]. More recent studies have shown that 670 nm light treatment provides significant protection to photoreceptors in retinas exposed to damaging levels of light [14–16]. We have previously reported that 670 nm light treatment is effective in maintaining retinal function, and in significantly reducing expression of markers of inflammation and oxidative stress in rat retinas damaged by bright white light exposure [15–17]. Although the underlying mechanism of its therapeutic effect remains controversial, current evidence suggests that 670 nm light has a direct effect on the key mitochondrial enzyme, the cytochrome c oxidase (CCO). Upon absorption of 670 nm wavelength light, the activity of CCO increased along with energy production in the form of ATP [18, 19]. Although unproven, this process is also thought to stimulate signalling pathways resulting in improved mitochondrial energy metabolism, antioxidant production, cell survival and regulation of non-coding RNAs [17, 20].
Prolonged exposure to an elevated concentration of oxygen (hyperoxia) is toxic to a number of tissues in the respiratory and central nervous systems [21, 22]. In the retina, early investigations in neonatal and adult rabbits and in adult mice demonstrated that exposure to hyperoxia can cause severe damage to photoreceptors [23–25]. The most commonly-observed pathological effects in the hyperoxia-induced mouse model are photoreceptor and endothelial cell death, increased inflammation, oxidative stress, erosion of the blood-retina barrier (BRB) and loss of functional vision [26, 27, 29–31]. These changes are site-specific, such that the irreversible loss of photoreceptors is most prominent in the circumscribed area of the inferior retina, approximately 500 μm from the optic disk [32].
Although the precise mechanism for the photoreceptor vulnerability to hyperoxia is not completely understood, it is postulated to be initiated and sustained by a "toxic cycle" of events [26], involving hyperoxia-induced oxidative stress in the outer retina through generation of free radicals and reactive oxygen species (ROS). Given the ineffective or lack of autoregulatory mechanism for the oxygen supply in the outer retina [33], prolonged exposure to hyperoxia will inevitably cause an increase in ROS production by the photoreceptors. Generation of ROS will subsequently trigger various pathological changes, such as oxidative damage, particularly in photoreceptors. These light sensitive cells contain a large number of polyunsaturated fatty acid (PUFA), that are also highly sensitive to ROS [34]. The hyperoxia-induced depletion of photoreceptors can also contribute to the rise of oxygen tension, ROS accumulation which in turn leads to further cell death, and progression of degeneration. These changes are also featured in the later stages of Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP) [35, 36], suggesting that hyperoxia may be a suitable model for investigating novel rescue strategies to slow down the progression of these diseases.
In this study we aimed to examine the effects of pretreatment with 670 nm light on levels of oxidative stress, apoptosis and inflammatory response in the hyperoxia-induced retinopathy in adult mouse retina.
The quantitative analyses for the average total number of TUNEL + photoreceptors in NT and Tr animals at different timepoints are summarized in Figure 6. The data show a sharp increase in TUNEL + cells associated with increased period of exposure to hyperoxia in NT retinas (3d to 14d, black bars). Although there is also an increase in TUNEL + cells in the Tr animals over the same period, TUNEL + cells only begin to accumulate in significant numbers until 7d exposure, and there are significantly fewer TUNEL + cells in Tr animals at each timepoint.
We used antibodies against Cox Va and acrolein to qualitatively and quantitatively evaluate the effect of 670 nm pretreatment on retinal metabolism and oxidative stress in animals exposed to hyperoxia. Because the damage resulting from hyperoxic exposure occurs mainly in a 'hotspot' in the inferior retina these analyses were carried out using images taken from that region. To further assess the level of oxidative stress, we used real time quantitative PCR to measure the heme oxygenase-1 (Hmox-1) mRNA expression.
Baseline immunoreactivity to acrolein was determined from control retinas (0d; Figure 8B, red). A 3-fold increase in acrolein immunoreactivity above baseline was observed in 3dNT retinas (Figure 8B, black bar), increasing to 20-fold at 7d, 36-fold at 10dNT and 37-fold in 14dNT. In contrast, there was no significant increase of acrolein immunoreactivity in 3dTr retinas above baseline (Figure 8B, red); after 7 days of exposure to hyperoxia there was a 20-fold increase in acrolein immunoreactivity above baseline, comparable with 7dNT retinas. However, acrolein immunoreactivity was maintained at this level at the later timepoints in the Tr groups (10dTr and 14dTr).
Expression of Hmox-1, C3 and Fgf-2 genes were analysed by quantitative RT-PCR to monitor the hyperoxia-induced stress responses of the NT and Tr retinas.
Expression of C3 increased over longer periods of hyperoxia exposure (Figure 10B) in both Tr and NT animals. In the NT group (black bars), this increase above baseline was significant at 7d and 14d. At 10d and 14d, there were significantly higher levels of C3 expression in NT retinas (black bar) compared to Tr retinas (red bars) (p < 0.05).
A small and not statistically significant upregulation of Fgf-2 was detected at 3d in both Tr (Figure 10C, red bar) and NT animals (Figure 9C, black bar). After 7d hyperoxia, there was a 10-fold up-regulation of Fgf-2 in the NT retinas, compared with a 26-fold upregulation in Tr animals. Levels of expression were significantly different between 7dTr and 7dNT animals (p < 0.05). Levels of Fgf-2 continued to increase in NT animals at 10d and 14d; however, in Tr animals there was a fall in Fgf-2 expression at 10d to approximately 15-fold above baseline, which was maintained at 14d in the Tr group. At 10d and 14d, expression levels of Fgf-2 in NT retinas were higher compared to Tr retinas, showing significant difference at 14d (p < 0.05).
These findings corroborate earlier studies showing that hyperoxia causes oxidative stress, photoreceptor-specific cell death, and retinal inflammation [30, 32, 38]. Those studies show that (i) hyperoxia-induced changes are evident by 3d exposure to hyperoxia, (ii) that there is a focal point of pathology in the inferior central retina, and (iii) this pathology spreads to other regions of the retina over time.
In addition, the present findings show that pretreatment with 670 nm light effectively offsets photoreceptor death induced by oxidative stress. The data demonstrate that pretreatment with 9 J/cm2 of 670 nm once daily for 5 consecutive days in this model: (i) delays the onset, and slows the progression of photoreceptor death, and (ii) downregulates the associated oxidative stress markers, acrolein and Hmox-1. This decrease in oxidative stress leads to the attenuation of damage to the retina and the reduction of expression of proinflammatory C3 expression and reduced expression of the stress-inducible neuroprotectant, Fgf-2. Significantly, treatment of 670 nm light alone did not cause measurable damage in non-challenged retinas.
The timecourse of photoreceptor degeneration in this model has been reported previously [30]. In the present study, we find that the severity of the hyperoxia-induced damage in photoreceptors is significantly reduced, but not prevented, by pretreatment with 670 nm red light. We used two methods to quantify damage to photoreceptors: measures of ONL thickness, and counts of numbers of apoptotic (TUNEL positive) photoreceptors. Analyses of ONL thickness, the cumulative measure of cell loss, indicates that 14dTr animals have an ONL thickness profile approximating that of 10dNT animals (Figure 2), suggesting that in this model 9 J/cm2, 670 nm light treatment slows hyperoxia-induced degeneration by around 4 days. Counts of apoptotic photoreceptors (Figures 4 and 5) along the vertical meridian, a definitive indicator of the rate of photoreceptor loss, support this interpretation. The levels of cell death in 14dTr and 10dNT retinas; 10dTr and 7dNT were almost identical (Figures 4, 5 and 6), suggesting that 670 nm light delays progression of hyperoxia-induced cell death.
Hyperoxic exposure was previously demonstrated to induce oxidative stress, which differentially affects photoreceptors [31, 38, 39]. The high PUFA content, increased oxygen tension in the outer retina, and the continuous exposure to light render the photoreceptors vulnerable to oxidative stress [40]. The present data confirms those observations and indicates that irradiation with 670 nm light ameliorates oxidative stress such that there are minimal changes in cytochrome oxidase immunoreactivity, and lower levels of expression of the oxidative stress indicators, acrolein and Hmox-1.
Acrolein, the by-product of lipid peroxidation, and the stress-inducible Hmox-1 gene are both reliable indicators for oxidative stress and have been linked to a range of degenerative conditions, including AMD [37, 41]. In the present study, we observed changes in acrolein (Figure 8B) and Hmox-1 (Figure 10A) expression profiles indicative of oxidative stress at 7 days of hyperoxia exposure (both NT and Tr). At 10 and 14 days, the NT retinas continued to show upregulation of these markers, implicating progression of oxidative stress. However, in the treated retinas in these time points (10dTr and 14dTr) there were no further increases in acrolein and Hmox-1 expression levels. In addition, the intensity of immunolabelling for cytochrome oxidase in these retinas remained unchanged, suggesting that 670 nm light treatment maintains mitochondrial metabolism, leading to the attenuation of hyperoxia-induced oxidative damage.
Mitochondrial dysfunction increases oxidative stress, and has been implicated in the development of several retinal degenerative conditions including AMD, diabetic retinopathy and glaucoma [42–45]. Therefore, any treatment strategy aimed at preventing oxidative stress may prove beneficial in slowing the progression of retinal degeneration. Several reports showed that 670 nm light treatment reduces oxidative damage, including a rat in vivo model of methanol-induced retinal toxicity [12] and animals exposed to damaging bright light [16, 17]. In the latter study, the levels of expression of the oxidative damage indicators, Hmox-1[17] and inducible nitric oxide synthase [16] were downregulated following 670 nm light treatment. Similarly, it has been reported that transcranial delivery of 670 nm light attenuates secondary oxidative damage in rat optic nerve following partial transection [46]. Moreover, findings from studies of Parkinson's disease [5, 47] and Multiple Sclerosis [9] also show that treatment with 670 nm light mitigates oxidative stress in these experimental models. Taken together, these observations provide strong evidence that 670 nm light ameliorates oxidative damage in disorders where oxidative stress plays a key role in the progression of pathology.
The present study finds that exposure to hyperoxia causes a 20-fold upregulation of the complement component gene C3 in NT retinas, by 10d exposure; this upregulation occurs in conjunction with high levels of expression of the oxidative stress markers, and increased rate of cell death (Figure 5). However, in the treated retinas there was a much smaller rise in C3 expression (5-fold in 10dTr retinas, Figure 10B). This finding is consistent with reports from studies carried out in aged rodents [48] and in rats exposed to damaging bright light [15, 17].
