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Serge (Fabrice Luchini) is a retired great actor, living as a recluse amid the windswept landscape of the Île de Ré. Gauthier (Lambert Wilson), a fellow actor currently enjoying a career high as a TV heartthrob, visits Serge and tempts him to make a comeback with a production of Molière's play, The Misanthrope. Before agreeing, Serge insists on seven days of rehearsal.
Will Serge finally say yes? Will the pair of ego-centric actors survive their week of intense readings and occasional bike trips around the picturesque island? The addition of a mysterious Italian divorcée (Maya Sansa) as a love interest adds a deliciously romantic frisson to this hilarious and brilliantly acted take on the classic French comedy of manners.
Certificate: 15 Distributor: Artificial Eye
Dir. Philippe Le Guay, France, 2013, 104 mins, subtitles
Cast: Fabrice Luchini, Lambert Wilson, Maya Sansa


text: ℗1993 Haunted houses Salem (Mass.) Prince Frederick, MD Haunted houses mdu Downloadable audio books Massachusetts--Salem. Recorded Books 2017-10-22 9781417548309 1417548304 Alexander Roslyn Roslyn Alexander Recorded Books, Inc. Hawthorne Nathaniel Nathaniel Hawthorne 1804 1864 Hephzibah tries to shelter her brother from the evil of Judge Pyncheon in this novel set in Massachusetts. Downloadable audio books Fiction Audiobooks Unknown 'gen' value: snd Historical fiction ℗1993 en Domestic fiction Occult fiction The house of the seven gables 57028459 Unabridged. 1993 57028459

subset: commoncrawl


text: News HRE President Discusses Aftermarket Wheels at 2013 SEMA Show Alex Nishimoto writerNovember 8, 2013 Alex Nishimoto writerNovember 8, 2013 Share this article in: Facebook Twitter Google Plus Email Free Price Quote From a Local Dealer View Special Offers No Obligation, Fast & Simple Free New Car Quote Change Car Select Make Acura Alfa Romeo Aston Martin Audi Bentley BMW Buick Cadillac Chevrolet Chrysler Dodge Ferrari FIAT Ford Genesis GMC Honda Hyundai Infiniti Jaguar Jeep Karma Kia Lamborghini Land Rover Lexus Lincoln Lotus Maserati Mazda McLaren Mercedes-Benz MINI Mitsubishi Nissan Porsche Ram Rolls-Royce smart Subaru Tesla Toyota Volkswagen Volvo Select Model GO 1. Vehicle Option Trim Exterior Color No Preference Black Blue Brown Gold Green Orange Red Silver White Yellow Interior Color No Preference Beige Black Blue Gray Green Other Red White Buying Time Frame Within 48 hours Within a week Within two weeks Within a month More than a month Payment Method Undecided Loan Lease Cash Trade In? Yes No 2. Contact Info First Name Last Name Address City State -- AL AK AZ AR CA CO CT DE DC FL GA HI ID IL IN IA KS KY LA ME MD MA MI MN MS MO MT NE NV NH NJ NM NY NC ND OH OK OR PA RI SC SD TN TX UT VT VA WA WV WI WY Zip Code Phone Email 3. Dealer Selection Receive your free dealer pricing information by completing your contact information! The 2013 SEMA show was overflowing with aftermarket wheels, but not every set of rims is created equally, as president of HRE Performance Wheels Alan Peltier told us at the wheel maker's booth. As a former aerospace engineer for Northrop Grumman, Peltier knows a thing or two about precision and quality.The Vista, Calif.-based wheel manufacturer has been producing forged wheels since 1993. We got an in-depth look at HRE's facilities in an episode of The Downshift earlier this year. On the SEMA show floor, Peltier again explained the company's design and manufacturing process. HRE starts with forged aluminum blanks, which weigh about 100 pounds each before being sent to the lathe and CNC mill for machining. A series of blanks was on display at HRE's booth, and you could see the progression from the raw material to the finished product. Peltier said that HRE's process for manufacturing forged wheels isn't much different from other wheel companies, but the brand's attention to detail in all phases of production — especially design — is what sets it apart.In a somewhat disturbing revelation, Peltier told us that no certification is needed to produce and sell wheels in the U.S., which means practically anybody can put a new wheel on the market. Despite that fact, HRE employs numerous engineers and is one of only a handful of U.S.-based companies to have TUV certification, the qualifications needed to sell aftermarket wheels in Europe. Peltier wouldn't say what percentage of wheels at the show he deemed to be high-quality, but he did name a few companies he believed to be around the same level as HRE. Among the names dropped were BBS and Rays, which puts HRE in some lofty company.In his nearly 15 years with HRE, Peltier has seen many trends come and go in the aftermarket wheel industry, but he believes the move toward larger wheels will persist. As cars grow in size, so too will wheels. Demand for lightweight wheels will also continue to be high, thanks to the many performance benefits they offer. Unfortunately, Peltier tells us the cost of forged wheels won't be going down anytime soon, as prices are dependent on the aluminum suppliers.At HRE's booth, several impressive cars were displayed wearing HRE wheels, including a Ferrari F12 Berlinetta and a custom 1972 Chevrolet Camaro "TT" built by Steve Strope. Check out the photos of both cars along with HRE's wheel collection below. Share this article in: Facebook Twitter Google Plus Email HRE President Discusses Aftermarket Wheels at 2013 SEMA Show /16 Advertisement to Skip 1 | 16 2 | 16 3 | 16 4 | 16 5 | 16 6 | 16 7 | 16 8 | 16 9 | 16 10 | 16 11 | 16 12 | 16 13 | 16 14 | 16 15 | 16 16 | 16


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Dubai Maritime City Authority to handle registration and licensing of maritime businesses in Dubai
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Dubai Maritime City Authority to handle registration and licensing of maritime businesses in Dubai
Dubai Maritime City, the world's first purpose-built maritime centre and member of the Dubai World Group, has recently announced that registration and licensing of all maritime businesses in Dubai, which was previously the responsibility of Dubai's Department of Economic Development (DED), will now be handled by the Dubai Maritime City Authority as part of initiatives to provide a centralised point of access for all maritime-related activities in the emirate.
Under the new setup, Dubai Maritime City Authority will facilitate various maritime-related transactions including trade name, issuance of license, renewal of license, amendment of license and cancellation of license. To ensure a smooth transition, Dubai Maritime City Authority announced that it has informed all relevant government departments and concerned parties about the new structure and the specific responsibilities now being handled by the Authority.
"Dubai Maritime City represents a new era in the maritime industry as we open new possibilities and provide innovative solutions to address evolving challenges in this highly dynamic sector. With Dubai Maritime City Authority assuming maritime regulatory responsibilities, we are now well on course of realising the maritime centre's vision of catering to all the requirements of the global maritime industry," said Adel Kalantar, Director- Business Support Services at Dubai Maritime City.
"We are pleased to give Dubai Maritime City Authority the opportunity to share and benefit from DED's expertise in the registration and licensing of businesses. We believe that due to its expertise in the maritime industry, Dubai Maritime City will certainly provide great benefits to the maritime sector and national economy as well as promote efficiency and transparency in the delivery of services to the business community," stated Ali Ibrahim, Deputy Director General for Executive Affairs at DED.
The establishment of DMC realises the vision of H.H. Sheikh Mohammed Bin Rashid Al Maktoum, Vice President and Prime Minister of the UAE and Ruler of Dubai, to create a fully integrated environment that supports the sustained development of Dubai's maritime sector and contributes to the development of the national economy.
The move is also in accordance with the Dubai Maritime City Law No. (11) of 2007 that was passed into law by His Highness Sheikh Mohammed Bin Rashid Al Maktoum. The law tasks DMCA to enhance Dubai's position in the maritime industry, and to oversee the development of specific maritime sectors such as maritime services, maritime management, vessel and yacht registration, vessel and yacht ownership and charter, maritime and educational research, vessel and yacht design and building, maritime shipment organisation, maritime exhibition, conferences, training and workshops; maritime tourism and maritime specialised arbitration.
"This move is not only a simple transfer of functions; it represents a commitment to raise the level of performance and exceed the expectations of our clients in the global maritime sector, who can now expect more value-added premiums because Dubai Maritime City Authority has been established specifically as a maritime authority," added Kalantar.
On completion, Dubai Maritime City will feature a fully integrated community for business, industrial activities, residential and academic and recreational amenities designed with a unique maritime-themed lifestyle.
Top Headlines
- dubai maritime city authority signs mou with confitrama - italian ship-owners' association parties forge synergic collaboration to promote mutual gro
- Dubai Tourism transfers registration and licensing of maritime activities within Dubai to Dubai Maritime City Authority
- Dubai Maritime City Authority and Dubai Police discuss steps to enhance registration and licensing for Dubai's commercial and leisure maritime boats
- Dubai Maritime City Authority awards Dubai Department of Economic Development
- Dubai Maritime City Authority


