text:
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Australian Broadcasting Corporation
Late night news & current affairs
LOCATION: abc.net.au > Lateline > Archives
URL: http://www.abc.net.au/lateline/content/2003/s829626.htm
Broadcast: 10/04/2003
Defence expert on post-Saddam complications
The possibility of Turkish involvement in this conflict would provide not just the potential for more bloodshed, but also an added strain on the humanitarian effort in the region. Tony Jones speaks to retired US Air Force Colonel Sam Gardiner, now an adviser to the US Government on the humanitarian fallout from the war with Iraq. Colonel Gardiner is also a visiting professor with the National Defense University and American air war college in Washington.
Compere: Tony Jones
Reporter: Tony Jones
TONY JONES: Well, the potential for Turkish involvement in this conflict would provide not just the potential for more bloodshed, but also an added strain on the humanitarian effort in the region.
We'll cross now to Washington where I'm joined by retired air force Colonel Sam Gardiner, now an adviser to the US Government on the humanitarian fallout from the war with Iraq.
Colonel Gardiner is also a visiting professor with the National Defense University and American air war college in Washington.
Sam Gardiner, you've actually said that the US will lose this war if it fails to address the impending humanitarian crisis.
Tell us why you've said that?
COLONEL SAM GARDINER (RET), US GOVERNMENT ADVISER: Well, Tony, it's almost as if there are two battles in this war.
The first battle was against the military forces of Iraq, and the regime.
That's almost done.
The second battle requires almost as much ... no, it requires more skill and almost as much speed, and if we don't undertake it quickly, that's the image that we're going to have.
It has a bunch of things to it.
Immediately it's the health care problem.
We're hearing from Baghdad that the doctors aren't getting to the hospitals, they're short on medical supplies.
We hear in Basra that rather than go to the hospitals, the doctors are staying home and trying to prevent their houses from being looted, and we heard yesterday ... very painful thing ... the hospitals in Basra were looted.
So it's a very ... that first level is very painful.
That's going to be the image we see.
TONY JONES: Do you think the military planners are aware that they're effectively racing against the clock here?
COLONEL SAM GARDINER (RET): I don't think they are.
In fact, when I hear the Vice-President and the Secretary of Defence almost talk about this plan as if it were a success, I know they don't.
You see, the military guys that understand this ... I mean, I guess I'm one of those retired guys embedded in a TV studio, but frankly I've spent a long time studying this kind of stuff.
It's not just taking down the bad guys, that you as the occupying power are responsible for the health and welfare of the people that you have occupied.
And we're not prepared to do that.
We don't yet have security in any of the cities that have been taken, except for the port of Umm Qasr.
That's the only place where the relief organisations are now going in and assessing needs.
TONY JONES: Give us some of the statistics here, if you can?
What's the extent of this looming humanitarian crisis.
It's a country after all of more than 20 million people.
COLONEL SAM GARDINER (RET): Right.
Well, you can sort of start it in parts.
I think the first problem is going to be emerging will be the water.
We have had what looks like a general failure of the electric grid in Iraq.
There's no place that you hear of that has electricity.
The consequence of that means that the probably 1,500 water pumping stations aren't pumping water.
It also means that the sanitation system isn't working so raw sewage is going into the rivers that we see people drawing water from.
We're going to have to get in there and very quickly try and restore those water pumping stations, and that's not going to be easy because the pumps are probably going to be burned out, so that's the first thing.
The second thing is going to be the food part of it.
This is a country that has essentially been on food welfare for 10 years.
People aren't very good at sustaining themselves.
The food will probably begin to run out about the end of the month, about the end of April.
It won't be until maybe the middle of May before major food stores start to come in, and then the problem, Tony, is almost one that -- to understand is mind-boggling -- how do you distribute food to over 20 million people?
Well, before going into the war, the answer was we would sort of use the system that had previously been set up, which was -- there were interestingly about 40,000 food distribution points.
The notion was we would use that database that had the list of all the people who needed food and that would be what was used.
But if you look at the looting that's going on, today it was the computer centre in Baghdad.
My guess is that those lists no longer exist.
So in other words we're starting out with a total chaos and the people that get food, if you can't sort that out, were the strong, and it's the weak that need it.
So I don't think we're ready and the problem keeps getting worse.
TONY JONES: I've heard that the scale of the operation that will be required to feed the people of Iraq could only be compared to something like the Berlin airlift in the 1950s after the Russians put up the Berlin Wall.
COLONEL SAM GARDINER (RET): You know, actually I would say that that probably even underestimates it.
I think that if you look at any of the humanitarian disasters that the world has faced -- whether in Africa, whether it was the Kosovo operation, anywhere there's been a major sort of global focus on humanitarian things -- that is -- those are about one quarter of the size of the Iraqi problem.
In other words, the world has never seen a humanitarian problem this big before.
Just to give you an example, the US agency for international development has only 62 people in there to deal with that.
My sense is they never appreciated what they were getting into, and the plan never did.
TONY JONES: You've obviously looked closely at this plan.
Is it going to work or are in the end we going to see people starving, more looting, chaos in the streets?
COLONEL SAM GARDINER (RET): I think we're going to see more looting and chaos in the streets.
I think the images -- and these are the images we can't stand, if there's going to be a victory -- will be of children who are very sick with diarrhoea, women and children begging for water.
It doesn't take many of those images to begin to dominate that image of the statue of Saddam Hussein coming down in the square yesterday.
TONY JONES: I suppose the generals are going to say you're being a bit impatient here.
We're still in the process of trying to win this war.
We've gone very fast, we still haven't won the war, let us win the war and then worry about the humanitarian side of things.
Have they got it the wrong way around?
COLONEL SAM GARDINER (RET): They do.
You had to have been ready for this.
I mean, we can't -- there isn't a time frame where people can say, "I can go without water".
There isn't a time frame when people can say, "I can go without medical care while I wait for you to win the battle".
And -- see, here's where the plan begins to show in its weakness.
If you don't have security in the cities, then the humanitarian organisations don't go in and start their work.
They're not working.
There are no humanitarian organisations inside Iraq right now with the exception of the Red Cross and doctors without borders who are in Baghdad, and yesterday they announced they were ceasing operations.
So you have to have security.
Basra has to be secure before UNICEF and the other relief organisations are going to go in there and begin to assess the needs and they can begin to satisfy the problems.
TONY JONES: All right, Colonel Sam Gardiner, thank you very much for that reality check.
Thank you for joining us and we'll speak to you again no doubt as this progresses.
COLONEL SAM GARDINER (RET): Certainly.


text:
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subset: commoncrawl


text:
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text:
Hilary Duff leaving a pilates class in Studio City (2/4)
+ Your lesbian sex fantasy of the day [Hollywood Tuna]
+ Mark Wahlberg is a dick? You don't say . . . [The Superficial]
+ Kate Upton in nothing but body paint [Celebuzz]
+ What's sexier, Candice Swanepoel or the car? [Drunken Stepfather]
+ Damn I want to bang Emmy Rossum [Popoholic]
+ Victoria's Secret almost makes Valentine's Day bearable [Guyism]
+ 45 Amazing Places [Caveman Circus]
+ Lolo Jones wants sex [Busted Coverage]
+ Bikini Flashback: Jessica Alba [Socialite Life]
+ Duchess Kate in a bikini [Dlisted]
+ Nice shorts [Double Viking]
+ Drunk girl fight! [Brobible]
+ Stacey Dash is losing it [Evil Beet]
February 13, 2013 - 3:00 am


text:
Kentucky Halloween Parties
Some of the best parties of the year happen around Halloween time - everyone can cut loose, and enjoy a day or evening of festivities in costume. Getting to dress up is what sets apart Kentucky Halloween Parties from gatherings during the rest of the year - whether you're attending an after hours masquerade for adults, or a family friendly gathering filled with candy and activities for the kids. Kentucky Halloween Parties are something that can be enjoyed no matter what your age, as long as you're ready to enjoy as many tricks as treats!
|The Benton Farm Haunted House
|251 days ago


text:
Crutchfield Audio/Video CableLabels™
Crutchfield Customer Review (What's this?)
It is one of the most useful freebees that Crutchfield supplied with my receiver purchase. Not only that but they are clear and easy to read and easy to apply to the various cables.
Pros: Useful, and easy to apply to cables and easy to read
Cons: None


text:
Terry McGovern
1,319pages onAdd New Page
this wiki
this wiki
Terence "Terry" McGovern is an American film actor, television broadcaster, radio personality, voice-over specialist, and acting instructor.
McGovern was the English voice for Bass Armstrong in the DOA2: Hardcore games.
Roles in Dead or AliveEdit
- DOA2: Hardcore games (2000) - Bass Armstrong (credited as "Terence McGovern")
External linksEdit


text:
Saturday, Feb 22, 2014
ARJUNA MAHENDRAN, the chief investment officer, Emirates NBD: "My five- to 10-year view on gold is it will probably settle close to $1,100 to $1,150 an ounce. At that time I will start buying. But I won't buy for the long term at this point. "At this point I can trade it. I can buy at $1,200 and run up to $1,400 and then sell. I will be buying and selling within that band of $1,200-$1,400, but for the long term I will wait till it falls down to $1,100, which it will once when the Fed really gets into the earnest mode of tapering, which will happen by the middle of the year or so. Then the gold prices will come down to $1,100 to $1,150.
"I have five per cent gold in my global balanced portfolio. That's a hedge against inflation. Inflation will come but we don't know when. That's problem. It will happen in the next five years, that's what I reckon. As signs of inflation picks up I might raise that weight to eight per cent to 10 per cent."
"If you think long term, I don't think it will be lower than $1,100 to $1,150 because that is the marginal cost of production.
"If economic momentum picks up — and at the moment I am long in equities — and equities perform much on what I expect them to do, at some point I might be selling equities and the way to protect me there against inflation is not through cyclical companies but through gold. It will depend on the macro dynamics and how that affects portfolio performance.
"The other scenario that lends to buying gold is when there arises concerns of global slowdown, concerns of the pace of tapering with the economic growth becoming weaker and people in need of some safe assets. Then people will start buying gold. But our view is the underlying health of the United States is still there, and we still believe — that's our core view — that the tapering, that $10 billion less per month will occur in every single Fed meeting in the coming months."
By Gaurav Ghose Financial Features Editor
Gulf News 2014. All rights reserved.
© Copyright Zawya. All Rights Reserved.


text:
Our written sentences and translations can be used under the Creative Commons Attribution 2.0 license (CC-BY 2.0).More information
If you love this content, please consider a donation.
TagsView all tags
Another form of art which was highly developed by them was sculpture.
added by alexmarcelo, 2011-05-05 23:50
➜ #877792
linked by alexmarcelo, 2011-05-05 23:50
Sentence #877793
You cannot translate sentences because you did not add any language in your profile.


text:
Join Route 66 "On the Roof" for our 2017 Season Release Party!
$20 gets you all the food and drink (includes beer and wine) you can handle watching the best team in baseball while partying with Route 66 and hearing our special 2017 Season Announcement!
Sponsored by Murphy's Bleachers MONDAY NIGHT AUGUST 29TH AT 6:30PM
(Cubs vs Pirates)
PRICE: $20 (Includes all you can eat and drink!)
Buy tickets here!