Dysregulation of C3 plays a highly significant role in retinal diseases, and dysregulation of complement is highly associated with risk of AMD [49, 50, 52]. Several lines of evidence suggest that oxidative stress triggers complement activation [53, 54], which in turn mediates local inflammation. Tissue damage may result from cell-mediated attack, or by the formation of membrane attack complex, which kills cells. The low levels of C3 expression in the treated retinas in this study, suggest that 670 nm light is a potential therapeutic tool applicable to retinal degenerative conditions where inflammation is involved, such as AMD.
Several studies of retinal degeneration report an increase in expression of neuroprotective factors such as Fgf-2 over time, which protects the retina by delaying, or in some cases, reducing photoreceptor cell death [51, 55–57]. It has been reported previously that exposing the retina to a hyperoxic environment induces changes in the expression of Fgf-2[29, 55]. The current study also demonstrates that Fgf-2 expression is modulated by 670 nm light in hyperoxic conditions, although the effect is complex.
In this model, cell death in the ONL increases over time spent in hyperoxia, and at the 7d timepoint there are high levels of cell death in the NT group, and only low levels of cell death in the Tr group (Figures 5 and 6). Consistent with a role in neuroprotection, Fgf-2 expression is higher in the 7dTr group (low levels of cell death) compared with the 7dNT group (Figure 10C). However, Fgf-2 expression is significantly lower in 10dTr animals (compared with 10dNT) which is consistent with a finding that by 10d exposure to hyperoxia there are high levels of cell death, even in the retinas of treated animals. Beyond this timepoint Fgf-2 expression remains approximately static. The explanation for the lowering of levels of Fgf-2 in 10dTr and 14dTr is not immediately apparent, but may reflect the limitations of the efficacy of 670 nm light in offsetting the effects of hyperoxia. However, the reasons why 670 nm light treatment reaches a plateau, or declines, at this stage cannot be explained until we have a better understanding of its mechanism of action.
The present findings indicate that the mechanism of action of 670 nm light is likely to involve signalling pathways activated by oxidative stress in the retina. It is generally accepted that oxidative stress initiates and facilitates the progression of hyperoxia-induced damage in the central nervous system and in the retina [31, 58]. High oxygen tension is believed to induce metabolic disturbances in the PUFA-rich photoreceptor outer segments that trigger formation of ROS [35]. Accumulation of ROS leads to oxidative stress, and in turn to inflammation, and ultimately loss of functional vision [59, 60]. Exposure of the retina to 670 nm light has been suggested to initiate key signalling pathways that activate transcription factors [61] to modulate pro/anti-oxidant balance in tissues [46], inflammatory responses [16, 17] and cytoprotection [12–15]. The present results support those findings in that the data indicates that 670 nm light treatment limits oxidative stress and proinflammation, reducing retinal stress and cell death.
Several reports have suggested the important role of mitochondria in mediating the effects of 670 nm light irradiation [18, 28]. First, the mitochondrial cytochrome oxidase has been proposed as the endogenous primary photoacceptor molecule in the reception of 670 nm light triggering secondary cellular processes such as enhanced energy-rich adenosine triphosphate (ATP) synthesis and other various modulatory effects [18, 20]. Second, 670 nm light was suggested to influence retrograde signalling between the mitochondria and the nucleus, resulting in enhanced synthesis of DNA and RNA [28]. Third, the intra-mitochrondrial activities of nitric oxide (NO) and the cytochrome oxidase have recently been proposed as a novel mechanism of action of 670 nm light [62, 63]. NO controls oxygen consumption of the tissue through reversible and competitive binding to cytochrome oxidase [64]. In a recent review, Poyton and Ball provided a mechanistic explanation suggesting that 670 nm light may cause dissociation of NO from the cytochrome oxidase complex allowing NO to bind effectively to oxygen during tissue damage [65].
Here, we have demonstrated that hyperoxia-induced oxidative stress, cell death, retinal stress and inflammation were significantly mitigated, but not abolished, by 670 nm light treatment. Oxygen toxicity has been shown to cause oxidative stress and inflammation triggering photoreceptor cell death which are also implicated in the late stages of retinal degenerative conditions in humans, such as AMD, RP and Retinopathy of Prematurity (ROP) [66–68]. Hence, 670 nm red light treatment has the potential to slow the progression of retinopathies and conditions involving oxidative stress.
All procedures were in accordance with the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research, and with the requirements of The Australian National University Animal Experimentation Ethics Committee. C57BL/6J mice aged P90 (n = 12/group) of mixed sexes were reared in low (5 lx) light levels with a 12 h light, 12 h dark cycle. Food and water were available ad libitum.
Animals were divided into 2 groups: 670 nm light-treated (Tr) and nontreated (NT). All experimental groups contained equal proportions of male and female C57BL/6J mice in all experiments. The treated animals received 670 nm light treatment prior to being placed in a clear plastic chamber, and exposed to 75% ± 0.5% oxygen, maintained using a computer-controlled feedback device (Oxycycler; Biospherix, Lacona, NY). The nontreated animals were placed in the oxygen chamber the same time as the 670 nm light-treated groups. Oxygen exposure commenced at 9:05 AM in all experimental groups. The animals were sacrificed and tissues were collected at 5 time points 0 day (0d, control), 3 days (3d), 7 days (7d), 10 days (10d) and 14 days (14d) exposure to 75% oxygen. Control animals were sacrificed at 0d (no O2) following 670 nm light treatment (Treated Controls), or without the 670 nm light treatment (Nontreated Controls). Tissues were collected at 9:00 AM of each time points.
All experimental groups (NT and Tr) were transferred into a clear plexiglass. The Tr groups were taken into the treatment room prior to 670 nm light treatment procedure. The 670 nm LED array (Quantum Device, WI, USA) was positioned so that the mouse eyes were approximately 2.5 cm away from the light source. Animals were exposed to 670 nm light for 3 minutes, once daily at 9:00 AM, for 5 consecutive days at 60 mW/cm2 delivering an energy fluence of 9 J/cm2 at eye level. Mice from the NT groups were transferred into separate room while the Tr animals were undergoing treatment.
The nontreated animals are designated with the following group names: 0dNT, 3dNT, 7dNT, 10dNT and 14dNT. The 0dNT animals were not exposed to hyperoxia and did not receive 670 nm red light treatment. The 670 nm light-treated groups of each time point are designated as follows: 0dTr, 3dTr, 7dTr, 10dTr and 14dTr. The animals from 0dTr group were not exposed to hyperoxia but did receive 670 nm light-pretreatment.
Mice were sacrificed by cervical dislocation. Excised retinas from the right eye of each animal were collected and stored in RNAlater® (Ambion, Applied Biosystems, Foster City, CA) overnight at 4°C for quantitative RT-PCR. Left eyes were marked at the superior aspect of the limbus for orientation, enucleated and immersion-fixed in 4% paraformaldehyde in 0.1 M phosphate-buffered saline (PBS) at pH 7.4 for 2 hours. Tissue was rinsed thrice in 0.1 M PBS and left in a 15% sucrose solution overnight for cryoprotection. The next day, eyes were embedded in Tissue-Tek OCT Compound (Sakura Finetek, Tokyo, Japan), and snap frozen in liquid nitrogen. The eyes were cryosectioned at 16 μm thickness, in the sagittal plane, to allow a dorsal to ventral observation of the retina using Leica CM1850 cryostat (Leica Microsystems, Nossloch, Germany). Sections were mounted on gelatin and poly-L-lysine-coated slides and dried overnight at 50°C before being stored at -20°C.
Cryosectioned C57BL/6J mouse retinas from the NT and Tr groups at all timepoints were stained with TdT-mediated dUTP nick end labelling (TUNEL) using an established protocol [69]. To identify the layers of the retina, DNA-specific dye Bisbenzimide (BBZ) Hoechst (1:1000, Calbiochem, CA) was used. Quantitative assessment of cell death was conducted using parameters outlined in the following section.
To quantify the level of hyperoxia-induced photoreceptor cell loss and apoptosis in the nontreated and treated groups, we used 2 methods: outer nuclear layer (ONL) thickness measurement and counts of photoreceptor nuclei density and TUNEL-positive (+) cells. Measurements of ONL thickness and counts of photoreceptor nuclei density were done in four main areas of the retina (Figure 1A); the inferior periphery (IP), the inferior central (IC), superior central (SC) and superior periphery (SP), using digital photomicrographs taken from the bisbenzimide-stained sections. In at least 4 retinal sections per animal, 10 measurements of ONL per section were obtained. To account for obliquely cut retina, we measured and recorded the thickness of the ONL, as well as the thickness of the retina, from the inner to the outer limiting membrane (OLM-ILM). The ratio of the ONL to the OLM-ILM was used for analysis. ImageJ software (National Institute of Health) was used to count photoreceptor nuclei density across the four main areas of the retina. The values obtained were normalised against the number of photoreceptor nuclei in the nontreated control retinas (0dNT) and the results were expressed in percentages. Secondly, the number of TUNEL + cells in the photoreceptor layer was counted across the retina, from inferior to superior, and either expressed per unit area and/or total number of TUNEL + cells, in 3 sections per animal. Counts of TUNEL + cells in control animals were used to determine baseline levels of cell death. Results from 12 animals from each group were averaged and analysed.
Immunohistochemistry (IHC) was performed using standard protocols for fluorescent imaging. Briefly, frozen sections of the retina were placed in 70% ethanol followed by 2 rinses in 0.1 M of PBS. All sections were permeabilised with an antigen retrieval solution (Immunosolution Pty Ltd, Australia) for 45 mins at 37°C, followed by blocking with 10% normal goat serum (Sigma Aldrich, St Louis, MO, USA) for 1 h before incubation with the primary antibody for 24 h at 4°C. Primary antibodies used are mouse monoclonal antibody against cytochrome oxidase Va (1:100; Mitosciences, USA) and rabbit polyclonal antibody against acrolein (1:500; Cell Sciences, USA). Following rinses with 0.1 M PBS, sections were treated with a secondary antibody of either rabbit IgG conjugated with Alexa Fluor 594 or mouse IgG conjugated with Alexa Fluor 488 (1:1000, Molecular Probes, OR, USA) for 24 h at 4°C before incubation with the DNA-specific dye bisbenzimide Hoechst (1:10 000) for 2 min. Slides were coverslipped using a mixture of glycerol gelatin (Sigma, St Louis, MO, USA) and water.
Sections were examined, scanned and analysed using Carl Zeiss LSM 5 Pascal confocal microscope (Germany), LM Zeiss Apotome (Germany) and Zeiss Axioplan. During image collection, the photomultiplier settings and exposure times for each fluorescent channel were kept constant to allow comparison of protein levels between sections.