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Type: Improvement
Status: Closed
Priority: Minor
Resolution: Won't Fix
Affects Version/s: 0.4
Fix Version/s: 0.5
Component/s: None
Explore the intersection between Writables and Avro to see how serialization can be improved within Mahout.
An intermediate goal is the provide a structured document format that can be serialized using Avro as an Input/OutputFormat and Writable
- All
- Comments
- Work Log
- History
- Activity
- Transitions
I think that this is definitely stale, but it is a pity to lose such nice work.
(drew tends to do nice work)
I think this has gone fairly stale... there's no use of Avro as yet otherwise, and this lives already in github. Is there any reason to move forward with this patch in Mahout?
Tracking some interesting things happening over at
AVRO-493 that would be a viable alternative to following the pattern established by MAPREDUCE-815
pushed to github: http://github.com/drewfarris/mahout-avro-testbed
need to update for the latest version of avro (1.3.1) in addition to getting back to work on this in earnest.
Status update w/ new tarball which contains a maven project (mvn clean install should do the trick)
README.txt included, relevant portions included below:
Provided are two different versions of AvroInputFormat/AvroOutputFormat that are compatible with the mapred (pre 0.20) and mapreduce (0.20+) apis. They are based on, code provided as a part of
MAPREDUCE-815 and other patches. Also provided are backports of the SerializationBase/AvroSerialization classes from the current hadoop-core trunk.
When writing a job using the pre 0.20 apis:
Add serializations:
conf.setStrings("io.serializations", new String[] { WritableSerialization.class.getName(), AvroSpecificSerialization.class.getName(), AvroReflectSerialization.class.getName(), AvroGenericSerialization.class.getName() });
Setup input and output formats:
conf.setInputFormat(AvroInputFormat.class); conf.setOutputFormat(AvroOutputFormat.class); AvroInputFormat.setAvroInputClass(conf, AvroDocument.class); AvroOutputFormat.setAvroOutputClass(conf, AvroDocument.class);
AvroInputFormat provides the specified class as the key and a LongWritable file offset as the value.
AvroOutputFormat expects the specified class as the key and expects a NullWritable as a value.
If an avro serializable class is passed between the map and reduce phases it is necessary to set the following:
AvroComparator.class, RawComparator.class);
So far I've been using avro 'specific' serialization, which compiles an avro schema into a Java class. see
src/main/schemata/org/apache/mahout/avro/AvroDocument.avsc. This is currently compiled into classes o.a.m.avro.document (AvroDocument|AvroField) using o.a.m.avro.util.AvroDocumentCompiler (eventually to be replaced by a maven plugin, Generated sources are currently checked in.).
Helper classes for AvroDocument and AvroField include o.a.m.avro.document.Avro(Document|Field)Builder, o.a.m.avro(Document|Field)Reader. This seems to work ok here, but I'm not certain that this is be best pattern to use, especially when there are many pre-existing classes (such as there are in the case of vector.
Avro also provides reflection-based serialization and schema-based serialization, both should be supported by the infrastructure that has been backported here, but that's something else to explore.
These are quick and dirty and need much cleanup work before they can be taken out to the dance.
see o.a.m.avro.text, o.a.m.avro.text.mapred and o.a.m.avro.text.mapreduce:
- AvroDocumentsFromDirectory: quick and dirty port of SequenceFilesFromDirectory to use AvroDocuments. Writes a file containing documents in avro format; file contents is stored in a single field named 'content', contents are stored in the originalText portion of this field.
- AvroDocumentsDumper: dump an avro documents file to a standard output
- AvroDocumentsWordCount: perform a wordcount on an avro document input file.
- AvroDocumentProcessor: tokenizes the text found in the input document file, reads from the originalText of the field named content and writes original document+tokens to output file.
Running the examples:
(haven't tested with the hadoop driver yet)
mvn exec:java -Dexec.mainClass=org.apache.mahout.avro.text.AvroDocumentsFromDirectory \ -Dexec.args='--parent /home/drew/mahout/20news-18828 \ --outputDir /home/drew/mahout/20news-18828-example \ --charset UTF-8' mvn exec:java -Dexec.mainClass=org.apache.mahout.avro.text.mapred.AvroDocumentProcessor \ -Dexec.args='/home/drew/mahout/20news-18828-example /home/drew/mahout/20news-18828-processed' mvn exec:java -Dexec.mainClass=org.apache.mahout.avro.text.AvroDocumentsDumper \ -Dexec.args='/home/drew/mahout/20news-18828-processed/.avro-r-00000' > foobar.txt
The Wikipedia stuff is in there, but isn't working yet. Many thanks (apologies) to Robin for the starting point for much of this code and hacking it to pieces so badly.
Those discussions seem pretty future tense and very much not something that will work in v20.
I suspect providing a writable wrapper that implements avro serialization may not bet the best way to go here. After looking at hadoop/avro api/code the best approach may be to implement something like AvroSerialization/AvroDeserializer/AvroSerializer. I need to look more closely at
MAPREDUCE-815 and MAPREDUCE-1126 because much of the work for this has probably been done there already.
Very rudimentary exploration of using avro to produce writables.
Uses the avro specific java class generation facility to produce a structured document class which is wrapped in a generic writable container for serialization.
- clases on o.a.m.avro are produces from schema in src/main/schemata/o../a../m../avro/AvroDocument.avsc using o.a.m.avro.util.AvroDocumentCompiler
- provides a generic avro Writable implementation in o.a.m.avro.mapred.SpecificAvroWritable
- see the test in src/test/java o.a.m.avro.mapred.SpecificAvroWritableTest to see how this can be used
'mvn clean install' will run the whole shebang.


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Chesieres RestaurantsRead about the top 3 restaurants in Chesieres, Switzerland restaurants and browse unbiased reviews of the best Chesieres restaurants.
Le Sporting
#1 of 3 restaurants in Chesieres
What can I say about this restaurant? A much better question would be: What canâ…
Le Francis
#2 of 3 restaurants in Chesieres
Le Francis is a creperie / pizzeria. Deco and lighting scheme aren't especiall…
Chez La Croix
#3 of 3 restaurants in Chesieres
In the Swiss mountains, close to the French border, on the foot of the 'col de…


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Floor Decals are a great way to give directions at a large event or trade show. They're also an innovative branding tool and can be used on any type of floors.
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Receive your order in as little as 3 business days when you select our fastest shipping option! As soon as your order is placed, you can monitor its progress from the "My Account" dashboard. We will send you a tracking number as soon as your order has shipped.
For an additional cost of $4.44, our team of professional Graphic Designers will check your file to ensure it is optimized for print.
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text:
The City Retreat
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Old style Young's boozer set in the corner of a truly monstrous concrete slab of an office building. Once inside you'll soon forget about that. Clientele seem to be the cast of The Office. Beer is naturally good (Young's don't allow tardy cellar keeping as a rule), food is cheap pub fair - but served really fast. Staff are really friendly and jolly. Overall, quite a good little bolt-hole the sort of place the tourists ign
74 Shoe Lane Fleet Street London
London, London, Thames Valley
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Palm Applications from Your PC
Pendragon Forms 3.0 makes it easy to design a simple database on your PC and turn it into a Palm application to your Palm handheld. Use your Palm for data input, then easily re-sync the data between Palm and PC. It's slick, and it's simple, once you get the hang of things.
The database design process is quite simple. Pendragon Forms lets you define the standard field types: text (255 characters maximum), numeric (up to 15 digits, with support for scientific notation up to e308 and down to e-324), 9-digit currency, option 1-to-5 (the Palm application lets you choose 1, 2, 3, 4, or 5), popup list, multi-selection (using checkboxes), date, time, date and time together, Yes/No, and signature. New records are automatically filled with date/time, user name, and record IDs. If you don't want to start from scratch, you can generate a form from a database table.
You are limited to 250 fields per form – far more than most well-designed Palm applications would use anyway. The company says you can have a theoretical limit of 32,000 records, but recommends no more than 5,000 for speedy searching and sorting.
Pendragon Forms 3.0
There are several special features you can invoke, such as creating a cascading popup. In such a relationship, a selection made from a popup list determines which list of values is displayed for the next field. For example, on your Palm device you could choose "Washington" in the state field and see a list of Washington cities displayed in the Cities field which follows; answer "California" and you'll see a different Cities list. You can also create what Pendragon calls a Jump Popup field: Answers to a question can automatically take you to different sections of your input screen.
You can specify a field is read-only or required, and you can specify a default value. For numeric fields you can specify minimum and maximum values and limit entries to integers, while text fields can be set to a maximum length and specify an edit mask.
The Palm user can quickly sum, average, and count the values. You can also define calculations using Pendragon Forms' scripting. Fortunately, scripting is fairly easy to learn, and the user guide is amply illustrated.
On the Palm side the generated application also lets you quickly find values in a particular field as well as sort the list of records by any field. Your application can run only any Palm handheld with OS 3.0 or higher with HotSync 3.0 or higher, including the Palm III, V, and VII series.
There is limited multi-table processing. You do this by creating a parent form and a subform. Each must share a field (the key to the one-to-many relationship).
Synchronization is simple, and the program gives you control over which records on the Palm stay there. For example, you may be using the Palm application as a data collection device and want all records transferred to the PC. In my test application I wanted a complete synchronization between PC and Palm; all records were merged. You also have several filtering capabilities; used in a multi-user environment, for example, you can select which records are sent to Palm user #1 and which go to user #2. You can also create user groups to make repetitive synchronization tasks easier.
Though the program will work without Access 97 or 2000, you may want to have a copy loaded on your system. Once you're ready to implement your design, you must "freeze" it, meaning you can only make minor changes. If you need to add a field, you'll have to copy your design and work on the copy. The trouble is you can't copy the data as well, so you'll need a database tool such as Access to perform that task.
Pendragon Forms includes a tabular option for display and edit of data on the PC, and you can export to Excel or ASCII formats with the click of a button. The program can work with both DAO (Access 97) and ADO (Access 2000) database engines, as well as ASCII files.
Overall I found Pendragon Forms easy to use, thanks in part to my experience with databases. My developer background also let me quickly grasp the principles of Pendragon Forms' application creation; a little experimentation was all it took to get the hang of things in about an hour. If this is your first development tool, expect to spend an hour or two more to get your first flatfile (single form) application created and working. But remember, you'll want to experiment with, and test, your application in great depth before you deploy it. Unlike other database tools, once you deploy your application your flexibility virtually disappears.


