text:
- Review
- Open Access
Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors
- Erik Serrao1,
- Srinivas Odde1,
- Kavya Ramkumar1 and
- Nouri Neamati1Email author
© Serrao et al; licensee BioMed Central Ltd. 2009
- Received: 08 January 2009
- Accepted: 05 March 2009
- Published: 05 March 2009
Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN) inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors.
- Viral Resistance
- Resistance Profile
- Amprenavir
- Darunavir
- Raltegravir
Though many potent inhibitors of the viral life cycle have arisen over recent years, HIV persists as a global pandemic with eradication unlikely in the near future. Over 33 million people, including 2.5 million children, are living with HIV worldwide as of December, 2007 [1]. Almost 7000 people are newly infected with HIV, and around 6000 die from AIDS, each day. Due to the lack of education about risky behaviors and the lack of access to treatment, low- and middle-income countries remain the largest producers of new HIV infections, with AIDS being the leading cause of death in Sub-Saharan Africa. Five percent of all adults are living with HIV or AIDS in this region [1, 2]. Worldwide spending on HIV/AIDS research, treatment, and prevention has risen from $300 million in 1996 to an estimated $10 billion in 2007, but the global need is projected to be much higher [2, 3]. Although novel estimation procedures have contributed to a more accurate, reduced 2008 global estimate of those living with HIV and AIDS in comparison to the past few years, this number remains staggering and ever increasing [1, 4].
The advent of highly active antiretroviral therapy (HAART) has brought with it a significant decrease in AIDS-related deaths over the last ten years. Prior to the development of raltegravir, HAART had been recommended to consist of at least three different drugs targeting separate stages of the HIV life cycle: two nucleoside reverse transcriptase inhibitors, plus either a non-nucleoside reverse transcriptase inhibitor such as efavirenz, or a protease inhibitor [5, 6]. Studies have shown that effective administration of these HAART regimens can result in a large-scale decrease in plasma levels of viral RNA, as well as a significant increase in CD4 cell count [7–9]. Furthermore, HAART has been shown to reduce the incidence of opportunistic infections and HIV-associated cancers, contributing to the significantly decreased number of HIV- and AIDS-related deaths each year (and correspondingly contributing to the much increased amount of people living with the disease each year) [10]. However, HAART regimens have been incapable of viral eradication, due in part to the viral establishment of reservoirs within latently infected and resting CD4+ T cells and CD8+ T cells [11–13]. Also, HAART has frequently led to the emergence of drug resistant viral strains [14, 15]. Hence, much innovation is essential for the success of future anti-HIV drug research.
An area of much recent progress has been that of HIV-1 IN inhibitor design. IN is an essential enzyme for viral replication, and it has no human homolog [for a recent review, see Reference [16]]. IN catalyzes the insertion of reverse transcribed viral cDNA into the host cell genome via a multi-step process. The first step in integration occurs in the host cell cytosol and is referred to as 3'-processing. During this step, IN cleaves a dinucleotide from each viral DNA terminus at a conserved CA sequence, yielding two reactive 3' hydroxyl groups. Following this processing step, IN associates with a number of viral and cellular proteins, forming a pre-integration complex (PIC), and then migrates to the nucleus. Within the nucleus the reactive hydroxyl groups are utilized in nucleophilic attack upon the host cell genome, a process known as strand transfer [17]. IN multimerization is also required for formation of the PIC. As a dimeric IN species is required for 3'-processing, the strand transfer step calls for a tetrameric IN arrangement. Proper integration of viral DNA into the host cell genome leads to viral protein expression, maturation, and propagation [18]. IN catalysis is vital to proper HIV-1 replication and sustained infection, and potent small-molecule IN inhibitors have been avidly sought over the last ten years as a supplement to HAART and a novel angle of attack against drug resistant viruses.
The birth of the diketo acids and the emergence of raltegravir
A previous large-scale, random screen of over 250,000 compounds yielded potent inhibitors, and the most active compounds proved to be 4-aryl-2,4-diketobutanoic acids, containing a distinct β-diketo acid (DKA) moiety that was capable of coordinating metal ions within the IN active site [19]. The active DKA containing compounds from this study showed a significant preference for strand transfer inhibition over that of 3'-processing in vitro. For example, the most potent compound, L-731,988, exhibited a 70-fold higher IC50 value of 6 μM for 3'-processing compared to its 80 nM IC50 value for strand transfer inhibition. Importantly, L-731,988 exerted a completely inhibitory effect upon HIV-1 infection in a cell-based assay at a concentration of 10 μM. In a follow-up study [20], it was found that the DKA and target DNA binding sites on IN overlap and are both distinct from that of the viral DNA, and also that the DKAs bind with a 1000-fold higher affinity to IN in complex with 3'-processed viral DNA than to non-complexed IN (10–20 μM versus 100 nM).
The DKA pharmacophore was subsequently transferred to a naphthyridine carboxamide core, conferring similar antiviral activity and strand transfer selectivity [28]. The most active inhibitor from this class, L870,810 (Figure 1), showed very promising activity, with IC50 values as low as 4 nM against multidrug-resistant viruses [29]. L870,810 soon became the second IN inhibitor to enter clinical trials. However, liver and kidney toxicity surfaced after long-term treatment in dogs, bringing a premature end to the drug's clinical progress [30]. This relative success with diketo acid structural analogs led to the derivation of a class of N-alkyl hydroxypyrimidinone carboxylic acids, which showed nanomolar activity against HIV-1 IN in enzymatic assays and a good pharmacokinetic profile (modest oral bioavailability, low plasma clearance, and good half-life) in rats [31]. MK-0518, also known as raltegravir (Figure 1), emerged as the most promising pyrimidinone carboxamide derivative and soon became the first IN inhibitor to progress into Phase III clinical trials. Though multiple resistant mutations have surfaced in both treatment-experienced and treatment-naïve patients [32], MK-0518 has exhibited low nanomolar and strand transfer selective in vitro IN inhibition, an IC95 value of 31 nM in the presence of normal human serum (NHS), and synergistic effects in combination with multiple current antiretroviral drugs [15, 33]. Raltegravir (a.k.a. Isentress™) became the first FDA approved IN inhibitor in October of 2007 and is currently being administered as a new addition to HAART regimens.
Me-too drugs
Comparable to every innovation, promising new drugs will be quickly followed into the market by multiple analogs, most striking in their similarity to the original. With an average cost of $2 billion to bring a single drug to market [34] and only one in three drugs producing revenues that match or exceed these average research and development costs [35], one can imagine the temptation for pharmaceutical companies to forego the pains of innovation and rather simply modify current leads. There have been differences of opinion regarding the value of these so-called "me-too" drugs [36, 37]. Some view that me-too products are essential for drug optimization and progress, and that they generate vital marketplace competition, leading to better quality and lower costs. Still others argue that slight structural modifications producing negligible improvements in drug activity are a waste of time and effort, and that the vast amount of money spent on competitive advertisement could be invested instead into actual innovation or the development of orphan drugs. One of the clearest examples of me-too product generation can be seen in the statin drug market. There are currently six 3-hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) commercially available. However, there has yet to be a large, randomized trial comparing the clinical effects of equivalent doses of each statin upon prevention of vascular disease. The six drugs differ slightly in pharmacokinetics, and knowledge gained throughout their design and development about the health implications of high cholesterol has been beneficial. However, their structures, functions, and clinical effects are highly homologous, and over 90% of physicians have been shown to utilize at most three different statins for all of their incident prescribing [38]. Another obvious instance of me-too production has been the evolution of AstraZeneca's Prilosec (omeprazole) to Nexium (esomeprazole). There are only two differences between the two drugs – Prilosec contains a racemic mixture of the D- and S-isomers of omeprazole while Nexium contains solely the more potent S-isomer, and Nexium is protected by patent and far more expensive than Prilosec. Furthermore, Nexium has been shown in clinical trials to be only marginally more effective than Prilosec in control of stomach acid levels [39]. Though there have been several examples of me-too drugs providing a substantial increase in efficaciousness or decrease in toxicity – such as derivatives of the anthracycline chemotherapeutic daunorubicin [40] and the beta blocker propanolol [41] – very few FDA approved me-too drugs actually exhibit a significant enhancement of activity in comparison to their predecessors. In fact, of the 1035 drugs approved by the FDA between 1989 and 2000, only 361 contained new active substituents, and less than half of these received a priority FDA review due to the low likelihood of providing a significant advantage over existing treatments [42].
An area in which me-too drug generation has been especially prevalent recently is that of HIV-1 IN inhibitor design. Although raltegravir has become a modern blockbuster anti-HIV drug, multiple viral amino acid mutations have already been identified that confer robust viral resistance to the drug [43]. Specifically, mutations causing invulnerability to raltegravir have been shown to contribute to an almost 25% virological failure rate within 48 months of treatment [44]. This viral drug resistance most often results from the substitution of one of three amino acids – Y143, Q148, or N155 – usually in combination with at least one other mutation [44]. The specific substitutions of G140S and E92Q are typically associated with N155 and Q148 mutations, and the G140S/Q148H/R double substitution has been shown to result in a >400-fold viral resistance to raltegravir [45]. While the G140S mutation displays only a weak resistance to raltegravir (IC50 = 30 nM), the Q148H IN mutant is strongly resistant (IC50 > 700 nM). Interestingly though, G140S has recently been shown to effectively restore the poor replication ability of Q148H to near WT levels, illustrating its compensatory nature [46]. Even with this resistance profile, raltegravir has been the target of an excessive amount of me-too research and development over the last two years. Though, again, there have been historical instances of me-too drugs significantly benefiting patients and instigating medical progress, they have for the most part only benefited pharmaceutical companies. Although it is definitely possible that the next blockbuster anti-HIV drug could be a raltegravir lookalike, we hypothesize that raltegravir me-too drugs, targeting a virus that exhibits an extraordinary rate of resistance evolution, will experience a low probability of success in the clinical setting due to viral resistance and cross-resistance issues.
Me-too or second generation?
Raltegravir me-too analogs
Most of the recent raltegravir me-too drugs comply with the general diketo acid pharmacophore structural requirements – or a hydrophobic aromatic (usually fluorobenzyl) component and a variable acidic component linked to either side of a DKA linker (Figure 1). This linker usually consists of a γ-ketone, an enolizable α-ketone, and a carboxylic acid, but the carboxylic acid has been substituted with other acidic (tetrazole and triazole) and basic (pyridine) bioisosters [49]. Whereas the aromatic DKA pharmacophore substituent confers strand transfer selectivity, the acidic component contributes to 3'-processing inhibitory potency [50, 22].
Clinically tested me-too IN drugs
Research into second generation DKA inhibitors shortly after the FDA approval of MK-0518 led to the design of a set of tricyclic hydroxypyrroles that mimicked the common DKA metal binding pharmacophore. Optimization of a derived set of 10-hydroxy-7,8-dihydropyrazinopyrrolopyrazine-1,9-dione compounds resulted in one of the first raltegravir me-too leads, MK-2048 (Figure 1). MK-2048 has exhibited an IC95 of 40 nM in the presence of 50% NHS, favorable pharmacokinetics, and potent antiretroviral activity against four IN mutants displaying raltegravir resistance [51, 52].
GS-9137 (elvitegravir)
Early modification of the DKA motif by Japan Tobacco resulted in the design of a group of 4-quinolone-3-glyoxylic acids [49] that retained the coplanarity of DKA functional groups. A potent compound from this original study contained only a β-ketone functional group and a carboxylic acid functional group, which were coplanar, and showed a 1.6 μM IC50 value in a strand transfer assay. Derivatives of this parent compound exhibited up to a 7.2 nM IC50 value in strand transfer assays and a 0.9 nM EC50 in an antiviral assay. This activity proved that a monoketo motif could be an efficacious alternative to the accepted DKA. A 2005 license agreement between Japan Tobacco and Gilead Sciences led to the clinical development of GS-9137 (a.k.a. elvitegravir) [Figure 1, [43]], a quinolone carboxylic acid strand-transfer specific inhibitor that displayed an IC50 of 7 nM against IN and an antiviral EC90 of 1.7 nM in the presence of NHS. In terms of pharmacokinetics (Additional file 1), in rat and dog elvitegravir displayed a 34% and 30% bioavailability, a 2.3 h and 5.2 h half-life, and a 8.3 mL/min/kg and 17 mL/min/kg clearance, respectively. Interestingly though, its half-life in human was shown to increase from 3 hours when dosed alone to 9 hours when boosted with the protease inhibitor, ritonavir [53]. Similarly, its bioavailability increased 20-fold when administered in combination with ritonavir. These observations back a valid argument that elvitegravir may become a second-generation IN inhibitor, in that its significantly improved pharmacokinetic profile when boosted may increase patient compliance by allowing a simple once daily treatment (raltegravir is administered twice daily). Similar to raltegravir, though, elvitegravir has been shown to provoke T66I and E92Q viral resistance mutations, as well as substitutions of amino acids flanking raltegravir-induced substitution sites (Q146P and S147G) [54].
In studies to develop follow-on analogs of S-1360, the two involved groups jointly discovered a novel lead naphthyridinone, GSK-364745 (Figure 1). This compound contains a hydrophobic fluorobenzyl substituent flexibly linked to a chelatable quinolone region. GSK-364735 inhibited IN in an in vitro strand transfer assay with an IC50 of 8 nM, and it showed an antiviral EC90 value of 40 nM in MT-4 cells in the presence of 20% NHS. Acceptable pharmacokinetics were achieved, with bioavailabilities of 42%, 12%, and 32%; half-lives of 1.5 h, 1.6 h, and 3.9 h; and clearances of 3.2 mL/min/kg, 8.6 mL/min/kg, and 2 mL/min/kg in rat, dog, and rhesus monkey, respectively (Additional file 1). However, when tested against mutant viruses, the compound exhibited greatly decreased activity – 17-fold reduction against T66K, 210-fold reduction against Q148K, 73-fold reduction against Q148R, and 23-fold reduction against N155S [55].
A pyrimidine carboxamide similar in structure to raltegravir was recently propelled into Phase II clinical trials by a separate group. This compound was different from raltegravir in that raltegravir's 1,3,4-oxadiazole group was substituted with a cyclic sulfonamide moiety (Figure 1), but its in vitro potency was similar with an IC50 value of 20 nM. However, multiple mutations were almost immediately observed to have occurred in viral response to treatment with BMS-707035, which included V75I, Q148R, V151I, and G163R [32]. Unfortunately, the severity of resistance conferred by each of these mutations has not been disclosed, nor have pharmacokinetic properties of the drug. What is known, however, is that the drug did not last long in Phase II trials, and testing was abruptly terminated in early 2008 [56]. An explanation of the termination of the trial has not been publicly provided.
Novel me-too classes
This group pushed on in their search for raltegravir me-too drugs with further SAR studies upon the above N-alkyl hydroxypyrimidinone lead compounds (Figure 3). As a benzyl amide substitution of a free carboxyl instilled nanomolar activity upon said compounds, a library of over 200 different amide modifications was synthesized and screened for inhibitory potency [57]. A 4-fluoro-substituted benzene was shown to be optimal for IN inhibition, with an IC50 value in enzymatic assays of 10 nM. However, though compounds optimized in this fashion were active in the enzymatic assay, they lacked potency in cell based assays. The thiophene ring in the 2-position of the pyrimidine core was shown to have little effect upon the interaction of the compound with IN, and so this position was chosen for more dramatic changes influencing physiochemical properties of inhibitors. Introduction of a basic group to a 2-benzyl derivative resulted in increased cell permeability and inhibition of viral replication in the presence of fetal bovine serum (FBS) with a CIC95 of 300 nM (compound 3). This compound showed an oral bioavailability of 59% and 93%, a half-life of 1.73 h and 6.78 h, and a plasma clearance of 14 mL/min/kg and 0.5 mL/min/kg in rats and dogs, respectively. However, weak activity in the presence of 50% NHS exposed the mobile nature of chosen 2-position substituents. In response the phenyl group at this position was removed and the NH methylated, to confer reduced lipophilicity (and reduced plasma protein binding) but maintain the presence of the mandatory amino group. Compound 4 was thus born, exhibiting a 95% human plasma protein binding and a 400 nM CIC95 in the presence of 50% NHS. Pharmacokinetics of compound 4 included an oral bioavailability of 27% and 90%, a half-life of 0.43 h and 6.0 h, and a plasma clearance of 75 mL/min/kg and 2 mL/min/kg in rats and dogs, respectively. Separately, smaller acyclic amines were substituted into the 2 position and similarly assayed for activity [57]. It was found that a dimethylaminomethyl substituent separated by an sp3-carbon spacer bestowed significant cell based potency, at a CIC95 of 78 nM in 50% NHS (compound 5). In rats, dogs, and monkeys, compound 5 had a prolonged plasma half-life (2.1, 4.8, and 1.9 h, respectively), moderate to low clearance (16, 1.9, and 15 mL/min/kg, respectively) and moderate to excellent oral bioavailability (28%, 100%, and 61%, respectively) [57].
A further optimization study analyzed the enzymatic and pharmacokinetic implications of a different, t butyl substitution at the C-2 position of the pyrimidine scaffold of the above compounds [Figure 4, [59]]. Further introduction of a benzylamide to the right side of the scaffold proved necessary for activity in serum conditions. Multiple derivatives were designed using the N-methyl pyrimidone scaffold, including a sulfone (compound 11) and an N-methyl amide (compound 12) that showed CIC95s of 20 nM and 10 nM in 50% NHS, respectively. This encouraging data inspired further substitutions of the 2-N-methyl carboxamide, for optimization of pharmacokinetic behavior. An unsubstituted amide 13 exhibited a promising inhibitory profile (IC50 = 20 nM in enzymatic assay, CIC95 = 10 nM in 50% NHS), prompting multiple further substitutions of the N-methyl residue with an N-ethyl (compound 14) and an i N-propyl (compound 15). The pharmacokinetic profiles of 11, 12, and 13 were not optimal (Additional file 1), and none of these substitutions were beneficial in this respect. Bioavailability was 17%, 18%, and 23%; half-life was 1.8 h, 1.6 h, and 3.6 h; and plasma clearance was 37 mL/min/kg, 24 mL/min/kg, and 55 mL/min/kg in rat for 11, 12, and 13, respectively [59].
Bicyclic pyrimidones
Validation of resistance profiles of me-too raltegravir analogues
Effect of single mutations on IN sensitivity to clinically tested inhibitors.
Prediction of future me-too resistance profile similarities
With the above data significantly validating the reliability of our docking technique, we moved forward with the prediction of resistance profiles of selected me-too raltegravir analogues (Figure 8). Here, we will describe the interactions of one of the most potent (in terms of in vitro IC50 inhibition of IN) compounds from each of the above-described classes of me-too inhibitors with the 1BL3 IN crystal structure. The dihydroxypyrimidine-4-carboxamide compound 2 exhibited an IC50 value of 10 nM against IN [31]. However, our predicted interaction profile for this compound shows that it will most likely be ineffective against raltegravir-resistant viruses. We show that compound 2 interacts with 1BL3 IN residues D64, T66, E92, D116, Q148, E152, S153, and N155 – virtually the exact binding pocket as raltegravir. The N-methylpyrimidone compound 11 exhibited an IC50 value of 20 nM against IN [58]. Our predicted interaction profile for this compound encompasses the 1BL3 residues D64, T66, E92, D116, G140, Y143, Q148, E152, and N155 – virtually the exact binding pocket as raltegravir. The dihydroxypyrimido-pyrazine-1,6-dione compound 16 had a moderate IC50 value of 100 nM against IN [60]. Our predictive docking procedure calculated an interaction profile including IN residues D64, E92, D116, and Q148. E92Q and Q148R mutations have already been observed to confer 7-fold and 35-fold resistances to raltegravir, respectively. The bicyclic pyrimidone compound 17 has displayed a potent IC50 value of 7 nM against IN in vitro [61]. However, our predicted interaction profile implicates the 1BL3 residues D64, T66, E92, D116, Y143, Q148, and E152 as contact points. This is virtually the same binding pocket as that of raltegravir. Finally, the pyrrolloquinolone compound 26 has exhibited an IC50 value of 13 nM against IN [64]. Again however, we show that this compound will interact with IN in a considerably similar manner to that of raltegravir, contacting residues D64, E92, D116, G140, and E152. If our predictions prove to be correct, these candidate drugs will probably fail to replace raltegravir. Though me-too evolution into a new blockbuster drug is always a possibility, the above IN me-too drugs appear to have a small chance of improving the clinical outlook of HIV patients with raltegravir-resistant viral strains.
As me-too drugs have been historically shown to be minimally progressive in terms of improvement of disease prognosis, their lack of utility is exemplified in the case of HIV. A plethora of polymorphic resistance mutations have almost instantly arisen in response to both raltegravir and the purported second-generation IN inhibitor, elvitegravir [74]. It is clear to see that the virus is capable of eventually avoiding interaction with many a once potent inhibitor, and attempts at recreating these original interactions will most likely fall victim to the same mode of viral escape. Although some pharmacokinetic properties may be optimized through me-too drug development research, and some profitable drugs may be cleared for marketing, the long term efficacy of most of these drugs will likely be susceptible to the ever present mutational ultra-competence of HIV. As stated earlier, there is a thin line between drug development and me-too spawning. Simple pharmacokinetic improvement can drastically augment the daily lives of patients and the quarterly profits of companies, but the simple fact remains that HIV will most likely not be eliminated by a 2% increase in oral bioavailability. Dramatically diverse classes of molecules look to be required for inhibition of viral enzymes in a long term fashion. Thus, in our eyes, the only hope for complete viral eradication is innovation.
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


