In the heart of the Esterel red rocks, on the Corniche d'Or, between Théoule-sur-Mer and Saint-Raphaël, the areas of Agay and Antheor offer the most beautiful and surprising landscapes in the Var. The contrast between the crystal-clear blue waters of the sea (to discover when wandering around in creeks and on beaches), the ochre colours of the rocks and the lush greenery offer views worthy of master paintings.
Some properties indulge in the luxury of private beaches, boat houses, pontoons or even private moorings.
In the hills, premium villas, hidden from sight, reveal breath-taking sea views, from Cap Roux to beyond Le Dramont.
This area in the Var offers a wild environment, much sought-after for its quietness and its preserved nature, comprising the area of Anthéor on the way to Cannes, and the area of Agay, with its port, its restaurants and shops, on the way to Saint-Tropez.
The real estate agency MAGREY & SONS, specialized in the sale and rental of luxury villas in Anthéor and Agay, will assist you throughout your project.


OSHA will host two additional stakeholder meetings to help develop a proposed rule for Injury and Illness Prevention Programs -- referred to as "I2P2."
The meetings are scheduled for July 20 in Washington and Aug. 3 in Sacramento, CA. The purpose of the meetings is to gather information to develop and implement a plan for employers that proactively identifies and corrects workplace hazards, the agency said. Meetings previously were hosted in Texas and New Jersey, and another is scheduled for next week in Washington.
OSHA is asking stakeholders for their thoughts on the proposed regulation, which agency administrator David Michaels called a "commonsense rule" that places the impetus for protecting workers and reducing hazards on the employer.
"Instead of waiting for an OSHA inspection or a workplace tragedy to address workplace hazards, employers would be required to create a plan for identifying and remediating hazards, and then implement this plan," Michaels said in a speech earlier this month at the American Society of Safety Engineers' Safety 2010 Professional Development Conference and Exposition in Baltimore.


Our One Bedroom Suites are a part of a villa having a hall, dining table, kitchen and balcony. Extremely popular with guests, be it a family or a group of friends, it serves as an ideal home away from home.
The One Bedroom suites in Goa have been furnished with a double bed, a wardrobe fitted with an electronic safe, A/C and ceiling fans. A functional kitchen, designed for your cooking pleasure, is fully equipped with crockery, cutlery, cooking utensils, a fridge, microwave oven, cooking range and an electric kettle. Other facilities include a washing machine, iron and ironing board.
In addition to all of this, the resort entitles guests staying here to room service, daily housekeeping, the pool side bar and the two swimming pools.
These tastefully designed two bedroom Suites feature a spacious living room, two bedrooms that open out to your balcony and mini private garden. Perfect for families and small gatherings these Two Bedroom Suites are situated hardly 5 minutes walk from famous Sinquerim Fort Aguada Beach Candolim North Goa.
The two bedroom suites have been furnished with a double / twin beds, a wardrobe fitted with an electronic safe, A/C and ceiling fans. A functional kitchen, designed for your cooking pleasure, is fully equipped with crockery, cutlery, cooking utensils, fridge, microwave oven, cooking range and an electric kettle. Other facilities include a washing machine, iron and ironing board.
Overall service is very good. Hope to see you soon again.


An agricultural officer at Mpatsa Agricultural Extension Planning Area (EPA) and a metal scrap businessman plying his trade in the area of Traditional Authority Tengani in Nsanje are in the cooler for alleged theft of farm inputs.
Nsanje police officer in-charge Assistant Commissioner of Police Maurice Makwinja identified the suspects as Godfrey Mukhondiya, 33, who works as Agricultural Extension Development Officer (AEDO) and Thoko Chitowe, 29.
Makwinja said the suspects allegedly stole bags of fertilizer, treadle pumps and two bicycles from the EPA's warehouse between April 5 and June 7, 2017 whose value is yet to be established.
"We arrested the two suspects following a complaint from the District Agricultural Development Officer (DADO) that some items were missing. The DADO had written the District commissioner and copied the letter to us on the issue. Upon receiving the communication, we made follow ups and arrested the two," Makwinja said.
He said the stolen items were donated by some non- governmental organizations for distribution to farmers in the area of Senior Chief Tengani.
Makwinja further said the second accused was used as a conduit in the crime.
On the value of the stolen items, the Assistant Commissioner of police Makwinja said the value of the stolen items was yet to be established.
But sources within the agricultural system claim the items were valued at about K2.4 million.
The suspects are expected to appear before court on Wednesday and will answer charges of theft.
Godfrey Mukhondiya hails from Katutula Village in Traditional Authority (T/A) Mwaulambya in Chitipa district while Thoko Chitowe comes from Chikunkhu Village. T/A Tengani in Nsanje.


The second advertisement we will be featuring from the 1940 Story City Herald Anniversary Number book is from the Story City Butter Tub Company. The Butter Tub Company was a family owned business in Story City for 85 years.
In 1883 Hactor Hill came to America, making his home for short time at his uncle's folks, Bor Enge, at Roland, Iowa. Not long after his arrival to this country he started work at Mr. Thompson's cooper shop in Ames. This shop was moved to Story City in 1887. When Mr. Thompson in 1891 sold his business, the Hill family bought it. Hactor Hill was in the cooper business for 42 years until his death in 1933.
Hactor's sons and grandsons owned and operated the Story City Butter Tub Co until a tornado hit Story City in 1976. The building was demolished in the storm. At that time it was the oldest building in Story City.
As you can see from the 1940 ad, the Butter Tub Co. was not only producing quality butter tubs, they also sold coal, stokers, and specialized in roofing. The company specialized in roofing for many years. In fact, Hactor's great grandson, Paul Hill, is currently in the roofing business in Story City.
Story City Butter Tub Co. photo late 1800s.