text:
Read Our Full Review & Parent Discussion Questions Here
|Rating Descriptor
|British Columbia
|Not Rated
|Not Rated
|Not Rated
|Not Rated
|Not Rated
|Not Rated
|Canadian Home Video
NEW: Listen to our Parent Previews Podcast and take control of media and technology in your family!
News About "Rudy"
Cast and Crew
Rudy is directed by and stars Sean Astin.
Home Video
The most recent home video release of Rudy movie is September 30, 2003. Here are some details…
Re-released in 2003 as a Deluxe Edition, lowly Rudy's high hopes are presented in high quality digital video and Dolby Digital sound. The two-disc set includes the inspiring motion picture sound track, as well as original trailers and featurettes. While the bonus materials are rather sparse, there is something included that is very worthwhile an interview with the real Rudy. It is touching to listen to him recount his own tale, with tears in his eyes.
- Theatrical trailer(s)
- Includes CD soundtrack
- "Rudy: The Real Story" featurette
- Original featurette
- "First Down with Sean Astin" featurette
- Isolated music score
- Talent files
- Widescreen anamorphic format
- Number of discs: 2


text:
|Message view
|« Date » · « Thread »
|« Date » · « Thread »
|"Timothy Bish (JIRA)" <jira+amq...@apache.org>
|[jira] [Closed] (AMQNET-201) WCF binding to support request reply message exchange
|Fri, 08 Jul 2011 19:57:17 GMT
[ https://issues.apache.org/jira/browse/AMQNET-201?page=com.atlassian.jira.plugin.system.issuetabpanels:all-tabpanel ] Timothy Bish closed AMQNET-201. ------------------------------- Resolution: Won't Fix Closing this since there's no votes and no volunteers to work on it. > WCF binding to support request reply message exchange > ----------------------------------------------------- > > Key: AMQNET-201 > URL: https://issues.apache.org/jira/browse/AMQNET-201 > Project: ActiveMQ .Net > Issue Type: Improvement > Components: WCF > Affects Versions: 1.1.0 > Reporter: Mark Pollack > Assignee: Jim Gomes > Priority: Minor > > I remember a while back there was some discussion on a JIRA issue where there was an explicit decision not to implement the request reply message exchange pattern in the WCF binding. I think this is not the correct decision. Request/Reply is a natural interaction for messaging systems, though clearly not the default. Implementation options are to use a temporary queue as the return destination or to setup a standard queue but create a message listener with a selector. Just for reference the TIBCO WCF binding supports request reply message exchange. A customer driven motivation behind this is that usually everyone creates request/reply endpoints over http transport in WCF. When they want to switch transports to messaging they discover (in MSMQ case) that they can't and would have to redesign their entire web services design to accomodate using JMS transport. This is simply not needed. Please reconsider and let's discuss more. -- This message is automatically generated by JIRA. For more information on JIRA, see: http://www.atlassian.com/software/jira
|View raw message


text:
Offer - Walkers French Fries Variety Snacks 18g x 12 per pack
Product Description
Snap them in half, take a nibble.
Start at one end and crunch your way through, there's plenty of delicious crispiness to munch through before you've got to reach for the next one.
Go on - pick one out and munch away.
French Fries are a long and tasty pleasure, it just so happens they are 79 calories per bag.
99 Calories or less range... Squares™, French Fries™, Wotsits™, Quavers™
Product Information
- Brands: Walkers
- Dietary & Lifestyle: Vegetarian
- Options: On Offer
French Fries
Store in a cool dry place.
Made in a factory that also handles: barley, soya, celery, mustard
Return To Address
If dissatisfied, tell us why, where purchased and return the packet(s) and contents, (together with the multipack wrapper if applicable) to:
Consumer Services Department,
Walkers Snack Foods Ltd,
PO Box 23,
Lines open Monday to Friday 9am to 5pm
Applies to UK and Republic of Ireland only.
Your statutory rights are not affected.
Visit us at www.walkers.co.uk
Country of Origin
Country of Packing
Walkers Snack Foods Ltd,
PO Box 23,
Package Type
Heat Sealed
Other Information
Box Contents:
4 x Ready Salted, 4 x Cheese & Onion, 4 x Salt & Vinegar
Full Product Name:
Salt & Vinegar Flavour Crispy Potato Snack
Ready Salted Flavour Crispy Potato Snack
Cheese & Onion Flavour Crispy Potato Snack
Store in a cool, dry place.
1 Servings
Allergen Information
Allergens can be found in the ingredients list
Contains Milk
Allergy Advice: For allergens see highlighted ingredients
Cheese & Onion:
Potato Granules, Potato Starch, Sunflower Oil, Cheese & Onion Flavour [Lactose (from Milk), Dried Onion, Dried Cheese (from Milk), Flavour Enhancer (Monosodium Glutamate), Glucose, Sugar, Flavouring, Colour (Paprika Extract)], Salt, Colour (Annatto)
Ready Salted:
Potato Granules, Potato Starch, Sunflower Oil, Salt, Flavour Enhancer (Monosodium Glutamate), Colour (Annatto)
Salt & Vinegar:
Potato Granules, Potato Starch, Sunflower Oil, Salt & Vinegar Flavour [Flavouring, Salt, Acid (Citric Acid), Potassium Chloride, Flavour Enhancers (Monosodium Glutamate, Disodium 5'Ribonucleotide)], Salt, Colour (Annatto)
Dietary Information
Suitable for Vegetarians
Nutritional Data
Cheese & Onion:
|Typical Values
|Per 18g(%*) Pack
|Per 100g
|331 kJ
|1839 kJ
|79 kcal (4%*)
|438 kcal
|2.9 g (4%*)
|16.0 g
|of which saturates
|0.3 g (1%*)
|1.4 g
|11.9 g
|66.0 g
|of which sugars
|0.6 g (<1%*)
|3.5 g
|0.9 g
|5.0 g
|0.9 g
|5.0 g
|0.39 g (7%*)
|2.18 g
|Each inner pack contains 1 serving
|* Reference intake of an average adult (8400 kJ/2000 kcal)
Ready Salted:
|Typical Values
|Per 18g(%*) Pack
|Per 100g
|328 kJ
|1822 kJ
|78 kcal (4%*)
|434 kcal
|2.9 g (4%*)
|16.0 g
|of which saturates
|0.3 g (1%*)
|1.4 g
|11.7 g
|65.0 g
|of which sugars
|0.2 g (<1%*)
|1.1 g
|0.9 g
|5.0 g
|0.9 g
|5.0 g
|0.45 g (8%*)
|2.50 g
|Each inner pack contains 1 serving
|* Reference intake of an average adult (8400 kJ/2000 kcal)
Salt & Vinegar:
|Typical Values
|Per 18g(%*) Pack
|Per 100g
|331 kJ
|1839 kJ
|79 kcal (4%*)
|438 kcal
|2.9 g (4%*)
|16.0 g
|of which saturates
|0.3 g (1%*)
|1.4 g
|11.9 g
|66.0 g
|of which sugars
|0.2 g (<1%*)
|1.2 g
|0.9 g
|5.0 g
|0.9 g
|5.0 g
|0.41 g (7%*)
|2.30 g
|Each inner pack contains 1 serving
|* Reference intake of an average adult (8400 kJ/2000 kcal)
Customer Reviews
23 January 2016
0 of 1 found this review helpful.
More variety needed
My kids only like the ready salted variety, so only one third of the pack is useful. Ocado, you need to offer more variety!
06 June 2015
0 of 1 found this review helpful.
Great Snack
Really enjoy these tasty low calory snacks. We scrunch half a pack of our least favourite flavour up into a round of bread & butter to make a 'crisp' sandwich. I enjoy the variety BUT like other shoppers would like see ready salted only available as well.
31 July 2013
Love these, especially in the evening with a beer. Just wish it was a 14 pack like in the picture.
08 July 2013
1 of 1 found this review helpful.
why can't we have plain
Agree that a multi pack of plain would be preferable to the mixed pack.we hate salt and vinegar but the plain are great for a treat when weight watching
08 February 2012
1 of 2 found this review helpful.
Wish they sold just plain ones!
The cheese and onion ones always get left in our house and this multi-pack is all that Ocado sell. The Worcester sauce ones are lovely - wish they'd stock them too - I buy them elsewhere instead.
- Tesco Price Match
- ** Matched to Tesco's standard retail price on 24-May-2017 at 05:30. See our Terms and Conditions for full details.
- Disclaimer
- These summary details have been prepared for information purposes only, and are designed to enhance your shopping experience on the Ocado website. While we have taken care in preparing this summary and believe it is accurate, it is not a substitute for your reading the product packaging and label prior to use. You should note that products and their ingredients are subject to change. If you do require precise ingredient information you should consult the manufacturer, whose contact details will appear on the packaging or label.
- Ocado is therefore unable to accept liability for any incorrect information. Where this description contains a link to another party's website for further information on the product, please note that Ocado has no control over and no liability for the contents of that website.
- You should also note that the picture images show only our serving suggestions of how to prepare your food - all table accessories and additional items and/or ingredients pictured with the product you are purchasing are not included.
- This data is supplied for personal use only. It may not be reproduced in any way whatsoever without Ocado Limited's prior consent, nor without due acknowledgement.


text:
lilo mohamed
Once Upon A Time, A Teacher... - Poem by lilo mohamed
A summer course
started in July
She asked us to write, a pile
of words on our first day.
She made fun of my way
I hated her that day.
And there comes a day
were we get the chance to chat a lot
and guess what she wasn't that evil
I loved her and i guess she loved me back too.
Summer flushed away
giving winter a chance to come crashing.
A gloomy day in a similar
Class room, the news of her
death hit me Like an explosion of a nuclear boom.
The rising of her soul to the dear Lord
with heaven gates opening up for her soul,
at the command of the one and only Lord.
she left me to the hungry jaws of life,
praying for her to rest in peace
May the Lord bless her soul
and wash her body with the cold ice.
RIP Mrs. Eman
Topic(s) of this poem: death
Comments about Once Upon A Time, A Teacher... by lilo mohamed
Read this poem in other languages
This poem has not been translated into any other language yet.
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lilo mohamed's Other Poems
Famous Poems
Phenomenal Woman
Maya Angelou
Still I Rise
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The Road Not Taken
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If You Forget Me
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Edgar Allan Poe
Caged Bird
Maya Angelou
Rudyard Kipling
Stopping By Woods On A Snowy Evening
Robert Frost
A Dream Within A Dream
Edgar Allan Poe


text:
Embedded Object treated as an image
I just wanted to share a little personal experience with Microsoft Word. I have my personal word document which contains an embedded zip object containing my Todolist files. I keep it as a single capsule for portabiity reasons. I just have one observation that when the object is copied using Word's clipboard operations and pasted to Explorer and even after that closing the Word document you would be getting a message like 'You placed a large image in the clipboard'.
I admit that binary objects are images from the DEV perspective but just thought Word should be more explanatory in the nature of the message when it comes to addressing and clearing the doubts of a non-tech-savvy person.
This applies to Microsoft Word 2003.