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About Skunner
About Me
About Me
London, Ontario, Canada
Music, Football, Guitars
Favourite Team
Favourite Team
Manchester United
FM on FB
Skunner replied to olfrud's topic in Football Manager General DiscussionEA has Fifa Superstars as an app on Facebook.
Who still plays FM08?
Skunner replied to WhaleOilBeefHooked's topic in Football Manager General DiscussionI think I have the best attacking force in the PL right now in my game with West Ham. I have 3 strikers in Nathan Delfouneso, Alex Tarweh Nimely and Toto Tamuz. They all just power through any defense. Quite nifty because if one of them has a slump in form, the other will start firing away the goals. Brilliant midfield as well. My defense is going to need some work soon though as they're all getting up there in age.
Sending Young Talent Out On Loan
Skunner replied to tomsmith1989's topic in Football Manager General DiscussionHalf my reserve and youth teams refuse to go on loan to feeder clubs. I wish I could fine them for blatantly refusing to go where I tell them to.
Who still plays FM08?
Skunner replied to WhaleOilBeefHooked's topic in Football Manager General DiscussionI'm still on FM08. My main save, I'm currently playing as West Ham for the 3rd season. I'm in 2016 I believe. The big 4 as turned into the Big 3 now. Manchester United still playing strong, Manchester City has become the other big team who causes me most of my problems, and my West Ham team are the other big club. Chelsea and Arsenal have sunk to Top Half or Midtable finishes. Basically a battle between everyone for 4th spot. Finished 3rd my first season after Roy Keane got the sack after finishing in 15th, then Manchester United decided to sign him as manager, and he's made a hell of a team. Then second season, I was able to pull off 1st place on the last game of the season. Basically it came down to me winning and Man City losing or drawing. I ended up drawing the game, and I though City had me done for, and they ended up drawing their game which kept me up top. I have Bolton as a feeder club as well since they sunk down to Championship level. Portsmouth, Sunderland and Everton are both Championship level teams too.
Skunner replied to Mr m's topic in Football Manager General DiscussionExtract the installer? If you have the disc, you don't need to extract anything.
FM2009 FAQ - Updated for 9.3.0
Skunner replied to Glenn Wakeford's topic in Football Manager General Discussion*EDIT* Forgot my video card. Out of curiosity. Will it run on my computer? I remember I played the demo, but I can't remember how well it ran, I know it did run. My specs: Windows XP eMachines T6216 AMD Athlon 64 Processor 3200+ 2.01 GHz, 384 MB of RAM NVIDIA GeForce 6100 I actually have 512 MB of RAM but it's not registering it when I go to the properties on My Computer, but System Information reads it. I reckon it may not work, so I should just pass on it?
Skins not showing up in preferences
Skunner replied to oldhammad's topic in Skinning HideoutI can't seem to get the BBC Sport skin from sortitoutsi to work. I'm using FM 08, I know I'm doing everything right, because I have another skin I'm using. I'm not sure if I'm correct, but FM07 skins won't work on 08 will they? Because I had a look through the graphics in it, and it still has FM07 headers and stuff. But it was in the FM08 category which leaves me confused. Not a big deal, it's a really nice skin, but I'm using another one that's nice as well. Was just wondering if the issue had been brought up before and if it was figured out.
Funny Screenshots Thread
Skunner replied to Diego_Werderdona's topic in Football Manager General DiscussionLOL @ Your manager name.
Where are FM gamers from?
Skunner replied to Gundo's topic in Football Manager General DiscussionCanada. London, Ontario to be more specific. But I've lived in Glasgow.
players in scotland
Skunner replied to robsafc's topic in Football Manager General DiscussionThe Old Firm in the EPL actually reminds me of something I read on soccernet recently. http://soccernet.espn.go.com/columns/story?id=603057&sec=england&root=england&lpos=spotlight&lid=tab2pos2&cc=5901 That's the article, and It really doesn't sound like that bad of an idea to be honest. It could help the SPL in a lot of ways if done right. But I doubt it will ever happen, but It is a pretty neat concept to think of.
Can SomeOne Explain The MLS Drafts
Skunner replied to joshmay07's topic in Football Manager General DiscussionTo be honest, I'm Canadian, and I still understand it. It's a pretty stupid concept to be "different" yet it fails to be any better. All it does is confuse. I prefer the real way. The European... And well everything other country in the worlds way.
I will pay an extra $20 for the ability to add a league to the game.
Skunner replied to x3widRacin's topic in Football Manager General DiscussionI would love to have my league in. I know the teams are in there... Well atleast most of them. But sadly I doubt it will ever happen. And to be quite honest, It's not even that big of a deal, because I would probably only play it once since the league isn't structured along with MLS, so I'd be stuck in that league, and I really know nothing about it, and also the fact that I'm clueless about MLS's stupid table format. Adding leagues would be nice though, but for me, the big thing is if the league connects to major leagues. I probably wouldn't care for a league if it didn't connect to a major league like the Premiership. Although, I do admit, if the Scottish Highland leagues were in, I would venture into those. But if any leagues would be needed, I would vote for lower in the English leagues as they connect to the premiership. But it's no big deal really. SI should focus on the gameplay, making improvements, making the game even better than it already is.
Worldwide Soccer Manager 2009 in Canada
Skunner replied to jdarvwill's topic in Football Manager General DiscussionI seen WSM 2007 in EB Games once. It was used I think, although it was on the shelf roughly the the time it came out.
unbelieveable run of form; is this possible?
Skunner replied to OriginalGrowler's topic in Football Manager General DiscussionNot the Derby jynx!
unbelieveable run of form; is this possible?
Skunner replied to OriginalGrowler's topic in Football Manager General DiscussionI would find that amusing if that happened to Arsenal. But look at Hull's run of form. Quite shocking, staying up there with the best, and holding their own against the big sides. They're doing really well for being just promoted.


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Licensed Contractors: Are They Worth the Extra Expense?
People nowadays are very much smart and brainy in choosing licensed contractors for their remodeling or construction of any new home. It is safer to have licensed contractors as these contractors are given with a license by the Government after the supervision and analysis of their work. Hence licensed contractors have great importance in the task of home making. They make the experience pretty good for their clients.
There are many incidents of building collapsing and other accidents of such kind being noticed these days. So, it's highly necessary to hire a licensed person to get the construction related work done and thus, ensuring the safety of your home and loved ones. These licensed contractors have highly trained professionals who have years of experience in their respective field working under them. Also right from the designing to the paper work they assist the owners and get the work done for them from the beginning till the end.
This is hence a hassle-free option for people who think to construct or remodel their home. Moreover, these contractors come with insurance and it covers all the risks that arise due to their professional's work and when something goes wrong in their work and when they are liable to pay, it covers them. Hence choosing a contractor and hiring them is a very safe option for building construction and maintenance activities. This ensures the safety of your home and family. They are a better option than taking a risk with one's home.


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Parents' Council Area
We are hoping to enlist the support of new parents this year to help support the school as it grows.
Parents' Council Committee
Roisin McFarland
|Vice Chairperson
Philip McCrellis
Sara Mallon
|Mary QuinnAisling Mullan
We are always looking for new members to help us out. No matter what your commitment is we would love to have you involved.
We plan to relaunch our Phoenix Parents' Council in the new year, but in the meantime we would be very happy if you would let us know if you would like to support us this year. Everyone has something to offer and the only requirement to join the group is that you have a child at the school!
Don't be nervous or daunted by the thought of coming along to one of our meetings. We are friendly, but we do understand it can be difficult for parents to take take the first step. The meetings are just an opportunity for parents to get together over a cup of coffee and a bun. A chance to get to know new people, as well as discussing how we can support the school.
The Parents' Council is a special group. As an integrated school which was set up by parents who wanted an alternative to segregated education in NI, we value your voice! Everyone who has a child at school is entitled to join the council. We have a Committee who take on organisational roles, but you can be part of the council without this, if you feel it would be too much of an undertaking.
SURVEY: We plan to use a survey to collect information from parents to help plan effectively to encourage your involvment, for example; best time for meetings, how much time you would like to give, ideas for future work? We look forward to hearing from you and working with you this year.
Parents' Council Useful Information


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Cabin 1 – Sleeps up to 6
This charming stand alone 1950's knotty pine cabin is nestled in the Jeffrey pines. One bedroom has a king and the other has 2 twins. The sleeping options are flexible with 2 bedrooms and a queen sleeper sofa in the living room. The kitchen and dining area are open to the living room with exposed beam ceiling and wood burning fireplace making this a great place to relax with a family or group of friends.
- King Bed and 2 Single Beds
- Shower over bath
- Dogs Accepted
- Toaster
- Hairdryer
- Sofa Bed
- Kitchen
- Non-Smoking
- Microwave
- Cable/Satellite TV
- Tea/Coffee Maker
- Fireplace


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Loading in 2 Seconds...
Loading in 2 Seconds...
Chapter 8 Chemical Reactions of Inorganic and Organic Compounds. Chemical Reactions. Chemical reactions are processes in which one set of chemicals are converted to a new set of chemicals Chemical reactions are described by chemical equations. Evidence for Chemical Reactions.
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.
Single Displacement
(AKA Single Replacement)
Na2S + ZnCl22 NaCl + ZnS(s)
Mg(NO3)2 + 2 NaOH Mg(OH)2(s)+ 2 NaNO3
K2CO3 + 2 HCl (H2CO3 + 2 KCl)
H2O + CO2 + 2 KCl
NH4Cl + KOH (NH4OH + KCl)
NH3 +HOH+ KCl
HNO3(aq) + NaC2H3O2(aq)
HC2H3O2(aq) + NaNO3(aq)
HClO4 + NaOH H2O(l) + NaClO4
Methanol CH3OH
Ethanol CH3CH2OH
Dimethyl ether CH3OCH3
Diethyl ether CH3CH2OCH2CH3
Methanoic acid
Ethanoic acid
Methyl methanoate
Methyl ethanoate
Methyl amine
Ethyl amine


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Results 1 to 2 of 2
Thread: Field Name Appear In Query
12-13-02, 13:40 #1Registered User
- Join Date
- Jul 2002
- Posts
- 35
Unanswered: Field Name Appear In Query
I need the field name of a table to appear as data in a query.
How could I do this?
12-15-02, 13:24 #2Registered User
- Join Date
- Dec 2002
- Location
- Ireland
- Posts
- 4
in your sql query you need to use: describe my_tbl_name
so if your table is members
you may have had a select query: select * from members
you now use: describe members
I have not tested this to make sure that it works as I have never had a use for it but if it does I would be interested in knowing. If it doesn't let me know and I will see if I can get someting that does.