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Frequent hand washing with a trusted brand like Safeguard helps reduce bacteria which can cause cross-contamination.
Skin conditioning ingredients help prevent dry skin.


Just a short post today. I have a lot of irons in the fire, and all of them need tending.
I just found out today that my oldest granddaughter won her classroom spelling bee, yesterday. Yay! The word was "concrete", and I'm sorta tickled. Who knows? Maybe she'll be a writer some day. LOL.
On the writing front, I'm juggling two first drafts, and waiting for word from the publisher on Chucklers – Book 1. Until recently, I've been pushing mainly on End Point Pangaea, and pretty much ignoring Year 12. But considering how long it seems to take going through a publisher, I've decided to begin concentrating more on Year 12. Money's getting too tight, and I've got to do something to get an income stream going. I've thought about my options, and since Y12 is going to be self-pubbed, it will take less time to get it edited, published, and start earning revenue.
So that's taking most of my time now. I know I'll be jumping back and forth at times between Y12 and EPP, but Y12 will have to be my main project for a while.
In addition, watch for a new short story out in the near future. In 2012, I had a short story published in an anthology called Explorers: Beyond the Horizon. That story was The Burning Land, and it was pretty well received. The rights to the story reverted back to me last year, and I've been toying with the idea of self-publishing it since that time.
Of course, the catch to self publishing is the fact that you have to pay for editing, formatting, and cover art on your own, then hope you make enough in sales to earn that investment back. Editing is usually the biggest cost, but this one was already edited before it went into the anthology. The second biggest cost is usually cover design. And in order to publish The Burning Land, I would have to invest money in a cover for it. And since it's a short story, I wouldn't feel right charging more than Amazon's 99¢ minimum price.
Now, if you aren't an author, you may not know this, but Amazon slants their percentages to encourage authors to charge $2.99 or more. The way it works is that an author charging $2.99 or more, gets to keep 70% of the money earned on the story. Anything below the $2.99 price point only earns 35%. AND they don't allow you to charge less than 99¢ at all (with a very few, tricky exceptions).
So if I were to get a decent cover for this short story, it would likely cost me a couple of hundred dollars. Let's call it $150, for now, just for giggles. If I charge the minimum of 99¢ for the story, for each copy sold, I get back 34¢. At that rate, I would have to sell nearly 450 copies just to break even, and since short stories by unknown authors don't sell well to begin with, that would take more time than it's really worth.
But last month I won a contest. The prize was a free cover by author and cover artist Denise Lhamon. Woohoo! And that means that I can afford to publish TBL after all. So while it won't make me rich, by any means, it will mean at least a little money in the coffers while I continue working on the other books.
That's all I have for now. Time to get back to work. So stay safe, and I'll talk to you again next week.


How's it going? A crowd of indie developers are selling a lots of their games which includes some of the biggest ad lib games on the market. Gamers can dub their own price—from 1c to $1,000—suitable a make over at large of games that would go to the john for around $80 if sold separately. Anyone who buys the package can feel change undivided's mind hither themselves as genially; customers can send any amount of their purchases to two bigger nonprofit groups. The sellathon, nicknamed the "Ignoble Container" not later than the studios entangled with, is certainly epic. The games included in the containerize are Mankind of Goo, Gish, Lugaru, Aquaria, and Penumbra Overture. Each of these titles has proven to be a unalloyed birch, and the end that five away studios are working together to put out them shut up shop by to gamers in behalf of no signification what much they stick to roister is unusual. As Jeff Rosen of Wolfire explained to Ars in a current talk, the close-knit cleverness of community aggregate indie developers is mostly leading for the selling's existence.


I am tryingto setup raidmanager between and XP 24K and an XP20K.
I could create the CA sync pair between the 2 xp's find but cannot get HORCM working.
pairdisplay -g catest -l works find in both sites showing the status of the local LDEV.
Refer to the command log(C:\HORCM\log0\horcc_bkpdc002_log.txt) for details.
11:19:15-0a7f8-03736- [pairdisplay] Invalid muno(10) is used in remote devname(Drive12T).
[Cause ]:The MU# of the volume to be operated is not appropriate.
[Action]:Please confirm the mu#(MU#1/2/3 cannot be used for HORC, and MU#1/2 must be P-Vol for HOMRCF, MU#1/2/3 must be P-VOL for UR) for the specified group using pairdisplay command.
Please note that from the XP web console I am able to operate the sync pair without problems.
I would appreciate any inputs on this.
2. HOMRCF may use the $HORCC_MRCF envir var, which sets the exec environment for XP BC commands. This var determines if the command applies to XPCA or XPBC. If you use the XPCA only, its not necessary to set this var.
from here you can see the permitted LDEVs/(LVMs) for the appropriate MU#.
but last time I wrote a HORCM file for CA, you did not specify an MU (mirror unit) number.
You only use MU with Business Copy...... right??????
Remove the MU number (10 in your examples above) and it will be assumed that it is CA rather tha nBusiness Copy.


