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It seems that not all are welcoming the latest announcement by Airbus that they will consider design changes. The A350's largest customer to date (or potential customer) is making noises that it will have to delay signing until the design is firmed up. Doesn't sound happy about the possible delay in EIS either....
Analysts said that, if Airbus switched to an all-new design, customers would probably have to wait an extra two years, until 2012.
"However, this puts us in a dilemma, because we will get an aeroplane nearly ... two years later than originally envisaged," said Baker.
"And of course we will have to go to the market and buy aeroplanes that would fill in the gap, or else even look at an alternative because airlines cannot freeze their plans because a manufacturer cannot deliver in the time that we require.


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Re: [rest-discuss] Best way to design URI namespaces with related resources?
Expand Messages
- On 2/28/08 4:28 PM, jjn1056 wrote:
> Now the first problem we have is to decide the best way to create a[snip]
> URI hierarchy for photos that belong to users.
> From a programming perspective we prefer the second choice since itI'm working on a project in which we faced a similar challenge. The URIs we
> allows us to have a base controller for the photos and then
> discoverable 'filter' path parts below that which can inherit or
> enhance the behavior. From our perspective that's a lot better than
> have to duplicate the photo controller behavior for stuff under our
> user controller (and again where ever else we end up have sets of photos).
> What do you think of this choice and reasoning?
launched the project with follow your /users/100 and /photos/201 approach, with
no hierarchy information for photos belonging to users. However, we are changing
We will still maintain the /photos/201 URIs, but they will simply redirect to
our canonical /users/100/photos/201 URIs. We settled on this structure because
we believe it conveys the proper hierarchy.
As far as programming goes, we're using the routing features of the framework we
use to allow us to keep the same controller structure we currently have, but the
routes are set up as such that we don't have to duplicate any code.
> Our second problem has to do how an item that is part of a collection[snip]
> of items (say a particular photo in the big list of photos from the
> above example) can carry the context of it's containing set and yet
> meet the needs for canonical uris that seem to be an important part of
> designing REST websites. Here's an example of what I mean.
> Now here's our idea of what a similar resource would be like if theTo me, this URI looks as if you are viewing a user resource via a photo and not
> user navigated to a photo via a user:
> GET /photos/201/user/100
the other way around, as you have suggested. The hierarchy here isn't logical to me.
In our case, again, we settled on conveying the ownership of the photos in the
canonical URIs, so in every place that "photos" appear in a collection of items
(for example, at /photos), they still link to /users/100/photos/201.
Of course, you can contrast this with flickr, which uses /photos/{username}/201,
but, in this case 201 refers to the photo resource, which I think is logical.
Ben Ramsey
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subset: commoncrawl


text:
Relationships are at the very heart of Desire Street's mission and vision for transforming urban communities — our approach of encouraging, equipping, and connecting local leadership rests on the quality of our relational involvement. Therefore, everyone from the volunteers and donors who invest their time and money in urban communities to our staff, board of directors , and advisory board are valuable members of the Desire Street team.
- Home
- About Desire Street
- Our Ministry Heartbeat
- The Desire Cup
- Meet Danny Wuerffel
- Connect
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text:
You Only Die Once Unisex Sweatshirt black
My favorite new must have for the road!
This crewneck Sweatshirt features my You Only Die Once artwork
8.0 oz. fabric weight
50/50 cotton/polyester
Reduced pilling and softer air-jet spun yarn
1x1 athletic rib knit collar, cuffs and waistband, with spandex
Double-needle stitched collar, shoulders, armholes, cuffs and waistband
Quarter-Turned To Eliminate Centre Crease
This sweatshirt will last for years. It is very comfortable and great for the holidays. Good quality material that needs no ironing.
Each sweatshirt is made to order so unfortunately there are no returns. Please choose your size carefully.


text:
February 25th, 2017
One of the largest parades in Arizona! Over 50 years of celebrating our local heritage, this parade is a highlight to the weekend of Lost Dutchman Days every February. Offering rodeo, carnival, vendors, live entertainment, and more! This is a chance for businesses and non-profit organizations to join in and expose their cause to thousands of spectators! For more information click here.
Photo taken by the City of Apache Junction's drone
Thank you to our 2017 participating businesses:
Click here to download the LDD Parade flyer Click Here to download the registration form


text: Hey everyone, I recently got the update (2.2) on my Droid X. After downloading it, my phone rebooted and got stuck on the screen with the Motorola logo. I looked on this message board and saw that taking the battery out and putting it back in could solve this problem, and it did (as long as I rebooted while plugged in). I have noticed that whenever I turn off my phone, when I try to turn it on I get the same problem in that the phone is stuck on the Motorola screen indefinitely (I gave it about an hour with no change). It seems random, but after taking out the battery and putting it back in 5 or 6 times it boots up, but the next time I turn off my phone the same thing happens. What can I do to fix this? As a point of reference, I received a call (the ringtone went off on the phone) while "stuck" on the Motorola logo screen, but I couldn't answer it. Thanks in advance for all your help. -Digs


text:
Warning! This shopping deal is older than 14 days and is likely expired.Scroll down this page (or click here) to see similar deals submitted recently
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Red Oak Virginia in Charlotte county.
Red Oak, Virginia is located in Charlotte county within the zipcode 23964. With a total of 0 golf courses in Red Oak, it lies at an elevation of 596 feet above sea level. The current date and time in Red Oak Virginia is November 20, 2017, 6:58 am. Add a course for free by clicking here or contact us here.


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A Modern Way of Placing Food Orders at Kempinski Hotel Ajman
Kempinski Hotel Ajman has implemented a modern way of ordering food without even getting up from your sun lounger on the beach or dialing room service.
"We have placed the unique pyramids with QR codes on them in our guestrooms so that guests can scan the code with their smart phones or tablets and this automatically opens up the food and beverage menu. Guests can then place their orders with a few simple clicks. Menus are available in four different languages: English, German, Arabic and Russian," explained Director of Food and Beverage, Anish Kuttan.
"Since our resort is well-known for its stunningly beautiful, white-sand beach, we are delighted to give our guests the opportunity of ordering food simply by scanning the QR code while lying on their sun beds. The QR codes are placed on the sun lounger umbrellas, which makes them very easily accessible. One of the reasons why we chose this technology is for the convenience it gives to our "smart guests", those who are inclined to technology. The highlight is definitely the speed of ordering - the moment you place your order, it is in the system and is directly forwarded to the kitchen. It's the ease of ordering and the quickness of delivery that makes everything hassle-free," added Kuttan.


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When I was younger I had a good example of how to be sad and depressed. I took on all the behaviors and thought processes and made them my own. It took years to realize I was the reason I was unhappy, luckliy it took less time to get happy back in my life than it took to lose it. Here is a personal list of the things I had to get rid I teach these to my clients and it works.1. Lose the news, particularly t.v. and social media. Unless you are diligent about only listening to the fun and happy news.
2. Negative engery sucking friends, this is particularly hard because most of us don't want to be alone. Trusting that new healthier friends will come into our lives is a challenge. It is worth the risk to have a happy life in my opinion.
3. Lose your own bad attitude. Nothing gets in our way faster than being hyper critical of our selves and others. Criticism and judgment drive us deeper into saddness and depression.
4. Drop the sugery foods and diet drinks, start eating healthier and with moderation. It may seems hard to believe but food impacts mood. We manage stress better with a healthy diet of real food not processed and water.
5. Let go of your belief that you are just lazy and start moving again. We are not geared to be lazy we just get into bad habits, and luckliy we can get out of bad habits. Working out does not have to be painful, find ways to make it fun.
Which one of these five can you get rid of in the next thiry days to improve your life?
Greta Jaeger, Licensed Professional Counselor and Certified Life Coach (404) 259-1335


text:
Plan & Diagnosis
Implant Placement
The bone around the implant grows and integrates with the implant surface during the healing phase, which will last between 3-4 weeks and a few months depending on the type of implant placed.
Temporary restoration
If the implant is in a visible area, a temporary restoration may be placed while the site heals.
Placement of implant abutment
When healing is complete, your dentist will place the final abutment, a small piece that connects the implant to the crown. Your dentist will take an impression of the implant site to order the crown, bridge or denture from a dental laboratory.
Final crown
When the final crown is returned from the lab, the temporary tooth will be removed and the final crown will be put into place.
Just like natural teeth, implants require regular check-ups and conscientious oral hygiene. With appropriate care, the long-term function of implants can be maintained. Your dentist will guide you on cleaning and hygiene measures.
Straumann Bone Grafting Solutions for Bone Loss
Some patients may not have enough bone to support a dental implant. In this case, your doctor can perform a 'bone grafting' procedure to help your body build new bone for the implant placement.
Reasons for bone loss include:
What is "bone graft" material?
Bone graft material is the substance used to build the bone volume necessary for implant placement by helping to regenerate vital bone. Straumann provides effective bone grafting materials that are tested, trusted and designed to deliver excellent results.
Your dental professional will help determine which type of bone graft material is best for you.
Sources of bone graft material include:
Bone Grafting Procedure
A bone graft procedure happens either before or during the implant placement, depending on the amount of bone needed.
Since every surgical procedure carries potential risks, patients should always consult a dental professional to evaluate whether dental implants are the option for them.