text:
|Message view
|« Date » · « Thread »
|« Date » · « Thread »
|Nick Kew <n...@webthing.com>
|Re: mod_mbox development plan
|Sun, 03 Jul 2005 07:35:59 GMT
Roy T.Fielding wrote: > On Jul 2, 2005, at 7:46 PM, Maxime Petazzoni wrote: > >> The first thing that has to be done is, of course, get rid of the hard >> coded HTML and switch to something more flexible. Careful with "getting rid". I haven't looked at it myself, but I wonder if cleaning it up and keeping it as an option at least would be preferable. > Two main solutions >> are available : >> >> - a template system such as ClearSilver >> - XML + XSLT > > > I guess I am having a hard time bridging that leap from goal > to a fairly specific solution. What are the real advantages of > being flexible on the server? I mean, as opposed to simply using > a fixed data format with XHTML and class names? That could be the basis for a "best of both worlds" approach: (1) An output format that is basically clean XHTML with hooks for CSS. (2) Where that is considered inadequate, expand it with your own elements from other namespaces such as FoaF and DC, or if necessary your own invention. Try to make them optional! (3) Now this can be the basis for your XML+XSLT approach. But it leaves server admins with more flexibility than that, and those who want to avoid the overhead of XSLT have the option to do so - e.g. using the XMLNS framework. > [chop] -- Nick Kew
|View raw message