text:
Q: Diffrerent exceptions when creating files on external storage I am receiving different crashes when creating files on external storage in non appliation specific folder. This code works fine for most users, but failing for some. I am using approximately following code when creating files:
public static boolean isExternalStorageAvailable() {
    String state = Environment.getExternalStorageState();
    return (Environment.MEDIA_CHECKING.equals(state) || Environment.MEDIA_MOUNTED.equals(state));
}

public File getTargetDirectory() {
    File root = Environment.getExternalStorageDirectory();
    File directory = new File(root, "DIRECTORY");
    directory.mkdirs();
    return directory;
}

public static void createFile() {
    if (isExternalStorageAvailable()) {
        File file = new File(getTargetDirectory(), "filename.dat");
        if (file.exists())
            file.delete();
        file.createNewFile();
        //other code...
    }
}

I have following permission in the AndroidManifest.xml:
<uses-permission android:name="android.permission.WRITE_EXTERNAL_STORAGE" />
<uses-permission android:name="android.permission.READ_EXTERNAL_STORAGE" />

I am receiving different Exceptions (wrapped in java.io.IOException) when createNewFile() is executed:
libcore.io.ErrnoException: open failed: EACCES (Permission denied)
1   libcore.io.Posix.open
2   libcore.io.BlockGuardOs.open    BlockGuardOs.java, line 110
3   java.io.File.createNewFile  File.java, line 941

libcore.io.ErrnoException: open failed: ENOENT (No such file or directory)
1   libcore.io.Posix.open
2   libcore.io.BlockGuardOs.open    BlockGuardOs.java, line 110
3   java.io.File.createNewFile

These exceptions happen on different Android devices running different OS versions. This folder is basically drop in folder where app is writing data for user to transfer to different devices. So user can copy this folder from his PC.
Could it be some kind of read only permission issue?

redpajama_set_name: RedPajamaStackExchange


text:
H1N1, SCMS and the Japanese Bureaucracy
« Miike Takashi and Contemporary Japanese Cinema
Alt-SCMS: The JIU Media Studies Department Media Workshop »
Alt-SCMS is over and done with - and not a single person sick or quarantined (so far?). It was a great success: nearly 250 participants, great help from Josai International and Waseda universities, and cooperation all around. You're used to many people taking too long to read their papers at conferences like this, but it was as if this time everyone understood the special circumstances behind this gathering and managed themselves admirably. The National Film Center put on a great screening of Ogino Shigeji animated shorts, including one, An Expression (1935), in color; a Saito Torajiro slapstick short; Naruse Mikio's Each Night I Dream; and Ishida Tamizo's stunning Flowers Have Fallen. And every film earned a hearty round of applause. The film directors Kurosawa Kiyoshi and Aoyama Shinji did a great talk on the state of their work and the industry (more on that later). And USC and the MacArthur Foundation hosted a wonderful final party at Super Deluxe. Markus Nornes, Akira Lippit and I ended up being the main organizers, but there was a lot of help from many directions.
It was one of the stranger conferences one could encounter. Everyone had to get a health check at the door (a body temperature of over 38 degrees C could have earned you a trip to the hospital and quarantine), fill out a form declaring your condition and whereabouts, wear a mask throughout the conference, declare which panels you attended, and use hand sanitizing liquid every time you entered and left a room. The atmosphere was a bit surreal:
The entrance to JIU with the health check.
My panel full of masked strangers! I wasn't sure if they were going to rob me or what!
But everyone took all this in stride and actually had a lot of fun.
Now I don't want to put down the seriousness of the H1N1 virus or the need to take precautions, but there was a lot that was questionable about the situation. First, the reaction of health officials in Japan. Putting aside the problem of implementing policies that still treated the virus as extremely deadly even long after it was clear it was not, or that concentrated so much on foreign viral invasions they ignored domestic infections, the policies were bureaucratic and political. On the day SCMS was cancelled, we saw NHK showing images of a major international sports festival taking place in Japan with lots of foreign athletes and visitors. Were any of them forced to wear masks? No, and probably because Japan wants to get the Olympics. Other cities or wards had international conferences, but with none of these restrictions. It really seems like Chiyoda Ward health bureaucrats just decided they did not want anything to occur on their turf, so they erred on the side of trying to cancel the conference (and according to the SCMS mailing, it was Chiyoda that tried to force cancellation even before a single case of H1N1 had appeared in Japan; some news reports in Japan erringly said it was just SCMS chickening out). They probably feared the media in Japan, which has been positively awful, exposing poor students and school principals to excessive public exposure just because someone came down with a mild case of the flu (with this kind of exposure, anyone with H1N1 is going to hide that fact - and thus spread the flu some more). One has to question a system where the bureaucracy rules by avoiding problems (and foreign impurities!), not by dealing with them; where the public demands a parental state to the extent of lashing out at even the smallest mistake; and a media which profits off of a subjectivity that, demanding an impossible perfection, remains in perpetual anxiety and in need of media frenzy.
The day after SCMS was cancelled, NHK broadcast news that Governor Ishihara had announced a new program of public support for international conferences. Hah! Don't make me laugh! Maybe the lesson of SCMS is this: you better think twice about holding an international conference - or the Olympics for that matter - in Tokyo.
There was blame to spread around. Perhaps JIU shouldn't have gone to the health office in the first place (is there any legal requirement to do that?). Perhaps SCMS could have been more courageous - and not have sent out such a gloom and doom e-mail when surveying the membership. And perhaps a lot of those who cancelled could have been braver themselves.
But it was their loss. We had a ton of fun, and an experience we'll never forget. Some events like the NFC screening got a much better attendance than they would have otherwise; and Japanese cinema really took the center with some great panels. Everyone was united with a common purpose by the absurd environment. SCMS should always be like this!
Signed: Your masked avenger!
UPDATE: I found a video online showing the event.