text:
At Valley Gardens, we strive to make sure our pupils are happy in school and feel safe. In order to do this we have a support network that pupils can call upon if they experience any difficulties. This network involves the form tutors and heads of year who are very experienced in addressing issues that pupils face. The vast majority of parental inquiries and complaints can be dealt with directly by this team. Details of the pastoral teams are below :
Head of Year 5: Karen Ferguson
5CB Emma Campbell / Lynn Kerr
5CR Dawn Charlton
5HK Sarah Harker / A Goel
5MW Deborah McMorrow
5SN Gill Sinclair
5TW Thomas Dibdin
Head of Year 6: Matthew Hope
6BU Sean Burnside
6DR Nyima Dryang
6GB Scott Gibson
6KN Rachel Knowles / Kate Grimshaw
6MY Julie Murray
6SC Vicky Scurfield
Head of Year 7: Jonathan Roys
7GY Kristian Grundy
7HL Sarah Hill
7HS Natalie Horsman
7HW Hannah Hardwick
7ST Charlotte Dent
7VC Sarah Vickers
Head of Year 8: Neil Wallbank
8DL Mark Dougall
8FA David Fairlamb
8HY Helen Heaney
8JO Lynn Johnson
8OR Helen Orchard
8WI Susan Winterburn


text:
On June 16th, 2014 we submitted this technical comment letter detailing why the proposed Liquefied Natural Gas (LNG) Export Facility in Lusby, MD cannot move forward because of significant flaws in its environmental review.
The comment letter was submitted to the Federal Energy Regulatory Commission (FERC), the federal agency with authority over proposals to export and import natural gas. As we've discussed in previous posts, FERC is the federal agency that is responsible for assessing the environmental impacts of LNG export proposals pursuant to the National Environmental Policy Act (NEPA).
The proposal to export LNG from the Chesapeake Bay via the existing, Lusby MD import terminal is bad news for upstream watersheds and communities like the Susquehanna. This is because LNG export from the Chesapeake is specifically tied to development of shale gas reserves like the Marcellus and Utica, shale reserves which underlay much of the Susquehanna River Basin and Pennsylvania.
Development of these shale plays is and continues to occur via the use of hydraulic fracturing, an inherently polluting industrial practice that, in order to extract shale gas, disturbs wide swaths of intact forest, meadow, and farmland, disturbs headwater creeks and vital fisheries habitat, and threatens groundwater supplies with its deep-earth injections. Furthermore, its infrastructure – like new and expanded pipelines, compressor stations, and the like – is already converting valuable cropland and threatening public safety and well-being throughout the downstream Lower Susquehanna. For instance, the proposed, controversial Lancaster Co. natural gas pipelines are part and parcel of helping bring gas from upstream watersheds to the export facility in the Chesapeake.
These and other environmental impacts associated with shale gas development in the Susquehanna and Mid-Atlantic are what FERC's environmental review should have considered. Unfortunately, FERC has turned a blind-eye to these types of impacts, and refused to consider them as it moves forward in trying to authorize LNG export from the Chesapeake Bay. In fact, FERC not only refused to consider impacts to upstream communities like the Susquehanna, it also refused to even perform a robust study, choosing to perform an abbreviated review – called and Environmental Assessment – instead of a thorough, probing review – called an Environmental Impact Statement.
Lower Susquehanna Riverkeeper will continue its strong, science-based advocacy to ensure decisionmakers rightfully consider the full-range of impacts that an LNG export facility in the Chesapeake will mean for upstream communities and watersheds like the Susquehanna.


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Sunday, April 25, 2010
Starving Parents Moving Company
Forget the Starving Students Movers, they would have charged $1200 minimum to move our daughter from San Jose to Ukiah. Ron and I drove down to San Jose, rented a U-Haul truck, bought lunch for a few of her friends to thank them for helping out, and with their help we had that puppy loaded up and ready to roll in an hour with all her earthly possessions. Then Ron drove it to Storage in Oakland, I picked Sudi up and took him down to the Storage so he could help us unload the furniture that Sudi is inheriting from his sister for his summer sublet that begins in June (and later his own place with friends in the fall), and then we took Sudi and his girlfriend out to dinner. The plan for Sunday is to drive the U-Haul truck to Ukiah, where we will unload at the house, then return the truck (one-way rental). The one-way truck rental plus the storage unit (together) cost less than one month's rent in my daughter's former apartment in San Jose. Ron dubbed us the Starving Parents Moving Company. Truthfully, we have never starved, but we were plenty hungry by the time we had shifted all that furniture and done all that driving; and we have been plenty damn frugal in order to put these children through college. We are still trying to figure out how to break the news to our daughter that we can't afford to pay for the propane gas to heat our house and pay Sudi's tuition (it's either/or), so she will have the privilege of joining the Starving and Freezing Parents Moving Company as an honorary member. We're smiling all the way to the poorhouse. Those beautiful children are worth all the trials and tribulations. And the warmer weather is just around the corner, so we'll be forgoing the air conditioning instead of forgoing the heat any minute.
Posted by Amy at Woza Books at 4:26 PM
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text:
THE LANGUAGE OF LOVE. STUDENT:LORENZO MAZZA CLASSE:4^A. TABLE OF CONTENTS. What does the expression "the Language of love" mean? Why is it difficult to express emotions? Why do people often choose to use poetry to speak about love?
Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.
The languageof love is the way we express ourfeelingsto the personwe love.
The languageof love embodiesthreemaincategories:
Expressingouremotionsisreallytough, because
we are scared to knowtheloved.edperson'sresponse.
We are scared to be rejected, so weoften
refusetodeclareour love.
According to Andreas Cappellanus,'s "De Amore", therewerespecificphasesof the process of Love:
Nowadays the act of courting is generally a
male's function, even if there are many cases
where the woman courts the man.
The most common court forms are:


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|134 m²
|Property type
|Minimum Stay
|2 nights
Our camp is newly constructed and located on 409 Lake Breeze Rd in Hackberry Louisiana. We completed the build in the Spring of 2015. This is a 3 bedroom, 2 bathroom camp with all the amenities of home. The master bedroom has a queen bed. One guest room has 2 full beds. The remaining guest room has 2 sets of bunk beds, with the bottom being a full mattress and the top being a twin mattress on each bed. Each bathroom is complete with a full size shower and bathtub. The living room, master bedroom, and the bunk room have flatscreen TVs. The camp is also equipped with surround sound in the living area, as well as speakers on the outside porch and downstairs area for your entertainment. The kitchen is equipped with a stainless steel refrigerator, oven, and dish washer. Our kitchen is stocked with all the essential items you may need to cook a delicious meal. We have a laundry room, complete with a front loading washer and dryer. Our outside porch is very spacious, overlooking the canal. We have an outdoor furniture set and a primo grill to enhance your outdoor experience. Downstairs is another bbq pit and outdoor table with chairs. In addition, we have a two covered boat slips, one reserved for our guests. Our circular driveway allows an easy entrance and exit for boat trailers. We hope you enjoy your stay!
Check-in 4pm
Check-out 11am
Unless previous arrangements have been made.
Our property is located in Hackberry, Louisiana. Our camp is on Lake Breeze Road, close to Hackberry Rod & Gun Club. Although we do not have a boat launch, we do have a covered boat slip reserved for our guests. Our camp is located on a quiet canal that leads into Joe's Cove. Joe's Cove leads directly into the ship chanel. From there, you are minutes away from Spicer's Marina, Big Lake, and many other wonderful fishing areas. In addition, we are only minutes away from Holly Beach and Johnson Beach, where you can enjoy some beach time and surf fishing. You have the option of fishing in the marsh or fishing in the gulf. Crabbing is a must-do! Hackberry also has a public swimming pool, where you can take a dip in the heat of the summer. Hackberry offers exceptional duck hunting during the winter months. Our camp is brand new, construction complete in the Spring of 2015. We have plenty of room for your family and friends, with all of the amenities of home. We hope you enjoy all that Hackberry has to offer during your stay!
|Rate Period
|Weekend Night
|Monthly *
My Standard Rate
2 night minimum stay
|Notes: Rates are based on 6 guests; add C$64 per night, per additional guest
|Property Damage Protection
* Approximate monthly rate. Actual rate will depend on the days of the month you stay.