text:
Suppressor of cytokine signaling 1 blocks mitosis in human melanoma cells
- First Online:
- Received:
- Revised:
- Accepted:
DOI: 10.1007/s00018-012-1145-8
- Cite this article as:
- Parrillas, V., Martínez-Muñoz, L., Holgado, B.L. et al. Cell. Mol. Life Sci. (2013) 70: 545. doi:10.1007/s00018-012-1145-8
- Citations
- 912 Downloads
Hypermethylation of SOCS genes is associated with many human cancers, suggesting a role as tumor suppressors. As adaptor molecules for ubiquitin ligases, SOCS proteins modulate turnover of numerous target proteins. Few SOCS targets identified so far have a direct role in cell cycle progression; the mechanism by which SOCS regulate the cell cycle thus remains largely unknown. Here we show that SOCS1 overexpression inhibits in vitro and in vivo expansion of human melanoma cells, and that SOCS1 associates specifically with Cdh1, triggering its degradation by the proteasome. Cells therefore show a G1/S transition defect, as well as a secondary blockade in mitosis and accumulation of cells in metaphase. SOCS1 expression correlated with a reduction in cyclin D/E levels and an increase in the tumor suppressor p19, as well as the CDK inhibitor p53, explaining the G1/S transition defect. As a result of Cdh1 degradation, SOCS1-expressing cells accumulated cyclin B1 and securin, as well as apparently inactive Cdc20, in mitosis. Levels of the late mitotic Cdh1 substrate Aurora A did not change. These observations comprise a hitherto unreported mechanism of SOCS1 tumor suppression, suggesting this molecule as a candidate for the design of new therapeutic strategies for human melanoma.
KeywordsSOCS1 Cdh1 Cell cycle Tumor suppressor
Anaphase-promoting complex/cyclosome
- BrdU
Cyclin-dependent kinase
Cyan fluorescent protein
Fluorescence resonance energy transfer
Insulin receptor substrate 1
Janus kinase 2
Mitotic arrest deficient 2
- Mdm2
Murine double minute 2
Src homology 2
Suppressor of cytokine signaling
Signal transducer and activator of transcription
Yellow fluorescent protein
The frequent reduction of SOCS gene expression in human cancers indicates that SOCS proteins have a role as tumor suppressors. Decreased SOCS gene expression due to promoter methylation has been observed in advanced human cancers including melanoma [1, 2, 3, 4, 5, 6, 7]. In agreement with a proposed role in tumor suppression, SOCS1-deficient mice show myeloproliferative disorders and lymphomas [8, 9, 10]. In addition, SOCS1-deficient fibroblasts are susceptible to transformation by CBL and TEL-JAK2 oncogenes [11], whereas SOCS1 overexpression in tumor cells blocks proliferation [6, 11]. SOCS deficiency correlates with enhanced invasion and angiogenesis of melanoma cells [12]. Treatment with an analog of the SOCS1 protein SH2 domain has antiproliferative effects on prostate tumor cells; although the mechanism is still unclear, it appears to involve reduced cyclin levels and interference with cell cycle progression [13].
SOCS proteins direct the turnover of cellular targets through the formation of a complex with the Elongin-Cullin E3 ligase complex [14, 15]. In this way, SOCS modulates the ubiquitination of a variety of proteins, which are subsequently recognized by the proteasome and degraded. Proteins whose ubiquitination is modulated by SOCS include JAK2 [16], the insulin signaling intermediates IRS1 and IRS2 [17], the NF-kappaB subunit RelA [18], and focal adhesion kinase [19], among others. Although some studies describe that some SOCS targets, including JAK/STAT, are involved in signaling events that promote proliferation (for example, the activation of cyclin D promoters [20, 21]), others report suppression of proliferation by the same pathways [22, 23]. Through a mechanism involving the SH2 domain and C terminal SOCS box region, SOCS1 can induce p53-dependent senescence in fibroblasts. In addition, SOCS1 is required for the p53-dependent response to constitutively active STAT5A [24].
The wide variety of tumors that show SOCS gene promoter methylation suggests that, in addition to its effect on upstream signaling pathways, SOCS modulates the cell cycle at its core. Given the importance of ubiquitination in the cell cycle and the potential role of SOCS as an adaptor for ubiquitin ligases, SOCS proteins might target one or more key regulators of cell cycle progression. The mammalian cell cycle is regulated by a group of protein complexes, each composed of a catalytic subunit termed cyclin-dependent kinase (CDK) and a regulatory subunit, cyclin. The CDK phosphorylates key regulators of cell cycle progression only when associated with a cyclin, which are cell cycle phase-specific [25, 26]. Phosphorylation of substrates by CDK is regulated through its association with one cyclin molecule per kinase subunit [27]; CDK complexes are inactivated through the ubiquitination and proteolytic degradation of the cyclin subunit [28, 29]. Ubiquitination of cyclins and other relevant cell cycle proteins, and thereby the coordination of cell cycle progression, depends on the anaphase-promoting complex/cyclosome (APC/C). The APC/C is a large ubiquitin E3 ligase complex coordinated by two homologous mitotic coactivators, Cdc20 and Cdh1 [30]. Substrate selection by Cdc20 and Cdh1 results in the sequential degradation of individual target proteins in each step of mitosis; whereas APC/C-Cdc20 targets the anaphase inhibitor securin and initiates chromosome separation, APC/C-Cdh1 promotes degradation of spindle proteins such as Aurora kinases and Cdc20 itself [31]. Because of its role in the metaphase-anaphase transition, APC/C-Cdc20 activity is controlled through the spindle assembly checkpoint [32]. Direct interaction of the mitotic checkpoint complex and the activity of CDK1 inhibit APC/C-Cdc20 as long as the spindle checkpoint is engaged [33, 34, 35]. Only a few early APC/C substrates, for example NEK2, are degraded before spindle checkpoint inactivation. These substrates seem to be ubiquitinated through direct interaction with the APC/C core complex [36]. Loss of Cdh1 activity has been reported in many cancers, either directly through downregulation [37], or indirectly through loss of the Cdh1 activator PTEN [38]. The accumulation of various APC/C-Cdh1 substrates is also associated with tumor progression and poor prognosis [39].
Here we show that SOCS1 overexpression inhibits in vitro growth of the human melanoma cell lines BLM, MeWo, HT-1080 and UACC-257. In addition, we found that SOCS1 expression inhibits in vivo growth of metastatic BLM melanoma cells. The mechanism of growth suppression involves a block in G1/S and M phases, and SOCS1 association to Cdh1. SOCS1 expression leads to Cdh1 ubiquitination, a marked reduction in Cdh1 levels and concomitant accumulation of the alternative Cdc20. We did not find a significant association between SOCS1 and the latter APC/C adaptor. In accordance with the Cdh1/Cdc20 imbalance, SOCS1-BLM arrest concurs with cyclin B1 and securin accumulation and NEK2 degradation. Levels of Aurora A, a well-characterized anaphase substrate of Cdh1 [40], were not altered in BLM-SOCS1 cells.
Taken together, these results implicate SOCS1 in cell cycle progression, and suggest that the SOCS1-dependent balance between Cdh1 and Cdc20 controls proliferation of human melanoma. Strategies mimicking SOCS1 effects might therefore be of interest in defining new therapeutic strategies for melanoma treatment.
Materials and methods
Mice and cells
Nude mice on the BALB/c background were obtained from Harlan (Barcelona, Spain). Procedures were approved by the CNB Animal Use Ethics Committee in compliance with national and European legislation. Human MeWo, HT-1080 and UACC-257 melanoma cells were obtained from the American Tissue Type Collection (Manassas, VA), and human BLM melanoma cells were kindly donated by Dr. J. Teixidó (CIB/CSIC, Madrid, Spain).
The Flag-SOCS1 sequence was recovered by polymerase chain reaction (PCR) from the pEF-FLAG-I/mSOCS1 construct (from Dr T. Willson, Walter and Eliza Hall Inst., Victoria, Australia) using oligonucleotides 5′NheI-SOCS1 (5-ATGCTAGCATGGCGCGCCAGGACT ACAAG-3) and 3′Sac1-SOCS1 (5-GAGCTCTCAGATCTGGAAgGGGAAGG-3) and cloned into pIRES2Ac-GFPNuc (BD Clontech, Palo Alto, CA) to obtain pIRES2-AcGFP1Nuc-flagSOCS1.
Human Cdh1, Cdc20 and SOCS1 were amplified by PCR using the oligonucleotides listed below and cloned into pECFP-N1/pEYFP-N1 (Cdc20) and into pECFP-C1/pEYFP-C1 (Cdh1 and SOCS1) (Clontech): Cdc20: 5′EcoRI (5′AAGAATTCATGGCACAGTTCGCGTT CGAG3′) and 3′AgeI (5′ACCGGTTTACAGCGGATGCCTTGGTGGATG3′). Cdh1: 5′EcoRI (5′ATGAATTCAATGGACCAGGACTATGAGCGG3′) and 3′XmaI (5′CCCGGG TTACCGGATCCTGGTGAAGAG3′). SOCS1: 5′EcoRI (5′ATGAATTCAATGGCGCGCC AGGACTACAAG3′) and 3′XmaI (5′CCCGGGTCAGATCTGGAAGGGGAAGG3′).
Cell culture and transfection
Cells were cultured in Dulbecco's modified Eagle's medium (DMEM) with 10 % fetal calf serum (FCS; both from Invitrogen, Carlsbad, CA). Cells expressing SOCS1 protein were generated after transient transfection (5 × 106 cells), using JetPei reagent (Polyplus, Illkirch, France), with 15 μg of pIRES2-AcGFP1Nuc-flagSOCS1 (BLM-SOCS1) or empty pIRES2-AcGFP1Nuc (control), followed by selection in G418 (100 μg/ml; Invitrogen) for in vitro analysis of tumor cell growth. To test the SOCS1-mediated effect on Cdh1 levels, BLM cells (3 × 105 cells) were transiently transfected with different amounts (1–5 μg) of pIRES2-AcGFP1Nuc-flagSOCS1 or empty pIRES2-AcGFP1Nuc. To determine Cdh1 ubiquitination, BLM cells were transfected with 4.5 μg Cdh1-GFP and 4 μg pcDNA3.1-HA-ubiquitin [41] or with 1.5 μg of pIRES2-AcGFP1Nuc-flagSOCS1, alone or with 4.5 μg Cdh1-GFP and 4 μg pcDNA3.1-HA-ubiquitin.
Tumor cell growth analysis in vitro and in vivo
SOCS1-transfected or control cells were cultured (105 cells/plate) in DMEM with 10 % FCS. Cultured cells were harvested daily by trypsinization, and viability assessed by Trypan blue exclusion staining. BALB/c nu/nu mice received intradermal (i.d.) injections in the right flank with BLM-SOCS1 (48 h post-transfection; BLM-SOCS1) or control cells (106 cells in 50 μl PBS). Tumor growth was measured every 3–4 days using a Vernier precision caliper.
Cell synchronization and drug treatment
Cell synchronization
We used the double-thymidine release method to synchronize BLM cells in early S phase. BLM-SOCS1 or control cells were incubated with 2 mM thymidine (Sigma-Aldrich, St. Louis, MO; 0.4 × 106 cells, 16 h, 37 °C) washed three times with PBS and released into fresh DMEM (8 h, 37 °C). After an additional thymidine treatment (16 h, 37 °C), cells were released from early S phase and harvested by trypsinization at 0, 3, 5, 7, and 9 h. To measure cell cycle progression, ethanol-fixed samples (15 min, 4 °C) were stained with 5 μg/ml propidium iodide (PI; Molecular Probes, Carlsbad, CA) containing 100 μg/ml RNase A (Sigma-Aldrich; 1 h, 37 °C) and DNA content analyzed by flow cytometry. To synchronize cells in early M, BLM–SOCS1 and control cells were treated with 100 ng/ml nocodazole (Sigma-Aldrich; 0.4 × 106 cells, 16 h, 37 °C), then washed twice with PBS and resuspended in nocodazole-free medium. Cells were harvested by trypsinization at 0, 3, 5, 7, and 9 h, and DNA content analyzed by flow cytometry after PI staining.
BrdU pulse-chase experiments
BLM-SOCS1 or control cells were incubated in complete medium with 10 mM BrdU (Sigma-Aldrich; 0.4 × 106 cells, 30 min, 37 °C) then washed three times with PBS before adding BrdU-free medium. Cells were harvested by trypsinization at 0, 3, 5, 7, and 9 h, fixed with ice-cold ethanol (30 min, 4 °C), incubated in 2 M HCl [30 min, room temperature (RT)], and neutralized with 0.1 M sodium tetraborate, pH 8.5. Cells (106/ml) were resuspended in PBS-BT (PBS, 1 % bovine serum albumin [BSA], 0.5 % Tween 20) and incubated with 20 μl anti-BrdU-FITC antibody (Becton–Dickinson, San Jose, CA; 45 min, RT). After washing with PBS-BT, cells were resuspended in PBS-BT containing 5 μg/ml PI and 100 μg/ml RNAse A (1 h, 37 °C). Finally, the percentage of BrdU-containing cells and DNA content were analyzed by flow cytometry.
Proteasome inactivation
BLM-SOCS1 or control cells were incubated in complete medium with 10 μM MG132 (Sigma Aldrich, 4 h, 37 °C) prior to lysis and evaluation by Western blot.
Western blot and antibodies
BLM-SOCS1 and control cells (2 × 107cells) were lysed, and the lysates were electrophoresed and analyzed in Western blot, as described [42]. Anti-SOCS1 (ab9870), -NEK2 (ab55550) and -securin (DCS 280) antibodies were purchased from Abcam (Cambridge, UK), anti-Cdc20 (H-1759), -p53 (FL-393), -ERK1 (C-16) and -ERK2 (C-14) were from Santa Cruz Biotechnology (Santa Cruz, CA), anti-cyclin D3, -cyclin E, -CDK1-4 and –p19ARF were from BD Transduction Labs (Cell cycle sampler kit I; San Diego, CA), anti-Cdh1 (DH01) was from Thermo Scientific (Fremont, CA), anti-phospho-p53 (16G8) from Cell Signaling (Danvers, MA), anti-cyclin B1 (GNS-1) and -Aurora A from BD Pharmingen (San Diego, CA) and horseradish peroxidase-conjugated secondary antibodies from Dako (Glostrup, Denmark).
To determine Cdh1 ubiquitination, BLM cells transfected with SOCS1 or cotransfected with SOCS1/Cdh1/HA-ubiquitin or with Cdh1/HA-ubiquitin. Cells were lysed using a detergent buffer (20 mM triethanolamine pH 8.0, 300 mM NaCl, 2 mM EDTA, 20 % glycerol, 1 % digitonin with 10 μM sodium orthovanadate, 10 μg/ml leupeptin, and 10 μg/ml aprotinin) 24 h after transfection, immunoprecipitated using anti-Cdh1 or -HA mAb (HA.11; Covance, Princeton, NJ) and analyzed by Western blot with anti-Cdh1 mAb. In the case of anti-Cdh1 immunoprecipitates, the blot was developed using ExactaCruz E reagent (Santa Cruz Biotechnology) following the manufacturer's protocol.
BLM-SOCS1, BLM-Cdh1, BLM-SOCS1/Cdh1 or control cells (3 × 104 cells/well) were plated on collagen-coated coverslips (20 μg/ml, 1 h, 37 °C, Sigma-Aldrich) and cultured (48 h, 37 °C). Cells were washed in cold PBS, fixed with 4 % paraformaldehyde (10 min, RT) and permeabilized with 0.2 % Triton X-100 in PBS (10 min, RT). To avoid non-specific binding, cells were treated (1 h, RT) with PBS containing 1 % BSA, 0.1 % goat serum, and 150 mM NaCl. Cells were stained with anti-tubulin (30 min, RT, Sigma-Aldrich), -cyclin B1 (30 min, RT) or -p-histone H3 (Ser 28) antibodies (1 h, RT; Millipore, Bedford, MA), followed by Cy5-goat anti-mouse or -rabbit IgG (30 min, RT; Abcam, Cambridge, UK). After washing, cells were mounted with Vectashield medium containing DAPI (Vector Laboratories Inc., Burlingame, CA). Fluorescence was evaluated on an Olympus IX81 laser-scanning confocal microscope.
Measurement of CDK1 activity
BLM-SOCS1 and control cells (2 × 107) were lysed, and lysates were centrifuged and processed as described [43]. Briefly, we incubated 900 μg protein with 3 μl anti-cyclin B1 mAb (3 h, 4 °C), followed by protein A. For the kinase reaction, immunoprecipitated protein was added to 5 μg GST-H1 or cdc25 in kinase buffer. Phosphorylated GST-H1 or cdc25 were detected by SDS-PAGE and autoradiography.
FRET analysis
FRET was measured by photobleaching as described [44], using BLM cells transiently cotransfected with 0.5 μg SOCS1-CFP and 0.5 μg Cdh1-YFP, with 0.5 μg SOCS1-CFP and 0.5 μg Cdc20-YFP or with 0.5 μg Cdc20-CFP and 0.5 μg Cdh1-YFP constructs to assure a 1:1 YFP:CFP ratio. Cells (5 × 104 cells/well) were cultured in coverslip chambers (Nunc) precoated with collagen VI (20 μg/ml, 60 min, 37 °C), and 48 h after cDNA transfection, imaged on an Olympus IX81 microscope with a PLAPON 60X03 objective (aperture 1:40) and FV10-ASW 1.6 software. FRET efficiency was calculated from three independent experiments using at least 50 images from each.
Statistical analysis
Statistical analyses were performed using Student's two-tailed t test. For FRET analysis, statistics were obtained using Graph Prism 5.0 software (GraphPad). We used non-parametric t test to compare two subject groups and two-tailed Mann–Whitney U test for correlation analysis. Data are given as mean ± SEM (***p < 0.001).
SOCS1 protein expression by human melanoma cells inhibits their in vitro and in vivo growth
We tested the effect of SOCS1 expression on in vivo melanoma cell growth. BLM cells expressing SOCS1 (BLM-SOCS1) or mock-transfected (control) were injected i.d. into nude mice, and tumor growth was analyzed over a 25-day period. SOCS1 expression also inhibited in vivo BLM cell growth (Fig. 1c). Whereas 50 % of BLM-SOCS1 cell recipients did not generate a solid tumor, the remaining 50 % showed a smaller tumor area than controls (at 25 days, mean ± SD = 31.5 ± 2.8 mm2 vs. 65.1 ± 4.1 mm2, respectively; Online Fig. 1). The data indicate that SOCS1 expression blocks both in vitro and in vivo expansion of melanoma cells.
SOCS1 expression disrupts human melanoma cell cycle transitions at G1/S and G2/M
To analyze G2/M in detail, we synchronized cells in early M phase using the microtubule polymerization inhibitor nocodazole. In agreement with a slow G1/S transition, nocodazole treatment was less effective for the accumulation of BLM-SOCS1 cells in mitosis when compared to mock transfected controls (37 % ± 3.6 for BLM-SOCS1 vs. 80 % ± 10.0 for controls at time 0 h; Fig. 3b, Online Fig. 3). Nonetheless, part of BLM-SOCS1 cells accumulated in mitosis. In contrast to arrested control cells, which resumed mitosis and passed to G1/S after nocodazole release, cell cycle distribution of arrested BLM-SOCS1 cells did not change significantly after nocodazole release (Fig. 3b, Online Fig. 3), again indicating a G2/M arrest of BLM-SOCS1 cells.
To exclude interference from the G1/S transition, we analyzed the population of cells that were actively progressing through S phase. Briefly, BLM-SOCS1 or control cells were incubated in medium with 10 mM BrdU for 30 min, and subsequently chased in BrdU-free medium for the indicated time. In agreement with a defect in S phase entry, BLM-SOCS1 cells were labeled less efficiently with BrdU (Online Fig. 4). A comparison of BrdU-positive cells however showed an increased accumulation of BLM-SOCS1 cells in G2/M after a 9 h chase period (55 % ± 3.7 vs. 26 % ± 4.7 for controls) (Fig. 3c), confirming the additional defect in G2/M. These data confirm that SOCS1 expression inhibits G1/S and, as a secondary barrier, blocks the G2/M transition in human melanoma cells.
SOCS1 expression in human melanoma cells alters protein levels of G1 phase regulators
G1/S arrest similar to that observed here was reported in hepatocellular carcinoma cells treated with a JAK inhibitor, and was associated with reduced STAT3 activation [46]. In other studies, however, STAT3 activation is associated with cell cycle arrest [22]. Since SOCS proteins are involved in the regulation of the JAK/STAT pathway [47], we used Western blot to evaluate the effect of SOCS1 on JAK/STAT activation in BLM cells. As indicated for several tumor cell types [48], BLM cells showed constitutively active JAK2/STAT3. SOCS1 expression triggered a marked reduction in p-JAK2 and p-STAT3 (Fig. 4b). Total JAK2 and STAT3 protein levels were nonetheless similar in BLM-SOCS1 and control cells. Our results show that SOCS1 expression in melanoma cells alters cyclin D and cyclin E levels and increases p19ARF and p53 expression, thus inhibiting G1/S transition. In accordance with previous reports, these results show that SOCS1 can regulate an excessive cytokine response, not only by blocking the JAK/STAT pathway directly but also by inducing p53-dependent cell cycle arrest [24].
SOCS1 expression by human melanoma alters protein levels of M phase regulators
M phase depends on the activation of individual proteins, which are successively degraded as mitosis progresses [49]. To further evaluate the SOCS1-induced blockade of M phase, we used Western blot to analyze BLM-SOCS1 and control cell lysates with mAb specific for mitotic markers. Compared to controls, BLM-SOCS1 cells showed nearly complete absence of NEK2 (Fig. 5c), which is degraded early in mitosis [36]. In contrast, we observed accumulation of proteins that are normally degraded in the metaphase-to-anaphase transition [49], such as securin and cyclin B1 (Fig. 5c). Proteins levels of Aurora A, a protein kinase degraded late in mitosis [50], showed no alterations (Fig. 5c). To test whether cyclin B1 accumulation altered the activity of its associated kinase CDK1, BLM-SOCS1 and control cell extracts were immunoprecipitated with anti-cyclin B1 mAb, and the activity of associated CDK1 was determined in an in vitro kinase assay using cdc25 and histone 1 (H1) as substrates. The results showed that CDK1 immunoprecipitated from BLM-SOCS1 was more active than that from controls (Fig. 5d). Taken together, these data show that SOCS1 expression in BLM cells results in metaphase arrest.
SOCS1 expression alters M phase protein levels through Cdh1 degradation
To test whether SOCS1 can target Cdh1 for degradation, we evaluated association between SOCS1 and Cdh1 using fluorescence resonance energy transfer (FRET) photobleaching. BLM cells were transiently transfected with Cdh1-YFP and SOCS1-CFP, with Cdc20-YFP and SOCS1-CFP or with Cdc20-CFP and Cdh1-YFP as control, and FRET was determined by confocal microscope. We confirmed that the transfection ratio corresponded to equivalent (1:1) protein expression levels using specific mAb in Western blot as well as individual measurement of YFP and CFP fluorescence. Heterodimeric complexes between Cdh1 and SOCS1 were detected specifically at the nucleus (FRET efficiency: 11.62 ± 0.94), while no significant interaction was detected between Cdc20 and SOCS1 (FRET efficiency: 2.70 ± 0.57) or between Cdc20 and Cdh1 (FRET efficiency: 1.44 ± 0.51) (Fig. 6c, d). Our data show direct and specific association between SOCS1 and Cdh1 in the nucleus, consistent with a role for SOCS1 in the degradation of this APC/C cofactor.
Finally, untreated or MG132-treated BLM-SOCS1 cells were lysed and cell extracts immunoprecipitated using anti-Cdh1 mAb. Western-blot analysis with the same mAb revealed a laddered pattern typical for protein ubiquitination in cells treated with the proteasome inhibitor (Fig. 6e). We lysed MG132-treated BLM-Cdh1/HA-ubiquitin or BLM-SOCS1/Cdh1/HA-ubiquitin cells and immunoprecipitated the extracts with anti-HA mAb. Western-blot analysis of these immunoprecipitates with anti-Cdh1 mAb verified the presence of ubiquitinated Cdh1 in MG132-treated cells, which increased when SOCS1 was coexpressed (Fig. 6f). These results confirmed that, through interaction with SOCS1, Cdh1 is ubiquitinated and degraded by the proteasome.
Several lines of evidence point to a role for SOCS1 as a tumor suppressor. SOCS1/IFNγ–deficient mice are more susceptible than normal mice to T lymphoid leukemia, probably due to the activated state of T lymphocytes in the absence of SOCS1 [10]. Human tumor cells have developed mechanisms to prevent SOCS1 expression, which endows them with a greater capacity for proliferation and resistance to apoptosis [13]. Loss of SOCS1 results critical for enhanced invasion and angiogenesis of melanoma cells [12], and SOCS1 hypermethylation predicts progression of malignant melanoma [7]. Here we used several SOCS1-negative human melanoma cell lines (BLM, MeWo, HT-1080 and UACC-257) to show that SOCS1 expression regulates their proliferation both in vitro and in vivo. Although tumor suppression by SOCS1 is well documented, the mechanisms by which SOCS1 prevents cell proliferation remain largely unknown. SOCS1 was initially identified as a negative regulator of cytokine signaling and the JAK2/STAT3 pathway [54, 55]. SOCS1 is expressed as a response to JAK2/STAT3 activation and participates in a negative feedback loop, limiting membrane receptor phosphorylation and JAK2 activity [54, 55]. Although SOCS1 is thought to contribute to tumor suppression by inhibiting a constitutively active JAK2/STAT3 pathway in hepatocellular carcinoma and other carcinomas [6, 11, 13], other studies associate activation of the JAK2/STAT3 pathway with cell cycle arrest [22, 23]. Thus, although the JAK2/STAT3 pathway appears to have tumor-promoting and -suppressing effects, SOCS1 expression is consistently suppressed in a wide variety of tumors including melanoma [12]; these findings suggest that SOCS1 has a JAK2/STAT3 pathway-independent role in tumor suppression.
Using a combination of cell synchronization experiments and SOCS1 expression, we show here that SOCS1 inhibits cell cycle progression at the G1/S transition and in mitosis. We observed decreased expression of cyclins D and E, both needed for activation of G1-associated CDK (CDK4/6 and CDK2, respectively). In addition, we found accumulation of p19ARF. SOCS1 target proteins JAK2 and STAT3 can promote G1/S progression through expression of cyclins D and E [56]; conversely, JAK2/STAT3 inhibition in tumor cells is linked to G1/S blockade and downregulation of cell cycle molecules such as cyclin D [57, 58]. In BLM melanoma cells, SOCS1 overexpression also suppressed JAK2/STAT3 activation and correlated with decreased levels of cyclin D3 and E, suggesting that G1/S blockade in our model follows the JAK2/STAT3 pathway. As shown in Cdh1-deficient cells [59], we not only found reduced cyclin E levels reminiscent of a suppressed JAK2/STAT3 pathway but also detected increased levels of the Mdm2 inhibitor p19ARF and the Mdm2 target p53 [45] in BLM-SOCS1 cells; a p53-dependent mechanism has been implicated in cell senescence [24] indicating that it might also participate in the G1/S blockade we observed.
Our data show that SOCS1 expression also affected M phase progression, and arrested cells in metaphase. No JAK2/STAT3 pathway involvement has thus far been reported in mitosis. Visual inspection of BLM-SOCS1 cells indicated metaphase blockage, which was subsequently confirmed by analysis of mitotic markers. The main protein complex involved in mitotic progression is the APC/C, which targets substrate proteins for ubiquitination and subsequent destruction by the proteasome [49]. The APC/C undergoes complex regulation through its association with Cdc20 or Cdh1, and through checkpoint-dependent phosphorylation [60]. SOCS1 targets Cdh1 in BLM cells; our FRET analysis showed that SOCS1 specifically associated with Cdh1 but not Cdc20. As a result of this association with SOCS1, Cdh1 was ubiquitinated and degraded by the proteasome. Hence, SOCS1 expression lowers Cdh1 but not Cdc20 levels in BLM cells. Since Cdc20 is a target for the ubiquitin ligase activity of APC/C-Cdh1 complexes [31], SOCS1-mediated Cdh1 degradation might account for Cdc20 accumulation. In accordance with a role for SOCS1 in Cdh1 degradation, cells from mice lacking Cdh1 show proliferative defects and mitotic block reminiscent of BLM-SOCS1 cells, as well as increased Cdc20 levels [59].
Although Cdh1-deficient cells have been analyzed before [59], the exact nature of the cell cycle blockade in these cells is not completely understood. Mitosis is governed by an APC/C-driven feedback loop, in which metaphase-to-anaphase transition is a crucial step [61]. Progression from metaphase to anaphase involves securin degradation, which allows for separase activation, cohesin ring degradation and finally, sister chromatid separation [25]. Correct transition from metaphase to anaphase also requires CDK1 inactivation through degradation of cyclin B1 [26]. In SOCS1-expressing BLM cells, lack of Cdh1 prevents cyclin B1 degradation, resulting in the metaphase arrest observed. This cell cycle transition is blocked following expression of constitutively active CDK1 [61], which maintains inhibition of APC/C-Cdc20 without Cdc20 degradation [35]. These data indicate that in BLM-SOCS1 cells, the cyclin B1/CDK1 complex sustains metaphase and prevents APC/C-Cdc20 activation. Simultaneously, the APC/C continues to degrade substrates that do not depend on mitotic checkpoints, such as NEK2 [36, 62]. NEK2 degradation might also interfere with mitosis progression in BLM-SOCS1 cells, since recent reports suggest a role for NEK2 in abolishing MAD2-Cdc20 control of the metaphase checkpoint [63]. Finally, destruction of targets late in mitosis, including Aurora A and Cdc20 itself, again depends on Cdh1 [31, 40]; Cdh1 degradation and metaphase blockade nonetheless prevent BLM-SOCS1 cells from reaching this stage. The combination of markers indicates that Cdh1 is the main SOCS1 target in mitosis and explains why SOCS1 overexpression causes accumulation of cells in metaphase. In accordance with these results, we observed that simultaneous expression of Cdh1 overcame the effect of SOCS1 on BLM cells, and mitosis was partially recovered.
Our results show direct interaction between SOCS1 and Cdh1, SOCS1-mediated Cdh1 ubiquitination, and a relationship between SOCS1 expression and Cdh1 downregulation. These findings indicate a role for SOCS1 in Cdh1 degradation. Since SOCS1 expression is partially regulated by JAK2/STAT, SOCS1 provides a link between this pathway and cell cycle progression. Although most of BLM-SOCS1 cells showed G1/S blockade, we detected additional defects in M progression, suggesting that SOCS1 expression establishes two barriers to cell transformation. The methylation status of the SOCS1 gene promoter might explain the divergent effects on cell proliferation observed in different models of JAK2/STAT3 activation. Our data show that SOCS1 has an important function in the control of human melanoma cell cycle progression and indicate that it should be considered in the design of strategies for human melanoma therapy.
We thank Dr. J. Teixidó for BLM cells, T. Wilson for the pEF-FLAG-I/mSOCS1 construct and J Zalvide for the pcDNA3.1-HA-ubiquitin construct. We also thank C. Bastos and C. Mark for secretarial and editorial assistance, respectively. VP receives a postdoctoral fellowship from the Fundación Sandra Ibarra de Ayuda contra el Cáncer. KvW is financed by a JAE-doc fellowship of the Spanish National Research Council (CSIC). This work was supported by the Fundación Sandra Ibarra de Ayuda contra el Cáncer, the Fundación Genoma España (MEICA), the European Union (Innochem LSHB-CT-2005- 518167; FP7 Integrated Project Masterswitch no. 223404), the Spanish Ministry of Science and Innovation (MICINN; SAF2008-02175; SAF 2011-27370; SAF-2007-63624) and by the Spanish Instituto de Salud Carlos III (ISCIII) RETICS Program (RD08/0075 RIER; RD07/0020).