text:
Sapphire Radeon HD 7950 3GB Vapor-X OC with Boost Video Card Review
It really feels like AMD are a little lost at the moment and don't know how to handle what NVIDIA are throwing at them. Normally you'd see a company take one of two approaches when it comes to combating a competitor. The first is you'd go and drop the price on your current video cards to bring them in at a stronger price point against the competition. The second option is that you'd release higher clocked models at a similar price point to what you have now to fight the competition.
The thing is, though, we've seen AMD do both of these things, which is a little weird. The price drop alone, though, hasn't helped AMD in the same way as you'd expect, because NVIDIA have come in at a much stronger price point than you'd normally expect. Because of this we saw AMD release the GHz Edition of its high-end HD 7970 and today we're looking at a new version of the Radeon HD 7950 that AMD have just released.
So what is AMD bringing to the table with new HD 7950 Boost? We'll find out in just a moment, first we need to take the time to check out what's going on with the package today which due to the nature of getting such an early sample from Sapphire means we don't have a retail box.
Once we've done that we'll move onto the card itself, check out the specifications and also talk a little about the new Boost feature that AMD have implemented. Once we've done that it will be time to move into the testbed, take a quick look at the cards that we'll be using in our graphs today and finally get into the performance side of things to see just what this new variation can offer.
Looking at the box you can see the new design is similar to that we saw from the Vapor-X HD 7970 GHz Edition video card we looked at when it launched. You can see the new "Boost" feature is mentioned on the front of the box, along with a lot of the other standard information.
As for the bundle you can see we're lacking a driver CD which doesn't come as much of a surprise considering again the early nature of the video card when we received it.
You can see we've got a full size HDMI cable, CrossFire bridge, DVI to VGA connector along with two power connectors which include a Molex to 6-pin PCIe power connector and dual Molex to 8-pin PCIe power connector.
PRICING: You can find products similar to this one for sale below.
United States: Find other tech and computer products like this over at Amazon's website.
United Kingdom: Find other tech and computer products like this over at Amazon UK's website.
Canada: Find other tech and computer products like this over at Amazon Canada's website.
- Page 1 [Introduction and Package]
- Page 2 [The Card and Specifications]
- Page 3 [Benchmarks - Test System Setup]
- Page 4 [Benchmarks - 3DMark 11]
- Page 5 [Benchmarks - Unigine Heaven Benchmark]
- Page 6 [Benchmarks - Tom Clancy's H.A.W.X. 2]
- Page 7 [Benchmarks - Mafia II]
- Page 8 [Benchmarks - Lost Planet 2]
- Page 9 [Benchmarks - Aliens vs. Predator]
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subset: commoncrawl