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So Knoedler Gallery's Ann Freedman didn't only traffick in forged Motherwells and Pollocks; she moved a couple of fake Barnett Newman paintings, too. But, I guess, because the owners of them didn't sue, we haven't seen images of those works. Which doesn't mean they're not out there. Or that they haven't been seen. In fact, at least one Newman painting was included in a high-profile gallery exhibition in New York, and at the Guggenheim in Bilbao, making it one of the most prominent paintings in the whole Knoedler forgery scandal.
The details come from the complaint filed by Freedman earlier this month as part of a defamation lawsuit against dealer Marco Grassi, which Art Market Monitor has posted. Freedman sued Grassi for giving a fairly nonspecific quote about how she hadn't done her due diligence before selling dozens of previously unknown AbEx masterpieces brought to Knoedler by Glafira Rosales. I'm struck by how incidental Grassi's actual comments are, especially compared to the extensive details which Freedman lays out in her complaint. It's almost like she is suing someone just so she can inject her version of the facts into the public discourse on the case, attempting to bolster her own claim that she's a victim of Rosales' deceptions, not a collaborator or enabler.
And so Freedman goes artist by artist, describing all her gallery's research efforts, and piling up the comments and credentials of the art world experts she says saw--and praised, i.e., authenticated--the Rosales paintings. She mentions two Newmans. For Untitled (1949, a 59x34-in Newman canvas, the list included Ann Temkin, who curated the Philadelphia Museum's Newman retrospective; Richard Shiff, who co-authored the artist's catalogue raisonne; directors and curators from the Albright-Knox, who she said tried to acquire the painting; and the National Gallery's Harry Cooper:
These experts and scholars likewise believed in the authenticity of this painting. For example, when Cooper viewed it, he stated that it was "beautiful" and "bore a relationship to the feeling in Stations of the Cross," a well-known Newman work."Believed in the authenticity of this painting." Imagine Freedman, the president of the oldest art gallery in the country, hosting a group of museum officials one evening in 2007, and then asking them what they thought of the Barnett Newman piece she'd just hung. If they asked where it had come from, she'd have said, what? From a private Swiss collection? Who would be the one to cast doubt on the authenticity of the painting in that context?
Another expert was even more deeply involved with the 1949 "Newman," though; art historian David Anfam included it in his 2008 show, "Abstract Expressionism: A World Elsewhere," that inaugurated Haunch of Venison's New York space after Christie's purchase of the gallery. The exhibition, stuffed with works borrowed from both museums and other dealers, was technically a non-selling show, though as Roberta Smith's scolding review noted, Haunch of Venison's statements on the matter were coy, dissembling, or both. Smith counted a dozen, but based on the number of gallery-organized loans, I figure at least 30 of the 62 works in the show could have been for sale. And sure enough, in Freedman's lawsuit, she says that Anfam had "eagerly marketed [the Newman he borrowed] to potential purchasers."
[MAY 2014 UPDATE: The NY Times' Patricia Cohen cites unspecified court documents to describe how fear of litigation kept skeptical scholars from speaking out publicly, but it didn't shut them up entirely:
And in June 2008, months after Dedalus started asking questions, three Barnett Newman experts -- John O'Neill, Carol Mancusi-Ungaro and Yves-Alain Bois -- concurred that what was said to be a Newman, from Knoedler, hanging at the Beyeler Foundation in Switzerland was a fake. But as Mr. Bois wrote in an email to the Beyeler, he and his colleagues were "told not to make a public announcement" by a lawyer for the Barnett Newman Foundation, who feared a lawsuit.June 2008 would be Art Basel season. I can't see what exhibition at the Beyeler might have included a Newman, though.]
Smith's review mentioned "an unfamiliar Newman" as a worthwhile element of the Haunch of Venison show, but there was none visible in installation shots online. [And of course, Christie's deleted HoV's website after the gallery was folded into the auction house's private sales division.] So I headed to the Strand to pick up a remaindered copy of Anfam's catalogue for the show.
In his essay for a New York School show in New York, blocks from dozens of well-known masterpieces on constant view, Anfam said he sought works that provided "freshness and variety." So "a hitherto almost [sic] unknown Newman from his annus mirabilis of 1949" must have fit right in.
Whatever my original interest in seeing what a successful fake ur-Newman looked like, it couldn't compare to the odd sense of skeptical anticipation I had flipping through the catalogue. There were four Newman's in Anfam's show, and as I saw each one, I wondered if it was the fake.
It didn't matter that I had the title and dimensions of the forgery; suspicion still tainted that first look. The expectation of uncovering a forgery had me questioning every work, searching for anomalies. That zip didn't look right. The brushy, translucent fields are obviously off. That's just a poorly proportioned copy of a classic. And in each case, of course, the work turned out to be an authentic Newman with immediately unassailable provenance. The Newmans Newman had painted had been set at odds with my mental image of what a Newman "should" be.
It reminded me of Mel Bochner's contribution to the "Artists & Photographs" box published by Multples, Inc. in 1970, titled Misunderstandings ( A theory of photography). Bochner had been collecting quotes about photography on note cards, which no art magazine had wanted to publish. When Marian Goodman asked him for a piece, he mixed six of the quotes with three he made up on his own. As he told triplecanopy & rhizome in 2010:
To this day, I have never revealed which are which. Under the principle "One rotten apple spoils the barrel," the intention of this act of forgery was to undermine any possibility of belief in the text. The "groundlessness" of the quotations became the equivalent of what I viewed as the groundlessness of photography itself, focusing attention on the artificiality of any framing device. I saw this as an attack on one of the main tenets of minimalism, Frank Stella's claim that "what you see is what you see."What you see is what you see. The Knoedler forgeries blow that up both coming and going.
I've tried to preserve, or at least approximate my sense of doubt here, by not captioning the images from the HoV catalogue. I'm sure you can figure it out, though, even without doing math or looking at img file names. It's one of those "Now that you mention it" moments. The others are, of course, unassailably authentic, with provenances and documentation and history that only emphasizes the Knoedler painting's complete lack of the same.
And meanwhile, the other Knoedler/Rosales Newman, Untitled (1950), is still a mystery. Like the 1949 forgery, it was selected for a 2007-8 show organized by the Guggenheim and Terra Foundations titled, "Art in the USA: 300 Years of Innovation," but it ended up staying home. [Though the show also traveled to Moscow, Shanghai, and Beijing, Freedman's complaint only says that Untitled (1949) went to the Guggenheim Bilbao.] Anyway, I hope (1950)'ll turn up, too.
Meanwhile, I'd like to make an open offer to the current owner(s) of the Knoedler/Rosales Newmans, to buy them for a fair price. Assuming they can be authenticated, of course.


text:
WIP-Justin's Coronation Clothing guide by Gneiss-chertWatch
©2013-2017 Gneiss-chert
Justin's portrait here fav.me/d6wyqgr Since I got asked a lot about what the rest of his Kingly clothing looked like I figured I would share what I have so far. I will color him later. I have a x-mas picture coming wednesday, a contest picture, and a commission to do first.
He has a dark blue version that has less gold decorations to it for travel.
Novel summary: fav.me/d6qwfe2
Justin Arisdale ©1998-2014 Michele Scott Gneiss-chertArt is ©2013-2014 Michele Scott Gneiss-chert
Novel series The Silver Dolphins Saga ©2013-2014 Michele Scott Gneiss-chert, and ©Victoria Mummert BloodAngel28 All rights reserved. My work may not be reproduced, copied, edited, published, transmitted or uploaded in any way without my written permission. My work does not belong to the public domain.
I love how regal those clothes look, truly fit for a king.
And there is so perfect look the design so cool so class the elegance of the clothes and the character really impressed
Great design ! This outfit is really awesome; fits him perfectly ! OuO
Those clothes remind me a little of Ganondorf, from TLOZ Awesome job!
AH HA! NO WAY!! Gannondork lol!
Thanks! Did you see his portrait pic(in the description), I had to share this because it was just a bust and everyone asked what he looked like!
I really like the design choices you made for his clothing! The color scheme is great, and the cape looks pretty epic!
Thank you very much for the awesome complement! The red and gold trim was a new idea. In 2000 it was a black cape with grey lining. I though that is to much black. I really like adding the extra gold. It is a coronation after all!
This does look indeed really good I like how well you do the details there ^^
You're welcome, I do think you did better job on your work though ^^
I thank you, but I like your armor sets just as much! You can always expand the current styles you have to add flair. I have redesigned my characters outfits a few times!
Razen's armor I hope to keep it as it is quite much, I think it has enough detail there for now but whatever going for his clothing... That will be there to solve later ^^ So far I'm quite satisfied to what I got, though I might portray Razen wearing his armor more often I just like it all that much!
Great design on the race and the uniform!
Verry good Job this is so amazing
this took you a lot of work right?
Thank you very much!Oh yes a many hours! Now I need to color it!
I got asked what it looked like so I out it up unfinished.
I love how he looks with the black and gold!
Thanks you for the complement! It is a nice look for him!
You'll have let me know what you think of his blue version. I will have a side view up wednesday and then the whole thing after that.
It's epic but it could need more epicness. =I
Oooo! What does it need besides stunning coloring? I am very open to opinion!
I'm just waiting for shading. I expect a lot from the MAJESTIC CAPE OF EPICNESS, again.
Oh yes!! I want to color this but I got to my other projects done!
LOL! That is a promise!
Awesome sauce :3


text:
[foo t-hohld] /ˈfʊtˌhoʊld/
a place or support for the ; a place where a person may stand or walk securely.
a secure position, especially a firm basis for further progress or development:
They gained a foothold in the New York market before beginning their national campaign.
a ledge, hollow, or other place affording a secure grip for the foot, as during climbing
a secure position from which further progress may be made: a foothold for a successful career
1620s, from foot (n.) + hold (n.). Figurative use by 1650s.
Tagged: f
Read Also:
- Footie
[foo t-ee] /ˈfʊt i/ noun, Informal. 1. . /ˈfʊtɪ/ noun 1. a variant spelling of footy
- Footier
[foo-tee] /ˈfu ti/ adjective, footier, footiest. Northern British Dialect. 1. poor; worthless; paltry. /ˈfʊtɪ/ noun 1. (informal)
- Footing
[foo t-ing] /ˈfʊt ɪŋ/ noun 1. the basis or foundation on which anything is established. 2. the act of one who moves on , as in walking or dancing. 3. a secure and established position. 4. a place or support for the ; surface to stand on; foothold. 5. a firm placing of the ; […]
- Footing-piece
noun, Building Trades. 1. one of a series of horizontal transverse timbers supporting a platform or staging.