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Vivica A. Fox Reveals Her 'Alter Ego' Makeover
We've seen him transform the Real Housewives of Atlanta and Michelle Willams and now celeb photographer Derek Blanks turns his camera on actress Vivica A. Fox. For her theme the foxy actress goes for the glam and gory. On one side she is an angel. On the other she is a fire-walking blood-curdling vamp. In the behind-the-scenes video Fox is so in character it's clear the bad girl in her is all about raising hell.
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- If you take this option you pay only interest in the first three to six months of your loan.
- For the remainder of your loan you will pay both interest and principal to settle the balance.
- Yes, we use our technology to search a vast amount of data before we approve your loan.
- With your permission we use leading Credit Reference Agencies to check your business and personal credit reports.
- Yes. We only charge interest up until the day you settle.
- We have no hidden fees or charges.
- Our loans are provided quickly, and are not secured by any collateral.
- Customers appreciate the speed and flexibility this offers.
- We deal with small businesses in which owners have a personal stake and believe in their future success, so directors should not have any problem with personal guarantees.
- We believe that a combination of high-tech and high-touch allows us to make more informed decisions.
- Though we do not have a banking relationship, we do review the customer's bank statements, as cash flow and financial management are also important risk factors.
- Our ability to provide the loan is reinforced by the backing we receive from major private equity investors.
Naturally, returning customers who were good payers will be eligible for a lower rate on a new loan.
There are absolutely no obligations, and no application fee. Once you have received approval, you can decide whether or not to proceed.
- For the PAYT product: We will agree upfront a daily percentage of your Visa and MasterCard sales transactions – and this will be automatically deducted by the processor. So the payment will fluctuate directly in proportion with your daily card sales.
- For the term loan product: We collect payments via a monthly direct debit. We also accept bank transfer, debit card and PayPal if you wish to make additional payments at any time.
- We practice ethical and responsible lending at all times, and provide loans only to those businesses deemed able to repay.
- However, we are aware that not every eventuality can be foreseen. If you find you are struggling to repay on time, speak to your account manager (0800 8488480), who will help you find a way forward.
Don't despair. If your business circumstances change even slightly after a few months, give us a call and we will re-evaluate.
Yes, providing you have met your payments on time and your business continues to perform.
- Yes. We will renew your loan as soon as you like, providing your business continues to perform.
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text:
Herds suffering long-term bovine tuberculosis (bTB) breakdowns are to be considered for a more tailored and hands-on management approach in partnership with farmers' private vets.
According to the Animal Health Veterinary Laboratories Agency (AHVLA), the plans to become a "standard business as usual activity" in both England and Wales, follows feedback from stakeholders and recognises a "more proactive approach" is necessary to combat the disease.
From yesterday (February 3, 2014), herd breakdowns lasting more than 18 months will be subject to what the agency calls "enhanced case management procedures" aimed at helping herd owners regain official bTB-free status, while reducing the risk of future breakdowns.
This approach seeks to:
- enhance support for cattle keepers;
- identify and deal with the factors causing persistent infection;
- reduce risks posed to contiguous premises;
- reduce the impact on farming businesses and general taxpayers;
- monitor and review the effectiveness of measures applied; and
- use the skills and knowledge gained to inform management of future breakdowns.
According to the agency, the farms chosen to take part may be based on:
- number of reactors and compensation costs;
- results of postmortem examinations;
- length of breakdown;
- herd size and dynamics including movement volumes;
- herd or business history; and
- local epidemiology.
Trained AHVLA veterinary officers will be assigned to each case and are to consider a number of issues to determine their approach, including internal movement controls, test interpretation, testing patterns, trading options, support from others, such as the South West TB Farm Advisory Service and The Farming Community Network, and epidemiological support work.
Official vets will be consulted for local knowledge and herd health issues that may be of significance, said the AHVLA. They will also be invited to attend an on-farm meeting, for which they will be paid.
The agency is to measure the success of these enhanced actions, it said, by pairing herds for epidemiological comparison, as well as carrying out farmer questionnaires, quantitative measures and internal case reviews.
For more information, visit the AHVLA's website.