text:
Web storage
Web storage, sometimes known as DOM storage (Document Object Model storage), provides web application software methods and protocols used for storing data in a web browser. Web storage supports persistent data storage, similar to cookies but with a greatly enhanced capacity[1] and no information stored in the HTTP request header.[2] There are two main web storage types: local storage and session storage, behaving similarly to persistent cookies and session cookies respectively.
All major browsers support Web storage, which is standardized by the World Wide Web Consortium (W3C).[3]
Web storage can be viewed simplistically as an improvement on cookies. However, it differs from cookies in some key ways.
Web storage is intended for storing information client-side (and never transmitted to the server), while cookies are intended for communication with server and automatically added to headers of all requests, if applicable.
Storage size[edit]
Web storage provides far greater storage capacity (5 MB per origin in Mozilla Firefox,[4] and Opera; 10 MB per origin in Google Chrome,[5] 10 MB per storage area in Internet Explorer;[6] 25 MB per origin on BlackBerry 10 devices) compared to 4 kB (around 1000 times less space) available to cookies.
Client-side interface[edit]
Unlike cookies, which can be accessed by both the server and client side, web storage falls exclusively under the purview of client-side scripting.
Web storage data is not automatically transmitted to the server in every HTTP request, and a web server can't directly write to Web storage. However, either of these effects can be achieved with explicit client-side scripts, allowing for fine-tuning of the desired interaction with the server.
Local and session storage[edit]
Web storage offers two different storage areas—local storage and session storage—which differ in scope and lifetime. Data placed in local storage is per origin (the combination of protocol, hostname, and port number as defined in the same-origin policy) (the data is available to all scripts loaded from pages from the same origin that previously stored the data) and persists after the browser is closed. Session storage is per-origin-per-window-or-tab and is limited to the lifetime of the window. Session storage is intended to allow separate instances of the same web application to run in different windows without interfering with each other, a use case that's not well supported by cookies.[7]
Since data is stored per origin (which includes protocol, hostname and port number), WebStorage does not suffer from cookie Weak Integrity and Weak Confidentiality issues, described in RFC 6265 sections 8.5 and 8.6.
Interface and data model[edit]
Web storage currently provides a better programmatic interface than cookies because it exposes an associative array data model where the keys and values are both strings. An additional API for accessing structured data is being considered by the W3C Web Applications Working Group. [8]
Browsers that support web storage have the global variables
sessionStorage and
// Store value on browser for duration of the session
sessionStorage.setItem('key', 'value');
// Retrieve value (gets deleted when browser is closed and re-opened) ...
// Store value on the browser beyond the duration of the session
localStorage.setItem('key', 'value');
// Retrieve value (persists even after closing and re-opening the browser)
Data types[edit]
// Store an object instead of a string
localStorage.setItem('key', {name: 'value'});
alert(typeof localStorage.getItem('key')); // string
// Store an integer instead of a string
localStorage.setItem('key', 1);
alert(typeof localStorage.getItem('key')); // string
// Store an object using JSON
localStorage.setItem('key', JSON.stringify({name: 'value'}));
alert(JSON.parse(localStorage.getItem('key')).name); // value
The W3C draft is titled "Web Storage". "DOM storage" has also been a commonly used name, though it is becoming less so; for example the "DOM Storage" web articles of the Mozilla and Microsoft developer sites have been replaced with "Web Storage" articles.[10][11][12][13]
The "DOM" in DOM storage does not literally refer to the Document Object Model. According to the W3C, "The term DOM is used to refer to the API set made available to scripts in Web applications, and does not necessarily imply the existence of an actual Document object..."[14]
Web storage management[edit]
Storage of web storage objects is enabled by default in current versions of all supporting web browsers, with browser vendors providing ways for users to natively enable or disable web storage, or clear the web storage "cache".[15]
Similar controls over web storage are also available through 3rd party browser extensions/add-ons.
Mozilla Firefox and Google Chrome physically store web storage objects in sqlite databases, where as Opera and Internet Explorer physically store web storage objects in per-site XML files. [16]
In Firefox, web storage data is stored in the webappsstore.sqlite file in the user's profile folder.[17]
In Chrome, web storage data is stored in the user's profile folder - typically "\AppData\Local\Google\Chrome\User Data\Default\Local Storage" on Windows, and "~/Library/Application Support/Google/Chrome/Default/Local Storage" on OS X.
In Opera, web storage data is stored at either "\AppData\Roaming\Opera\Opera\sessions\autosave.win" or "\AppData\Local\Opera\Opera\pstorage\" depending upon Opera version.[18]
In Internet Explorer, web storage is stored under "\AppData\LocalLow\Microsoft\Internet Explorer\DOMStorage".
See also[edit]
- ^ Opera Web Storage, 2011 http://dev.opera.com/articles/view/web-storage/
- ^ AndyHume.net, 2011 http://blog.andyhume.net/localstorage-is-not-cookies
- ^ Web Storage. W3.org. Retrieved on 2011-06-12.
- ^ John Resig: DOM Storage. John Resig, ejohn.org. Retrieved on 2011-06-12.
- ^ "Issue 21680002: Up the window.localstorage limit to 10M from 5M. - Code Review". chromiumcodereview.appspot.com.
- ^ Introduction to Web Storage. Microsoft Developer Network, msdn.microsoft.com. Retrieved on 2014-08-05.
- ^ W3C: Web Storage draft standard. Dev.w3.org (2004-02-05). Retrieved on 2011-06-12.
- ^ W3C: Indexed Database API. W3C. Retrieved on 2012-02-12.
- ^ W3C, 2011 http://dev.w3.org/html5/webstorage/
- ^ "DOM Storage". Mozilla Developer Network. Archived from the original on June 4, 2011. Retrieved 2011-06-12.
- ^ "Web Storage API". Mozilla Developer Network. Retrieved June 28, 2017.
- ^ "Introduction to DOM Storage". Microsoft Developer Network. Archived from the original on June 8, 2011. Retrieved 2011-06-12.
- ^ "Introduction to Web Storage". Microsoft Developer Network. Retrieved June 28, 2017.
- ^ W3C: Web Storage draft standard. Dev.w3.org (2004-02-05). Retrieved on 2011-06-12.
- ^ "How to enable, disable, or clear your browser's "Web Storage" cache - MIDAS Knowledgebase". mid.as.
- ^ "html - How is HTML5 WebStorage data physically stored?". Stack Overflow.
- ^ "html5 - Where does Firefox store javascript/HTML localStorage?". Stack Overflow.
- ^ "local storage - Where the sessionStorage and localStorage stored?". Stack Overflow.