Digital images of the acrolein and Cox Va-labelled sections obtained from confocal microscopy were processed and analysed using ImageJ software. Consistency in the analyses was ensured by using identical parameters with respect to section thickness (z-stack), areas sampled for analysis, antibody concentrations, duration of incubation times, and microscope configuration.
Five identical fields of interest were chosen in the inferior region per retina (n = 3). During the image quantification, the described areas were marked by a rectangle drawn from either the tip of the outer segments to outer plexiform layer or along the inner segments. Intensity of fluorescence from each rectangle (one area) was measured and the value was plotted as number of pixels/field (Cox Va, green; acrolein, red). The values obtained from each animal were averaged and presented in a histogram.
Total cellular RNA was extracted from individual retinas and purified using the RNA extraction kit protocol (RNAqueous-Micro kit; Ambion). The purified RNA was quantified on a spectrophotometer (ND-1000; Nanodrop Technologies, Wilmington, DE). The integrity of the samples was assessed using a bioanalyser (2100 Bioanalyzer; Agilent Technologies, Santa Clara, CA). The cDNA was synthesized by reverse transcription using reverse transcriptase or first strand cDNA synthesis kit following the manufacturer's protocols (Superscript III; Invitrogen, Carlsbad, CA).
Quantitative analysis of expression levels for genes Hmox-1 (Mm00516005), C3 (Mm00437838), Fgf-2 (Mm00433287) and was determined by RT-qPCR using Taqman® probes that were combined with the Gene Expression Master-Mix (Applied Biosystems, Foster City, CA). StepOne Plus qPCR machine was used with the StepOne software v2.1 (Applied Biosystems) for analysis. Glyceraldehyde 3-phosphate dehydrogenase (Gapdh) was used as a reference gene. The variabilities were accounted for by performing the Taqman amplification assay in duplicates (individual sample variability) with triplicate biological samples to account for individual animal differences. The fold changes were determined using comparative cycle threshold (Ct; delta-delta ct).
Data were analysed using non-parametric tests, Kruskal-Wallis followed by Mann–Whitney U or parametric ANOVA test with Bonferroni corrections. Results are presented as mean ± Standard Error of the Mean (SEM). P value of <0.05 was considered significant.
Age-related macular degeneration
Association for research in vision and ophthalmology
Adenosine triphosphate
Blood-retinal barrier
Cytochrome c oxidase
Cytochrome oxidase Va
Cycle threshold
Complement component 3
Fold change
Fibroblast growth factor 2
Far red
Glyceraldehyde 3-phosphate dehydrogenase
Heme oxygenase – 1
Inferior central
Inferior periphery
Inner limiting membrane
Inner segments
Messenger RNA
Near infrared
Nitric oxide
Outer limiting membrane
Optic nerve
Outer nuclear layer
Outer segments
Polyunsaturated fatty acid
Quantitative polymerase chain reaction
Retinopathy of prematurity
Reactive oxygen species
Retinitis pigmentosa
Superior central
Superior periphery
Terminal deoxynucleotidyl transferase dUTP nick end labeling
The authors wish to thank Dr Peter Kozulin for the invaluable technical assistance. The authors are thankful to the animal facility at the Research School of Biology of The Australian National University for the care of the experimental animals. This work was supported by the Australian Research Council Centre of Excellence in Vision Science.
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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Provides training on Federal regulations and recommended procedures for identifying, serving and recording services, including but not limited to providing priority of service, to Veterans and covered persons. For front-line staff, including veterans' representatives and others, AJC operators and discretionary grantee/subgrantee front-line staff.
[AT] Connects internet portal that offers resources that can be helpful to businesses, non-profit organizations and other employers. It is a joint effort between SilverTech Inc. and the University of New Hampshire to develop an information platform for assistive technology (AT).
ETA contracted with Mathematica Policy Research to evaluate the extent to which the State LMI Improvement (SLMII) grant programs achieved their stated purposes. This webinar discussed the results of the Mathematica evaluation and provided insights that will inform future workforce and economic development decision making.
A one hour training that explored several topics including assessments, job searching, smart goal setting, developing an effective Individual Employment Plan, establishing and maintaining rapport with clients, and balancing priorities. Participants received practical information and strategies that they could easily implement in their work with clients as well as administrative duties.
A Listening Session that consulted participating employers, labor organizations, State Workforce Agencies and other program relevant experts on model legislative language and guidance for implementing Subtitle E- Self-Employment Assistance of the Middle Class Relief and Job Creation Act of 2012.
A Listening Session that consulted participating employers, labor organizations, State Workforce Agencies and other program relevant experts on model legislative language and guidance for implementing Subtitle E- Self-Employment Assistance of the Middle Class Relief and Job Creation Act of 2012.
The Center for Law and Social Policy (CLASP) has just released a new toolkit designed to aid state and local policymakers, program operators and advocates in identifying federal funding streams that can be used to support integrated service delivery. The toolkit includes a scan of federal programs that could potentially be used to support integrated service delivery in the following areas: 1) employment and career advancement; 2) income enhancements and work supports; and, 3) financial and asset building services. Among the programs included in the scan are the Workforce Investment Act, Temporary Assistance for Needy Families Block Grant, Community Services Block Grants, Social Services Block Grant, Supplemental Nutrition Assistance Program, and others.
The Department of Commerce's Census Bureau has introduced an Internet tool that helps users access data from multiple indicators in one place.
The U.S. Department of Labor has unveiled a new online toolkit to guide employers through the process for hiring veterans. The free toolkit is designed to assist and educate employers who have made the proactive decision to include veterans and wounded warriors in their recruitment and hiring initiatives.
The U.S. Department of Labor's Office of Disability Employment Policy (ODEP) announced a series of new products through the Campaign for Disability Employment that are designed to promote the hiring, retention and advancement of people with disabilities, and dispel negative stereotypes about disability and employment. The products include two Public Service Announcement (PSA) discussion guides, seven posters as well other campaign outreach tools.
The State Sector Strategy Toolkit is a collaboratively developed, web-based tool intended to help states to design and implement statewide sector policies and frameworks that position their regions to strengthen regional, skills-based economic competitiveness. The Toolkit contains information, resources and templates to be used by state policy makers in launching and managing a state sector strategy. The Toolkit was developed as part of the National Governor's Association State Sector Strategy Learning Network, in conjunction with its two project partners - The Corporation for a Skilled Workforce (CSW) and the National Network of Sector Partners (NNSP).
The Employment and Training Administration has released a new guidebook that is intended to provide youth program planners and service providers with practical information about allied health occupations in order to create or expand programs and services leading to allied health opportunities for youth and young adults. A simple checklist is provided on the first page of the appendix that may prove useful to youth service providers and planners as they begin to think about what is needed to start an allied health program in their community. Training and Employment Notice No. 10-10 provides more information on the guidebook. Click here for access to the guidebook.
The state of Oregon is making its Career Pathway Roadmap Web Tool source code available to state agencies, educational institutions, and organizations for download. The tool was developed by Oregon's Career Pathways Initiative in partnership with the Oregon Department of Community Colleges and Workforce Development and Oregon's 17 community colleges through the Oregon Pathways Alliance. Through the WebTool more than 250 career pathway roadmaps have been developed across Oregon's 17 colleges. The Web Tool was developed with funds from the U.S. Department of Labor Employment and Training Administration and the Oregon Community College Strategic Reserve Fund."
An interactive, self-paced Web guide on ETA's grant-making process, designed specifically for small community organizations and first-time applicants for ETA funding. The guide addresses ETA's grant-making mission; its funding priorities; the Agency's grant application solicitation and evaluation processes; and "how-to" guidance on crafting responsive and potentially competitive grant applications. Podcast: Grant Applications 101: What You Need to KnowToolkit Homepage Grant applicants — and grant recipients — are almost always asked to supply employment, poverty, economic and/or population data. ETA's Office of Workforce Investment Guide to State and Local Workforce Data will help you to quickly and easily locate such data
The National Association of Development Organizations (NADO), in partnership with the Missouri Association of Councils of Governments and Development District Association of Appalachia, has published a self-assessment and resource toolkit designed to assist executive directors of regional councils, along with policy board members, in conducting an organizational analysis. This resource is intended to help regional development leaders explore the various aspects, challenges, and opportunities of governing and operating a high-performing regional council, and to evaluate their own organizations against various characteristics of successful regional councils. Other related resources: Innovation in Action articles- http://www.workforce3one.org/view/3000929249738360965
The technical assistance materials on this web page apply to the following Department of Labor grants: 1) High Growth Job Training Initiative; 2) Community-Based Job Training Grants; and 3) Aging Worker Initiative. These materials support the Office of Management and Budget (OMB) approved High Growth and Community-Based Job Training Grants General Quarterly Reporting Forms and Instructions (i.e. 9134-Report Form and Narrative).
The National Center for O*NET Development has announced the redesign of the O*NET Code Connector Web site (www.onetcodeconnector.org). The newly re-designed O*NET Code Connector provides improved, more user friendly assistance to workforce professionals who are determining the correct O*NET-SOC codes for job orders, job applicants, and UI claimants. Key items from the O*NET Database are displayed so that workforce personnel can quickly select an O*NET-SOC code.