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In her August 22nd op-ed, "Prisoner release: 'Justice, justice, thou shall pursue,'" Sarah Stern falsely led readers to believe that she was solely or at least primarily responsible for the passage of the Koby Mandell Act, which created an office in the U.S. Department of Justice to capture and prosecute terrorists who have harmed or murdered Americans overseas.
Although Stern worked for the Zionist Organization of America (ZOA) during a portion of this effort, many others at ZOA made this happen. After the passage of this bill, Sherry Mandel, Koby Mandel's mother said, "We want to thank the Zionist Organization of America (ZOA) for initiating this fight for justice…. Koby would have deeply appreciated this fight for justice by the ZOA." Stephen Flatow, father of terror victim Alisa Flatow, said, "We want to thank the ZOA for being the only organization to have made this bill and this fight a priority and being relentless in this pursuit of justice."
The New York Times ran a full article saying that "an intense three-year campaign by Morton A. Klein, president of the Zionist Organization of America" was "important" on this issue. ZOA's campaign included ads in the New York Times and in newspapers around the country, organizing House and Senate press conferences on Capitol Hill, publishing op-eds and letters in newspapers, delivering speeches around the country, discussing the bill on TV and radio, and distributing a powerful ZOA booklet entitled, "The Forgotten Victims: American Citizens Murdered By Palestinian Arab Terrorists."
As Uriel Heilman wrote in the Jerusalem Post (6-8-05), "The ZOA…spearheaded the drive to get the bill passed last year," then quoted Morton Klein, president of ZOA: "We had met with many Department of Justice officials and there seemed to be a lack of interest in capturing Palestinian Arabs that murdered Americans. That's why we decided we really needed legislation." The Forward newspaper wrote (12-17-04), "The ZOA achieved one of its top legislative successes with the passage of the Koby Mandell Act…. Klein initiated the legislation."
And a key factor in the passage of this legislation was a private meeting between Morton Klein and the late Senator Arlen Specter from Pennsylvania, a close personal friend of Mort's, who promised Mort he would personally lead the fight to get this bill passed. Thanks in large part to Senator Specter, President George Bush signed the legislation into law as part of the omnibus spending bill in December 2004.
—Dr. Michael Goldblatt, Chairman of the Board, Zionist Organization of America


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The Little Ballerina by Zoe James Williams I love attending ballet rehearsals to draw the dancers in their various[…]Read more
Category: Interviews
Artists' Interviews
Introducing the Colosseum by Alexis Marcou
Introducing the Colosseum by Alexis Marcou Alexis Marcou is an artist & illustrator internationally renowned for his work in graphite. His style[…]Read more
How to Draw the Human Form; Figure Drawing by Jill Preston – March 2015
Drawing the human form is challenging and can be very frustrating. Yet it can be exhilarating and sublimely satisfying. The[…]Read more
Interview: Sandra Dieckmann – Nov 2014
What do you listen to when drawing? We all share a studio playlist here that we contribute to. It's[…]Read more
Interview: Carne Griffiths – Aug 2014
Who's your favourite artist, illustrator or designer? I am a huge fan of the surrealist automatic period of work,[…]Read more
Interview: Claudine O'Sullivan – July 2014
Who's your favourite artist/ illustrator or designer? It's so hard to pick even a handful! My artist inspirations have[…]Read more
Meet Derwent's New General Manager – March 2014
We'd like to introduce our new General Manager here at Derwent. Simon Wells joined us in January and we took[…]Read more
Interview: Dino Tomic – Feb 2014
We had the pleasure of interviewing artist Dino Tomic about his work as an artist. Here, he answers a few[…]Read more
Yi Lin Juliana Ong and the Derwent Art Prize – Oct 2013
Artist Yi Lin Juliana Ong won third prize in the inaugral Derwent Art Prize – here she tells us about[…]Read more
Paul Hiles and The Derwent Art Prize – Oct 2013
Paul Hiles, second prize winner of the inaugural Derwent Art Prize, tells us a little about himself and how it[…]Read more


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SF – SF Sketchfest Tribute: Fred Willard
December 1, 2016 by Colin Solan
Filed under Animation, California, Movies, Signing and Appearance Profiles, Television
SF Sketchfest pays tribute to comedian Fred Willard, with an event moderated by Kevin Pollak and appearance by special guests Christopher Guest, Robert Klein, Laraine Newman and more on Sunday, January 22, 2017 at 7:30pm.
Fred Willard is an American Comedy Treasure and has been an important part of SF Sketchfest's history for 15 years, first attending the festival in its second year. Tonight we celebrate the man himself with a special panel with Fred and some of his collaborators from over the years, including Robert Klein, Christopher Guest, Laraine Newman and more, moderated by Kevin Pollak. A Second City and Ace Trucking Company alumnus, Fred Willard is known for his quick wit and improvisational expertise. He has appeared in over 70 films, including "Waiting For Guffman," "Best In Show," "This Is Spinal Tap," "Roxanne," "Anchorman: The Legend of Ron Burgundy" and "WALL-E." He has appeared in over 1,000 television episodes, from "Get Smart" and "Fernwood 2 Night" to "Everybody Loves Raymond" to "Modern Family."
Presented as part of SF Sketchfest! It's the city's greatest comedy festival, with a variety of sketch and improv, film and television tributes and reunions, solo performers, podcasts and stand-up comedy performers. See the greatest names live and in person!
Marines Memorial Theatre (MMT)
609 Sutter Street, San Francisco, CA 94102
MO – How I Slept My Way to the Middle Signing
December 3, 2012 by Colin Solan
Filed under Missouri, Movies, Other, Signing and Appearance Profiles, Television
Comments Off on MO – How I Slept My Way to the Middle Signing
Kevin Pollak signs at Barnes & Noble on Friday December 07, 2012 at 5:00 PM.
Book Group
People who want a good laugh for the holidays should mark their calendars. One of Comedy Central's Top 100 Stand-up Comedians of All Time, Kevin Pollak will be here signing and discussing his book, How I Slept My Way to the Middle.
Barnes & Noble
8625 Northwest Prairie View Rd Spac, Kansas City, MO 64153


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Category: Stock Vector | Comment: ( 0 )
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March 16, 2006 at 9:07 am #61340
Of course. The developer cannot in any case withhold the funds paid If you want to pull out of the contract due to (there'll be clauses I guess in your contract) his failure to meet an essential legal contractual condition. He would be in fact breaching the contract as a result.
Put the case in the hands of a trustworthy lawyer (PM Mark, the forum administrator to supply you with names) and you'll have your moneis paid back aswell as some compensation in the form of legal interest which ranges between 3-6% (it changes every year).