text:
Aberdeen Caledonian Thistle Celtic Dundee Hamilton Academical Hearts Kilmarnock Motherwell Rangers Ross County St Johnstone
Aston Villa Barnsley Birmingham City Blackburn Rovers Brentford Brighton & Hove Albion Bristol City Burton Albion Cardiff City Derby County Fulham Huddersfield Town Ipswich Town Leeds United Newcastle United Norwich City Nottingham Forest Preston North End Queens Park Rangers Reading Rotherham United Sheffield Wednesday Wigan Athletic Wolverhampton
LINE-UPS: Andy Carroll on the bench for West Ham as Newcastle visit Upton Park
WEST HAM striker Andy Carroll only starts on the bench against his former side Newcastle United.
The former Toon striker has only just returned from injury and manager Sam Allardyce wants to bring Carroll up to match fitness slowly.
Newcastle name an unchanged side from last Sunday's defeat againt Manchester City.
West Ham: Adrian, Jarvis, Rat, Collison, Taylor, Noble, Collins, Diame, Downing, C.Cole, Johnson
Subs: Jaaskelainen, Carroll, Maiga, Morrison, Diarra, J.Cole, Chambers
Newcastle: Krul; Santon, Williamson, S.Taylor, Yanga-Mbiwa; Tiote , Anita, Cabaye; Sissoko, Remy, Gouffran.
Subs: Elliot, Haidara, Dummett, Obertan, Ben Arfa, Shola Ameobi, Cisse


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text: INDIANAPOLIS, Nov. 18, 2013 /PRNewswire/ -- Cialis is turning 10. As Cialis marks its 10 th anniversary this week, Lilly is looking back on the last decade in men's health. Conversations that used to be taboo for men are now taking place in bedrooms and exam rooms. Men with conditions like erectile dysfunction (ED) are talking more openly with their partners and their physicians. 1 Part of this evolution was the U.S. approval of Cialis for use as needed (5 mg, 10 mg, and 20 mg) on November 21, 2003, as the first and only oral ED medication that can work for up to 36 hours.* In the time since, Cialis has grown to become global share-of-market leader in sales among PDE5 inhibitors. 2 "Witnessing the evolution of Cialis since it entered the market 10 years ago, and the positive effects it continues to have on the treatment of erectile dysfunction, has been exciting," said Dr. Edward Kim, urologist, The University of Tennessee Medical Center. "Many of my patients have commented that the 36-hour dose and the daily dosing option have enabled them to become intimate without worrying about timing sexual activity around taking a pill. As an investigator and prescribing physician, I have been fortunate to participate, first-hand, in the evolution and development of this noteworthy pill for the treatment of ED." It is important to note that Cialis is not to be taken with medicines called "nitrates" such as isosorbide dinitrate or isosorbide mononitrate, which are often prescribed for chest pain; or with recreational drugs called "poppers" like amyl or butyl nitrite, as the combination may cause an unsafe drop in blood pressure. Since that first FDA approval, Cialis has been approved for once-daily use (2.5, 5 mg,) for ED, and for the signs and symptoms of benign prostatic hyperplasia (BPH), offering men the first and only single treatment option for two common urological conditions – ED and the signs and symptoms of BPH (Cialis 5 mg for once daily use).


text:
I Recomend this place Highly for their Professionalism, Honesty and ex... read more I Recomend this place Highly for their Professionalism, Honesty and excellent work performed and real Reasonable prices on their work. They are very friendly and hospitable. I had hit a deer with my truck (Silverado) and was expecting to spend alot more than the estimate that was coming out of my pocket with just basic insurance coverage. They made the truck look show room new again and its a 2002. I was expecting the repairs to take about two weeks, but they had it done in two days and looking great again. They are excellent at their work. The wife like the job they done, that she decided to get her windshield replaced this coming weekend. They also gave her a good price on it from what she was quoted from another shop a few months earlier. Overall they are a Down Home small city great place to do business with and will have my business when ever needed in the future along with anybody that needs a recommendation of a good shop, they will always get a thumbs up and a 5 star rating. Thanx Cory and L & S for a job well done
Steve got in there (200+ screws later through the dashboard) to fix wh... read more Steve got in there (200+ screws later through the dashboard) to fix what we thought was the heater core and he saw that it was something else and he fixed plus suggested we get the plugs changed while he had it open to save some major $$. I have known for a while we needed to get those changed (put it off as it was too expensive) but did not even think about it until he said something. Thanks for taking care of us and even offering to drive our finished van back to Bellevue as a courtesy. Also, a LOT cheaper quote (by far) than any other place I called on this. Definitely recommending you.
I have nothing but praise for the team at Cool Springs Collision for t... read more I have nothing but praise for the team at Cool Springs Collision for the repairs done on my car. The paint was near factory perfect and I couldn't visually discern that the car had ever been in an accident. I received excellent customer care and friendly service and would highly recommend this shop to anyone wanting first class service and repair to their car.