redpajama_set_name: RedPajamaCommonCrawl


text:
Q: MATLAB: Undefined function 'isfinite' for input arguments of type 'cell' I am pretty new to MATLAB. I want to make a pie chart of a dataset which contains categorical data:
 ?                      1836
 Federal-gov             960
 Local-gov              2093
 Never-worked              7
 Private               22696
 Self-emp-inc           1116
 Self-emp-not-inc       2541
 State-gov              1297
 Without-pay              14

I imported dataset whose size is 32561x1 and i converted it into categorical data using:
w = categorical(w)

now when i use the pie command in matlab:
pie(w)

it gives me the following error:
Undefined function 'isfinite' for input arguments of type 'cell'.
Error in pie (line 34)
if ~all(isfinite(x))

I am not understanding is my dataset too big for this pie chart? what can i do to generate a pie chart for this big categorical data?
Thanks in advance.

A: The categorical data type in 2014a didn't have support it does now (generally due to newness). In more recent versions you can pass the categorical array to pie directly. In 2014a passing the category counts will work, as any numeric array would. This is simple to do with the countcats function. While the categories function can return the category names as strings to use for labelling.
using the test case given by David in comments
A={'first' 'second' 'third' 'fourth' 'fifth'};
B=randi(5,20,1);
C={A{B}}.';                                     %'
C=categorical(C);

you can just call
pie(countcats(C))

and to include the labels:
pie(countcats(C),categories(C))


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Silver award winner at the World's Original Marmalade Awards 2018.
Deliciously fruity marmalade made with sun-ripened bitter oranges, wonderful on hot buttered toast. Can be used as an ingredient in many dishes from casseroles to steamed sponge pudding. Marmalade ice-cream is heavenly.


text:
Flip to Back Look inside
https://wheatmyermusic.com/wp-content/uploads/2019/12/Mine-Eyes-Have-Seen-the-Glory-NP.mp3
For Trombone/Low Brass Quartet
In 1861, the sight of Northern troops assembling in Washington, D.C. inspired Julia Ward Howe to pen the words to The Battle Hymn of the Republic, which begins, "Mine eyes have seen the glory of the coming of the Lord." Although originally intended to stimulate patriotic fervor, the text's potent depiction of biblical themes – God's certain and final defeat of evil, the looming eternal judgment of all souls, Christ's atonement on our behalf, and a clear call to sacrificial evangelism – the work became prominent in many American hymnals. As summer approaches with the major American holidays of Memorial and Independence Days you may be seeking appropriate music to use in recognition of God's providence and sovereignty. Here is one option for you, my arrangement of Ward's hymn titled Mine Eyes Have Seen the Glory, set for trombone/low brass quartet. It's a short piece, suitable for prelude, offertory, postlude, or other moments in your service, or would make a marvelous addition to a patriotic service or a summer bandstand concert. It is accessible and enjoyable for intermediate and higher level musicians. With rich harmonies and shifting colors, a twist on the traditional meter, and variations in tempo, it is a delight to the ears that underscores the implications of the unvoiced lyrics.
Categories: Band, Chamber Groups, Instrumental Tags: america, Battle Hymn, folk, patriotic, USA
Mine Eyes Have Seen the Glory is part of a growing collection of Americana Miniatures, short, mostly instrumental arrangements of characteristically American folk music. This arrangement is set for four trombones, or three trombones and tuba, but is also suitable for any combination of four low brass instruments in 'C'. The music is instantly recognizable and appealing to broad audiences and playable by musicians of moderate skill.
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A Hymn of Beginnings
https://wheatmyermusic.com/wp-content/uploads/2019/12/Hymn-of-Beginnings-BUNESSAN.mp3
Fantasia on BUNESSAN
For Solo Bassoon and Piano
Looking for a sacred bassoon solo? Well, you've found it! Utilizing the melody from Morning Has Broken(the traditional Gaelic tune BUNESSAN) A Hymn of Beginnings presents a familiar yet fresh treatment of the tune in this setting for solo bassoon and piano. Suitable as a prelude, postlude, offertory, meditative, or other functions in a sacred service it is also at home in a recital or concert program.
Ponder Anew
https://wheatmyermusic.com/wp-content/uploads/2019/12/Ponder-Anew-SCORE.mp3
a tone poem on LOBE DEN HERREN
Ponder: to think about carefully, especially before making a decision or reaching a conclusion.
Anew: In a new or different and typically more positive way.
These two words come from the third stanza of Joachim Neander's perennially popular hymn, "Praise to the Lord, the Almighty." And just as this stanza invites us to "Ponder anew what the Almighty can do," this orchestral hymn invites us to consider afresh the attributes and works of Almighty God. Ponder Anew is purely an instrumental work but the text and tune are so familiar that the words will spontaneously spring to mind as the theme unwinds. Thereby, the new harmonies, rhythms, and phrasings in Ponder Anew will likely elicit from the listener a new and different way of thinking about the text. So, as this new setting of the tune melds together peace, majesty, mystery, power, beauty, and grace it stirs the listener to "think carefully, in a new and more positive way, about what the Almighty can do."
The music in not particularly difficult and should be readily playable by high school or higher level musicians. Yet, both musicians and audience will find the power and intimacy of the work interesting and enjoyable with music that reflects the majesty and mystery of its subject.
https://wheatmyermusic.com/wp-content/uploads/2019/12/Something-a-Little-Different-Live.mp3
a polytonal etude
For Bb Tenor Saxophone and Piano
Something a Little Different is a brief excursion into bi-tonality for tenor sax and piano. It's a little bit jazzy, a little bit impressionistic, a little bit 20th century, and, well, something a little different. Suitable for intermediate and above players, this is a fun to piece to play and to hear. While it is unique and modern in its stylings, Something a Little Different is easy on the ears and very accessible for all kinds of audiences. It makes a great recital piece for the up and coming saxophonist to show off, or would work as a transition movement in a concert program, or for any program needing 21st century works.
Fairest Friend
https://wheatmyermusic.com/wp-content/uploads/2019/12/FairestFriend.mp3
For Flute, Horn or Trombone, Piano, Drum Set, Strings/Synth
Fairest Friend is a medley of two beloved hymns, Fairest Lord Jesus and What a Friend We Have in Jesus. It is set as a flute and horn (or trombone) duet with piano accompaniment. Optional rhythm and strings/synth may be used if available or to add color but the piece works well with the three principal instruments.
Duration: ~4:00
Oh, Shenandoah
https://wheatmyermusic.com/wp-content/uploads/2019/12/Oh-Shenandoah-NP.mp3
an American Folk Song
Some would say Oh, Shenandoah is the quintessential American folk song. But almost everything about the song is clouded in confusion and obscurity. When was is written? No one knows. It was first published in 1882 but is almost certainly much older than that. What is it about? Many people associate it with the Shenandoah Valley in Virginia but its lyrics repeatedly refer to the Missouri River which is hundreds of miles from Virginia. Many think that Shenandoah was an Indian chieftain and the song is about a love-sick frontiersman pining for the chieftain's unnamed daughter. Whatever the case, it's a song Americans love to hear and to sing. So, when looking for a traditional American tune to arrange for trombone quartet, Oh, Shenandoah was a very natural choice. Listen to this colorful and emotive arrangement for trombone/low brass quartet and see if images of the American countryside don't spring to mind!
What Child We Sing?
https://wheatmyermusic.com/wp-content/uploads/2019/08/What-Child-We-Sing-NP.mp3
Reflections on two carols
2/1/1/0 4/3/3/1 Timpani/Glockenspiel, Percussion (1), Harp, Piano, Strings
What Child We Sing? blends the melodies of GREENSLEEVES and NOEL NOUVELET into a new work for orchestra that explores the clash of transcendence meeting imminence at Christ's incarnation. Soft and ethereal whispers of strings and winds meet violent thunders of brass and percussion in contemplation of the awesome majesty of the Eternal Son wrapped in the harmless, delicate flesh of a newborn babe.
What Child We Sing? fits perfectly in the Advent or Christmas seasons with its strong exposition of traditional Christmas carols and would be suitable as a prelude, offertory, or reflective music in either liturgical or unstructured service. It has sufficient artistic metric to be suitable for the concert stage as well, although it is not at all difficult, being suitable for intermediate or higher level musicians. "
You are previewing: Mine Eyes Have Seen the Glory