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Check Out The Autumn Edition of Our Newsletter! Click Here:
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Anyone that knows me, knows that my pets are the loves of my life. From my very first dog to the five pets I own now. I will and do go out of my way to make sure their healthy, happy and very much loved. I ponder so many of life's issues. And the many things I see happening in this world sometimes scare me. And when I contemplate about how our world is constantly changing, and seeing incidences like what happened in Washington D.C. On September 16, 2013, a lot of times My mind wonders what if that was me that was randomly shot and killed . Or what if I died in a flood similar to what's happening in Colorado and my pets lived ? What would happen to them? I understand that many people in my circle don't understand the feelings I have for my pets. They are my children. And if I passed on , unexpectantly ,will my pets continue to be loved and taken care of ?
I'm still young but it won't be long before I hit middle age and I,like many pet parents have always assumed I will outlive my pets. One of my babies, LoLa Bella( a shih tzu) , was adopted by me when she was a puppy because the older lady had passed on. I can tell from what little time she had , my LoLa was spoiled. I'm sure the lady wanted to make sure she would be ok and I wish I could tell her she is. So now I ponder what if I died? Will my husband take care of the pets , or my friends or family? Would they end on the street or euthanized by a shelter ? The thought scares me and I recognized I need to make plans now for my pets.
I am going to venture out and say this issue is one many pet parents haven't thought about or planned. Well I've read many articles on this topic and I'm going to provide a list of things we as pet parents must do. Because wiith no prior arrangements you take a risk that your pets may become abused, neglected or homeless.
That lack of knowledge sends an estimated 100,000 to 500,000 pets to shelters each year after their owners die or become incapacitated.
Estate Planning for Pets 101
We've all heard about the 'pet' that inherits everything. This is truly an option but also illicits the most protest from relatives who think you must have lost your mind. Well one option that is viable is a 'Pets Trust.' This is much like a trust you make for children where the Trust is funded with assets and a Trustee is appointed to watch over the pet's caregiver. Legalzoom.com has a Pet Care Trust Agreement form that can be found on their website.
While trusts can be relatively expensive to administer and maintain, they add a layer of oversight: The trustee pays the money to your appointed caregiver and may regularly inspect your pet's health and living conditions. Having the person with the money be someone different from the person with custody of your animal creates a system of checks and balances.
If thats not a suitable option , another option is to include your pet in your 'Last Will & Testament,' appointing a caregiver and making a financial gift to that person.
Find Your Replacement ( Who will be listed in The Pet's Trust?)
Identifying a committed caregiver is the most important step in planning for your pet's future. Talk with everyone from your veterinarian to family members and pet-sitters about becoming your pet's designated caregiver. "A lot of people just assume, 'Oh, my son's going to take the dog, or my daughter's going to take the cat,' and then what happens is they don't want to take the pets," To avoid misunderstandings, I recommend getting commitments in writing.
Appoint an Understudy
You should also identify alternate caregivers. Suppose your designated caregiver might end up traveling frequently or living somewhere that doesn't allow pets. Always have at least one or two backups. And if you are limited on the people you trust with responsibility for your pets , create a panel of friends or family members in charge of selecting a long-term caregiver and arranging temporary care for your animal until a permanent situation is worked out.
Another great solution is you can write a 'Pets Letter of Wishes' that can "provide a powerful moral statement telling the Probate Court exactly what you and your pet want." This will protect your pet without taking the steps involved in making a 'will.' In this letter you can state who you would wish to care for your pets upon your death, what monetary funds should be used to help care for your pets, and list all contact information. Of course, it's very important that you discuss this with the persons named prior to writing the letter. Again ,It's also good to have an alternative person named in case circumstances have changed and your designee is unable to take the responsibility.
Establish Expectations
In addition to your Pets Letter OF WISHES, create an information packet that details your pet's medical history and daily care needs, because "obviously, a cat or a dog can't say, 'Oh, well, here's the food I eat, here's how much I eat, here's when I need my treats, here's when I need my walk.' " Make sure the information is easily accessible and specifies the standard of living you want for your pet, including medical care and end-of-life decisions.
I also recently discovered an organization entitled 'Safe Place For Pets.' Safe Place for Pets is dedicated to working in partnership with terminally ill pet owners to find new homes for their animal companions. What an awesome idea . It's also a great relief to those with a terminal diagnosis who want to be certain their pets are well placed and cared for. I also suggest checking your local area for organizations similar to this one.
Many types of wills and trusts exist, so it's crucial to prepare carefully and seek legal advice. Before talking with a lawyer, you should have a plan in mind. It's essentially "planning the same as you might if you were dealing with a young child."
Til Next Time…..
Posted in Cats, Dogs, Pet Owners, Pet Parents, Pets, Pets' Health, Wills & Estate Planning


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NJTPA is working on their long-range regional plan – Plan 2045: Connecting North Jersey. And they have various outreach efforts underway.
The outreach event for Jersey City will be at the Journal Square Farmers Market on Friday, May 19th from 11am to 7pm.
Please share this information with your neighbors. Also feel free to forward along. Take the survey at njtpa.org/plan2045 and to share the link with as many people as possible. The survey will be live until the end of June.
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We will be in Tokyo next week and have already booked several suggestions recommended on this board. But we still have not decided on our Sunday night dinner in Roppongi. We are trying to decide between Chinese Cafe Eight, Hainan Jeefan and Inakaya. I understand the first two are less expensive than Inakaya, but a Japanese friend of ours has raved about Inakaya, but hasn't been in awhile. We'd appreciate some feedback on these three suggestions or alternate choices.
Also, has anyone heard of Misogui-gawa in Kyoto? We have a lunch reservation there, but would like some feedback from someone who's been. We've also heard good things abuot Hyotei in Kyoto. If we had to decide between the two, which do you think would be better?


text: Human Rights Observatory Iraqi Government Training Thousands of Sunni Tribesmen Three senior U.S. defense officials with ties to the Iraqi government have told VOA that Iraq has recruited about 6,000 Sunni tribesmen fighters, a force many say will be critical in defeating Islamic State. Analysts said the large number was a step in the right direction. "There's 6,000 who are willing to work together — that may be even more important," said Michael O'Hanlon, a senior fellow at the Brookings Institution. "It's not so much that they're going to get great training in...Read complete article© Voice of America - Thursday, July 2nd 2015


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text: Let the debate begin. I have never been too fond of how calls sound from a Motorola phone. I have never owned a Samsung so I can't compare the two. I like the size of the Droid X but I think it will be too narrow. Plus I will save a lot of money by having 3 lines on AT&T instead of 2 lines on att and one on Verizon.


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liquid phase reactions and mass transfer
Hi all, I will be grateful to you for answers and suggestions to these queries. I am using Fluent 6.1.22 for all my CFD calculations.
Is it possible to model liquid phase reaction after mass transfer from another liquid phase in Fluent?
How can we use a multiphase model and a reaction model in some combination since they cannot be used simulatneously in Fluent?
Thank you for your patience.
|All times are GMT -4. The time now is 08:36.


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Descriptions are not just a way to transfer information and create bright images, but also a wonderful instrument to play with the dynamics of the text by changing the rate of development of the story. Undoubtedly, everyone who wants to become a pen wizard has to be well aware of how to manage the readers' attention, alternatively straining and relaxing their attention.
I believe all descriptions can be conditionally divided into static and dynamic.
Static Descriptions
Such descriptive blocks significantly slow down the pace of the narrative. You can meet them in scenes with smooth and unhurried rhythm. They are photo-like and often presented in the form of a single paragraph without any active actions.
Delivering a massive descriptive paragraph, the writer usually has two purposes:
Well, detailed descriptions of the appearance, face, and manners of a person point to the fact that the author deliberately draws our attention to the character, and therefore, will use him in future.
Thus, please avoid thorough describing characters of the third plan which will be mentioned only briefly, and then disappear forever. Note that the reader trusts you his attention, so you have to dispose of it properly.
Dynamic Descriptions
Dynamic descriptions are always associated with the rapid development of the plot. They are typical for motion scenes and scenes with dialogues.
Did you know that the pace of the scene is largely determined by the relation of the dialogue and narrative components? So please don't run to extremes:
Dynamic parts composed of descriptions and sometimes empty dialogues are common in modern fiction. They are easy to write and perceive. Note that it's not always convenient for the reader to put together a mosaic of scattered pieces of the description. Be sure to follow a description with actions rather than interrupt it.
Tips on Dealing with Descriptions
#1 Avoid too Much Look Alike Text Structures
Uniform shapes are the no.1 to avoid when building a large narrative blocks. Descriptions are not just chains of visual images! Not always the visual image provides a complete and correct view of the world. Be sure to work on sounds, sensations, and smells.
Also, be versatile. Even three sentences with similar structure evoke nostalgia, not to mention a huge paragraph that the reader will be unable to finish.
#2 Do not Overload Sentences with Too Much Sense and Too Many Facts
Your ultimate task is to make descriptions understandable and clearly conveying the atmosphere. That's why I believe you should avoid too complex structures with a lot of figures of speech, tall talk, etc.
Did you know that the longest grammatically correct English sentence belongs to William Faulkner and is composed of 1,292 words?
#3 Repetition is Not Always a Mistake
I bet you've read some recommendations on avoiding repetitions and tautologies. It is believed that the one and the same word used in the neighboring sentences spoils the perception, so it should be carefully replaced with synonyms. In most cases, it is true. But sometimes the repetition serves as a powerful mean of expression that focuses the reader on a particular word or image.
#4 Get Rid of Wordiness
In the hands of a beginner, descriptions may turn into a swamp pulling the reader down. Working with descriptions, always try to get rid of superfluous words and clarifications. If the hero is scratching his head, do not write that he does it by his hand – that's obvious.
Another variation of wordiness is long tedious descriptions of places, objects, and people that do not carry any meaning for the story. Why describe the corridor in details, holding the reader's attention for a long time, if the heroes will run through it for a few seconds and never return?
I am bringing to the fact that the writer must know exactly what he needs to describe. Paying a particular attention to this or that image, you focus the reader's attention and make it clear that the scene is really important. But when you scrupulously describe something, the reader gets overloaded and confuses between the important and unimportant.
#5 Use the Character's Point of View
Working with descriptions, you should not break away from the other components of the text. The place of the description in the text and its scope should be consistent with the structure of the scene.
Usually, when we write the text in the third person, we unwittingly act as an independent narrator. In my opinion, in both first- and third-person narratives the author has the full moral right to build relations based on the opinion of the narrator. This allows you to turn the usual description into something completely new and unique. And, of course, reveal the image of the hero.
I believe the author should not be afraid to express personal views in descriptions, as well as add some colors and exaggerate. Pay attention to classics – is there a shadow of constraint in their work? Definitely, not.
Lucy Adams is a blogger from buzzessay.com. She's a generalist that perfectly copes with a huge variety of topics. Lucy loves psychology, marketing, writing, education, and many other niches. Feel free to contact the responsible author and get your best blog post at no cost!
Hi, I'm Tim Ellis - I write a lot and I hope you enjoy what I write.
October 2017


text: Human Rights Observatory Rio Olympics Opening Ceremony Highlights Brazil, Environment There's nothing like the unique Brazilian vibe _ and the opening ceremony for the 2016 Summer Olympics in Rio de Janeiro will see no shortage of samba, culture, diversity and history as the South American nation proudly showcases its traditions and environmental wonders. Millions of television viewers from around the world are expected to watch the three-hour ceremony Friday night, which comes as the country is reeling from political and economic turmoil. Since the...Read complete article© Voice of America - Friday, August 5, 2016