text:
Williams have stuck to form throughout testing so far, adopting a low profile and completing a programme free of headline making glory runs. However, Valtteri Bottas topped today's timesheet as the team recorded qualifying simulation runs, on what was the Finn's final day in the car before the season-opener in Melbourne.
Here are five things we learnt on day two of the second test.


text:
Thursday, January 26, 2012
I am Famous!!!
5 comments:
WOO HOO Congratulations Emma, well done!! Gorgeous cards as always, Happy Australia Day, take careX:)ReplyDelete
Congratulations! What a wonderful feeling to have you work published! The cards are beautifully done. The ribbon is gorgeous...do you know the manufacture? Perhaps I can look for some here in the states. TFS!!!ReplyDelete
Thats great Emma! I love your cards. lucky gal! keep iy up hun!ReplyDelete
These cards are just gorgeous. I can see why they chose them for the magazine.ReplyDelete
Hi Emma. Good for you my friend! I have always known that you are famous, but I guess the magazine just took a little longer. lol... I love, love your cards that you made and I would so love to be able to buy one of those magazines. Is it possible to let me know how much they are and how much it would cost to mail me one? (If you have the time, if not no worries.) I think you should be very proud of yourself, and from the sounds of it your family is as well. I hope that you are all doing well and having a great start to the new year. Hugs, LisaReplyDelete
Thank-you so much for taking the time to leave me some love! I love reading all your comments and it always makes my day!