On the topic of Thai classroom assistants and are they useful to a foreign teacher? I have six teachers with me. (One for each level that I teach.) They are all different and they all need to be treated differently.
Friends of mind say that they give importance to student notebooks by grading them, giving stickers to those who have a complete set of notes , stamping them with positive comments - and giving points as part of their grade to those students who have complete, neat, and beautiful notebooks.
Wouldn't it be great if students could use some of thier social networking time to develop their English? This was the thinking behind a project I started with my Mathayom 3 students - 'A Tweet a Day'.
Here's a story about some very young but very sharp Thai and Chinese students.
Is it a case of too much monkeying around?
Games can reinforce what has been taught earlier in a lesson and can be used as a filler or as a reward for good work. But to expect foreign English teachers to spend the majority of their time entertaining students, especially adults, is, to me, just not right.
I come from a society and a culture where the copying of anything in or out of a classroom is simply looked on as cheating. Not only cheating the whole idea of education but cheating oneself out of any possibility of learning, not to mention a total disrespect of the student who goes to the trouble of learning the correct answers in the first place. So I was appalled beyond measure when I saw my first example of copying in my classroom at my first school in Phuket.
I've said it before, and I'll say it again: Thai schools love to put on a show. It's not always a GOOD show, but at least once every week or so, my school has some kind of event happening during morning assembly that lasts well into the school day.


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Westleigh House Farm is a 300 acre working sheep and arable farm. Just two miles from the nearest town of Bideford, seven miles from Barnstaple and just a few minutes from the beach, this makes Westleigh House Farm the perfect place to stay.
The Pines at Eastleigh is a Grade 2 Listed Georgian country house set in 7 hilltop acres with magnificent views over open countryside to Hartland Point and Lundy Island.
Log-fires, king-size beds, garden room bar with library, maps and a warm welcome await our guests.
This is exactly the sort of place to come and stay if you want a countryside escape. We offer a kind of rustic decadence to our guests. It's a wellies and fizz sort of place really.
Eastleigh Barton is a family owned working fram, peacefully set in beautiful Devon countryside. As a guest here you will be staying in the farmhouse, which dates back to the 16th Century, and still retains some lovely original features.
Situated in an attractive hillside position with magnificent far reaching views over the estuary of the River Taw to Saunton Down and up to the hills of Exmoor. The sandy beach of Instow is only two and a half miles away.