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Dec 12 (Reuters) - The change in leadership at Molycorp Inc
is a step in the right direction as it comes at a time
when the rare earth miner is battling falling prices and is
being investigated by U.S. regulators over the accuracy of its
disclosures, analysts said.
Shares of Molycorp, one of the few rare earth producers
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For some time, the Government has been concerned about the rise in the number of applications for judicial review (JR) which increased by up to 70% between 2007 and 2011. In a claim for JR, the claimant is asking the court to scrutinise how a decision has been made under public law. If the court finds in favour of the claimant, it may order the body who made the decision to either re-take that decision, or prohibit it from taking, or compel it to take, some further action. In order to ensure that parties work to resolve matters without issuing proceedings and thereby reduce the number of JR claims overall, the Ministry of Justice is continuing to implement a number of reforms to the JR process.
In addition to the changes introduced by the Criminal Justice and Courts Act 2015 (which are referred to in our previous briefing, a copy of which is available here), the Ministry of Justice has also amended the Pre-Action Protocol for Judicial Review (the "JR Protocol"). The JR Protocol sets out steps the court would expect parties to take before commencing an application for JR. The court may impose sanctions or adverse cost consequences on parties who fail to comply with the JR Protocol, unless that failure is due to extreme urgency. We summarise below the key changes to the JR Protocol, which came into force on 6 April 2015.
Alternative Dispute Resolution
Whilst parties have always been encouraged to settle a dispute without the issue of JR proceedings, it is now mandatory for a claimant to consider whether a form of alternative dispute resolution ("ADR") or complaints procedure would be a more suitable way to resolve the dispute. The appropriate form of ADR is dependent on the type of dispute or complaint, however examples include:
- discussion and negotiation;
- engaging in public authority complaint or review procedure;
- ombudsmen; and
- mediation.
Both parties may be required to provide evidence to the court that alternative means of resolving their dispute have been considered. A party's refusal to participate or failure to respond to an invitation for ADR could be considered unreasonable by the court, leading to the court ordering the party to pay additional costs. However, exploring ADR will not excuse either party failing to comply with time limits imposed by the JR Protocol[1].
Letter Before Claim and Letter of Response
A claimant must now outline any ADR proposals they suggest may resolve the dispute in the letter before claim. Accordingly, it is now mandatory for defendants to set out their response to ADR proposals suggested by the claimant and/or their own proposals on ADR in the formal response to the letter before claim. Under the updated protocol, where the claimant is a litigant in person, the defendant must include a copy of the JR Protocol within its letter of response.
As a result of the changes outlined above, it is possible that many parties in dispute may resolve their dispute through ADR without ever having to bring their claim before the court. This may save both money and time on behalf of the court as well as the parties. Therefore, JR proceedings should be viewed as very much a remedy of last resort. In principle, this could be good news for public/private sector bodies making decisions under public law principles, as claimants now have to ensure that, except in very urgent cases, they follow the steps outlined by the JR Protocol to increase their chance of resolving the dispute by exhausting other remedies. However, bearing in mind that JR claims are often brought on the basis of "a matter of principle" the chances of resolving the dispute through ADR may well remain low. Time will tell whether the new JR Protocol will achieve the Government's objective of reducing the number of JR claims overall and bring balance to the judicial review system.