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EU Commission and food agency met in France to address the possibility of tainted Chinese milk products entering Europe.23 September 2008
ANNECY -- The EU Commission on Monday asked the European Food Safety Authority (EFSA) to "urgently assess possible public health risks" of China's tainted milk scandal to consumers.
"There is no question of having milk products from China in the EU because we have banned all imports some years ago", EU Health Commissioner Androulla Vassiliou said at a meeting of European farm ministers in Annecy, in eastern France.
"But in case they have used some milk for the production of biscuits or other products we have asked EFSA to give us an opinion, whether this... can have any effect on the health of the people", she added.
The findings should be available on Wednesday or Thursday, said EFSA director-general Catherine Geslain-Laneelle.
No one knows yet if products containing traces of Chinese milk could find their way to Europe, she said, adding that some might be found for sale in "little Chinese shops".
The Chinese government announced Monday that up to 53,000 children had been hospitalised after drinking milk that was contaminated by the industrial chemical melamine.
Most had "basically recovered" after developing kidney stones, the main symptom of drinking the tainted milk, but 12,892 of them remained in hospital, a Chinese health ministry official said.
Vassiliou asked the Chinese authorities to introduce "more strict controls, not only for exports but also for local consumption. Because we already have children dying".
French agriculture minister Michel Barnier said earlier that Europe must increase checks on food imports in response to the Chinese milk scare.
Barnier, whose country holds the European Union's rotating presidency, said the Chinese milk problem "supports me in defending a memorandum ... on stepping up safety controls of imports to Europe".
He said that the aim was to "protect consumers, harmonise control methods and rules and also make sure that products entering Europe respect the same norms that we put on our producers".
The European Union imposed an embargo on Chinese dairy products in 2002, concerned with their poor industry controls.
Despite the ban, the European Commission asked EU nations to be aware of any Chinese milk products entering the region, urging member states to increase border controls.
[AFP / Expatica]


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- English
- français
Like a Bolt from the Blue: Phthalocyanines in Biomedical Optics
The purpose of this review is to compile preclinical and clinical results on phthalocyanines (Pcs) as photosensitizers (PS) for Photodynamic Therapy (PDT) and contrast agents for fluorescence imaging. Indeed, Pcs are excellent candidates in these fields due to their strong absorbance in the NIR region and high chemical and photo-stability. In particular, this is mostly relevant for their in vivo activation in deeper tissular regions. However, most Pcs present two major limitations, i.e., a strong tendency to aggregate and a low water-solubility. In order to overcome these issues, both chemical tuning and pharmaceutical formulation combined with tumor targeting strategies were applied. These aspects will be developed in this review for the most extensively studied Pcs during the last 25 years, i.e., aluminium-, zinc- and silicon-based Pcs.
- doi:10.3390/molecules17010098
- View record in Web of Science
Keywords: biomedical optics ; fluorescence diagnosis ; phthalocyanines ; NIR dyes ; photodynamic therapy ; Vitro Photodynamic Activities ; Sulfonated Aluminum Phthalocyanines ; Water-Soluble Phthalocyanines ; Chinese-Hamster Cells ; Bovine Serum-Albumin ; Internalizing Monoclonal-Antibodies ; Hexadecafluoro Zinc Phthalocyanine ; Photosensitizing Anticancer Drugs ; Poly(Lactic Acid) Nanoparticles ; Responsive Polymeric Micelles
Record created on 2012-03-01, modified on 2017-05-12


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MOVIE SYNOPSIS [ General Audiences ] Starred by Kokomi Sakura (see cast), this film directed by Yoshikazu Katô was premiered in TV or cinema in 2014. The movie "Seifuku nikki: Adokenai koshizukai" comes from Japan. You can watch Seifuku nikki: Adokenai koshizukai online on TV cable or theaters with original audio in Japanese at different dates. This film premiered in theaters in 2014.
Rating: 5 by 10 users./
Runtime: 60 minutes
Kokomi Sakura, Koi Azumi, Hotaru, Kikujirô Honda, Kihito Benimori, Tôshi Yanagi and Kôshido Matsumoto.
60-minute film (full movie) directed by Yoshikazu Katô.
The original audio of Seifuku nikki: Adokenai koshizukai has dialogues in or Japanese, it was produced in Japan.
It premiered in cinemas or television in 2014.
Screenplay written by Kazutoshi Kamata.
Masakazu Sô.
This film was produced and / or financed by Kato Eizo Kobo.
OP Eiga.
Without commercial breaks, the full movie Seifuku nikki: Adokenai koshizukai has a duration of 60 minutes; the official trailer can be watched in streaming on the Internet. You can watch this full movie free in English or Japanese in movie TV channels, renting the DVD or with VoD services (Video On Demand player, Hulu) and PPV (Pay Per View, Netflix).
See the page of this full movie, Seifuku nikki: Adokenai koshizukai in FULLTV Movies.


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Video Card Driver
Sound Card (Chip Set) Download
Please check your sound card (chip set) or model number and update to the latest version.
DirectX 9 Download
To enjoy Erebus2, you must have DirectX 9.0c and/or a higher version.
Check the version of your DirectX and make sure to download
the latest version if the version you have is earlier than the one mentioned.


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How it Works
|Check The Availability. Enter your zip code and the move date to find available moving companies and moving help in your area.
|Get Instant Moving Quotes. Instantly compare the moving prices side by side and obtain moving quote.
|Hire the Best Mover & Helpers. Compare the moving rates, reviews and hire the mover that is best for you.
Working with your moving company is necessary for a successful and smooth move. Establish a good and helpful communication with your crew. Here is how to do it.
Work With Movers
Whether you are relocating locally or out of state, you have several moving service choices. While full-service movers, labor helpers and do-it-yourself are the preferred options for local moves, self-service has become very popular for cross-country moves.
Types of Moves
Before you rent a moving truck, calculate the weight of your belongings or how many rooms you have to move. For a general idea of what size of truck you will need, you may use the guide most truck rental companies use.
How to Choose a Right Size Truck
Guide for students moving into a dorm room or campus apartment. Low-cost moving tips for students, learn how to save money on a move.
Students Moving
Whether you like it or not, relocating every 2 or 3 years is an integral part of military family life. Here is our guide to help you with the process of your next military move.
Moving Guide for Military Families
Here are funny and creative tips for renting a moving truck. The smart way to make a self-move less hectic.
Funny Checklist For Rental Trucks
|Price Quote With no Truck
|# of Movers
|First 2 Hours
|Additional Hours
|Price Quote With a Truck
|# of Movers
|First 2 Hours
|Additional Hours
Local moving companies and professional movers in Hartford, 44424
Find the best local moving companies in Hartford at MoversCorp.com. Whether it's a big or small move, simply enter your zip code to get access to cheap moving service providers in your local area. Our Hartford movers provide professional moving and packing services, furniture and appliance moves, moving boxes and supplies as well as affordable moving labor services such as truck loading help and truck unloading help. Need help moving a house or an apartment, or help to load and unload a rental moving truck? Hire full-service movers and moving labor helpers in Hartford, Ohio through our site. You will find professional movers and move help at discounted rates. They also provide in-home furniture moving service - from one room to another or from upstairs to downstairs. Moving labor service is ideal for people who move within the home or in the same apartment complex. And if you move yourself, you can hire movers to load and unload furniture at your destination at low cost. Each moving company in Hartford, OH lists the services and equipment they provide.


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John Carroll basketball coach Mike Moran is retiring after 25 years, leaving while still on top of his game. Full story »
Mount Union ensured the purple reign will continue under coach Vince Kehres with their 12th Stagg Bowl Division III championship. No NCAA football team has more titles. Full story »
Compelling storylines abound between Mount Union and St. Thomas heading into tonight's Stagg Bowl NCAA DIvision III national championship football game in Salem, Virginia. Full story »
Mount Union's quest for a title has Terry Talkin' to other area coaches about impact -- Terry Pluto (photos)Mount Union's quest for a title has Terry Talkin' to other area coaches about impact -- Terry Pluto (photos)As Mount Union goes for the Division III title, Terry Pluto talks to other area college coaches about the impact of the Purple Raiders. Full story »
Since taking over for Larry Kehres, Mount Union football coach Vince Kehres has a 41-2 record. Full story »
Mount Union football coach Vince Kehres is featured in the Washington Post with his 31-2 career record at the school, and a team that has outscored opponents 164-0 this season. Full story »
Larry Kehres is having fun watching his son, Vince Kehres, coach Mount Union to another Stagg Bowl championship game. Full story »


text: " Assessment | Biopsychology | Comparative | Cognitive | Developmental | Language | Individual... White Bear Phenomenon Pages in category "Thought suppression" This category contains only the following page. W White Bear Phenomenon Retrieved from "http://psychology.wikia.com/wiki/Category:Thought_suppression" Ad blocker interference detected! Wikia is a free-to-use site that makes money from advertising. We have a modified experience for viewers using ad blockers Wikia is not accessible if you've made further modifications. Remove the custom ad blocker rule(s) and the page will load as expected.


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Coaching Sessions
Wish you had someone to walk beside you in certain areas of your life? You can hire me as that person. Whether you're more comfortable with the term mentor or coach, I can help you find answers you're looking for.
Talking about coaching, here's something to know: a coach isn't a counselor or a consultant. A coach's primary task is to ask the right questions so that you can find the answers yourself. A good coach points out the turns in the road of your journey, encourages you to look at the whole picture, and helps you create your map so that you can figure out the best path to take so you end up where you want to be.
As a Life Coach
I have over twenty years of experience with helping people recognize what they need to get to where they want to be. Working one-on-on with clients about a specific issue they are working through. Whether you need help with home management, parenting, personality or your relationship, I will help you sort through the clutter, walk with you through the messy stuff until you are on the path you need want to be. I'll ask the right questions to give you the tools you need to recognize what you are doing and where you're going.
The need to know
- All coaching sessions are $75 for your first 60-minute session with me, and are done one-on-one via tele conference. The session fee includes a pre-meeting questionnaire, a personalized game plan written by me for moving forward, and up to 15 minutes of feedback afterwards.
- 45-minute follow-up sessions are $50 each and include continual follow-up written game plans and up to 15 minutes of feedback.
- 20 minute mini sessions are $25 each and are for new clients so we can chit chat so I get to know you.
- Payment is due in advance before meeting, and can be paid via PayPal or credit card.
- All sessions are confidential.
- ! am not a medical or legal professional, and my coaching sessions are not for the purpose of legal or medical advice or diagnosis.
- Space is extremely limited, so apologies in advance for the potential waitlist.
Fill out the form below, and I'll get to you as soon as I can. Clicking submit only indicates your interest, nor does it guarantee you a spot in my calendar. Thanks for understanding!
[ninja_form id=1]
Certified ECE (Early Childhood Education) (nutrition, child abuse, psychology)
Certified Home Decorating/Staging (home decorating, decluttering, staging)
Personal Coaching for personality issues (perfectionism, self-esteem, control)