text:
Originally posted by mungodave
reply to post by DogHead
Ya think?.... I have looked around there before but I didn't notice until this time after upgrading the Google earth.
That is a pretty big mountain range by our standards by all accounts, and pine Gap is geographically dead centre of Australia, jointly run by CIA NSA and NRO to the best of my knowledge.
Originally posted by watch_the_rocks
For the three things that need coolant, I'd say computers, air-con and ?. Drill head?
Originally posted by DogHead
I have actually been there, as in inside, not outside. I offered to answer questions in another thread but there were no takers. Perhaps people prefer fantasy to reality. Who knows.


text:
Massachusetts Senatorial Debate
Senator Kerry and Governor Weld debated state and national issues at Fanueil Hall in the last of a series of nine debates. They took questions from the moderator and each other and made closing statements.
People in this video
- Ken Bode Host PBS->Washington Week in Review
- John F. Kerry U.S. Senator [D] Massachusetts
- William "Bill" F. Weld Governor Massachusetts
Hosting Organization
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Republican Governor Weld debated incumbent Democratic Senator Kerry for his Massachusetts Senate seat.
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Incumbent Senator Kerry and Governor Weld met in the second of seven debates. Both are candidates for the U.S.…


text: In the deep hours of night, who should make an appearance but Braeburn! Lost so much sleep cause I wanted to draw this. I essentially just took Braeburn's pose from a scene in-show and drew it bigger. It was mostly practice for inking. I particularly like the way the text came out!