Thanks to two effusive research reports, Apple Inc. (Nasdaq: AAPL) stock cracked the $100-a-share milestone yesterday (Tuesday).
The close of $100.53 also marked an all-time closing high for Apple stock. The previous all-time closing high (before the 7-to-1 stock split in June) was $702.10, or $100.30 adjusted.
In early trading this morning (Wednesday) AAPL hit $100.77, edging past its previous all-time intraday high of $705.07 pre-split, or $100.72 adjusted.
As of yesterday's close, AAPL stock is now up 25.43% year to date, compared to just 7.2% for the Standard & Poor's 500 index.
The price rise also has made Apple by far the largest company in the world by market cap. The Cupertino, Calif.-based tech giant's $601 billion valuation is way ahead of the next largest company, ExxonMobil Corp. (NYSE: XOM) at $423 billion.
Given all the excitement about fall product launches, including the iPhone 6 and the long-rumored iWatch, it was only a matter of time before Apple shares crossed the $100 mark. But yesterday's Morgan Stanley (NYSE: MS) report by analyst Katy Huberty and another by RBC Capital Markets analyst Amit Daryanani forced the issue.
"We recommend adding to positions into the iPhone 6 + iWatch product cycles," Huberty said.
Huberty listed a broad range of catalysts for the Apple stock price, and raised her price target from $99 to $110 with an "overweight" rating.
Daryanani mostly saw higher-than-expected iPhone 6 sales as driving Apple stock, in addition to new iPads and the potential for "other major product lines."
Let's look at these catalysts in more detail.
First and foremost, there's the iPhone 6, which is expected to debut at a special event Sept. 9.
Supply chain data has forced Daryanani to reconsider his iPhone 6 estimate of 65 million units sold.
"Most supply chain data is pointing towards Apple gearing up to ramp 70-80 million iPhone 6 units across the two form factors (4.7"/5.5")," Daryanani, who also raised his price target for AAPL to $110, said. "This is a notable uptick from last year when the supply chain ramped 50-60 million units."
Meanwhile, Huberty noted that that iPhone loyalty has increased from 73% in December 2011 to 90% in March. The iPhone accounts for more than half of Apple's profits.