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New Braunfels Herald Zeitung (Newspaper) - January 11, 1996, New Braunfels, Texas Herald-Zeitung □ Thursday, January 11,1996 □ 5 Sports Day ■ To talk with Sports Editor Thomas Godley about Sports Day, call 625-9144. ext. 24. Herald-ZeitungSports Day rn. 'n The Press "One of the big issues is Jimmy has to shave his head." — Miami Dolphins owner Wayne Huizenga, joking to reporters about negotiations with Jimmy Johnsons and his contract as the team's new head coach. In the news Seguin Sidekicks open 1996 soccer season The Seguin Sidekicks soccer team will have tryouts for boys ages 12 and under on Saturday, Jan. 13 and Sunday, Jan. 14 from 2 p.m. to 4 p.m. at Seguin High School practice field on E. Court St. Registration begins at 1:30 p.m. for both days. The sessions are open to youth born between Aug. 1,1983 and July 31,1985. Players under the age limits may try out for the team. Anyone interested should be accompanied by a parent or guardian at the sessions to sign the necessary release form or pick one up in advance at Seguin Alternator, GBRA or Vivroux Sporting Goods. Players must wear shorts, soccer shoes and shin pads. Bring a soccer ball and No. 4 soccer ball. The Sidekicks Board approved the new team at the December meeting, and also approved Ken Kiel and Kenny Kykes as coaches for the team. After the spring league, the coaches and sidekicks board will evaluate plans for an additional team in the fall for boys under the age of 14. Seguin Sidekicks team was formed in 1994 to encourage player development through training and competitive play For more information, call Kiel at 327-3569, Dykes at 372-5356 or Rossi Flores Baseball practice sessions offered to local players Baseball players ages nine to 18 can sign up for practice sessions scheduled to begin March 1 at Home Run Batting Cages, 1563 Gruene St. in Gruene. The practices — which will provide quality instruction on hitting, fielding, throwing and game rules — will be led by Jim Pace and his staff. Pace, a successful coach and former semi-pro player, is a current college and high school umpire with 30 years of experience. The sessions are scheduled for after school and weekends. The cost is $15 per half hour All equipment will be furnished but players may bring their own. For more information, call Pace at 609-6676. CYO track to have sign-up The Catholic Youth Organization will be taking registration for track for youths (boys and girls) ages 4 to 17 on the following days and times: Saturday, Jan. 13 from 9 a m. to 12:30 p.m. Sunday, Jan. 14, from 8:30 a.m. to noon. All registrations will be held in front of Sts. Peter and Paul Catholic Church, 386 N. Caste!!, New Braunfels. While the CYO is a Catholic organization, all sports programs sponsored by the CYO including track, softball. basketball and soccer are open to all young boys and girls of the community. The CYO athletic programs have been developed to provide sports activities to local youth. For more information, call Anthony Klar, president of the CYO, at 609-1694 NB Youth Soccer kicks off The New Braunfels Youth Soccer club wit hold tryouts for the spring season at 9 am, Jan. 13 at HEB Soccer Fields on Live Oak Street. Players ages IO to 18 are invited to compete for a spot on the team. Fall Blitz players do not need to try out. The Blitz program is a paid professional training program with a staff of four outstanding trainers. Player development is the cornerstone of the program and BLITZ players are noted for having better skills than their opponents Recent UIL rule changes now allow high school soccer players to participate in the Blitz training which runs from Jan. 15 to May * 15. The progam has flexible times to help fit with players' schedules. The make up day is Jan. 20 at 9 a m. at the HEB Soccer Fields. For more information, call Steve Norris at 625-3734 for more information.Comal soccer delves into ^96 season NBHS set to defend district championship By THOMAS GODLEY Sports Editor High school soccer in District 52 has ranked among the best in the state during the past decade. This season is no exception. Two years ago the New Braunfels Unicorns boys' soccer team showcased the kind of talent emerging from Comal and surrounding counties. The Unicorns journeyed through the state playoffs, knocking off perennial 5A powers San Antonio McArthur, Klein and Tyler John Tyler en route to the 1994 state championship. A year later New Braunfels and Canyon met in the sectional round of the playoffs. The Cougars made it there by beating San Marcos and upsetting top-ranked Westlake. New Braunfels reached with a win over Georgetown. In the showdown of local crosstown rivals, the Cougars won I -0 and advanced to regional qualifying round against San Antonio Churchill. Tapping into a deep pool of club players, (more than 1,000 players signed up for local youth soccer programs last year) District 52 figures to field an equally strong group of teams vying for the 1996 title. At the front of that pack once again is New Braunfels. The Unicorns are ranked 10th in the area (the only Class 4A team in the poll) and have eight starters returning from a squad which finished in first place in district with an 18-4-1 record. Though the Unicorns lost Omar Hernandez and goal-keeper Matt White, NBHS coach Bob Rodriguez has plenty of club players back to carry out his ball-control, pass-oriented system. Marco Sanchez, Clif Steagall and Kyle Reneau hold down the midfield positions. Travis Baker, Sid Gosa and Michael Kawazoe are skilled defenders. Josh Motz and Stephen Rodriguez (out with a leg injury) are solid scorers at the forward spots. Andy Holtman has proven strong in the midfield and Bradley Brandenburg will replace White at goalie. Freshman transfer Joe Burke brings depth to the roster. "We've got a solid group of juniors and . seniors," Rodriguez said. This year we should be a more balahced team. I'm very optimistic about our chances. Barring any injuries, we should be in good shape to make a run to the playoffs." Rodriguez noted that Alamo Heights and Clemens are vastly improved and prepared to challenge for the district title. Canyon coach Danny Bueno is the first to say 1996 will be a rebuilding year for his Cougars. The team lost 11 seniors to graduation, and three other starters opted not to play soccer this season. Without scoring leader Vince Bueno, Canyon faces an uphill battle to keep alive its string of three consecutive trips to the playoffs. "We are very young," Bueno said. "But the potential is there. If we can continue to improve, then we might have a chance to get in to the WE' Canyon embarks on girls soccer program BY THOMAS GODLEY Sports Editor Kickin' in the new season Above, the New Braunfels boys soccer team is favored to defend their District 52 championship title. Left, Canyon High School begins its first years of girls soccer. The school hired Steve Zimmerman to take over as the new head coach. - *nr—Mala'"" —: ~ .. Herald-Zeitung photos by MICHAEL DARNALL playoff. It's going to be a very tough district The seniors we lost had been to the playoffs three years in a row." Though inexperienced, the latest group of Cougars are ready to re-establish that playoff tradition. Eric Rodriguez comes in as a freshman sweeper. Mike Mechler, Leighton White, Stefan Rohach lake over as defenders. C.J. Czelusta, Paul Paniagua, Rene Lopez, Raul Rodriguez are midfielders. Adrian Armendariez and Chris White step in at forwards. Ian Schilling, a freshman, will be the goalie. Coming off the bench will be Kumiss Schmidt, John Schmidt and Mitch McNeil. Canyon finished third in distnct and reached the regional qualifying playoffs. The final score was 3-0 in favor of Lockhart, but none that seemed to matter because the Canyon Cougarettes had won the larger battle before the game. After a year of coordinating, CHS officials this fall finalized the hinng of a coach to take over the girls' soccer team in 1996. Coach Steve Zimmerman comes aboard with goals to put the program immediately on the right track. "The school, parents and players are very excited," said Zimmerman, who played soccer at St. Mary's University in San Antonio. "We have several girls who played club soccer so we should be competitive this season." Currently about 15 girls have signed up to play. This year's team includes: Melissa Sal-davar, Sophia Reynosa, Rosio DeLeon. Jenny Hawkins, Erin Ousley, Melissa Pipken, Lisa Parra, Nicole Garcia, Laurie Hiracheta, Casey Richardson. Susanna Stites, Angel Schodts, Amber Anderson, Julia Schmidt and Leslie Zunker. "The girls understand that it's going to take some time," Zimmerman said. "The main thing is that the program is established and from here on we can build toward getting better." The New Braunfels Unicorns enter the 1996 campaign with playoff experience. NBHS coach Joey Trevino's troops finished at 8-9-1 and went two games deep into the playoffs. The Unicorns will have IO returning starters, including: Barbara Martinez, Audre Aguirre, Shawn Lindsey, Jennifer Alford, Leah Alba, Summer Scheel, Cynthia Escobeda, Patty Jo Maxey, Laura Schultz, Heather Barker and Kristi Hull. "We're a lot better off than last year," Trevino said. "There's a lot of talent back, and the girls have a better understanding of the game. That maturity should help us out in close games. I think we are capable of going further in the playoffs." The Smithson Valley Rangers head into their second season in District 52. New coach Kate O'Reilly brings three years of experience from South San Independent School District. The Rangers opened with two 1-0 wins in scrimmages against Marble Falls and McCollum. On Tuesday, they lost to Austin 4-0, but O'Reilly is confident the Ranger will improve on their 2-11-2 season in 1995. Returning starters are Haley Adcock, Cambry Clark, Kelly Naim, Kelly Roberts (goalie) and Bethany Welch. Dawn Gibson, Jenny Kuhn, Roberta Legg. Tara Mahoney.Jill Rust and Ori-an Thompson round out the starting lineup. Elizabeth Bell, Jennifer Brended Lauren Jenkins Lauren Ramsey, Michelle Ritchey and Diane Zuniga." "We are a very young," O'Reilly said. "We will have three freshmen starting this season. Our goal is be a controlled passing team. I think by district we should be competitive " Offensive shutdowns cost Rockets two games By MICHAEL A. LUTZ AP Sports Writer HOUSTON (AP) — The Houston Rockets have had terrible short circuits in two of their last three games, both against top teams in televised games. Is there a pattern here? The Rockets hit only three of their first 18 shots in Tuesday night's 88-82 loss to San Antonio. They were I-for-11 from 3-point range in the first half and finished 4-for-26. Sam Cassell, the Rockets' clutch shooter, was 0-for-5 on 3-pointers and Robert Horry was O-for-6. The Rockets were held to a season-low 34.8 percent shooting from the field and lied a season low with 82 points. Coach Rudy Tomjanovich was amazed at his team's ineptitude on the offensive side. "We missed layups and outside shots," Tomjanovich said. "We were just hoping somebody could break out of it and hit a three. You have to give our defense credit for holding a high-powered offense like they have to under 90 points." But the Rockets couldn't find the basket. It wasn't because they didn't get good shots. "If we didn't have open shots, you'd have to worry," Tomjanovich said. "But we were getting good shots. We just have to keep working and those shots will fall for us." It was a repeat of the second quarter in Chicago on Jan. 3 when the Rockets hit I -for-15, going from a three-point lead to 17 points down at the half. Houston lost 100-86. Against the Spurs, who beat the Rockets for the second time this season, the Rockets wasted a solid defensive effort. The Spurs had only two field goals in the fourth quarter and still won with David Robinson in foul trouble. "Everybody struggled, but it's one of those situations where it doesn't really concern us," Mario Elie said. "It's all about hitting shots. In the NFL, a quarterback runs hot one week and cold the next. NBA glance Tuesday's Dames Charlotte 92. Toronto 91 New York 98 Boston 93 Orlando 92. New Jersey 84 Atlanta 104, Sacramento 88 San Antonio 88, Houston 82 Seattle 97, Milwaukee 92 Indiana 91, Dallas 84 L A. Clippers 106. Phoenix IOO L A Lakers 106, Minnesota 104 Golden State 109, Vancouver 103 Wsdnsiday1! Qames Boston 113, Sacramento 104 New Jersey 92, New York 79 Washington 98, Philadelphia 93 Chicago 113, Seattle 87 San Antonio 92, Cleveland 86 Denver 91, Vancouver 85 Portland 90, Miami 89 Atlanta at Toronto. 7pm ¥ X JL One bit, two bits... JAR Gymnastics All-star chaerlaad-ers took second place in the Senior All-Star division for their cheer/dance performance in the third annual San Antonio Spurs Chaerleading Competition. Cheerleading squads from all over the state competed in the event at the Alamodome. Th# JAR team looks to repeat their performance at the Texas State Cheerleading Competition in San Marcos on Jan. 20. The squad includes Holly Reynolds, Kellye Cunningham, Brittany Winzeter, Shannon Eichmann, Amber Jendrusch, Kristi Spencer, Tiffany Cries, Amanda Farrar, Cathy Stewart, Kristen Johnson Mid Autumn Fishbeck. Submitted photo Jones envisions Super Bowl without Jimmy Johnson By DENNE H. FREEMAN AP Sports Writer IRVING, Texas (AP) — lf the Dallas Cowboys win the Lombardi Tri>phy, owner Jerry Jones wants only his fingerprints on it Jones has chafed under the praise former coach Jimmy Johnson received for putting together a team that won back-to-back Super Bowls. There's a commercial from the past ihai told it all. Johnson was driving a car to the Super Bowl (hat passed a hitchhiking Jones on a dusty road without picking him up "I'd like to ck) lhat commercial over and I can tell you for dang sure I d he driving the car this lime," Jones said "I wouldn't mind somebody else getting that dust.'' Jones tries to downplay the fact he w ants to show Johnson he doesn't need him to win a Super Bowl But Jones said when he hired Barry Switzer, just about anybody could do John son's job. However, the Cowboys lost to San Francisco in the NFC title game last year They get another shot on Sunday in Texas Stadium against the Green Bas Pack ers. On Tuesday. Jones didn t wan! lo reveal all of his innermost feelings about w inning a Super Bowl withins his former Arkansas teammate. "I hear that talk and I guess its logical to relate to part of it," Jones said "But that s a small thing in comparison to winning the Super Bowl for everything ii winild mean "lf we win ii wiilioui Jimmy then you're not going to hear ilk* allude to ii or wink about ii Just having a chance to gel thai trashy again is all I need Johnson was in charge ol all the personnel nkvves and Jones tell hun he was left inn. particularly on draft day In Johnson's k*ok. he tells how Jones requested that the coach talk to him when the national JA' cameras were turned on in draft central so he could appear involved in ihe decision making ;
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text:
Isaiah 910's New York Debut - April 6-10, 2015. - Completed
tornado visited upon Columbia, MS on December 23, 2014. There was loss
of life and heavy damage to the town. In the aftermath of the storm Isaiah 9:10 became our mantra. I met the recovery team at Woodlawn
Church the day after Christmas. When I left Columbia that day
to drive back to West Monroe I thought to myself I had just seen the last
true pioneers. The only difference is they had smartphones and tablets - Tom
MalmayIsaiah 9:10 - The bricks are fallen down, but we will build with hewn stones: the sycomores are cut down, but we will change them into cedars.Intelligent Web Maps - Columbia, MS Tornado Dec. 23, 2014 - Click here VOX - What Instagram tells us about the Hong Kong protests, in one map - Full Article - Click hereThe fantastic map of Instagrams during the Hong Kong protests is
fascinating in its own right: it's a really clear way of showing both
the movement's human heart and its scope. But it also makes an important
point about the tactics of the protesters — specifically, one thing
they're doing right that a lot of other demonstrators do wrong. Tom Malmay, who runs a disaster planning group in Louisiana, used software from Geofeedia
to map and timestamp Instagrams from the Hong Kong protests. The result
is pretty amazing: a map that shows you when and where the photo was
taken. If you scroll photos by time using the tool at the bottom, you
basically get a historical on-the-ground tour through the protests: Intelligent Web Maps - Hong Kong Protests Click here