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Known as one of the most environmentally friendly cities in the country, Portland is home to many of the top colleges in Oregon, including several notable liberal arts colleges. Most colleges and universities in Oregon are considered small to midsize, and only three are large research universities.
Here are the top 20 universities in in Oregon that provide excellent education and quality of living.
20. Northwest Christian University, Eugene
Northwest Christian University is a private institution that was founded in 1895. It has a total undergraduate enrollment of 496, its setting is urban, and the campus size is 8 acres. It utilizes a semester-based academic calendar. Its tuition and fees are $27,270.
NCU is a University that fosters wisdom, faith, and service through excellent academic programs within a Christ-centered community. NCU aspires to be a University characterized by its commitment to equip students to discover and answer God's call in their lives.
NCU achieves this vision through academic excellence and faithful stewardship in a Christ-centered community that develops purposeful graduates.
When applying to Northwest Christian University, it's important to note the application deadline is rolling. Scores for either the ACT or SAT test are due July 1. It is less selective, with an acceptance rate of 71.9 percent.
Academic Life
The student-faculty ratio at Northwest Christian University is 15:1, and the school has 76.7 percent of its classes with fewer than 20 students.
The most popular majors at Northwest Christian University include: Business, Management, Marketing, and Related Support Services; Education; Psychology; Multi/Interdisciplinary Studies; and Biological and Biomedical Sciences.
The average freshman retention rate, an indicator of student satisfaction, is 65.5 percent.
Student Life
Northwest Christian University has a total undergraduate enrollment of 496, with a gender distribution of 38.7 percent male students and 61.3 percent female students. At this school, 28 percent of the students live in college-owned, -operated, or -affiliated housing and 72 percent of students live off campus.
Northwest Christian University is part of the NAIA athletic conference.
Campus Services
Northwest Christian University offers a number of student services including nonremedial tutoring, placement service, and health insurance.
Northwest Christian University also offers campus safety and security services like 24-hour foot and vehicle patrols, late night transport/escort service, lighted pathways/sidewalks, and controlled dormitory access (key, security card, etc).
Alcohol is not permitted for students of legal age at Northwest Christian University.


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ABOUT The Unlimiteds
The Reno Air Races have been thrilling spectators for years. In this scene, commemorating the event's 30th anniversary, two of Reno's greatest champions are shown nearly scraping paint after rounding the pylons in Sunday's Gold "Unlimiteds" class race. Rare Bear the legendary F8F Bearcat, in its vintage orange & white paint scheme, still to this day holds the record for the fastest piston-driven airplane, and was flown for years by racing great Lyle Shelton. In its familiar red, white and blue colors and shining silver nose is the highly-modified P-51 Mustang, Strega, flown by many-time champion Bill "Tiger" DeStefani.
The Unlimiteds was painted in 1994, and was one of John Shaw's very first aviation paintings. The original mixed-media / gouache painting was first unveiled in September of that year during Air Race week, at the opening of the National Museum of Racing in Reno, Nevada. Published in Reno by a small, independent company as an open-edition poster and limited-edition lithograph, this image remains one of the all-time favorites of this subject ever produced. In 2009, Liberty Studios released an all-new canvas giclee reproduction of this classic, so for the first time this classic can be enjoyed in the same large size and vibrancy as the original.


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In a recent decision in the Northern District of Illinois, a trial court granted summary judgment in favor of a school district in a lawsuit stemming from the arrest of a local resident who was leafleting and proselytizing about Christianity on the sidewalk in front of a high school. The case reminds school districts of their rights to prohibit expressive activity by community members near school grounds, but also contains important warnings that such prohibitions not go too far.
Duehning v. Aurora East Unified School involved a lawsuit by Josiah Duehning, a local resident of Aurora, Illinois, who often travels to high schools and colleges in the area to hand out pamphlets and engage students in conversations about Christianity. Duehning was a frequent presence on the sidewalk in front of East Aurora High School, and though he had been told in the past to cross the street, he regularly ignored those warnings to no consequence. On August 28, 2014, however, when Duehning ignored the direction of an East Aurora High School Dean of Students to leave the sidewalk in front of the school, and instead moved off the sidewalk onto school property to talk to a group of students, the Dean called the school's police liaison officer. The officer required Duehning to identify himself, directed him again to leave the sidewalk in front of the school, and when Deuhning refused, physically restrained him, warning "I WILL take you down." Duehning was subsequently arrested and searched, and a knife was found on his person.
Duehning sued, raising a plethora of legal challenges against the school district, the liaison officer, and the City of Aurora. Most of the claims centered on Duehning's argument that he had a First Amendment right to free speech that allowed him to leaflet and prosthletize on the sidewalk in front of the school. In granting summary judgment in favor of the defendants, the court focused on a somewhat confusing technicality to dismiss the First Amendment and other claims. Specifically, because Duehning had continued to pass out literature and converse with students despite the Dean's admonition, the Court found that Duehning had not actually had any constitutional deprivation of his First Amendment or other rights and so could not support such claims.
The court did address a few substantive issues of note for school leaders. Notably, the court rejected an argument by Duehning that because picketing employees were allowed to picket on the sidewalk in front of the school under the Illinois Labor Dispute Act, 820 Ill. Comp. Stat. 5/1.5, an evangelist like himself should also be allowed to exercise his First Amendment rights in the same space. The court noted that an evangelical was not similarly situated to a labor picketer, and so such claim must fail.
Moreover, although the court decided in the school district's favor, a comment about the use of sidewalks in front of schools warrants notice. The court noted that there is a "tension between maintaining traditional public fora, such as sidewalks, for First Amendment activity, and permitting school districts to effectively manage school property and property immediately adjacent on behalf of students." The court cited a U.S. Supreme Court case, Grayned v. City of Rockford, which held:
Just as Tinker made clear that school property may not be declared off limits for expressive activity by students, we think it clear that the public sidewalk adjacent to school grounds may not be declared off limits for expressive activity by members of the public. But in each case, expressive activity may be prohibited if it 'materially disrupts classwork or involves substantial disorder or invasion of the rights of others.'
Although the Court did not find a violation here in light of the technicality noted earlier, the reference to Grayned is an important warning that sweeping prohibitions on expressive speech on sidewalks adjacent to school grounds may be vulnerable to First Amendment challenges. Such prohibitions should be carefully reviewed with legal counsel in light of this case.


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Dutch LLC invests in PLM for growth
22 June 2015 | News | Source: Katie Smith
US fashion powerhouse Dutch LLC is implementing NGC's Extended PLM software to help streamline its global operations as it continues with its expansion strategy.
The owner of the Joie, Equipment and Current/Elliott brands operates six stores and an online website. The software, which combines fashion PLM and Supply Chain Management (SCM), will provide all of Dutch LLC's brands with an end-to-end solution, from initial product development and line planning to global sourcing, production management and inbound visibility.
Features such as workflow calendars, global collaboration and exception dashboards will help further streamline productivity.
"Our Extended PLM can be a strategic platform to help Dutch LLC continue its rapid growth and expansion," said Mark Burstein, president of sales, marketing and product development at NGC.


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Hop aboard this ferry and follow in the footsteps of famous artist Jean-Paul Riopelle as you discover an island renowned for its natural beauty and delicious cheeses. The island is home to many species of birds, including the thousands of migratory geese passing through in the spring and fall.
Capacity: 293 passengers, 23 vehicles
Distance: 7.8 km (5 mi.)
Ticket office: L'ISLE-AUX-GRUES FERRY TERMINAL, 125, chemin du Quai, L'Isle-aux-Grues, Québec, Canada, G0R 1P0
Activities and services
- Entertainment
Signs and shuttles
- Tourist signs (green)
Restaurant and food services
- Vending machines
- Full access (Kéroul)
Related services and activities
Schedules and rates
April 1, 2017 - December 31, 2017 (Approximate dates)
- Crossing time : 30 minutes


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M.U.G.E.N Development Help
For problems with creating content for M.U.G.E.N.
Child Boards
Code LibraryExample code implementations to use and learn from.857 Posts in 105 Topics
Adding Custom Stages Into Font/Stage.sff Tutorial
October 14, 2017, 01:45:42 pmLast post by DaHatMan
Tips, Tricks, Tutorials3232 Posts in 307 Topics
Re: Pos (Triggers)
November 09, 2017, 06:34:25 pmLast post by VGames
MUGEN ClassA more detailed look into MUGEN's docs. Discuss, add clarity and features, talk about bugs, ask specific questions.1118 Posts in 312 Topics


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Phone:+1 716-324-5971
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GraphicRiver Little Boy with a Tooth in His Hand 4851486
Category: Stock Vector | Comment: ( 0 )
GraphicRiver Little Boy with a Tooth in His Hand 4851486
Stock Vector \ Characters \ People
Care \ Health \ Healthy \ Hygiene \ Hand \ Little \ Smile \ Tooth \ Repair \ Mouth
Stock Vector - Little Boy with a Tooth in His Hand 4851486 by @ GraphicRiver
Stock Vector \ Characters \ People
Graphics Files Included: Vector EPS; Layered: No; Minimum Adobe CS Version: CS.
little boy with tooth in his hand wishes desire to tooth fairy. This image is a vector illustration and can be scaled to any size without loss of resolution. All parts of the image are editable. EPS file included.
Winter Girl Wearing Stripped Scarf; Girl with Dog Shopping at Sale Time; Oval Frame with Woman and Sea Side; Set of Funny Cartoons Super Hero Girls; Girl with Spa Elements Portrait Frame; Woman with Shawl on Seaside ; Woman Wrapped in a Towel on Beach .
Keywords: baby, boy, care, cartoon, character, child, childhood, cute, cutout, dental, dentist, desire, drop, face, fairy, fall out, fun, hand, health, health care, healthy, hygiene, kid, little, medicine, mouth, repair, smile, tooth.