text:
Surrogate R-spondins for tissue-specific potentiation of Wnt signaling
View ORCID ProfileVincent C. Luca, Yi Miao, Xingnan Li, Michael J. Hollander, Calvin J. Kuo, K. Christopher Garcia
Vincent C. Luca
1Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, and Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA
3Department of Drug Discovery, Moffitt Cancer Center & Research Institute, Tampa, Florida, 33612, USA
ORCID record for Vincent C. Luca
For correspondence: Vince.Luca@moffitt.org kcgarcia@stanford.edu
Yi Miao
Xingnan Li
2Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
Michael J. Hollander
4Department of Bioengineering, Stanford University, Stanford, California 94305, USA
Calvin J. Kuo
K. Christopher Garcia
Secreted R-spondin1-4 proteins (RSPO1-4) orchestrate stem cell renewal and tissue homeostasis by potentiating Wnt/β-catenin signaling. RSPOs induce the turnover of negative Wnt regulators RNF43 and ZNRF3 through a process that requires RSPO interactions with either Leucine-rich repeat containing G-protein coupled receptors (LGRs) or heparin sulfate proteoglycans (HSPGs). Here, we describe the engineering of 'surrogate RSPOs' that function independently of LGRs and HSPGs to enhance Wnt signaling on cell types expressing a target surface marker. These bispecific proteins were generated by fusing an RNF43- or ZNRF3-specific single chain antibody variable fragment (scFv) to the immune cytokine IL-2. Surrogate RSPOs mimic the function of natural RSPOs by crosslinking the extracellular domain (ECD) of RNF43 or ZNRF3 to the ECD of the IL-2 receptor CD25, which sequesters the complex and results in highly selective amplification of Wnt signaling on CD25+ cells. Furthermore, surrogate RSPOs were able substitute for wild type RSPO in a colon organoid growth assay when intestinal stem cells were transduced to express CD25. Our results provide proof-of-concept for a technology that may be adapted for use on a broad range of cell- or tissue-types and will open new avenues for the development of Wnt-based therapeutics for regenerative medicine.
The Wnt/β-catenin pathway controls cell fate determination and tissue homeostasis in all metazoans1. Pleiotropic Wnt signaling exhibits differential effects on a wide array of cell types and is therefore tightly regulated by several host-encoded enhancers and inhibitors. R-spondin proteins (RSPO1-4 in mammals) potentiate Wnt signaling by antagonizing negative regulators of the Wnt receptor Frizzled2. The effect of RSPO is remarkably potent, and co-administration of Wnts and RSPOs can result in signaling outputs that are several hundred-fold greater than those of Wnt alone3.
RSPO-mediated enhancement occurs via an indirect mechanism that greatly increases expression levels of the Wnt receptors Frizzled (Fzd) and LRP5 or LRP6 on the cell surface. In the absence of RSPO, the transmembrane E3 ligases RNF43 and ZNRF34 ubiquitinate the intracellular regions of Fzd, which results in the internalization and degradation of both Fzd and associated LRP5/6 proteins (Fig 1A). RSPO proteins are comprised of two Furin-like domains (Fu1, Fu2) followed by a thrombospondin domain (TSP) and basic region (BR). The Fu1 domain of RSPO binds to the extracellular domains (ECDs) of RNF43 or ZNRF3 while the Fu2 domain binds to the ECD of a co-receptor, the Leucine-rich repeat-containing G-protein coupled receptor 4, 5 or 6 (LGR4-6)5-8. This crosslinking event induces endocytosis of the RSPO-LGR-E3 ligase ternary complex, which sequesters RNF43 or ZNRF3 from Fzd and, in turn, potentiates Wnt signaling (Fig 1B). It was recently determined that RSPO2 and RSPO3 can function independently of LGRs by binding to heparan sulfate proteoglycans (HSPGs) on the cell surface via their TSP and BR domains9. These data suggest RSPO are modular molecules consisting of an RNF43/ZNRF3 binding domain that is necessary for the potentiation of Wnt signaling and an LGR/HSPG-binding domains that facilitates internalization of the complex.
Figure 1. The R-spondin signaling mechanism.
In the absence of RSPO, ZNRF3 drives membrane clearance of Fzd receptors to negatively regulate Wnt signaling. RSPO-mediated crosslinking of the ECDs of RNF43 or ZNRF3 and LGR4, LGR5, or LGR6 sequesters RNF43/ZNRF3 to restore Fzd surface levels, thereby potentiating Wnt activity. Surrogate RSPOs mimic the function of wild type RSPOs by cross-linking RNF43 or ZNRF3 to tissue-specific markers known to undergo endocytosis upon ligand binding. PDB files 5UK57, 4F0A25, 3S8Z, and 3S9426 were used to generate the images above.
Biomedical applications of recombinant RSPOs have been widely explored in the field of regenerative medicine, especially in the context of the small intestine where RSPOs function to promote the renewal of stem cells at the base of the crypt10,11. For example, recombinant RSPO1 protects animals from both experimentally induced colitis and from lethal doses of chemoradiation by stimulating intestinal regeneration12. Furthermore, the addition of exogenous RSPO is critical for the proliferation of intestinal organoids10, an in vitro model system for intestinal epithelium studies. Interestingly, it has been recently reported that Wnts and RSPOs play non-equivalent roles in intestinal stem cell (ISC) self-renewal through a feedback loop, in which Wnts drive the expression of LGR5 and RSPOs induce ISC expansion13, raising the possibility that targeting the pathways individually or in concert may be associated with unique therapeutic outcomes.
Potential obstacles for the clinical use of Wnt agonists include toxicity, off-target effects, and diminished potency caused by RNF43/ZNRF3-mediated antagonism. Wnts are powerful morphogens and hyperactivation of the Wnt pathway has been implicated in the development of several human cancers14. RSPOs are promising candidates to selectively boost innate Wnt activity while circumventing off-target effects associated with global Wnt agonism. However, our ability to target RSPOs to specific tissue or cell types is restricted by the expression profiles of RSPO receptors, since HSPGs are ubiquitously expressed and LGR expression is restricted to subsets of tissue stem cells. To develop precisely targeted RSPO mimetics, we engineered synthetic protein ligands that phenocopy RSPO-mediated Wnt signal enhancement via an LGR- and HSPG-independent mechanism. These "surrogate RSPOs" function by cross-linking the RNF43 or ZNRF3 ECD to an immune cell surface marker (CD25) that is known to undergo internalization upon ligand binding15, thereby mimicking RSPO-mediated sequestration of RNF43/ZNRF3 (Fig. 1). Surrogate RSPOs selectively boost Wnt signaling in CD25+ reporter cells and human colon organoids, and their modular design allows them to be adapted to target virtually any cell type, a feature that has major implications for the development of Wnt-based therapeutics.
Isolation of RNF43- and ZNRF3-specific scFvs using yeast surface display