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The concept of eliminating HIV-1 infectivity by elevating the viral mutation rate was first proposed over a decade ago, even though the general concept had been conceived earlier for RNA viruses. Lethal mutagenesis was originally viewed as a novel chemotherapeutic approach for treating HIV-1 infection in which use of a viral mutagen would over multiple rounds of replication lead to the lethal accumulation of mutations, rendering the virus population non infectious – known as the slow mutation accumulation model. There have been limitations in obtaining good efficacy data with drug leads, leaving some doubt into clinical translation. More recent studies of the APOBEC3 proteins as well as new progress in the use of nucleoside analogs for inducing lethal mutagenesis have helped to refocus attention on rapid induction of HIV-1 lethal mutagenesis in a single or limited number of replication cycles leading to a rapid mutation accumulation model.
The concept of HIV-1 lethal mutagenesis (see Glossary) was first described over a decade ago and was received with tremendous promise and enthusiasm [1]. Over the intervening years, it has become clear that the details regarding the molecular basis for HIV-1 lethal mutagenesis are more complicated than was originally believed and that it has been quite challenging to identify therapeutics that would allow for translation of a clinically-approved lethal mutagenesis therapeutic strategy for HIV-1 infection. Important encouragement in development of lethal mutagenesis as an anti-HIV-1 strategy occurred in the past few years from the discovery of the APOBEC (apolipoprotein B mRNA editing complex) family of cytosine deaminases (particularly the APOBEC3 family), for which the prevailing evidence indicates that members of this family represent an evolutionarily conserved defense mechanism against viruses as well as other molecular parasites [2]. The primary antiviral activity of these enzymes is C-to-U hypermutagenesis of single-stranded viral DNAs – which for HIV-1 occurs during the minus-strand DNA synthesis of reverse transcription and leads to G-to-A hypermutagenesis in the plus-strand DNA [2]. The observation that cells have evolved antiviral mechanisms involving lethal mutagenesis suggests that therapeutic approaches involving enhanced viral mutagenesis are ultimately seeking to mimic what has already been established in evolutionary time as a potent and effective antiviral strategy.
The early thoughts regarding the basis of HIV-1 lethal mutagenesis – as well as approaches envisioned for other RNA viruses – proposed that the slow accumulation of mutations introduced by a mutagenic nucleotide analogue over multiple rounds of replication, which would slowly elevate the virus mutational load until the induction of lethal mutagenesis (known as the slow mutation accumulation model). The discovery of the APOBEC3 proteins led to the realization that lethal mutagenesis could arise in a much more robust and rapid manner. Specifically, APOBEC3 proteins can induce HIV-1 lethal mutagenesis within a single round of viral replication [2–4]. This observation is important because the rapid accumulation of mutations for inducing lethal mutagenesis helps to eliminate many concerns regarding the clinical translation of such an antiviral intervention strategy with the slow mutation accumulation model. One concern, which is not supported by experimental data, is the selection of new virus variants with altered biological properties. Here, we argue that both a new conceptual understanding of HIV-1 lethal mutagenesis as well as promising new experimental approaches to induce rapid virus extinction with minimal cell toxicity provide the basis for renewed enthusiasm in the development of this novel antiviral strategy.
The basic concept of lethal mutagenesis is based on the idea of reaching the error threshold as well as a collapse of viral infectivity among virus variants within the population (reviewed in [5–7]). This is a novel antiviral strategy for the elimination of virus infectivity by the elevation of viral mutations and has yet to be reached by clinically approved therapeutics, though the possibility of ribavirin acting as a mutagen in the treatment of viral infections (e.g., hepatitis C virus, HCV) cannot be excluded. Such an outcome could occur by virus replication in the presence of mutagenic agents such as nucleotide analogues, or could arise through the action of cellular nucleic acid editing enzymes, such as the APOBEC3 proteins (Figure 1). Holland and colleagues published the first experiments with poliovirus and vesicular stomatitis virus (VSV) to show that elevated viral mutagenesis led to a negative outcome in terms of the adaptation and survival of the virus population [8]. The term `lethal mutagenesis' was coined by Loeb, Mullins and colleagues [1] in the first published account of the error catastrophe concept in HIV-1. Error catastrophe is a term used to describe the scenario for when the consensus sequence within the viral population (called the `master' sequence) is no longer the most fit and there is a drifting into the sequence space that can lead to noninfectious and nonfunctional virus genome sequences [9]. The ultimate movement of change in the `master' sequence to an unfit viral genome leads to the successful penetration of the error threshold and entry into error catastrophe. Complete loss of the `master' sequence represents virus extinction.
At the molecular level, lethal mutagenesis is initiated by an elevation of the viral mutation rate (i.e., enhanced mutagenesis). This increase in mutation rate can result in the generation of defective, but replication-competent viruses (called `defectors') that can interfere with the replication of non-defective virus, and therefore suppress overall viral replication [10–14]. The presence of viral `defectors' creates the situation of lethal defection (Figure 1), which is an intermediary step in the path towards lethal mutagenesis and ultimate virus extinction. Support for the lethal defection model comes from both experimental as well as computational data [10–14]. Continued viral mutagenesis during lethal defection leads to an intensification of lethal mutations that further extinguish viral infectivity. The kinetics for where, as well as how lethal mutations accumulate, is poorly understood, as are how these events interface with other viral and host-mediated mechanisms. An intriguing alternative to virus extinction via lethal mutagenesis is the reduction of viral infectivity by high replication fidelity, resulting in abated mutagenesis. In theory, prolonged replication at a low mutation rate would also result in virus extinction (Figure 1). This approach is similar to studies showing that high-fidelity viral mutants possess less virulence and may provide an alternative means for vaccine development [15, 16].
Chemical mutagens can damage DNA in living systems and are generally considered both poorly tolerated and carcinogenic agents but some have been successfully developed into anti-tumor chemotherapeutics [17]. As therapeutics become more patient-specific and disease-specific, the era of broad-spectrum chemical mutagen therapy has been reinvigorated by the study of lethal mutagenesis with viruses. Provided a high enough mutational burden, an irreversible genetic meltdown of the entire population causes its elimination [18]. Fortunately, the immense population size, genome structure, and adaptive requirements of most virus populations have positioned them very near the extinction threshold. Evidence for this first emerged in picornavirus studies where a mere twofold increase in viral mutation frequency was required to reduce viral titers by 99% [8]. Lethal mutagenesis has since been observed in many other RNA virus systems, including: HIV-1 [19, 20], poliovirus [21, 22], foot and mouth disease virus (FMDV) [23], and lymphochoriomeningitis virus (LCMV) [24]. Evidence in cell culture systems indicate that the clinically approved ribavirin regimen, used to treat HCV since 1998, elicits antiviral activity via lethal mutagenesis though this mechanism has not been fully established in vivo [25, 26]. These early studies provided evidence for lethal mutagenesis, but less attention was focused on potential mechanisms. The early HIV-1 studies with 5-hydroxydeoxycytidine suggested the slow accumulation model (Figure 2), whereby lethal mutagenesis occurred by a slow accumulation of mutations over multiple rounds of replication, ultimately causing virus extinction [1]. By analogy, many of the other lethal mutagenesis studies – even if not directly stating such a model – inferred this type of model for mutation accumulation leading to high mutational loads and eventual lethal mutagenesis.
Cell-culture based studies have shown promise for several viral systems, but the demonstration of lethal mutagenesis in vivo has been elusive. For example, phase II clinical trial results for KP-1461, a prodrug of KP-1212 (5,6-dihydro-5-aza-2'-deoxycytidine), a first-in-class viral mutagen for HIV-1, demonstrated there was perturbation of the mutation spectra, but no reduction in viral loads [27]. In particular, deep-sequence analysis of virus in these subjects revealed differences in the virus mutation spectra, but drug-exposed subjects showed no detectable differences in viral loads or CD4+ T cell counts, which are key prognosis markers for the level of HIV-1 infection. While retroviral recombination occurs at a high rate and could attenuate mutational burden among replication-competent virus, it is unlikely that it would prevent lethal mutagenesis or prevent any changes in viral loads or CD4+ T cell counts. One question that arises from these studies is whether KP-1461 could be effective as a monotherapy [27, 28], especially since the combined triple-therapy drug cocktail approach has been the standard for HIV-1-chemotherapy since the mid-1990s. Also, the clinically approved ribavirin regimen for treatment of HCV is administered in combination with interferon [29]. This suggests that the antiviral effect of KP-1461 may be enhanced in the presence of other antiviral agents. While monotherapy drug exposure typically leads to the rapid development of drug resistance, it is of note that there are no publications that document drug resistance to KP-1461. Taken together, these observations indicate that additional work is needed to document lethal mutagenesis of viruses in vivo.
As indicated above, the mechanism(s) of lethal mutagenesis had either directly stated (in the case of HIV-1) or had inferred (with other RNA viruses) the slow mutation accumulation model, where mutation accumulation over multiple rounds of replication was the envisioned mechanism (Figure 2). The discovery of the APOBEC3 proteins suggested that elevation of mutational load could occur rapidly, over a single or limited number of replication cycles. While early studies with HIV-1 used small molecules that could have been used to induce lethal mutagenesis in a rapid manner, concerns over the cytotoxicity of such molecules precluded intensive studies [1].
Lethal mutagenesis can be induced not only by drugs, but also by the human APOBEC3 family of proteins [2–4, 30–36]. The mechanism by which APOBEC3 proteins, the prototype being APOBEC3G (A3G), hypermutate retroviral genomes has been well-established [reviewed in [37], [38], and [39]]. Briefly, A3G is packaged into budding virions, after which the virion matures and binds to a target cell. In the target cell, A3G deaminates cytosines present in the minus-strand viral DNA during reverse transcription process. The deamination of cytosine to uracil causes a pre-mutatgenic lesion. This site templates for adenine during plus strand DNA synthesis rather than guanine. Deamination of cytosine by A3G during reverse transcription generates G-to-A mutation signatures in the resulting provirus [2]. However, its ability to mutate the viral genome depends on how well it can overcome HIV-1 viral infectivity factor (Vif) accessory protein. In a host specific manner, Vif targets A3G proteins for proteosomal degradation. By saturating A3G levels or less-stringent Vif alleles, A3G proteins can gain access to the nascent virions and mutate the viral genome as described above. An A3G deaminase-independent mechanism has been proposed as a major antiviral mechanism of action for HIV-1, however, this model remains controversial [40–43].
Cell culture work convincingly shows that these mutagen-inducing proteins can dispose of viral genomes in short order, i.e., over 90% loss in viral infection within a single replication cycle [2–4]. Because of the processivity of A3G once it engages the viral genome, evidence suggests the mutagenesis is a discrete all-or-nothing process [44, 45]. However, some studies suggest that A3G can contribute to sublethal mutagenesis [46], which include shaping the emergence of HIV-1 drug resistance [47–49]. Currently, the extent to which APOBEC3 proteins have contributed HIV-1 evolution remains controversial [50]; although, it is clear that HIV-1-infected patient samples reveal that APOBEC3 -signature mutations are actively found [51, 52].