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|Home | About | Journals | Submit | Contact Us | Français
It has been established that skeletal growth is stunted in lead-exposed children. Because chondrogenesis is a seminal step during skeletal development, elucidating the impact of Pb on this process is the first step toward understanding the mechanism of Pb toxicity in the skeleton.
The aim of this study was to test the hypothesis that Pb alters chondrogenic commitment of mesenchymal cells and to assess the effects of Pb on various signaling pathways.
We assessed the influence of Pb on chondrogenesis in murine limb bud mesenchymal cells (MSCs) using nodule formation assays and gene analyses. The effects of Pb on transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling was studied using luciferase-based reporters and Western analyses, and luciferase-based assays were used to study cyclic adenosine monophosphate response element binding protein (CREB), β-catenin, AP-1, and nuclear factor-kappa B (NF-κB) signaling. We also used an ectopic bone formation assay to determine how Pb affects chondrogenesis in vivo.
Pb-exposed MSCs showed enhanced basal and TGF-β/BMP induction of chondrogenesis, evidenced by enhanced nodule formation and up-regulation of Sox-9, type 2 collagen, and aggrecan, all key markers of chondrogenesis. We observed enhanced chondrogenesis during ectopic bone formation in mice preexposed to Pb via drinking water. In MSCs, Pb enhanced TGF-β but inhibited BMP-2 signaling, as measured by luciferase reporter assays and Western analyses of Smad phosphorylation. Although Pb had no effect on basal CREB or Wnt/β-catenin pathway activity, it induced NFκB signaling and inhibited AP-1 signaling.
The in vitro and in vivo induction of chondrogenesis by Pb likely involves modulation and integration of multiple signaling pathways including TGF-β, BMP, AP-1, and NFκB.
In spite of effort to reduce human exposure, lead toxicity continues to be a major environmental health concern in the United States and in other industrial countries. Although recent research has focused on understanding its toxic effects in the developing peripheral and central nervous system, Pb also impacts other developmental processes, including those that occur in the hematologic and skeletal systems (Hicks et al. 1996; Landrigan 1991; Nemoto et al. 2000; Waldron 1979). In fact, the skeleton has long been recognized as a major reservoir for ingested Pb (Barry 1975), and a number of reports demonstrate an inverse correlation between blood Pb concentrations and growth in terms of height, weight, and chest circumference (Schwartz et al. 1986; Shukla et al. 1989, 1991).
Given the strong epidemiologic data, as well as our findings that fracture healing and chondrocyte differentiation are affected by Pb, we have performed a series of in vitro experiments to elucidate the underlying mechanism of toxicity during chondrogenesis and chondrocyte differentiation. We employed micromass cultures of mesenchymal stem cells, a culturing technique that has been used previously as a model to study the early events of embryonic limb development (Ahrens et al. 1993). Cell lines with chondrogenic potential, such as C3H10T1/2 cells, and primary limb bud mesenchymal cells plated at high density undergo differentiation to form distinct cartilage nodules. Thus, besides being used to study limb development, these models have been used to define factors and signaling events involved in chondrogenesis (Weston et al. 2000; Weston and Underhill 2000). Transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) both induce chondrogenesis in mesenchymal stem cell populations (Chen et al. 1991; Frenz et al. 1994; Iwasaki et al. 1993; Joyce et al. 1990). Prostaglandin E2, through protein kinase A signaling also induces chondrogenesis (Biddulph et al. 1988b; Capehart et al. 1990; Clark et al. 2005), whereas retinoic acid is considered an inhibitor of chondrogenic commitment (Biddulph et al. 1988a; Jiang et al. 1995) possibly via down-regulation of TGF-β/Smad signaling (Yu and Xing 2006). Thus various signaling pathways are associated with chondrogenesis, but BMP signaling is particularly important because recombinant BMP proteins are currently approved for clinical use to enhance bone healing in tibia nonunions and spine fusion.
Regarding the signaling pathways, TGF-β and BMP signals are mediated by Smad transcription factors that bind to type I TGF-β receptors and are phosphorylated following lig-and binding to type II receptors (Massague et al. 1997; Mehra and Wrana 2002). Both the BMP receptor–associated Smads (1, 5, and 8) and the TGF-β receptor–associated Smads (2 and 3) are released into the cytoplasm upon phosphorylation, complex with Smad4, and translocate into the nucleus where they regulate gene expression. Because TGF-β receptor–and BMP receptor–associated Smads compete for Smad4 and other downstream signaling molecules, these pathways antagonize one another such that when one pathway increases, the other decreases (Candia et al. 1997). They also have opposing effects in chondrocytes in which TGF-β inhibits (Ballock et al. 1993; Zhang et al. 2004) and BMP promotes (Grimsrud et al. 1999, 2001; Leboy et al. 1997) chondrocyte differentiation. However, in mesenchymal stem cells, both TGF-β and BMP have been shown to enhance chondrogenesis, with the most robust effect in response to BMP signaling (Tuan 2003; Zhang et al. 2004). Assessing the impact of Pb on the propogation of these specific signaling events would provide mechanistic insight into how Pb may affect chondrogenesis and chondrocyte differentiation.
Regarding possible molecular mechanisms of toxicity, Pb has been shown to regulate and alter numerous signaling pathways. Pb has been shown block calcium signaling, inhibit Ca2+/phospholipid-dependent protein kinase C (PKC) signaling in neurologic tissues, and interfere with long-term learning and other functions (Pokorski et al. 1999; Vazquez and Pena 2004). Calcium-independent effects include neuronal release of γ-aminobutyric acid (Braga et al. 1999), induction of ERK1/2 (extracellular signal regulated kinase 1 and 2) and p38 (mitogen-activated protein kinase; MAPK) phosphorylation and activation in slices of catfish cerebellum (Leal et al. 2006) and rat hippocampus (Cordova et al. 2004), and activation of ERK1/2 in the GT1-7 neuronal cell line (Zhang et al. 2003) and in lung CL3 cells (Lin et al. 2003). In immortalized human fetal astrocytes, Pb induces vascular endothelial growth factor expression through activation of PKC/AP-1 signaling (Hossain et al. 2000).
In vitro studies have shown important Pb effects on chondrocyte phenotype, including decreased proliferation, inhibition of type X collagen expression and synthesis, and an increase in proteoglycan synthesis (Hicks et al. 1996). In addition, Pb has important in vivo effects on endochondral bone formation, as Pb-exposed mice and rats have altered growth plate morphology and decreased longitudinal growth (Gonzalez-Riola et al. 1997; Hamilton and O'Flaherty 1994). Correlating with this, we have found that Pb affects developmental/healing processes in the skeleton. This is based on our recent finding that Pb exposure inhibits fracture healing in mice (Carmouche et al. 2005). We have also shown that Pb alters TGF-β and parathyroid hormone–related peptide signaling in chondrocytes undergoing hypertrophic differentiation in culture, an important cellular process that occurs during skeletal development and growth, as well as during healing (Zuscik et al. 2002b). Thus, further elucidation of the molecular mechanism of Pb toxicity during skeletal healing and chondrogenic differentiation in developmental situations is of paramount importance. For the experiments in this study, we used primary limb bud mesenchymal stem cells obtained from stage E11.5 mice, as well as an ectopic bone formation model in vivo in mice, to demonstrate a robust chondrogenic stimulation by Pb. Signaling experiments in the cell model indicate that Pb enhances TGF-β signaling and impaires BMP signaling. Interestingly, although Pb increased chondrogenesis on its own in micromass cultures of the limb bud cells, it enhanced the chondrogenic effects of both TGF-β and BMP-2. When considering this finding from the perspective of the signaling data, it is clear that Pb mediates its effects on chondrogenesis in a Smad-independent manner.
We prepared stage E11.5 mouse limb bud mesenchymal stem cells (MSCs) by enzymatic digestion of limb bud tissue as previously described (Zhang et al. 2004). Briefly, CD-1 female mice were euthanized via cervical dislocation 11.5 days after induction of pregnancy, and embryos were removed and placed in Puck's saline containing glucose. With the aid of a dissecting microscope, forelimbs were removed with forceps and placed in a Puck's saline solution containing 10% chick serum (Gibco Invitrogen, Carlsbad, CA). Following harvest, limb buds were digested for 45 min in the identical solution supplemented with 0.1% dispase (Sigma, St. Louis, MO). After the digestion, cells were washed several times in serum-free Dulbecco's modified Eagle medium (DMEM) and counted. Freshly isolated cells were plated in micromass (105 cells/10 μL) with a DME/F12 mixture (40%/60%) supplemented with 10% fetal bovine serum (FBS; Gibco) as previously described (Zhang et al. 2004). One micromass was seeded per well in 24-well plates. After attachment of the cells, wells were flooded with 0.5 mL of the same culture medium mix and experiments commenced.
Three days after seeding of micromass cultures and treatment with various Pb concentrations and/or factors of interest, wells were washed once with phosphate-buffered saline (PBS; pH 7.4) and then fixed for 20 min with 1 mL 10% neutral buffered formalin (VWR, Buffalo Grove, IL). The cultures were then washed three times with sterile distilled, deionized water, with the last wash being left on the cells for 15 min. Subsequently, 0.5 mL 3% alcian blue (Sigma) in glacial acetic acid was added to each well for 24 hr at room temperature. After two washes with 70% ethanol and three washes with sterile distilled, deionized H2O, photomicrographs of the stained cultures were obtained. Quantification of alcian blue staining was performed using NIH Image (National Institutes of Health, Bethesda, MD). The threshold was standardized to detect nodule area, and the area of the staining was converted from pixels to square millimeters. The area and intensity values were recorded and used to determine staining intensity.