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Final Fantasy XV Wiki Guide
| Playstation 4
Xbox One
|Square Enix
|Square Enix
|Official Sites
|Official JP Website
Originally Final Fantasy Versus XIII, Square Enix officially announced that they had changed it to Final Fantasy XV at E3 2013. This is the first time two separately numbered Final Fantasy stories take place in the same universe - Fabula Nova Crystallis. All past instances had slight name changes or an extra number; i.e. Final Fantasy X-2, XIII-2, Lightning Returns, Crisis Core, Dirge of Cerberus.
Final Fantasy XV will be available for the Xbox One and PlayStation 4 consoles. The release date is still uknown, but alot of websites are saying that Square Enix is aiming for a March 2015 release date (link below).
Story & Characters
Set in modern times but with a touch of medieval influences, the story focuses on Noctis Lucis Caelum, the prince of a dynasty which rules a city state that has the last remaining crystal.
After the crystal is stolen by an invading nation, Niflheim, a global conflict ensues with all other nations wishing to gain it for themselves. Alongside the main protagonist, Noctis is joined by a military tactician Ignis Scienta, who can deftly handle a katana in battle, a melee fighter named Gladiolus Amicitia, gun-wielding Prompto Argentum, and head of the Royal Family Guards Cor Leonis. There's one other character that appears to get close with Noctis, even if her connection with him is still unknown. Her name is Stella Nox Fleuret, she seems to be strong and fight well with her rapier.
Against this backdrop of a world at war, Noctis Lucis Caelum and his closest friends embark on an epic journey to try and get the crystal back.
The gameplay is more action oriented instead of the traditional turn based or active time battle system that Final Fantasy is known for. It looks similar to the upcoming Lightning Returns: Final Fantasy XIII battle system or Kingdom Hearts.
Like Kingdom Hearts, characters can perform actions like double jumps according to player input and move with great speed. [1] Nomura confirmed that there will be summon elements in the game. [2] Plus enemies will be tied to specific job-types like dragon knight or summoner.
True to Final Fantasy fashion, the world map is an open environment that the player is free to explore and roam about via a car, an airship, or a famed Chocobo. Players will also be able to ride Magitek Armor mechas.
World Map
This is the world Map of Final Fantasy XV
In an interview with Famitsu, Tetsuya Nomura stated that sequels would be released after launch in a similar fashion to previous games like FFX and FFXIII. Almost nothing is known about these potential sequals however Tetsuya Nomura said they could be released at a much quicker pace than previously sequels in the FF franchise. They will take place in the same world as FFXV and it is likely they will continue the story of the main game or that of a specific character in a similar way Lightning has become the main focus of FFXIII.
E3 2013 Combat Trailer
Game development began shortly before Final Fantasy XV was unveiled back in May 2006 under the previously known title of Final Fantasy Versus XIII, announced alongside Final Fantasy XIII and Final Fantasy Type-0. During E3 2013, Square Enix renamed it to Final Fantasy XV.
Directed by Tetsuya Nomura of Final Fantasy VII, Final Fantasy XV is currently being developed by Square Enix's First Production Development team. The story and characters were conceived by Tetsuya Nomura and written by Kazushige Nojima, with the Kingdom Hearts II team in charge of the in-game action and the Final Fantasy VII: Advent Children crew handling the in-game cinematic scenes.
The original world and story concepts have continued as envisioned. The First Production Development team has expanded development to take full advantage of the next-gen consoles' capabilities to match enhanced action, gameplay and graphical fidelity of next-gen technology.
E3 2013 Trailer
Older FF Versus XIII Trailers
DKS3713 Trailer. Definitely a must watch for any Final Fantasy fan.
Top Wiki Contributors
Need assistance with editing this wiki? Check out these resources:


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Low-Fat Shrimp Pasta Salad
Total Time
Prep 15 mins
Cook 10 mins
Not sure about the serving size on this recipe because I have not made it yet and it does not tell you. I would guess about 4.
Ingredients Nutrition
- 1 1⁄2 cups spiral shaped pasta
- 1⁄4 cup chopped green onion
- 1⁄2 cup celery, sliced
- 1⁄2 cup frozen peas, defrosted
- 1 (6 ounce) can baby shrimp (I prefer the fresh)
- 1 carrot, grated
- 1⁄2 cup plain low-fat yogurt
- 2 tablespoons low-fat mayonnaise
- 1 teaspoon dry mustard
- salt
- pepper
- garlic powder (I prefer fresh garlic)
- Cook pasta until al dente (about 8 to 10 minutes in boiling water).
- Cool and rinse pasta.
- Mix well with other ingredients.
- Chill.
Most Helpful
This was excellant - my husband raved about it. I used fresh tiger shrimp.
This is the BEST psta salad I have ever made! I did add a few radishes too.
This is a great refreshing salad. I mixed the dressing ingrediants earlier in the day to give the flavors time to blend and mellow. All that dry mustard certainly adds a zing! I put a little dill weed in the dressing too and added slice black olives to the salad. Yum! Thanks Gingerbear!


text:
Every diamond we feature is certified conflict-free and adheres to The Kimberley Process. All of our diamonds are natural and non-treated and are responsibly mined from around the world.
Within our inventory, James Allen also offers CanadaMark diamonds which are of Canadian origin. They are tracked through audited processes and come with a unique certificate ensuring their origin.
|Item#: 494876
|Carat: 1.06
|Color: Y
|Clarity: SI2
|Cut: -
|Depth: 65.5
|Table: 59.0
|Pol/Sym:GD/ GD
|Fluor: Medium
|Girdle: Very Thin
|Culet: None
|Measur': 5.97*5.82*3.81
|Lab: GIA
|Item#: 272016
|Carat: 1.59
|Color: Y
|Clarity: I1
|Cut: -
|Depth: 75.6
|Table: 51.0
|Pol/Sym:GD/ GD
|Fluor: Faint
|Girdle: Thick
|Culet: Small
|Measur': 6.33*6.21*4.70
|Lab: GIA


text:
Narrow your search
This hybrid can shift between laptop, tablet, or kiosk modes, and includes a copy of Photoshop Elements 12.
You can dive into the various subcategories here for detailed suggestions for every need and budget, but on this page, we present the current laptops that are our personal favorites, because of style, power, value, or just because we like them.
Sony's unique attempt at a big-screen hybrid looks great and is reasonably priced, but it works better as a laptop than a tablet.
Pricing not available
The Sony Vaio Fit 14 is an all-around excellent laptop for the money that will satisfy the basic demands of everyday use for many people and look good doing it.
The Sony Vaio Duo 13 is ambitious, but less universally useful than other Windows 8 laptop-tablet hybrids. There may not be a real need for a slider-style PC.
The superthin, superlight Sony Vaio Pro 11 is everything we expect from an excellent ultrabook.
For those who want an excellent ultraportable laptop with more than just the latest Intel processors, the Sony Vaio Pro 13 Touch is it.
While there are certainly things to like about the Sony Vaio Duo 11, the design gets in the way of enjoying them.
If you like the idea of having a touch screen on your Windows 8 laptop, the Sony Vaio T13 Touch isn't a bad way to go.
With only a handful of 11-inch laptops still available, serious travelers are flocking to ultrathin 13-inch models instead. But the low price and good battery life of the Sony Vaio E keep it from being counted out.
Sony's first ultrabook, the Vaio T, doesn't fall far from the tree of other thin Sony laptops like the Vaio Z, but it's far more affordable: this is ultrabook-as-budget-laptop, not ultrabook as high-end computer.


text:
Alton Fitzgerald White, who plays the wronged Coalhouse Walker Jr. in Broadway's Ragtime, was himself wronged by New York City Police July 16 when he was mistakenly arrested at his building just hours before the Friday evening performance.
The New York Times reported that police have conceded White and three acquaintances were wrongfully arrested outside the lobby of White's Harlem apartment building on St. Nicholas Avenue, held for several hours and strip-searched. White missed the Friday performance, and subsequent shows over the weekend.
The police were responding to a report of Hispanic men with weapons at the building, but White, who is African-American, and his black acquaintances, were among those rounded up.
Although he was released Friday, White also missed the subsequent weekend Ragtime performances. Some cast members had no idea where White was until they read the weekend papers.
White told The New York Times he was talking to lawyers about pursuing a civil rights lawsuit against the police department. He believes he and the other men were arrested due to their skin color.
"When I was sitting in that jail cell, I realized that my perception about good and justice would never be the same," he told The New York Times.
The police department apologized, but said the men fit the description of a tip about drug-dealing, and told The Times that two of the six men arrested -- not White's acquaintances -- were charged with criminal drug possession. Strip-searching is apparently routine in felony drug cases.
White's other Broadway appearances were in Smokey Joe's Cafe (also in London), Miss Saigon and The Who's Tommy. He has worked at the Goodman Theatre, the McCarter Theatre and elsewhere.


text:
Cold Spot restaurant burns down; people asked to avoid area
DUNBAR POLICE DEPARTMENT Firefighters gather at the scene of the Cold Spot fire. Firefighters from three cities fought the blaze.
KANAWHA COUNTY EMERGENCY MANAGEMENT This is what the Cold Spot looked like at the height of the fire.
Firefighters who responded to a blaze at the popular Cold Spot pub in Dunbar say the building is a total loss.
The building was being demolished about 8 a.m.
The fire started about 3:30 a.m. Dunbar, South Charleston and Charleston firefighters responded to the blaze.
Kanawha County emergency services released a statement asking people to avoid the area:
"At the request of Dunbar Police all traffic please avoid the area of the Cold Spot Restaurant at the three way intersection of Dunbar Ave, Washington St W, and 7th Ave coming out of Charleston. This is due to the early morning structure fire."
The Cold Spot was known for its tasty wings and friendly neighborhood atmosphere.
The cause of the fire was still under investigation Saturday morning.