text: GREEN POWER: Canadian Context and International Developments SUMMERHILL GROUP MELISSA FELDER NOVEMBER 2002 OVERVIEW Overview of Green Power Canadian Context International Developments GREEN POWER: Benefits and Present Status Addresses air quality and additional environmental problems associated with the use of traditional fuel sources Supports diversity of supply and distribution of resources In Canada, non-large hydro renewables represent only 1.2 - 3% of the nation's electricity generation (Fig.), 3% growth forecast GREEN POWER: International Developments Electricity Structure in Canada GREEN POWER: Potential in Canada Potential in Canada is estimated to be significant: Current capacity: 3, 746 MW Achievable by 2010: 21, 360 MW GWh/a 100000 80000 60000 Ge o th e r ma l W in d 40000 Sma ll h y d r o Bio ma s s 20000 W av e Tid a l 0 Probe, 2002 0.0891 Biomas s 0.076 W ind, Cda 0.08 W ind, ON 0.1 Tidal Bar r age BC Hy dr o W av e ener gy , 1997 0.3 Solar PV , Natur al Gas 0.025 Nuc lear 0 0.02 Coal, ON Cda 0.05 Lar ge Hy dr o, Cdn $ pe r k W h GREEN POWER: Comparison of Generation Costs 0.35 0.29 0.25 0.2 0.15 0.113 0.06 0.08 0.03 GREEN POWER: Government Subsidies EUROPEAN ADVANCEMENTS, POLICY White Paper: Action Plan to double renewables' share of EU energy supply by 2010 (CTO, EU Directive) Germany: Feed-in tariffs for renewable energy (i.e. PV generators CDN 71 ¢/kWh in 1990s) Denmark: Tariffs & production tax credit – CDN 9.4 ¢/kWh Netherlands: World Wildlife Fund marketing campaign - increase customer base for green power by 40% over two years. 300 0 250 0 ~ 2500 MW MW 200 0 Installed wind generating capacity in Denmark (Probe, 2002) 150 0 100 0 50 0 0 1995 1996 1997 199 8 199 9 20 00 20 01 U.S. ADVANCEMENTS, POLICY National RPS: Calls for non-large hydro renewables to be 10% of supply by 2020 Production Tax Credit: Level is double that of Canada, extended duration ~ 1700 MW of windpower in 2001 State SBC: $ 135M – California Renewable Customer Credit State RPS: Texas – 400 MW by 2003; 951 MW in 2001 3000 Ex is ting Planned 2500 ~ 1700 MW Installed renewables capacity in Texas (Probe, 2002) Ins talled C a pac ity in MW W in d Lan dfill gas ( 19 MW ) 2000 So lar PV (1 MW ) Hy dro 1500 2 003 R P S G oal (1301 M W ) 1000 500 0 1 999 2 000 20 01 20 02 20 03 MELISSA FELDER firstname.lastname@example.com CANADIAN ADVANCEMENTS, POLICY Wind Power Production Tax Incentive: $0.012 /kWh, declines per annum by $0.001, short time frame. Favours specific renewable technology. Canadian Renewable and Conservation Expense (CRCE): Influential; however designed to underwrite feasibility studies, resource audits for new projects. Certification: EcoLogo product label. Federal Government Procurement: 20% of electricity from low and non-emitting sources; good example of demand-pull program however does not include other sectors GREEN POWER: Definitions Definitions vary across and within countries (Fig.) In Canada debate has centred around the role of hydro, biomass, biogas O nly new renew ables E ffic ienc y res ourc es C ogeneration M ine-bas ed m ethane H y drogen fuels Tire w as te D iges ter gas O c ean M unc ipal S olid W as te Landfill gas G eotherm al F uel c ell (no fos s il fuels ) N ew hy dro S om e hy dro (w ith or w ithout s iz e lim its ) W ind B iom as s S olar therm al S olar photovoltaic 0 5 10 15 20 N u m b e r o f S ta te s P e rm ittin g th is F u e l S o u rce 25


text:
|Property type
|Minimum Stay
Beautiful 2 Bedroom, 2 Full Bath Oceanfront condo located at Anderson Ocean Club
- Breathtaking views of the Atlantic Ocean from the 17th Floor, Corner Unit, Facing North
- Granite Countertops, Tile Floors, Crown Molding throughout
- Master Bedroom with (1) King-size Bed with Private Oceanfront Balcony
- Second Bedroom with (2) Full-size Beds with Private Balcony
- Living Room with a Queen-size Sleeper Sofa (with Private Oceanfront Balcony)
- Full Kitchen with Dishwasher and Coffee Maker
- (2) Full Bathrooms with Hair Dryers
- Washer and Dryer (inside the unit)
- Iron and Ironing Board
- (3) Flat Screen Televisions
- Non-Smoking
- (6) High Speed Elevators, Business Center, Fitness Center,
'Awakening' Full Service Day Spa, Full Service Nail and Hair Salon
Private Direct Beach Access
- Indoor Heated Pool, Indoor Heated Kiddie Pool,(1 ft), 12-person Indoor Hot Tub,
(2) Outdoor Pools, Outdoor Lazy Diver, Outdoor Hot Tub, Tiki Bar
- 1 mile from 'Broadway At The Beach'
- Walking distance to Minature Golf, Restaurants, Bars, Shopping
Keywords: Condominium
We are from NJ and fell in love with Myrtle Beach a few years ago. So many things to do for the kids (mini-golfing, pools, beaches, fishing, sightseeing, aquarium, minor league baseball) all within minutes.
The Owner purchased this condo in 2007
No other building like it in Myrtle Beach as far as design, view, location and high-end decor of the rooms.
You have the choice of walking straight out to the beach (private access) or staying and lounging poolside.
Floor plan and ocean view are good. Beds were very comfortable but living room furniture was not. Bed linens and towels were of poor quality. Unit needs deep cleaning .Would not stay here again.
This condo was absolutely perfect! All u need to bring is your clothes and beach stuff!! Everything esle is there! Susan is so awesome to rent from! Me and my family had the best vacation this week!
After a year away from Myrtle Beach after a stay in 2014 that left a bitter taste in my mouth, I relented to the wife and kids for our twin daughters vacation before high school graduation this year and tried MB one more time. I'm glad I did because Susan & Marks vacation home (yes it is a home) renewed my faith in traveling to MB. The place was clean, nicely appointed and as the wife and kids said when they walked in, WOW! Lol :~D. It is located right on the beach and is quiet and spacious. I would not have known we were in a condo unless you looked out on to one of the two balconies one of which wrapped around from the master bedroom all the way to the living room, and the other is off the second bedroom. The pictures do not do this home justice in the least! Keeping in mind that one goes to the beach to be outside, lol. But when you want to or have to go in and sleep, why not have a VERY nice place to do it? :~D Only reason they do not get 5 stars is because there was no butler service ;~).
My friends and I stayed at your beautiful condo (to celebrate their 75th. birthdays) and had a GREAT time! The unit was more than we expected. Very nicely decorated, the beds were sooooo comfortable! The balconies overlooking the beach were amazing. Kitchen very well stocked (although we didn't do much cooking, lol)! Hopefully, we will book again next year. We did learn that the parking lot next to the building can be used without cost for handicap persons with decal. Very helpful!! Thanks Susan and Mark.
Sue and Mark's condo was absolutely perfect. We are a family of 5 and there was plenty of room for all of us. It was clean and in a perfect location. We loved waking up to the gorgeous view of the ocean and Being able to walk right out to the beach was so nice with young children. We had a wonderful vacation and did not want to leave! We will definitely stay again. Thank you Sue for being so easy to work with and answering all of our questions so quickly. I look forward to our next stay!
This was a great little getaway for my husband, brother in law and sister in law. The condo was clean and very well stocked. The resort was lovely and right on the beach! We enjoyed the views and proximity to local attractions.