Cultures were harvested at various time points, and mRNA was prepared using Trizol reagent (Invitrogen, Carlsbad, CA) as directed by the manufacturer. cDNA was generated using the Advantage RT-for-PCR kit (Clontech, Mountain View, CA), and real-time quantitative RT-PCR was performed as described previously (Zuscik et al. 2002a, 2004). Briefly, reactions were carried out using the Rotor Gene Real-Time DNA Amplification System (Corbett Research, Sydney, Australia) according to the manufacturers instructions. cDNA samples were treated with RNase A (Roche Applied Science, Indianapolis, IN), and 50-ng aliquots were combined in a 20-μL final volume with 0.5 mM primers and the SYBR Green PCR Master Mix (Applied Biosystems, Foster City, CA). The PCR protocol began with 94°C denaturation (5 min) and then followed by 35 cycles of the following: 94°C denaturation (20 sec); 50–60°C annealing (20 sec; primer dependent); and 68°C extension (30 sec). Dilutions of the cDNA pool were used for each primer set to generate a standard curve, which was utilized by RotorGene software (Corbett Life Science, Sydney, Australia) to perform quantitative analyses. Data were normalized to the β-actin expression level for each sample. All samples were run in triplicate and repeated four times (n = 4).
Use of mice in this experiment was reviewed and approved by the University of Rochester Institutional Animal Care and Use Committee (IACUC). Mice were treated humanely with regard for alleviation of suffering. At 10 weeks of age, female C57/B6 mice were divided into three groups of 35 mice. Groups were exposed to 0, 55, or 230 ppm Pb (in the form of Pb acetate) in drinking water for 6 weeks before initiation of the ectopic bone formation experiment. Our group previously used an atomic absorption method to establish that these doses of Pb exposure correspond to environmentally relevant whole-blood Pb concentrations of 15 and 40 μg/dL for 55 and 230 ppm, respectively (Carmouche et al. 2005).
Ectopic bone formation was induced in mice by the intramuscular implantation of a gel foam substrate impregnated with cells expressing BMP-2. Specifically, C9 cells derived from murine C3H10T1/2 mesenchymal stem cells, which express BMP-2 under control of a doxycycline-repressible promoter, were cultured in DMEM with 10% FBS, 1% penicillin/streptomycin, 2 mM l-glutamine, and 1 μg/mL doxycycline to repress BMP-2 expression (gift from D. Gazit, Hebrew University-Hadassah Medical and Gene Therapy Center, Jerusalem, Israel). Nine days before implantation, doxycycline was removed from the medium to allow BMP-2 expression, which was confirmed using an ELISA kit (R&D Systems, Minneapolis, MN). As a negative control, wild type C3H10T1/2 cells were cultured in basal medium Eagle (BME) with 10% FBS, 1% penicillin/streptomycin, and 2 mM l-glutamine. Cells from both lines were washed, trypsinized, counted, and resuspended in medium at a concentration of 106 cells/100 μL. Surgifoam (type I collagen sponges; Pharmacia, Piscataway, NJ) was cut into 2 mm × 2 mm × 2 mm segments and soaked in medium, then excess fluid was removed. Aliquots (100 μL) of the cell suspension were micropipetted into each section of gel foam and incubated for 2 hr to allow cells to adhere.
Using an IACUC-approved surgical protocol, we placed C9 cell-impregnated gel foam segments into a muscle pouch in the right quadricep of each mouse; C3H10T1/2-impregnated gel foam was placed in the contralateral limb as a negative control. Ectopic nodules were allowed to develop for 3–28 days after implantation. At each time point, tissue was harvested, fixed in 10% formalin for 3 days, embedded in paraffin, and cut into 5-μm sections. Three sections 30 μm apart were stained with alcian blue and counterstained with alcian blue/hematoxylin. Three representative sections from each sample at day 5 and day 7 were analyzed using Osteometrics software (Osteometrics Inc., Decatur, GA). Cartilage cross-sectional area was measured for each slide and included in statistical analysis (for five nodules, n = 15 for statistical purposes).
We performed experiments to assess signaling on various pathways including TGF-β/Smad, BMP/Smad, NF-κB, TOPFLASH (basal c-fos-luciferase), AP1, and cyclic adenosine monophosphate response element binding protein (CREB). Reporter and control plasmids for each of these pathways was transfected into MSCs plated as a monolayer, and then cells were trypsinized and replated as a micromass as described above. Thus, MSCs were initially plated in monolayer in 6-cm dishes at a density of 8 × 105 cells per dish. Twelve hours after plating, cells were transfected with either P3TP-luciferase (Luc), 12 × Smad binding element (SBE)-Luc, NF-kB-Luc, TOPFLASH, AP1-Luc, or cAMP-responsive element (CRE)-Luc. These transfections were performed using Superfect (Qiagen, Valencia, CA) according to the manufacturers instructions. The SV40 Renilla-Luc plasmid was co-transfected to facilitate determination of transfection efficiency on a well-by-well basis, as previously described (Ferguson et al. 2000). The DNA:transfection-reagent ratio used for all experiments was 1:3 (weight/volume) with the following amounts of DNA in 0.6 mL medium: Reporter of interest, 2 μg; SV40 Renilla-luc, 10 ng. Eight hours after transfection, cells were trypsinized, counted, and re-plated in micromass culture as described above. Within 12 hr of replating, cells were exposed to various treatments; 48 hr later, cells were lysed and extracts were prepared using the Dual Luciferase Assay System (Promega, Madison, WI), as directed by the manufacturer. An Optocomp luminometer (MGM Instruments, Sparks, NV) was used to measure luminescence in the extracts.
After rinsing the cell layer with PBS, protein was extracted from micromass cultures using Golden lysis buffer containing protease inhibitor cocktail tablets (Roche Applied Science) as previously described (Samuels et al. 1993). The lysate was centrifuged at 12,000 × g and the insoluble material was removed. The protein concentration of the soluble material was determined via the Bradford Kit (Invitrogen). Aliquots of protein extract (25 μg) were separated by SDS-PAGE (10% polyacrylamide) and then transferred to a polyvinylidene fluoride membrane (Schleider and Schuell, Dassel, Germany). The blots were probed overnight at 4°C with the following rabbit anti-mouse polyclonal antibodies: phospho-Smad3 (Cell Signaling Technology, Danvers, MA), phospho-Smad1/5/8 (Cell Signaling Technology), or mouse anti-β-actin monoclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA). All primary antibodies were applied at a 1:1,000 dilution. Blots were further incubated for 1 hr at 20°C in the presence of horseradish peroxidase–conjugated secondary antibodies against rabbit or mouse (both from BioRad, Hercules, CA) at a dilution of 1:3,000. The immune complexes were detected using ECL-Femto (Pierce, Rockford, IL) and visualized via exposure of X-OMAT AR film (Kodak, Rochester, NY).
MSCs were placed in micromass culture and were treated with Pb in the presence and absence of BMP-2 (50 ng/mL) and TGF-β (5 ng/mL). After 3 days in culture, treatment with Pb resulted in a stimulation of chondrogenesis as measured by the presence of alcian blue nodules (Figure 1A). The effect was dose dependent with quantification of nodule formation showing a 2-fold increase present at 1 μM Pb and nearly a 3-fold increase noted at 10 μM Pb (Figure 1B). As anticipated, treatment of the cultures with BMP-2 or TGF-β led to an induction of chondrogenesis. Although the effect of BMP-2 was slightly greater (3.2-fold) than that of TGF-β (1.7-fold), the induction of chondrogenesis by both growth factors was enhanced by Pb (Figure 1B). In the presence of 10 μM Pb, BMP-2 induced chondrogenesis 5-fold and TGF-β induced a 3-fold increase (Figure 1B). Thus, Pb induces chondrogenesis and enhances the effects of both BMP-2 and TGF-β on this process.
To assess chondrogenesis in MSC cultures on the molecular level, the mRNA expression of Sox9, col2, and aggrecan were determined via real time RT-PCR. Consistent with the alcian blue staining shown in Figure 1, Pb dose-dependently enhanced the expression of these genes, with 10-μM Pb inducing a 2-fold increase in Sox9, a 5-fold increase in col2, and a 2.5-fold increase in aggrecan compared with untreated cultures (Figure 2). Also consistent with the alcian blue results, Pb enhanced both BMP-2 and TGF-β regulation of these genes. Specifically, BMP-2 induction of Sox9 and aggrecan was enhanced 2- to 3-fold by 1 and 10 μM Pb (Figure 2A,C). Furthermore, in the presence of both BMP-2 and Pb, col2 expression was increased to levels above that seen with either BMP-2 or Pb alone (Figure 2B). Comparatively, treatment with a combination of TGF-β and Pb caused an induction of Sox9, col2, and aggrecan that was generally less than the respective effect of Pb alone (Figure 2A–2C). These results further support the hypothesis that Pb influences chondrogenesis directly and influences chondrogenic regulation induced by BMP-2 and TGF β.
To complement the in vitro findings discussed above, chondrogenesis was examined in the context of an in vivo murine model of ectopic bone formation in which we used control C3H10T1/2 cells or C9 cells. A total of 1 × 106 cells were loaded into 2 mm × 2 mm × 2 mm type I collagen sponges and then implanted into the medial thigh musculature of C57/B6 mice pretreated with normal drinking water or water containing Pb (55 or 230 ppm) for 6 weeks. In control C3H10T1/2 cell implanted limbs, we observed proliferation of host mesenchymal cells at the periphery of the implant, but no cartilage tissue formed (Figure 3A). This is consistent with the requirement that BMP-2 is required to initiate the chondrogenic commitment of implanted and/or host cells. It should be noted that control cells did not support a chondrogenic response in Pb-exposed mice (data not shown). In limbs implanted with BMP-2–expressing C9 cells, the mesenchymal cell proliferation was associated with evidence of chondrogenesis beginning at 5 days (Figure 3A). Administration of Pb in the drinking water was associated with a dose-dependent increase in chondrogenesis in 5-day and 7-day tissue samples from C9-injected mice. Quantification of the cartilage content via histomorphometry at these time points confirms the dose dependency of the Pb effect, with the 230-ppm Pb level showing the most robust increase in cartilage area and the percent of the mesenchyme that consisted of cartilage (Figure 3B). These findings are consistent with the in vitro data presented in Figure 1 by demonstrating that Pb enhances BMP-2 induction of chondrogenic responses.
MSCs were transfected with the TGF-β/Smad3 responsive reporter p3TP-Luc and treated with Pb in the presence and absence of TGF-β. Alone, Pb did not alter reporter activity, whereas TGF-β (5 ng/mL) induced a 2.5-fold stimulation (Figure 4A). However, Pb enhanced the effect of TGF-β on the p3TP-Luc promoter, with a maximal 5-fold effect occurring at the 10-μM Pb concentration (Figure 4A). Consistent with these findings, Western blot analysis showed that Pb did not alter levels of phospho-Smad3 alone, but resulted in increased Smad3 phosphorylation in cells stimulated with TGF-β for 1 hr (Figure 4B). These results demonstrate that Pb influences TGF-β signaling and targets Smad3 signaling events.