text:
Nor can he plausibly pass himself off as a champion of tight-fisted spending restraint while throwing down a challenge to skeptical Republicans in another crucial issue of the campaign. At a May 24 campaign rally in Des Moines, Iowa, the president declared that "federal spending since I took office has risen at the slowest pace of any president in almost 60 years."
The Washington Post's Glenn Kessler fact-checked this claim and bestowed on the commander-in-chief the coveted "Three Pinocchios" designation.
Again, a quick check of numbers at the White House's own website gives the lie to Obama claims of cutting deficits and bringing the budget under control: the last budget signed by George W. Bush and passed by the Democratic Congress (for fiscal year 2008) amounted to $2.77 trillion with a deficit of $459 billion. The next year's budget (signed by Obama and again authorized by the Pelosi-Reid Congress) included a great deal of "emergency spending" for the Obama Stimulus Package and reached $3.52 trillion with a deficit of 1.4 trillion. In other words, deficit spending more than tripled in Obama's first year as president, and it's remained at comparably crippling levels ever since.
As Andrew Taylor fact-checks the White House claims for the Associated Press, the president "measures up" with a 9.7 percent spending increase in 2009 "much of which is attributable to Obama" and "a 7.8 percent increase in 2010, followed by slower spending growth over 2011-13. Much of the slower growth reflects the influence of Republicans retaking control of the House and their budget and debt deal last summer with Obama."
This summary raises one more crucial point indisputably indicated by universally accepted statistics: the dramatic difference in fiscal performance between Congresses controlled by Republicans and those dominated by Democrats. In fact, partisan majorities in the House of Representatives (where the Constitution stipulates that spending bills must originate) seem to matter more to the scope of deficit spending than whether a donkey or an elephant occupies the Oval Office.
President Obama rightly chides his Republican presidential predecessors for disappointing records of fiscal management, but fails to note that for all 12 years of the Reagan and first Bush administrations, and for the last two difficult years of the second Bush administration, Democrats wielded big majorities in the House.
It's no accident that Bill Clinton enjoyed a vastly better record of economic management in the six years (1996-2001) he hammered out budgets with a Republican House (and averaged a surplus of more than 1 percent of GDP) than the two years he collaborated with his fellow Democrats (and racked up deficits of 2.5 percent). By the same token, George W. Bush averaged deficits at a typical level of 2.5 percent of GDP during the six years he worked with Denny Hastert and fellow Republicans, but when Nancy Pelosi took over the House during his last two years, the numbers exploded to a disastrous rate of 6.7 percent.
In raw dollar terms, the last "all-Republican budget" of 2007 (devised entirely by a GOP president and approved by a Republican House) brought a modest deficit of $160.7 billion, while the first "all-Democratic budget" of the Obama era in 2010 (wholly attributable to President Obama, and passed by the Pelosi House) amounted to deficit spending of $1.293 trillion—or eight times more than the bad old days of Bush.
The bottom line of any honest, uninflected examination of readily available budgetary and employment numbers provides both bad news and good news for President Obama's reelection efforts.
The bad news: while he hardly qualifies as the devastating, prosperity-wrecking destroyer depicted in conservative propaganda, he certainly can't claim a good record as a job creator with fewer people working today than when he took office, and vastly more having left the labor force altogether.
But the good news for Obama from the raw numbers also suggests that the wild spending growth that Romney and company regularly (and rightly) decry has already begun to subside under the influence of the Republican House. Based on historical patterns, the deficit might well continue to decline in a second Obama term—as long as the GOP maintains control of Congress and exercises stern supervision of the administration's credit card.
Rush Limbaugh defends Rubio's debate answer: He's absolutely right that Obama knows what he's doing | Allahpundit
Time for Team Hillary to break out the gender card for young liberal women who prefer Sanders | Allahpundit


text:
Top Definition
The name given to fictional characters when you can't remember the real name.
Yea the guy who played in that movie was......um.....humperdink Rhino or something like that.
by The Burt of Punta Dilla Shorts December 27, 2006
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text:
Defiance - Waimea Bay by IsacGoulartWatch
©2008-2016 IsacGoulart
i thought this was a pretty funny picture.. here i was photographing people jumping off the rock, completely ignoring the "warning" sign.. speaks loads about the human nature.. our driving need to defy.
- This image is the exclusive property of Isac Goulart and is protected under the United States and International Copyright laws.
The image may not be reproduced, copied, transmitted or manipulated without the written permission of Isac Goulart.
Daily DeviationGiven 2009-01-22
Defiance - Waimea Bay by `isacg shows that signs aren't for everyone, just like jumping off hugeantic cliff side rocks aren't for everyone. A great photograph wrapped in a funny story, presented to you by isacg. ( Suggested by JacquiJax and Featured by zerocomplex )
i jumped off this rock once... makes me miss Hawaii!
of course no one listen to rules until they live about it. great shot by the way. keep up the great work artist.
Great shot, my wife has been to the island and seen them jump!! Incredible stuff!
Kaua'i does rock. It has some wacky signage, right now i'm thinking of some i saw along the Alaka'i Swamp Trail... I'm going to have to post an unusual trail marker sign from along that route...
Love the juxtaposition of your photo... sweet work
Love the juxtaposition of your photo... sweet work
Great timing, idea and post work.
funny and awesome! This looks so good, because this SO good!
... or perhaps the need to prove something to others. Excellent capture!
I love the devil may care attitude depicted here. Wonderful picture.
Nicely shot! Good one!
how'd u make the dark shading on the edges?
awesome picture
wow great shout i love the sense in your eyes to take this shout
Amazing! just amazing!
i wish i knew awesome people like this
This is awesome, I love it, and I love cliff jumping too!
I jumped from that rock (Towers) many times when i was in high school.
reminds me of myself and my friends when we were younger
outstanding idea !
ahah, no one listens to that sign,
its not even there anymoree.
its not even there anymoree.
yeah they took off the sign like the day after i shot this, cuz i went back later that week and it was gone.. kinda ironic. i was probably one of the last guys to photograph it.
Hah, I like this. =]
funny but dangerous at the same time. haha.
Perfect capture. We do that down here in Aus in certain areas. So much fun.
I have been on so many beaches with this exact scene, people just don't learn Beautiful composition and you were able to capture the reactions and such with the vignette. Wonderfully done.
brilliant!!! hahaha i loved it so much
this is brilliant.
Excellent picture, it captures more then just an image.
Be a rebel!
...like everyone else.
...like everyone else.
A truly great shot! Love it!
Congrats on the DD!
Congrats on the DD!
... they should probably listen to the sign. -_-v
Anyways, I really like your photo. It's very pretty! I like the person that's on the way down.
Anyways, I really like your photo. It's very pretty! I like the person that's on the way down.
Funny... the rock looks like a face in profile to me...
Haha, this is so cool. I love it. The colors (or lack of) are awesome. Fav'd.
Haha! Beautiful and funny.
excellent photo!!
perfect timing for the guy diving/reactions of those still on the cliff
only thing I have against it is probably the size of the vignette, other than that...the tones & everything else is spot on!
perfect timing for the guy diving/reactions of those still on the cliff
only thing I have against it is probably the size of the vignette, other than that...the tones & everything else is spot on!
great timing n composition!!
It's not a driving need to defy, it's sheer idiocy.
Great Pic!!!
Great picture... funny, just in the moment, and perfect post-processing. Well deserved DD!
eep :S you know that by the time they put that sign there a bunch of people had probably already died or been hurt....
great pic tho
great pic tho
Ha, wicked.
Haha this is fantastic!!!