text:
Edit Qualifications & Resume
To edit qualifications, simply edit the text and hit the 'update' button located at the top and bottom of the page.
To edit resume, replace your resume with an updated resume. Scroll to the bottom of the page, hit browse to select your updated resume. This opens your computer files. Find your resume file and hit 'Open". This will automatically replace your old resume wtih your new. Then hit 'update' button to save your changes.
DO NOT attempt to download a Word Perfect of PDF file. Our system can not accept those file types for review.


text:
I am a proud Soybu Community Leader and advertise their clothes weekly in my classes. I am glad that in late May I will get to host an evening at their Denver-area store to share this brand with folks IRL on 28 May. More details to follow but expect discounts, a gift, and loads of treats.
Here are some snapshots for their latest line and how it seamlessly fits into my lifestyle with my little ones.
The powerflex fabric of this legging has been super comfy and a fave to wear to my classes lately.
I am a shorty (5'3″) and this Alecia tank has been the best fit since the bombshell tank for my shorter torso so that I am not giving my yoga students a view of all the cleavage. This is my new go-to tank for when I am moving around a good deal.
This sweater is hands down my favorite thing to come out of the line. I had no idea how the fit would be so went up a size and hit is a bit looser in the middle and hem than I anticipated so be sure to order true to size. You can barely see them in this picture, but thumbholes!!
Check out Soybu to see the Mod Nouveau collection as well their new addition of plus sizes for women, the men's line, and the girls line. My boys are still SOL but these little animals get active in anything that they wear so it is no big deal that the rest of the family is covered.
Disclosure: I am a community leader for Soybu who receives clothing from their collections. All opinions are my own.
Also, all photo credits go to Terry Cabeen.


text:
New Video: Gucci Mane – Stutter
Gucci Mane just release his new visual to Stutter. "Stutter"is of the new project from Gucci Mane album "The Return of East Atlanta Santa" which is out now.
The So Icey artist has had a great year consider he was lock up at the beginning of year. Now has made over 10 million dollar since his release from prison. Gucci Mane has been on fire with hit producer Zaytoven and Travis Scott.
Watch the new video below and comment on this to let me know what do you think.
The Return of East Atlanta Santa Tracklist:
1. St. Brick Intro
2. I Can't
3. Walk On Water
4. Both ft. Drake
5. Stutter
6. Drove U Crazy ft. Bryson Tiller
7. Crash
8. Yet
9. Nonchalant
10. Last Time ft. Travis Scott
11. Bales
12. No Smoke
13. Greatest Show On Earth


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Online Bookstores Take Publishing Industry by Storm
`Harry Potter Series,' `Rich Dad, Poor Dad' Emerge as Best-Sellers This Year -
For Korean publishers, this year was one of the most tumultuous ever, with digital technology taking the industry by storm.
At the center of the changes and upheavals were the aggressive expansion of online bookstores and the debut of e-books in the market.
Amid the transition from the analogue to digital mode of sales and publications, frictions arose between the newcomers and the establishment, as well as controversies over how and whether to newly define copyrights.
Testifying to the strong impact from digital technologies, publishers, in a survey conducted by the biweekly Korean Publishing Journal, cited the clash between online and offline bookstores during the past few last months over the ``fixed price system'' as the top news story of the publishing industry this year.
As the online bookstores made strong inroads into the market with discount prices, the offline stores, including such giants as Kyobo Book Center and Youngpoong Book Store, even boycotted the worldwide best-selling ``Harry Potter'' series in desperate efforts to protect their business turf.
Even the Culture-Tourism Ministry and Fair Trade Commission intervened in the dispute, and it was narrowly settled only after the online stores and the publisher of the Harry Porter series yielded to the pressure for the fixed price system.
In the survey conducted by the biweekly journal, the publishers also cited the publication of e-books, the rapid growth of online stores, the pending revision of the copyright laws and the frenzy over the Harry Potter series as the other major news stories of this year.
As the survey shows, the growth of online stores was spectacular, with their market share expanding to 4 percent over one year, as compared to the 2 percent that their counterparts in the United States have maintained for four years.
One of the leading online stores, ``Yes24.com,'' posted an impressive 1,500 percent of growth in its turnover this year, with Alladin Inc.recording an over 20-fold growth, according to the publishers' biweekly.
The number of the online stores also grew sharply to more than 150, up from about 50 early this year.
The boom of online stores made a striking contrast with the dismal condition of conventional bookstores in local communities.
According to the byweekly, the number of conventional bookstores across the nation declined 25 percent, from 4,595 last year to 3,450 this year.
The flamboyant debut of e-books was another big issue of this year.
Even Yi Mun-yol, one of the bestselling writers in the country, granted his blessing to the new publishing media by putting his ``Hanulgil (A Way to Heaven)'' on sale via www.everbook.com in October.
However, the number of those who downloaded it totaled just 1,122 as of this Monday, with other books on the website still having poor sales records.
The lackluster performance of e-books has punctured the initial enthusiasm and expectations, and cynicism about the new media now prevails over the publishing industry.
However, the government, particularly the Information-Communications Ministry, is still putting its hopes on the potential of e-books as a new industry and is poised to invest about 23. …


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GG Boutique's Flagship Showroom in Brooklyn, Pretoria offers a wide range of quality and exclusive clothing that suits fuller figure women with different body shapes. We cater exclusively for sizes 14-24 and we offer designer suits, dresses, jackets, coats, tops, pants and skirts in the following categories:
To complete the look we also offer shoes (sizes 5-9), bags, scarves, jewellery and hats, giving you a total fashion and style solution. As a value add to our customers we also offer a paid alteration service to ensure the best fit of our outfits.
If you can't come to our Showroom in Brooklyn, Pretoria, we will bring the Showroom to you, through our Home Visits. These unique Home Visits allow you to try on clothes in the convenience and privacy of your own home or office.
For customers in Pretoria and Johannesburg, a home visit can be arranged relatively quickly. For customers beyond Gauteng, visits generally require a little more planning.
Interested in setting up a Home Visit? Contact GG Boutique today on 012 346 2209. Alternatively, click the button below and fill in the form and we will contact you. We can bring clothing that suits your lifestyle and personality right to your doorstep.
Many of our customers are busy professionals that don't always have the time to visit our Showroom during traditional shopping hours. Because we are not the average retail store, we actualize personal and convenient shopping for our niche clients who are too busy to find time for shopping:
Experience customer service never seen in South Africa as our Style Consultants open the store just for you. Browse at your leisure on a Sunday and have the entire Showroom to yourself. Personal Shopping is arranged by appointment only. To arrange your own Personal Shopping Experience, click the button below and fill in the form and a Style Consultant will contact you.
We offer a complimentary Style Consultation valued at R549 to all of our first-time clients. The goal of this value-added consultation is to help you define your style, find your fit and understand your colours.
We analyse your body shape and recommended suitable clothing, taking into account your personality. We also take personalized body measurements in order to furnish you with bespoke garments.
We also request clients to furnish pictures their favourite GG items or other (with our camera) that would be kept on file to assist in making informed choices in buying garments for clients, that would complement clients' existing wardrobe in many cases.
After your consultation, you will understand what styles work best for you, what doesn't and why. At GG Boutique, we know that when you look good you feel so much better. Knowing how to present yourself will give you the edge in business and life.