A3G and A3F remain at the center of much recent focus as powerful HIV-1 mutators [reviewed [53] and [54]]. Both A3G and A3F, along with A3B, possess the capacity to restrict other retroviral genera as well, including: the murine leukemia virus (MLV, gammaretrovirus) [2, 3, 33], human T-lymphotropic virus 1 (HTLV-1, deltaretrovirus) [34], foamy viruses (spumaviruses) [55], as well as the equine infectious anemia virus (EIAV, lentivirus) [3]. In addition to retroviruses, hepatitis B virus (HBV, a hepadnavirus) and adeno-associated virus (AAV, a parvovirus) are also susceptible to members of the APOBEC3 family [31, 32].
More recent work has focused on inducing HIV-1 lethal mutagenesis using drugs that have been approved for human use with other clinical indications and where cytotoxicity was likely manageable. A study with 5-azacytidine (5-AZC) demonstrated that HIV-1 lethal mutagenesis could efficiently occur at drug concentrations that had no cell cytotoxicity [19]. Since 5-AZC is a ribonucleoside analog, it was originally thought[26] that its antiviral activity would primarily be attributed to its incorporation into viral RNA and subsequent increase in HIV-1 mutation frequency [19]. In support of this, several studies have shown that 5-AZC can be incorporated into RNA [56–59]. One study further demonstrated that 5-AZC was a weak competitive inhibitor, having a 20-fold lower affinity than CTP for RNA polymerase II [60]. However, the HIV-1 lethal mutagenesis study with 5-AZC showed that the most potent antiviral activity of 5-AZC was associated with its effect on the early phase of HIV-1 replication (i.e., reverse transcription) rather than on the late phase of HIV-1 replication (i.e., RNA transcription by RNA polymerase II). In particular, while 5-AZC increased HIV-1 mutation rate in both the late and early phases of HIV-1 replication, it had the greatest effect on the early phase of replication. These data provide evidence that 5-AZC exerts its antiviral activity on both phases of replication through an increase in mutation rate. Although 5-AZC led to a modest increase in mutant frequency, similar increases in mutation rates have been shown to be sufficient to lethally mutagenize other RNA viruses [1, 8, 20, 23, 61]. As alluded to above, lethal mutagenesis modeling studies suggest that small increases in viral mutation rates should lead to a disproportionately larger decrease in viral infectivity [62, 63]. A recent experimental study with HIV-1 helps support this interrelationship between mutation rate and viral fitness [64].
A model to explain the mechanism for the 5-AZC antiretroviral effect on the early phase of the HIV-1 replication cycle was proposed. In this model, 5-AZC is first reduced by ribonucleotide reductase and is incorporated into viral DNA during reverse transcription (Figure 3). Once incorporated into DNA, the mutagenic base undergoes a spontaneous ring-opening step [65] resulting in a mispair with cytosine during synthesis of the plus strand [66]. Such a model implicates integration as a key step in repairing the induced mutations, and that the azapyrimidine base is excised by host DNA repair machinery. The incorporated mutatgenic base would then be replaced with guanosine, since it can base pair with the cytosine located in the plus-strand DNA opposite the abasic site – resulting in a G-to-C mutation. The incorporation of 5-AZC during plus strand viral DNA synthesis would ultimately result in DNA repair that would not create mutations. Therefore, HIV-1 lethal mutagenesis that is mediated by 5-AZC would specifically result in G-to-C hypermutation, which is what was observed [19, 67].
As APOBEC3 proteins can attack cytosine residues in minus-strand HIV-1 DNA, a recent study explored the concomitant lethal mutagenesis of both A3G and 5-AZC. Reduced viral infectivity and increased viral mutagenesis was observed with both the 5-AZC (i.e., G-to-C mutations) and A3G (i.e., G-to-A mutations); however, when combined, these mutagens had complex interactions. Nucleotide sequence analysis revealed that concomitant HIV-1 exposure to both 5-AZC and A3G resulted in an increase of G-to-A viral mutagenesis at the expense of G-to-C mutagenesis. A3G catalytic activity was required for the diminution in G-to-C mutagenesis. These studies are particularly important in providing the first indication for potentiation of the mutagenic effect of a cytosine analog by A3G expression, which can result in concomitant HIV-1 lethal mutagenesis.
Recent studies have shown that a combination of two clinically-approved cytosine analogs, gemcitabine (2'-deoxy-2',2'-difluorocytidine, a ribonucleotide reductase inhibitor) and decitabine (5-aza-2'-deoxycytidine, a cytosine analog mutagen similar to KP-1461), represent a promising new experimental approach to extinction of HIV-1 infectivity [68]. In combination, these two drugs reduced HIV-1 infectivity by 73% at concentrations that had minimal antiviral activity when used individually [68]. The observed decrease in viral infectivity coincided with a significant increase in mutation rate and resulted in a shift in the HIV-1 mutation spectrum. Analysis of HIV-1 DNA synthesis during reverse transcription indicated that there was a lack of correlation between the decitabine and gemcitabine infectivity loss and reduction in viral DNA synthesis. Therefore, these results indicated that lethal mutagenesis was the primary antiviral mechanism for inhibiting the generation of infectious progeny virus from provirus. Given that both are clinically approved drugs, there is clearly hope that clinical translation and testing of in vivo lethal mutagenesis could occur. Such studies in which drug combinations have been used to enhance HIV-1 mutagenesis have been extended to the combination of decitabine and resveratrol (a natural product known to possess inhibitory activity against ribonucleotide reductase) [69]. It should be noted that viral mutagens could perhaps be more effective in causing virus extinction when used with standard non-mutagen antivirals. For example, in tissue culture studies performed with FMDV (an RNA virus), viral populations were rapidly driven to extinction only in sequential treatment when the inhibitor was given first, followed by the viral mutagen [70]. This was far superior to the reversed sequential treatment or the simultaneous combination of inhibitor and mutagen.
Preclinical evaluation of decitabine and gemcitabine was recently reported in a mouse model for HIV-1 [71, 72]. These studies were the first to demonstrate that gemcitabine inhibits replication of a related retrovirus, murine leukemia virus (MuLV), in vivo using the MuLV-based LP-BM5/murine AIDS (MAIDS) mouse model at doses that were not toxic. Antiviral efficacy and toxicity of the drug combination in the same animal model was also investigated. The data demonstrated that the drug combination inhibited disease progression, as detected by histopathology, viral loads, and spleen weights, at doses lower than those that would be required if the drugs were used individually. The combination of decitabine and gemcitabine was found to exert antiviral activity at doses that were not toxic. Detailed analysis of provirus mutational loads was not reported, and such studies are needed to confirm that the observed antiretroviral activity is primarily associated with elevation of mutational loads. Nonetheless, such studies are promising in the establishment of in vivo models to investigate HIV-1 lethal mutagenesis as a prelude for human clinical trials, such as those conducted with KP-1461 [27].
Like many areas of AIDS research, the investigation of HIV-1 lethal mutagenesis has seen both peaks of enthusiasm and valleys of doubt. The initial enthusiasm for HIV-1 lethal mutagenesis waned once it was clear that there was no easy way to clinically translate the molecules used to induce lethal mutagenesis in cell culture. Also, concerns about the slow mutation accumulation to induce lethal mutagenesis caused apprehension over the remote possibility of virus variants emerging with new biological properties. Furthermore, concerns regarding the potential toxicity of small molecule viral mutagens must be addressed in order for the successful clinical translation of these therapeutic strategies. Such studies may include the Ames test that measures the mutagenic potential of a compound in bacteria [73], in utero studies in both rodent and non-rodent animal models to measure a chemical's teratogenic potential [74], and dose-escalation studies in animal models to assess chronic-compound exposure leading to carcinogenesis, among others (www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065007.htm).
The discovery of the APOBEC3 proteins led to the rejuvenation of the idea of HIV-1 lethal mutagenesis as a therapeutic strategy and provided evidence of evolutionarily conserved antiviral mechanisms that are based upon lethal mutagenesis. These naturally occurring antiviral mechanisms revealed that rapid mutation accumulation within a single or limited number of rounds of replication could efficiently extinguish HIV-1 infectivity. Finally, the discovery of drugs that have the potential for clinical use have further aided in raising enthusiasm once again for HIV-1 lethal mutagenesis as an intervention strategy. In regards to clinical translation, viral mutagens may be more effective in causing virus extinction when used with standard non-mutagen antivirals. Studies with FMDV (an RNA virus) revealed rapid extinction only with sequential treatment of the inhibitor first, followed by the viral mutagen [70]. Careful studies with HIV-1 should be conducted for similar consequences. Clearly, much basic science remains to be done, but a path towards clinical translation appears more realistic than was thought in the past.
This research was supported from NIH R01 GM56615, a Center for Drug Design Funding Agreement, and an AHC Translational Research Grant. M.J.D. was supported from NIH T32 DA007097.
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Home » Themes » People » Government - State
Percival InchboldPrint Page
The gates to the church commemorate Percival Inchbold who was a soldier in World War One, a Mayor of Wangaratta, and a State Government politician.
He served in World War One, and during the time of his service overseas, his medical records stated that he suffered from re-occurring bouts of scabies and pleurisy. He saw combat action in Rouen, France. On the 2nd May 1917 he received gunshot wounds to the face at Rouen, which kept him out of action for a total of 17 days, rejoining his battalion on the 19th May 1917.
On the 19th of September 1917, still at Rouen, he received shrapnel wounds to the left arm and thigh, which was noted as being severe. He was shipped over to England where he was hospitalised. He rejoined his battalion in the field in France, on 2nd February 1918.
On the 5th October 1918, again in Rouen, France, he received more shrapnel wounds – this time to the throat and shoulder. On the 18th of October, whilst at the Red Cross Hospital, his status was recorded as being dangerously ill. After spending several months in hospital recovering, Percival was discharged from the hospital on the 22nd January 1919, and continued his service until he was discharged on the 8th of June 1919, with the rank of Lance-Corporal.
After returning to Australia, Percival became a Yarrawonga shire councillor from 1921 to 1933, and then President of the Yarrawonga Council in 1922 and 1923-23, Wangaratta Borough Councillor from 1927 to 1936, and Wangaratta Borough Mayor from 1933 to 1934. After this, he did not seek to re-elect and retired in August 1936.
From 1935 to 1953, Percival was the Member of the Legislative Council (M.L.C.) for North Eastern Province and from 1950 to 1952, he served as the Minister for Education.
|Ovens and Docker Streets, Holy Trinity Cathedral, Wangaratta, 3677
|GPS Coordinates:
|Lat: -36.3552
Long: 146.321279
Note: GPS Coordinates are approximate.
|Monument Type:
|Monument Theme:
|Government - State
This entrance is a memorial to the Hon. Percival Pennell Inchbold who served with distinction both church and state
Born 28-2-1884 Died 8-7-1953
Presented by his family and friends


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Evidence of three defence witnesses recorded in Jaya case
Special Court trying disproportionate asset case against J Jayalalithaa on Thursday recorded the evidence of three defence witnesses.
Last Updated: May 23, 2013, 21:51 PM IST
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Bangalore: The Special Court trying the disproportionate asset case against Tamil Nadu Chief Minister J Jayalalithaa on Thursday recorded the evidence of three defence witnesses.
Judge MS Balakrishna then adjourned the matter to May 28 for further recording of evidence of defence witnesses and their cross examination since the Special Public Prosecutor Bhavani Singh and the interpreter sought time.
Jayalalithaa is facing charges that she accumulated wealth of Rs 66.65 crore disproportionate to her known sources of income when she was Chief Minister from 1991 to 1996.