text:
|Mail flights
|An email service is possible
| Weight
|Approx. 90 g
Vertical × horizontal (not including fringe) 62 x 182 cm fringe 9 cm
|[Material] linen 100% [model information] 158 cm full color wear [stretch / sheer] transparent and without elastic
|JP Post EMS
|Your order will be shipped to you via Japan Post EMS. Japan Post is a speedy delivery service that delivers to more than 120 countries. With an effective tracking system and insurance program, EMS is able to offer a secure delivery worldwide. You can track your package with the tracking code provided and it will be delivered within a week. See estimated shipping fee
|Credit Card
|We accept credit and debit cards.
The following credit and debit cards can be used:
•American Express
Start Date:01/02/2016 00:00 JST
End Date:29/02/2016 23:59 JST
This product cannot be shipped to United States from the store.
Please contact the store for further information.


text:
2015 NFL draft - Baltimore Ravens draft classNFL Draft Insiders, ESPN Insider
ESPN Insider's NFL draft experts recap the 2015 draft for the Baltimore Ravens, including Mel Kiper's draft grades, Todd McShay's favorite pick and more.Story | Conversation | May 05, 2015
NFL - Latest a TE Has Been Taken in a WhileNo one jumping for tight ends
With the Ravens' selection of TE Maxx Williams at No. 55 overall, that's the latest in the draft that the first TE has been drafted since 1994, when L...Story | May 01, 2015
Kiper, McShay and Sprow discuss who they project the Ravens to select in the upcoming draft.Story | February 24, 2015
Inside the Huddle Podcast - 5/3
John welcomes Ravens GM Ozzie Newsome, Steelers GM Kevin Colbert, and Bucs GM Mark Dominik to share their thoughts after the draft.Audio PodCast | May 03, 2013
2013 NFL draft - Baltimore Ravens draft guideESPN Insider staff, ESPN Insider
Mel Kiper, Todd McShay and ESPN Insider's team of NFL experts break down the draft needs and fits for the Baltimore Ravens. Would Manti Te'o be a good replacement for Ray Lewis?Story | Conversation | April 15, 2013
NFL - Five teams that must draft well this yearMatt Williamson, Scouts Inc.
Matt Williamson of Scouts Inc. identifies the five teams with the most work to do in the NFL draft.Story | Conversation | April 09, 2012


text:
America's Preschools in "A State Of Emergency"Rebekah Kuschmider
A new report released this week from Rutgers University's National Institute for Early Education Research Gives the US a failing grade for preschool funding. According to the Huffington Post:
Funding per student for state pre-school programs has reached its lowest point in a decade, according to "The State of Preschool 2012," the annual yearbook released by Rutgers University's National Institute for Early Education Research. "The 2011-2012 school year was the worst in a decade for progress in access to high-quality pre-K for America's children," the authors wrote. After a decade of increasing enrollment, that growth stalled, according to the report. Though the 2011-2012 school year marks the first time pre-K enrollment didn't increase along with the rate of population change…
…This means state pre-K funding per child has fallen more than $1,100 in real dollars from 2001-2002. "That's the lowest since we've been tracking pre-K," Barnett said. He called the cuts "severe" and "unprecedented." This is the first time NIEER has seen average, per-student spending slip below $4,000.
This comes hot on the heels of an Obama Administration push for universal preschool in America, an initiative that could even the gap between lower and upper income kids as they reach elementary school grades. Preschool is particularly valuable to low income children according to an article in Slate:
Research suggests that preschool only benefits children from these disadvantaged families (in particular, families that are below the poverty line, whose mothers are uneducated, or who are racial minorities). This could be because preschool acts as a kind of "equalizer," ensuring that for at least a few hours a day, these kids get the same high-quality interaction with adults as more advantaged children do, which helps to even the developmental playing field.
I simply can't see a downside to increasing access to high quality preschool for all kids in America. It may not be as beneficial to higher income kids as it is to lower income kids but it certainly wouldn't be detrimental to them. I think it should be part of public school and should be free for all families. DC has a preschool for all program and it's been very successful – in fact the NIEER report shows that DC is a leader in preschool spending and the access for kids as young as 3 to guaranteed preK in the public schools could be a model fo the nation. Not only is it an educational leg up for kids, it provides a much lower-cost child care option to the many two-working-parent households in the area.
Now, I'm sure some people will call me a tax-and-spend liberal who wants to hand out more money and programs and enable low income people to mooch off the taxpayers for child care and early childhood education. (You wouldn't be the first to say that about me. You wouldn't even be the first to say that about me this week.) But the undeniable fact is that for kids in lower income families preschool provides them with an educational benefit that can help orevent them from falling behind in later grades. I think that's worth a community investment.
It's past time we started providing high quality early childhood education to all American kids. It's the right thing to do.
Read more from Rebekah at Stay At Home Pundit & The Broad Side. Follow Rebekah on Facebook and Twitter too!
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- 44Promote
Art Print
find your wayby Mary Carroll
Collect your choice of gallery quality Giclée, or fine art prints custom trimmed by hand in a variety of sizes with a white border for framing.
Isn't that just beautiful!?
Thanks so much, micklyn! :)
Just wonderful
Thank you so much, Ally!
really love this!
Thanks so much, Carol!
Nice work!
Thank you, Gwenola de muralt!
Thank you, Guido!
Thanks so much, catspaws!
Thanks so much, Jess!
I love your titles! Very fitting.
I find it very hard to think of titles, so thank you, Jacqueline! :)
Oh Yeah! ✯ ✯ ✯ ✯ ✯ 👍
Thank you very much, Wayne!
Beautiful work!
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Onyx Mage - MTG Unused variant by IzzyMedranoWatch
©2014-2016 IzzyMedrano
The unused version of the Onyx Mage for MTG. If I remember correctly, the self mutilation was a little too much for the universe.
Great Artwork Amazing
sweet !
funny, because they talk about mutilating all the time in the lore. Scooping out someone's corneas to use like crystal ball contact lenses for one...
Very dark - I love it!
I really like this piece. Guessing that the card was in the Core Set, they probably wanted to limit graphic content to not shock new players. Now, put this guy in the Shard of Alara Block, and he'd be at home in Jund. Maybe Grixis, though he's a little too healthy looking to be from there. Great pose, and I can almost imaging the power hungry, angry yell while he carves his body up for payment.
Oh man Izzy I love this version I wish wizards went with it
First of all, I love this version, it would make for a killer promo. 2nd, I'm curious as to how the commissioning worked out on this one. Did they pay you for both versions? Did they suggest they try a different artist? If these questions are too personal feel free to ignore them. Lovely work!
I got the pitch to do the mage cycle and in excitement I took this guy to finish before sending in the sketch. It was my bad. They paid me only for the card they used.
Thanks for the reply! That's cool to hear you were so into the project, I could see myself doing something like that as well once I start working on Magic. Still, 2 great pieces came out of it
Spooky! Very well done!
Awesome job its too bad this didnt make it to a card or a promo version
I like this version. And I've seen way worse MtG-cards when it comes to violence depicted in the artwork. Strange decision ....
There are undead, horrors, blood and people killing each other on cards. But this awesome thing is "too much"...? Sorry, but I don't get it. Petty sad, but the art is awesome.
Self mutilation was too much for MTG ?
Dang! Too explicit....... but then they have Pain Seer in Theros, which I feel is way worse than this. But I guess that art just implies the cutting. Oh well. I do like this version more than what was used, aside from the swirly fire looking kind of cheesy.
Thanks very much for the kind words in such a great back handed compliment format.
I adore your art.
Beautiful job, cool colors, perfectly fit to the style of the whole. I'm impressed:>
What mutilation?! Body paint is now illegal!? Whateva WOTC.
Phyrexians dissecting people alive is ok, but a little self mutilation is not? Weird. Anyway, great work!
This is amazing
too bad it wasn't used, but I could understand why, it can be a bit of a trigger for some players : (
But self-mutilation is made awesome with pink sparkles and glowybits.
Isn't it always?!
But very awesome! You are too good for MTG
But really this does look fantastic, well done
But really this does look fantastic, well done


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Hi there,
I am getting Sky HD on Friday and I am very confused about what HD channels I will get as part of the "World" package with Sports and Movies mix.
I am particularly unsure about the following HD channels; BBC HD, ITV HD and CH4 HD, and whether or not I will get them as standard. Could someone please advise?? I would really like to know what HD channels I should have before the installer tries to leg it out the door!!
Also, I have looked a the sticky post about adding "Other" channels. But there seems to be a huge amount of them so was hoping that someone would post their reccomendations as to which ones are worth manually storing!! I presume that there is a lot of repeated content in these BBC variations for example.
NB: As its Sky HD im getting it is primarily HD channels that I am interested in, even if it is only partially HD.
Any advice would be much appreciated.