text: The two actors have been linked since last summer, after Chris' marriage to Gwyneth Paltrow ended and Jennifer had parted ways with long-term love Nicholas Hoult. While they never confirmed a romance, they were spotted out and about on numerous occasions. However in the last few weeks 38-year-old Chris has been seen getting cosy with actress Annabelle Wallis. 'There's talk he's messed her around quite a bit'"To be honest, she was blindsided by Chris. There's talk he's messed her around quite a bit. Granted, they were off and on, and it wasn't the most stable of relationships, but she's only found out through mutual friends that he's started seeing someone else," a source told British magazine Grazia."Chris is very good at making a person feel like they're the most amazing girl in the world. But it seems he'll have several women on the go at once. In the end, that's why Jen had to walk away."Annabelle has made her name on British TV show Peaky Blinders opposite Cillian Murphy, but she has also worked on Hollywood blockbusters, including X-Men: First Class with Jennifer.It's not just Annabelle that Chris is said to be romancing, with the source claiming he's having a flirt with other high-profile women too. One of his tactics is to apparently buy them book Vagina: A New Biography Book by Naomi Wolf."Chris read Naomi's book a while ago and became obsessed with talking about it. He was really into exploring the idea of female sexuality in relation to creativity and likes to recommend the book to women he meets. On a number of occasions he's even got the lady in question the book as a gift. It can come across as a bit full-on," the insider said.© Cover Media


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- Date: 16/12/2017
Date: 16/12/2017Raum - Via Ca' Selvatica 4/D - Bologna
Phone +39 051 331099
Date of last update: 11/07/2018, 14:49
In the presence of a strange object, evoking metaphysical memories, in between sculpture, installation and performance, And Where are all the People? presents "a structure built almost entirely of my position and the stature of that man over there". Who is he? Who are those other people?, Who are we? What unites and separates us in the figurative and peopled terrain of language?
more information and updates www.xing.it
from 10 pm to 11.30 pm
to be defined


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Charlotte was a contestant on the fourth series of The Crystal Maze, hosted by Richard Ayoade, alongside Judy Murray, Paralympic athlete David Weir, footballer Wayne Bridge and Countdown's Rachel Riley. Watch the episode here!
The Charlotte Show
Charlotte Crosby has always lived her life in the public eye and now it's time to see more of her than ever before with MTV's brand new reality series, The Charlotte Show, is back on Wednesday 30th January at 9pm, on…
Brand New Me Now In Stores
The next chapter in Charlotte Crosby's life – Celebrity Big Brother winner, MTV presenter, fitness DVD and book bestseller and one of the UK's best loved and funniest reality TV stars. In the two years since ME ME ME, national…
Drunk Histories
Charlotte appeared on Comedy Central's Drunk Histories in early 2017. Watch a short clip here
MTV launches brand new show Just Tattoo Of Us, creating the tattoo problems others have to fix
Wait no longer! The hotly anticipated new MTV show Just Tattoo Of Us, will be hitting our screens on Monday 3rd April at 10pm. The show, hosted by king and queen of reality Bear and Charlotte, sees pairs of friends,…
Charlotte Crosby is co-hosting the Capital North East Breakfast Show
Charlotte Crosby will co-host the Capital North East Breakfast Show for the week of February 27th. Charlotte will cover the Breakfast Show for a week alongside Capital North East's Drive presenter Martin Lowes, while regular Breakfast hosts Bodg and Matt…
Catch Charlotte on Storage Hunters
A brand new series of Celebrity Storage Hunters returned to our screens in 2016, which saw Charlotte looking for a bargain bin with host Sean Kelly.
Tipping Point
Charlotte joined comedian Jimmy Carr and boxer David Haye on the 2016 series of Tipping Point, hosted by Ben Shepard where they each attempted to win £20,000 for charity.
Celebs Go Dating
Charlotte took part in the first series of E4's Celebs Go Dating in 2016. You can catch up with the series here.
Catch Charlotte on New Matchmaking Show Celebs Go Dating
This summer six lovelorn celebrities will be on the market and off the shelf, as they desperately seek a soulmate. New E4 dating show, Celebs Go Dating will follow the nightly dates of some of our best-loved and lonely stars…
Tattoo Disasters
Charlotte was the voiceover for the Channel 5 series Tattoo Disasters UK, which showcases some of the UK's worst tattoos.
Charlotte screams on Derren Brown's Ghost Train at Thorpe Park
Charlotte Crosby Announced as the New Face of Leading Hair Enhancement Brand Easilocks
I've just signed up for @JamieOliver's #FoodRevolution You should too! Click here http://jamieol.com/FoodRevolution Filthy talk from @Charlottegshore on #FoodRevolution day! https://t.co/wyFXubDKjc pic.twitter.com/RIcYI2F0xi — Jamie Oliver (@jamieoliver) May 20, 2016
The Nostalgia SS16 Collection is here!
You can order my Spring Summer range directly through the In The Style website! Order online at https://www.inthestyle.com/charlotte-crosby
Order Live Fast, Lose Weight!
You can order Live Fast, Lose Weight now! Charlotte's healthy lifestyle guide is bursting with all her favourite tips and tricks for what to eat when you're out and about, that can fit into even the busiest of schedules. Charlotte…


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Recent Posts: Life is Returning
The Mind
I just watched an advert on FB about a trainer who was selling a course on facilitated behaviour change with the tagline that "the mind believes what you tell it", with the explanation that what you tell the mind with self-talk is a blueprint that the mind must work toward manifesting. Great, so it's as […]
For the Love of God
There have always been thieves in the recorded history of cultures on Earth, people who have broken the law around money and value in the material realm. Thieves have one thing in common, they put money or its equivalent object of material value ahead of their ability to truly know Love. This money first compulsion […]
Show down – a fiction.
The above picture is from the cover of a work of fiction, written in 1981 about a time of global crisis with a backdrop opening of the resignation of a Pope and the appearance of an enigmatic therapist. Here below is another work of fiction from me. ___________ As the orthodox structures of governance and […]
Points to ponder
The message of a top-line collapse rendering the Executive function of Corporations and governmental Cabinet Offices to a state of collapse is not a message that was ever destined to be easy to deliver. The ruthless behaviours that manifest from the bottom-line fixation of a stuck-addict seem easier to see than the bottom-line fixated antics […]
No Blame
There is a Name of God, The Gatherer, it is one of my service names, it is the name that energises my rôle as a Paradox Consultant as described on my page https://www.drt.global/corporate The Gatherer connects opposites as a defining factor of the word paradox. This manifestation of service connects the blue and the brown […]
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Tag Archives: valediction
The mastery of any field is arrived at by the exercising of power through experimentation. The Master of the Unified Field arrives similarly and practically despite theories that predict the existence or otherwise of the Unified Field. Creation is perfect … Continue reading
Posted in Addiction, Personal Tagged addiction, beauty, benediction, contradiction, diction, logos, malediction, Master, parousia, prediction, spirituality, truth, Universal, valediction, vernacular 2 Comments