MSCs were transfected with the BMP-responsive reporter 12 × SBE-Luc and treated with Pb in the presence and absence of BMP-2 (100 ng/mL). Pb itself did not alter reporter activity, but BMP-2 stimulated a 2.4-fold induction. Interestingly, Pb induced a dose-dependent inhibition of BMP-2–induced signaling on the 12 × SBE-Luc promoter, with a maximal 65% inhibition occurring at a concentration of 10 μM Pb (Figure 5A). Consistent with this finding, Pb did not alter levels of phospho-Smad1/5/8 alone, although it had a marked dose-dependent inhibitory effect on BMP-2 stimulation of Smad1/5/8 phosphorylation (Figure 5B). Effects were present by 30 min after exposure and were sustained at 1 hr. These results demonstrate that Pb strongly inhibits BMP-2 signaling (which is opposite the effect of Pb on TGF-β signaling) and suggest another mechanism by which Pb can affect the process of chondrogenesis.
Because Pb has no effect on basal TGF-β–Smad and BMP-Smad signaling, and has opposite effects on these signaling pathways in the presence of their respective growth factors, it is unlikely that the induction of chondrogenesis by Pb is related to direct regulation of Smad signaling. To determine the possible involvement of other pathways known to be important in the process of chondrogenesis, MSCs were transfected with AP1-Luc, NFκB-Luc, CRE-Luc, and TOPFLASH reporters, each containing multiple repeats of the respective consensus binding sites. Although there was no effect of Pb on CRE or TOPFLASH activity (Figure 6A,B), Pb caused a dose-dependent decrease in basal AP1 activity that was maximal (40%) in cultures treated with 10 μM Pb (Figure 6C). Finally, Pb induced a dose-dependent but not significant increase in NFκB activity (Figure 6D). These results suggest that influences of Pb on chondrogenesis may also be partially dependent on a direct alteration of AP1 signaling.
There is growing awareness of the pleiotropic effects of Pb, with targets of toxicity including multiple tissues that include the skeleton. In fact, at concentrations considered subtoxic, Pb is known to affect skeletal growth. The two most recent National Health and Nutrition Examination Surveys (NHANES II and NHANES III) have demonstrated that Pb exposure reduces skeletal growth independent of factors such as nutritional status, social/ economic class, and co-morbid diseases (Ballew et al. 1999). Moreover, significant developmental effects are apparent at blood concentrations as low as 4 μg/dl (Ballew et al. 1999). Thus, skeletal tissues, and particularly the growth plate, are among the most sensitive tissue targets of Pb. Representing a first step toward understanding the mechanism underlying the influence of Pb on the skeleton, findings presented in this article demonstrate that Pb targets mesenchymal stem cells and affects the determination of cell fate. Specifically, embryonic limb bud cells exposed to Pb display a severalfold increase in chondrogenenic commitment. Moreover, Pb induces the chondrogenic effects of both BMP-2 and TGF-β. Because embryonic limb bud stem cells also have the potential to differentiate into other mesenchymal tissues, Pb possibly also influences the cell fate on other cell differentiation pathways.
Pb has broad and complex effects on multiple intracellular signaling pathways. As mentioned above, Pb has been shown in various tissues to a) block calcium signaling and inhibit Ca2+/phospholipid-dependent PKC signaling (Pokorski et al. 1999; Vazquez and Pena 2004); b) induce ERK1/2 and p38 (MAPK) phosphorylation and activation (Lin et al. 2003; Zhang et al. 2003); and c) activate AP-1 signaling (Hossain et al. 2000). We have found that Pb affects neither basal BMP-2 nor TGF-β signaling; thus it is unlikely that the effect of Pb on chondrogenesis is related to a direct alteration of these signaling pathways. Moreover, although Pb enhanced the effect of BMP-2 on chondrogenesis, it acted as an inhibitor of Smad1/5/8 signaling. Further experiments demonstrated that Pb also regulates other signaling pathways, including AP-1 and possibly NFκB. Thus, it appears that the effects of induction of chondrogenesis and enhancement of TGF-β and BMP-2 on chondrogenesis are secondary to stimulation of other interacting signaling pathways.
Previous work has established that Pb regulates BMP and TGF-β signaling pathways. Oral administration of Pb chloride has been shown to cause a reduction in the expression of TGF-β in intestinal tissues in diabetes-prone NOD mice (Goebel et al. 1999). In an earlier study using chicken growth plate chondrocyte cultures (Zuscik et al. 2002b), we found that both Pb and TGF-β independently inhibit expression of the maturational marker colX, Interestingly, this study also showed that inhibition of colX by TGF-β was completely reversed by Pb. Furthermore, although neither Pb nor TGF-β alone affected the expression of BMP-6, in combination they induced its expression 3-fold (Zuscik et al. 2002b). Although these previous studies did not fully examine regulation of downstream signaling events, they did demonstrate a regulation of TGF-β signaling. When considered along with the current findings, it seems clear that the influence of Pb on chondrogenesis/chondrocyte differentiation is at least partially dependent upon the presence of TGF-β and activation of its Smad signaling pathway. Overall, our findings suggest that Pb exposure renders mesenchymal precursor cells more sensitive to TGF-β by increasing Smad3 phosphorylation and signaling. To our knowledge, this is the first demonstration of regulation of Smad phosphorylation by Pb in any cell system.
In the present study, we found that BMP signaling is also regulated by Pb. BMP receptor signaling occurs in a manner analagous to the TGF-β pathway, with Smad1/5/8 binding to the type I BMP receptor, followed by phosphorylation of these factors upon ligand activation (Miyazono et al. 2005). Using a polyclonal antibody that recognizes all three BMP receptor–associated Smads, we found that the basal phosphorylation state was not altered by Pb alone, but the induction of phosphorylation of Smad1/5/8 was markedly inhibited by Pb. Similarly, although Pb did not alter basal activation of the BMP-Smad responsive reporter 12 × SBE, Pb significantly reduced activation of this reporter by BMP-2. Thus, similar to TGF-β signaling, Pb regulates BMP signaling only during activation of the pathway by lig-and. Interestingly, the effects are opposite, with Pb inhibiting BMP-Smad phosphorylation and stimulating TGF-β-Smad phosphorylation. Overall, the potent inhibition of BMP-2–induced Smad1/5/8 signaling by Pb represents the most robust signaling effect identified to date in a skeletal cell type with regard to a candidate mechanism of Pb toxicity.
The complex regulation of the Smad signaling molecules makes it unlikely that the induction of chondrogenesis by Pb is cause by direct alteration of these pathways. Although BMP and TGF-β signaling pathways have antagonistic effects on some cells, including growth plate chondrocytes where TGF-β inhibits and BMP-2 stimulates maturation, both signals enhance chondrogenesis in mesenchymal stem cell populations (Hoffmann and Gross 2001). An earlier study has shown that BMP-4 stimulates chondrogenesis in C3H10T1/2 and MC615 chondroprogenitor cells through activation of the BMP-receptor–associated Smads (Hatakeyama et al. 2003). TGF-β signaling through Smad2 and Smad3 is associated with enhanced chondrogenesis in murine mesenchymal stem cells (Yu and Xing 2006). Additionally, the action of these factors is dependent on complex signaling, because it is clear that TGF-β and BMP signals act in combination with other signaling pathways. In ATDC5 cells, stimulation of chondrogenesis by TGF-β is mediated by activation of Smad pathways and the p38 and Erk1/2 MAP kinase pathways simultaneously (Watanabe et al. 2001). Furthermore, whereas Wnt/β-catenin signaling in vivo appears to stimulate osteogenesis over chondrogenesis (Day et al. 2005), in human mesenchymal stem cell cultures TGF-β acts synergistically with Wnt/β-catenin signaling to induce chondrogenesis (Zhou et al. 2004). Similarly, BMPs have been shown to act synergistically with Wnt/β-catenin signaling to induce chondrogenesis in C3H10T1/2 cells (Fischer et al. 2002). Overall, it is clear that BMP and TGF-β Smad signaling is critical for induction of chondrogenesis; however, these pathways are only a part of multiple signaling events that contribute to the regulation of chondrogenic commitment.
To extend these signaling results, we also examined the effect of Pb on other signaling pathways. Although no effects were observed on CRE and TOPFLASH activation using the respective luciferase-based reporters, the experiments showed that Pb inhibited basal AP-1-Luc reporter activity. AP-1 activation has been shown to inhibit chondrogenesis, so it is possible that the inhibition of AP-1 could be involved in the induction of chondrogenesis by Pb (Hwang et al. 2005; Tufan et al. 2002). The inhibition of AP-1 signaling in mesenchymal stem cells is in contrast to the findings in other cells where Pb induces AP-1 signaling activity. In a previous study (Zuscik et al. 2002b), we showed that Pb increased AP-1 and NFκB signaling in chick embryonic chondrocytes in culture. Furthermore, in vitro Pb exposure in rats results in activation of AP-1 and NFκB levels in multiple regions of the brain and in astrocytes in culture (Ramesh et al. 2001). In vivo Pb exposure results in increased NFκB signaling in renal tubular cells and results in nephritis in rats (Rodriguez-Iturbe et al. 2005). Similarly we found that Pb induces NFκB signaling in MSCs as measured by induction of NFκB-Luc reporter. However, because signaling on the NFκB pathway has been shown to destabilize Sox9 mRNA and inhibit chondrogenesis (Sitcheran et al. 2003), it is unlikely that Pb-induction of NFκB signaling seen in MSCs is directly causing an enhanced chondrogenic response.
The induction of chondrogenesis by Pb in the current study is consistent with findings observed in an in vivo murine model of fracture healing (Carmouche et al. 2005). Mice with Pb levels similar to those found in humans with Pb intoxication had delayed healing of stabilized femur fractures. The effect was dose dependent, and cartilage was observed to be a major target. Pb-exposed mice had increased cartilage volumes, delayed chondrocyte maturation, persistence of cartilage, and reduced bone formation (Carmouche et al. 2005). Overall, when considered along with the results of Carmouche et al. (2005), our findings in the present study further support the hypothesis that Pb is an inducer of chondrogenesis.
In conclusion, the present study establishes that in addition to affecting chondrocyte maturation, Pb accelerates the differentiation of mesenchymal precursors into chondrocytes. Although Pb alters BMP and TGF-β signaling, the mechanism through which Pb regulates mesenchymal cell fate determination is complex and likely involves modulation and integration of multiple signaling pathways. Increased understanding of the mechanisms through which Pb regulates stem cell fate and subsequently affects tissue repair is critical, given the sensitivity of these tissues and the ubiquitous presence of Pb in our society and in other industrialized and developing nations.
This work was supported by grant PO1 ES011854 from the National Institutes of Health (J.E.P. and R.J.O.).
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