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You hummed to yourself as you continued to kick some butt on Pokémon. Wrapped up in a blanket tightly, you were sitting at your desk. You were so concentrated on your game that you didn't hear or see Alfred sneaking up on you.
He smirked, pulling on the mask he'd bought for this special occasion. He knew how much you disliked getting jumped, but it was funny as hell. Also he adored the expressions on your face, so he wouldn't stop scaring you just yet.
He grabbed hold of your shoulders and you shrieked loudly, dropping your ds to the floor and falling out of your seat. His loud laughter filled the room as you struggled to get out of your cocoon. "Dammit! That's not funny!"
He shook his head, falling backwards onto your bed. "N-No! It most definitely is!" He crowed with laughter, clutching his sides. You growled at him, feeling tears prick your eyes. Why was it always like this with him?!
No matter how many times you'd earnestly asked him to stop he kept doing it! "Stupid Alfred!" You shouted and ran out of the room. What a jerk! You thought to yourself as you angrily pulled on your coat. Stepping outside into the cold air cleared your head and soothed your oncoming headache.
"Why can't he be nice like he used to...." you muttered to yourself as you stomped to the park. You just needed some time to calm down.... and to hatch an evil plan against him. You'd feel better after that.
Alfred stared at your ceiling, his hands behind his head. Did I go too far? He wondered, replaying your furious expression in his mind. He closed his eyes. Maybe he should stop.... After all, all he wanted was for you to remember at all times that he was there. But that wasn't the proper way, was it?
What would Artie do? He asked himself, turning to the Brit only in his dire need. He's a gentleman, he knows how to treat women right. Alfred imagined the Englishman in front of him, almost wincing as 'Arthur' started shouting at him.
"How could you do that to her! You're trying to show her you like her aren't you?! You need to apologise! Right now! Go looking for her, she probably needs someone to comfort her!"
"Yeah, yeah.... But if I go now, she'll punch me..."
Arthur sighed and rubbed the bridge of his nose. "Then wait for her, that way the moment she comes in, you can apologise."
Alfred grinned, thanking his mental projection. Pulling your blanket with him, he trailed downstairs and settled himself on the sofa to wait for you.
As the sky started darkening and the starts twinkled their way into view, you decided it'd been long enough for him to repent. Turning off your ds, which you'd managed to snag from the floor when you left and which was thankfully also not broken in any way, you got up from the cold swing you were sitting on.
You trudged home, less than enthusiastic about seeing the American again. Quietly you opened the door, shutting again slowly in the hope that Alfred wouldn't hear you or would already be asleep.
Walking into the living room you saw that both were true. The blond was on the sofa, breathing peacefully. You recognised the blanket entwined around him as your own and you narrowed your eyes as he snuggled into it.
Taking your shoes off, you padded upstairs on your socks, retrieving the mask he'd worn. It was stuffy wearing it and you knew if you looked in the mirror you'd give yourself a heart-attack. How did Alfred even survive sneaking up on you without catching a glimpse of himself and freaking out?
You crept closer to him, tapping him on the shoulder. He blinked sleepily and caught sight of you.
His bloodcurdling scream filled the house and you fell back trying to cover your ears form the sound. "Geez! It's just me!" You shouted, pulling the mask off and flinging it to the side. He trembled underneath the blanket, his eyes wide.
Whimpering, he pulled you closer ontop of him, wrapping his arms around you tightly. "A-Alfre-d, can't breathe-!" You gasped, trying to free yourself. He merely buried his face in your chest and sobbed.
Man, what a wimp! He could scare you as many times as he wanted and you got frustrated and ticked off. You frightened him once and he was reduced to a miserable wreck. A twinge of guilt racked your body and you sighed, pulling him closer.
"God, Alfie, man up a bit." He chuckled weakly, sniffling slightly. "Sorry about before." He murmured, glancing up at you. "I didn't want to- I mean, err, I just wanted to have some fun, I didn't want to make you hate me..."
You smiled at him, ruffling his hair up. "I'd say we're even now anyway." Rocking him slightly, you rubbed his back. He breathed out shakily, then nuzzled his face into the crook of your neck. "I don't think I'm going to let go of you now."
Blinking your eyes in surprise at his statement you pulled back to look at him. "Is that because you don't want to? Or because you're too scared to?"
He grinned sheepishly. "Both." A blush dusted your cheeks and seeing this his face turned pink as well. "Only if you promise not to scare me again."
Alfred kissed your cheek. "I promise." The whisper in your ear sent tingles down your body and you hugged him. "Good... because otherwise I'd have to kick your scrawny behind."
He shivered and laughed gently. "I know you will."
With that the two of you fell asleep, happily waking up to see each other again. You never scared each other again.... Though Alfred shrieked and jumped into your arms when he saw the mask lying on the floor in the corner of the room.
Scare me again and I'll- (AmericaXReader) by shihachiiWatch
©2013-2016 shihachii
This one seemed quite popular on the poll, so I got myself to write it ^^"
Based off my own experience as I freaking hate being jumped by people!
(and as my music is own loudly often, it happens quite a lot TT.TT)
Please enjoy and tell me what you think, feedback is as always greatly appreciated!
Also if you want to help decide which character and plot you read about next, please vote in the poll
Based off my own experience as I freaking hate being jumped by people!
(and as my music is own loudly often, it happens quite a lot TT.TT)
Please enjoy and tell me what you think, feedback is as always greatly appreciated!
Also if you want to help decide which character and plot you read about next, please vote in the poll
My gramps once came in my room and told me a meteor shower is outside,and I went to the back porch,and as soon as I stepped out the door,(it was nighttime,so I couldn't see a thing)a giant spider jumped out.and scared me so much that in my fright I turned around and punched my gramps in the face.
And it broke his nose. So if Alfred scared me,I would have most likely broke his face.
And it broke his nose. So if Alfred scared me,I would have most likely broke his face.
This is me, but with my mother giving something to me with my headphones, reading fanfictons in my dark room.
2 cute
Aaah god that would freak me out!
It's even worse when she does it at night because I can't see her and she brushes her fingertips across my legs and I usually end up accidentally kicking her in the stomach
Aw, Alfred's just adorable when he's scared!
I'm like the biggest wimp of them all. I nearly ran out of the theater during world war z. I mean seriously
Thats awsome tottalllyyy XD i wish i could watch it in theaters but i watched it on dvd -bows head in shame-
It's okay, I'd have been there with you, fleeing away from it!
YAY! than really sounds like something i would do
if someone I pranked reacted how al did I would nlaugh my arse off.
I most definitely would plan revenge, but if someone seriously reacted like Al did, I would feel really bad. Haha, it was a really cool story. You're a fantastic writer.
Thank you very much for saying so lovey!
And I would do the same no doubt!
And I would do the same no doubt!
You're welcome dearie.
Haha, I think a lot of people would but Al's reaction would make everyone feel bad.
Haha, I think a lot of people would but Al's reaction would make everyone feel bad.
If he tried to jump into my arms he'd most defiantly brake me in two!
I would have kicked his butt then scare the crap out of him. Yep Im mean but don't scare me unless you want to know what hell feels like.
Haha! Alfy! Dude, I love your stories!
This is adorable! X3 Loved reading it so much. <3 Nice work!
d'awww Alfie you cutie-pie ^^ hmm, speaking of pie...I'm hungry... lol.
Awww I love it!
I'm so glad to hear it love
Oh my god, I loved this! It was so cute!!
Aww Alfie you're an adorable wimp lol
Great story
Being jump scared is so not cool
Great story
Being jump scared is so not cool


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Book an announcement for publication online and in the next edition of the The Northern Echo
Robertina Blades
Published in the The Northern Echo on 16 November 12
BLADES (nee Bell) Suddenly on November 10, Robertina (Renee) aged 84 years, of West Rounton, formerly of Escomb. Dearly loved wife of the late Joe, loving mother of Josephine and Elizabeth, a dear mother-in-law of John and Dennis and a dearest gran of Helen and Raymond. Funeral service to take place at St. Oswald's Church, West Rounton, on Wednesday, November 21, at 11.30 a.m., followed by interment. Family flowers only, donations if wished may be given to church funds.
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