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Manchester United fans might be in sync with the rest of the league in labelling Chelsea 'boring' for the way they've gone about their Premier League dominance this season, but Old Trafford hero Gary Neville wants nothing to do with it. The ex-England right-back said that the Blues' title rivals had been pathetic in their challenge, urging people not to criticise Jose Mourinho's men as they're the only ones who have done their job properly. Chelsea beat Leicester City last night to establish a 13 point lead at the top of the table and, despite Arsenal having a game in hand, they can win the league if they beat Crystal Palace this weekend. In other club news Andreas Pereira is set to pledge his future to Old Trafford despite interest from PSG. It's said four European clubs have made contract offers to the 19-year-old, but he is keen to stay with United.
Gary Neville labelling his old club pathetic for this
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Divestment Team
Join our email list here ... and check the event calendar to attend our monthly meeting.
Divesting Fossil Fuels from Your Portfolio
Want to move your money to greener pastures? Come to the Belmont Library for our May 20 workshop on personal divestment. Learn how to move your money from dirty fossil-fueled institutions and investments to clean sustainable ones.
Tell Palo Alto City Council to #DefundDAPL and #Divest
Though oil may soon flow through the Dakota Access Pipeline (DAPL), our stand with the Standing Rock Sioux Tribe is far from over. As a follow-on to the recent successful downtown march and City Council appearances, 350SV and our alliance partners urge all members to take a moment to sign this petition. Palo Alto generally has a good environmental record, but its main banking partner is DAPL financier US Bank (holdings exceed $10M) and the City has another $7M with other DAPL financiers including Chase, Goldman Sachs, HSBC and Wells Fargo. Tell Palo Alto to do the right thing!
350 SV Divestment Team Supports Divestment at Stanford
Stanford has divested its endowment from coal extraction, but the job isn't done. The Fossil Free divestment campaign at Stanford is pushing the administration to #DivestTheRest. Be sure to check out their website at fossilfreestanford.org. Alumni, staff, and parents have a role to play in encouraging the Board of Trustees to choose divestment.
What We Do
Our strategy is to influence nearby cities, religious organizations, college campuses, and retirement funds to divest from fossil fuel companies and re-invest in sustainable energy. Currently, team members are working within four faith communities and one university (Stanford). We hope that as our team grows we will work on divestment campaigns for cities and employee retirement funds.
How We Do It
- We meet periodically to discuss and support our members' divestment related activities.
- We create, discover and share resources and links to useful information
- Through our meetings, chat group, and Google group we help each other stay abreast of developments in the nationwide divestment movement
- We provide information (and recommendations of speakers) to individuals and groups about socially responsible investment options
- We work with national 350.org to refine the communication among local groups across the country
Why We Do It
- Final Goal: keep 80% of the known fossil fuel reserves in the ground, to avoid catastrophic climate change
- Immediate goal: gain public acceptance that just as it's morally wrong to wreck the climate, it's morally wrong to profit from wrecking the climate. Get as many institutions and individuals as possible to discuss and begin divesting funds from the top 200 fossil fuel companies
- Intermediate goal: compel the influential people who sit on boards of colleges, religious institutions, retirement boards, as well as those in the investment community, to face the reality that if the fossil fuel companies fulfill their mission, they will wreck the earth
- Bring enough negative publicity to gradually revoke the social license that fossil fuel companies enjoy
For more information go to www.gofossilfree.org


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Credit by Examination and Portfolio Assessment. Through several methods, students may earn academic credit for college-level learning by taking an examination in the appropriate area. Credit granted usually can be used to satisfy specific and general degree requirements. Refer to the section Bachelor Degree Requirements found elsewhere in this bulletin.
The credit by examination procedures are reviewed and updated annually. A current brochure is available from the Office of Admission.
On a limited basis, portfolio assessment is another method used to earn academic credit for college-level learning. A portfolio is a formal, written document including a resume, detailed personal history, description of skills and competencies, and documentation to support the student's request for credit. Only limited credit has been approved using this method. More information on the portfolio assessment program can be obtained by contacting Office of Extended Education, (817) 257-7130.
Credit for Military Service The University follows, with limitations, the recommendations of the American Council on Education as published in the Guide to the Evaluation of Educational Experiences in the Armed Services in granting credit for military service schools.
Courses must be in the "baccalaureate/associate degree category" as defined by the ACE Guide. This precludes acceptance of vocational, technical or certificate category courses, or military occupational specialties or job experience.
For consideration of credit for military service schools, the applicant must
submit the following military records:
1. certified original of the DD Form 295, or
2. copy of the DD Form 214, or
3. course completion certificates, or
4. a Community College of the Air Force transcript.
The Office of the Registrar will assist persons eligible for veterans' education assistance benefits.
Nonresidential Course Work. The University examines all nonresidential learning experiences and grants credit on a case-by-case basis.


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Host of Sportsman Adventures, Captain Rick Murphy, joins the crew of Awesome Fishing Radio. Capt. Rick is always personable, and just like you see him on TV. Perhaps he is even more fun! Capt. Keiland Smith and Capt. Blake Smith spend a few great minutes with this friend of the family.
Capt Rick Murphy at Marine Supply show
Filed under: Awesome Fishing Radio, Saltwater Fishing | Tagged: Awesome Fishing Radio, Capt Blake Smith, Captain Keiland Smith, Captain Rick Murphy |


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Co-located at the Buddhist Temple of Toledo, Shobu Aikido of Ohio provides Aikido and Internal Power/Aiki training for adults and children in the greater Toledo area with weekly classes and seasonal seminars. Visitors are always welcome.
Aikido is a non-competitive martial art that can be practiced by almost anyone. Aikido techniques do not rely on physical strength but rather develops relaxed power through the focus of intention and Ki. The result is a creative method of non-destructive conflict resolution.
Aikido is practiced on many levels. The first level is includes the development of stamina, flexibility, and learning how to focus one's intention. The second level is built on the first and stresses self-defense techniques that teach the natural order of movement. In this process the students also become adept at ukemi, the art of rolling, falling and protecting oneself. Aikido provides the opportunity for the development of the entire person. It is a workout of the entire body and mind and results in increased strength, overall physically fitness, flexibility and centeredness.
At the third level students are gradually introduced to the secrets of receiving and harnessing the power of ki, they also develop spatial awareness and learn to judge proper timing and distance. During this training the goal is to establish and maintain an energetic connection to your partner and to lead them off balance. This eliminates the need for more destructive means of resolving situations.
The highest level of aikido is mind over matter. This involves the use of visualization techniques, the power of intention and ki, breath control and meditation. Aikido is truly a spiritual martial art that explores themind - body - spirit connection. This advanced level of training at Shobu Aikido reaches a level not easily found elsewhere. The student learns how to manifest power and effectiveness by the focusing of intention alone. This level depends on and can only be reached through the refinement of technique and the students own deepest feeling. For this reason it alternates between the physical and the spiritual.
In the process of practicing aikido, students inevitably find themselves less stressed and more energetic, better equipped to manage life's many conflicts with calm control. Aikido is great for adults and kids alike because practice encourages respect for self and others, self control, cooperation and responsibility.
Gasshuku or weekend long intensive seminars with William Gleason Sensei are available seasonally.
Children's aikido classes provide a friendly, non-competitive environment for students to become more physically fit, agile, flexible, aware, focused, and relaxed. They learn how to safely fall, roll and perform a variety of self-defense techniques in a supportive, comfortable setting, and parents like Aikido because kids learn how to be powerful without becoming destructive.
Musubi and Kokyu Tanden Ho
"Aikido is the study of wisdom. If you cannot control and trust yourself - if you cannot see yourself clearly - you will never have any knowledge or trust of others and you certainly will not be able to conrol them. The purpose of Aikido training is not to create aggressive fighters but to refine wisdom and self-control. As a student of Aikido, you must study to improve and polish yourself, not to compete with others.
"The key to this process - and the heart of Aikido - is musubi. This word translates loosely into English as 'unity,' or 'harmonious interaction.' In practice, musubi means the ability to blend, both physically and mentally, with the movement and energy of your partner. Musubi is the study of good communication. In any interaction between people, communication exists, whether acknowledged or not. It is up to the participants in the interaction to determine whether the communication will be productive or useless, friendly or hostile, true or inaccurate. Musubi, as it is refined, can mean the ability to control and alter interaction, changing a hostile approach to a healthy encounter or an attack into a handshake.
"Musubi is both a method of learning and the goal of study. Musubi, in its ultimate refinement, relates to the achievement of a sense of universal harmony and, in technique, the ability to control encounters for the good. But can such ability be achieved by forcing, coercing, or frightening a person into learning it? No. Musubi must be taught and studied according to the principles it exemplifies so that the Aikido student's consciousness may be refined along with his physical movement. Musubi must be taught through good interaction and firm but kindly guidance.
"Learning to respond to attacks with musubi is a long and difficult process. One cannot strike at a beginner and tell him, 'Don't fight! Blend! Blend!' The beginner will not blend but react with fear and aggression, the instinctive reactions to threat. The beginner will attempt to defend him- or herself by struggling or by hurting the attacker.
"In Aikido the goal is to tame and control these animal instincts, not stimulate them. This is why, especially for beginners, we often use various kinds of grabs as attacks. The beginning student is not equipped to deal with real attacks - like strikes or kicks - with either mental calm or proper physical movement. Grabs allow the beginner to study techniques without fear for physical safety's interfering with learning the correct responses. Instead of engaging in struggle and competition, the student polishes both movement and mind. The student studies control - of him- or herself, of the partner, and of the relationship between them. Grabs have the advantage of providing a physical contact between practice partners so that both may be able to feel what makes a movement work. If there is no physical contact, beginning students will find it hard to explore the mechanics of technique.
"Practice for beginners may often start with static grabs. These allow the study of correct posture, footwork, and body position. Students may then progress to moving grabs, which allow the development of a sense of timing and distance and the exploration of the spatial relationships between them and their partners. Students can begin learning to adjust to various degrees and kinds of force, speed, and direction. They can start to build confidence in their ability to communicate with their partners, to build up their intuitive senses of their partners' movements and intents.
"Cooperation is very important in Aikido training. Almost all practice is done with a partner, and the relationship between partners must be a manifestation of musubi. Both nage and uke bear this responsibility. While nage must train to blend with, rather than struggle against, attacks, uke must learn to attack in a way that is appropriate to the technique being studied and to provide the proper conditions for learning. In a simple example, if the teacher has demonstrated a technique involving a forward throw, it is appropriate for uke to push forward. If instead uke pulls backward, attempting to thwart nage's technique, this will only reduce practice to a struggle and neither student will learn how the technique works. Advanced students can benefit from unexpected attacks, free practice, and attempts at reversals, but this is after years of studying basic techniques and learning what conditions require what actions."
Later on, Saotome Sensei relates the concept of Musubi to Kokyu Tanden Ho, one of the most fundamental techniques in Aikido and a featured technique in the 6th Kyu test.
"...Another important feature of musubi is operating in your encounter on that crowded street. As you meet the pedestrian who is walking toward you, your reactions reflect and respond to the other person's, rather than conflicting with them. The conjunction of you and the other pedestrian represents a continuous and smooth flow of energy, a give and take of force and direction. This is another - and perhaps the most important - element of musubi, namely, learning to feel and use the unity of energy.
"This is why kokyu tanden ho, as O Sensei said, is the most fundamental training in musubi. Kokyu tanden ho is not a fighting technique at all but a study in physical relationship and movement. In this exercise, two partners sit opposite each other in seiza, with uke grabbing nage. Nage, using the whole body as a coordinated unit, attempts to unbalance uke. The purpose of kokyu tanden ho is to discover the principle of circular energy. As uke firmly grasps nage's wrists and provides resistance, nage receives the energy that uke gives him and returns it through uke's center of balance. All parts of nage must act in unity. Nage must meet uke's grab extended, with his arms acting like a spring, so that he can recoil and again extend. He must breathe in as uke grabs and breathe out as he returns uke's force. His mind must remain flexible and receptive.
"Kokyu tanden ho is a noncompetitive exercise, not a contest of strength. Uke provides enough resistance to challenge nage but not so much as to make execution of the technique impossible. Nage does not struggle to throw uke but uses this training to study balance, breathing, and unity of physical and mental energy. However, as your training advances, you will find that your partner's physical strength can work to your advantage. Because kokyu tanden ho works on the principle of musubi, on absorbing and returning energy, the effect is that uke and nage combine energies. Nage has the use of both his own and uke's strength. The more uke resists and uses his strength, the greater the tool that nage has at his disposal. This circularity of energy is the essence of musubi.
"You should apply the principles of musubi that you learn through practicing kokyu tanden ho to all your Aikido techniques. It is musubi that will allow you to reach the point where physical size and strength make no difference in your ability to execute technique. If you fail to grasp the principles of musubi and to put them into practice, you will always be at the mercy of the strength of others and will always be in danger of reverting to competitive struggle."
I hope this excerpt sheds some light on the mystery surrounding Kokyu Tanden Ho and clears some of the confusion and misconceptions regarding our practice, the way we practice, and the art of Aikido in general. The Principles of Aikido is one of several well written books featured in our dojo store (http://www.toledoaikido.com/dojo-store-aikido1.htm). So please check it out, and I'll see you all on the mat. Gassho.
-Andre ("Muketsu")
Okugyo Keiko With Jay Sensei 11/07
This is a compilation of Jay Senseis Keiko held at the Shobu Okugyo retreat in Vermont with Bill Gleason Sensei in November of 07. Often, Bill Sensei leads the morning class, and Jay Sensei leads the afternoon class to help us digest and retain what Bill Sensei presented that morning. Enjoy!
Wise man!
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Gordon-Conwell to Confer 11 Degrees at May 18 Jacksonville Commencement
Thursday, May 16, 2019
Supplying programs and resources to ministers around the world for personal and corporate renewal.
Branch of the Shoemaker Center particularly focused on equipping ministers and lay leaders to communicate biblical truth.
Bringing Gordon-Conwell to communities in today's landscape with some of the littlest access to theological-education.
The Ockenga Institute
Central to the vision of Dr. Harold John Ockenga, a founder and the first president of Gordon-Conwell, the Harold John Ockenga Institute exists to equip the Church for renewal, global outreach and cultural transformation. The Institute lives out its mission by extending the vision and capabilities of Gordon-Conwell through two major departments: The Shoemaker Center for Church Renewal and the Hispanic Ministries Program.


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An aspiring film maker has taken a step closer to his Hollywood dream by winning a top competition.
Greenshaw High School sixth former Jack Spring has won the 16- to 21-year-old category at the IAC British International Amateur Film Festival 2014 for his film Doors Opening.
Doors Opening
The 17-year-old will receive his award in front of a 300-strong audience including some of the world's top film makers at the festival in Bedford later this month and said he hopes the accolade could be a springboard for him.
Doors opening is a short film that wordlessly tells the story of a woman who goes to attend an appointment only to meet a sinister man. It impressed the judges through the unique way it has been put together - each shot is just one second long and the whole piece is backed by the sound of a ticking clock.
Jack, who lives in Poulton Avenue, Sutton, said: "It's a bit weird, but I come up with all my ideas in the shower - that was where I had this idea.
"I don't know where it came from, but I just thought I wanted to make a film where all the shots are only a second long. I had the idea first and then I came up with the story.
"The shoot itself didn't take that long, we did it in one day over the course of eight or nine hours. It was the editing that took the time - that must have taken about 25 hours. All that for a two-and-a-half minute film!
"I think the award judges were impressed with the format."
Jack has already set up his own film company, Blue Light Media, and has made several short films as well as taking on commercial projects. He works for Waitrose in Banstead and has recently been given the chance to make a documentary about the company.
Jack added: "I'm hoping to go to York University and from there I guess I would like to get to Hollywood. I want to be a film director and be able too look back when I'm retired at a huge load of DVDs - or whatever the format will be then - that I've made."
To watch more of Jack's films, visit https://www.youtube.com/user/mightymariner1.


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22. Head sluices of Main Eastern Canal at Baroon from end of wing wall.
Photographer: Unknown
Medium: Photographic print
Date: 1873
Photograph from the Crofton Collection: 'Public works including the Manora Breakwater and the River Son canal system' taken in 1873. Initiated by Colonel C.H. Dickens in 1853, the Son Canal System involved the construction of an anicut across the Son river at Dehri. A main western canal branched off above the anicut on the left bank and a main eastern canal branched off to the right. The project began in 1869 and was completed in 1875, costing 15 lakh rupees. The canal helped provide irrigation for a large area and was also open for navigation on the river.


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Exhibitors > Fowler and Co
Stand 49
Fowler and Co, established in 1986 and based in Brighton, produce beautifully designed and hand crafted contemporary furniture to order and a range of unique products exhibited at the East London Design Show.
Ben Fowler has designed furniture ranges for some of Britain's well known high street names such as Ercol, The Conran Shop, Habitat, the Futon Company and Marks and Spencer where his designs have been awarded a prestigious Design Guild Mark. Fowler and Co are pleased to exhibit the 'Hat Tree' a pleasing sculptural design solution that keeps hallways and bedrooms tidy.
Talk to... Ben Fowler
Fowler and Co Ltd,
Scott Workshops,
37 South Street,
East Sussex BN41 2LE
Tel: 01273 423111