Our surrogate RSPO design concept involves the fusion of two components: (i) a RNF43- or ZNRF3-binding protein and (ii) a tissue-specific targeting protein that binds to a surface receptor. Administration of the surrogate RSPO protein will cross-link ECD of RNF43 or ZNRF3 to the target and mimic the function of natural RSPOs by sequestering or internalizing the complex. We isolated the RNF43- or ZNRF3-binding protein components for the surrogate RSPOs by selecting single-chain variable fragments (scFvs) from a published yeast display library of ∼1×109 sequences derived from human B-cells (Fig. 2A)16. The scFvs were obtained by performing two parallel sets of selections against either the RNF43 ECD or the ZNRF3 ECD using magnetic activated cell sorting (MACS) and fluorescence activated cell sorting (FACS). After several rounds of selection, we isolated a panel of different RNF43- or ZNRF3-specific scFvs (Fig. S1), and the clones "R5" and "Z6" were chosen for incorporation into surrogate RSPOs based on their ability to robustly bind to RNF43 and ZNRF3, respectively, in a fluorescence-based assay (Fig. 2B).
Figure 2. Characterization of RNF43- and ZNRF3-specific scFvs used for generation of surrogate RSPOs.
(a) Cartoon schematic of yeast-displayed scFv binding to biotinylated RNF43 or ZNRF3 ECDs. (b) Flow cytometry dot plots depicting the binding of R5 and Z6 scFvs to RNF43 and ZNRF3, respectively. R5- or Z6-expressing yeast were stained with 1 µM concentrations of biotinylated RNF43 or ZNRF3 ECDs, respectively, and binding was detected using fluorescently labeled streptavidin. Surface expression of R5 and Z6 was detected with an antibody to the c-Myc epitope. Negative controls are unstained R5- or Z6-expressing yeast. (c) Construct design for R5-IL2 and Z6-IL2 surrogate RSPOs. (d) & (e). SPR was used to measure the binding of R5-IL2 or Z6-IL2 to RNF43 and ZNRF3, respectively. Cartoons (left) depict the orientation of streptavidin (SA)-coupled RNF43 or ZNRF3 ECDs and the R5-IL2 or Z6-IL2 analytes on the sensor chip. Curves (center) indicate a series of injections of R5-IL2 (3-fold dilutions, maximum concentration 3 µM) or Z6-IL2 (2-fold dilutions, maximum concentration 1 µM). Dissociation constants were obtained by plotting maximum RU values and fitting to a 1:1 binding model (right).
Design, expression and purification of surrogate RSPOs
Membrane clearance of RSPO signaling complexes has been reported to require the internalization of the receptors LGR4-6 17. We therefore selected the immune cytokine IL-2 to act as a proxy for RSPO-LGR binding in our surrogate RSPO constructs based on its ability to induce endocytosis of its cognate receptor, CD25 15. We generated two surrogate RSPO constructs, one targeted to RNF43 and one targeted to ZNRF3, by fusing R5 to IL-2 (R5-IL2) and Z6 to IL-2 (Z6-IL2). Single-chain constructs were designed such that R5 or Z6 is connected to the N-terminus of IL-2 via a flexible 5x(Gly-Ser) linker (Fig. 2C), which allows R5/Z6 and IL-2 to independently bind their respective targets. R5-IL2 and Z6-IL2 were expressed in insect cells using Baculovirus and both proteins eluted from a gel filtration column as monodisperse peaks, which indicates favorable biochemical behavior (Fig. S2).
Biophysical characterization of surrogate RSPO-receptor interactions
We used surface plasmon resonance (SPR) to measure the binding affinity of R5-IL2 and Z6-IL2 for RNF43 and ZNRF3, respectively. We determined that R5-IL2 bound to RNF43 with a dissociation constant (Kd) of 58 nM, and that Z6-IL2 bound to ZNRF3 with a Kd of 80 nM (Fig. 2D and 2E). R5-IL2 did not cross-react with ZNRF3, and Z6-IL2 did not cross-react with RNF43 (Fig. S3). We also used SPR to determine that R5-IL2 bound to CD25 with a Kd of 8.4 nM and that Z6-IL2 bound to CD25 5.7 nM, both of which values are similar to the reported Kd values of the wild type CD25-IL2 interaction (Fig. S4)18,19. Collectively, our SPR experiments revealed that (i) R5 and Z6 bind to their respective targets with similar affinities, (ii) that the affinities of surrogate RSPOs fall within the range of those reported between wild type RSPOs and RNF43/ZNRF3 (5 nM to 10,000 nM) 7,8, and (iii) that CD25 binding is retained in the surrogate RSPO format.
Surrogate RSPO-mediated enhancement of Wnt signaling
We performed a luciferase reporter assay to test the selectivity of R5-IL2 and Z6-IL2 in potentiating Wnt signaling. We compared the activity of surrogate RSPOs on HEK 293 Super Top Flash (STF) Wnt reporter cells, or on HEK 293 STF cells that had been retrovirally transduced with CD25. In the CD25-expressing cells, R5-IL2 increased WNT3a reporter activity up to 9.5-fold, and Z6-IL2 increased WNT3a activity up to 41-fold (Fig. 3A). The greater activity of Z6-IL2 relative to R5-IL2 is consistent with a previous report that ZNRF3 is the dominantly expressed homolog (relative to RNF43) in HEK 293 cells2. Given that natural RSPOs are cross-reactive, and that sequestration of both RNF43 and ZNRF3 may be required for the potent activity of RSPOs, we posited that R5-IL2 and Z6-IL2 would have increased potency when co-administered. We therefore incubated the cells with a 1:1 mixture of R5-IL2 and Z6-IL2, and found that this combination increased WNT3a activity by 148-fold (Fig. 3A). However, in the untransduced cells, addition of R5-IL2, Z6-IL2, and R5-IL2+Z6-IL2 led to increases in WNT3a activity of only 2.7, 3.9 and 5.8-fold, respectively (Fig. 3B), indicating that surrogate RSPO activity is highly selective for cells expressing CD25.
Figure 3. Surrogate RSPOs potentiate Wnt signaling.
(A) Representative Luciferase reporter assay measuring surrogate RSPO potentiation of Wnt activity in CD25-expressing cells. CD25-expressing HEK STF 293T cells were treated 20% WNT3a conditioned media and various recombinant proteins (RSPO2 Furin domains 1 and 2 (25 nM), R5 (500 nM), Z6 (500 nM), IL-2 (500 nM), R5-IL2 (5 nM, 50 nM, 500 nM), Z6-IL2 (5nM, 50 nM, 500 nM), or a 1:1 mixture of R5-IL2 and Z6-IL2 (5 nM each, 50 nM each, 500 nM each). The Luciferase signal fold change is normalized to WNT3a alone. Error bars represent standard deviation of n=3 technical replicates. Statistical significance of WNT3a alone versus each condition was determined by using one-way ANOVA on log-transformed data. * P<0.05, ** P<0.01, *** P<0.001. (B) A reporter assay was performed under the same conditions as in (A) using uninfected (CD25 negative) HEK STF 293T cells. * P<0.05, ** P<0.01, *** P<0.001.
In both CD25 positive and CD25 negative cells, we found that a mixture of conditioned WNT3a media and RSPO2 (Furin domains 1 and 2) elicited a response that was 286- to 304-fold greater than that of WNT3a alone (Fig. 3A, 3B), which is similar to the previously observed levels of RSPO-mediated enhancement 3. As negative controls, we treated cells with WNT3a conditioned media supplemented with either R5, Z6, or IL-2. The R5 scFv and IL2 cytokine did not substantially potentiate WNT3a signaling (Fig. 3B), however, the Z6 scFv exhibited mild Wnt-potentiating activity that resulted in 10-fold or 12-fold increases in signaling in the HEK293 STF and CD25-expressing cells, respectively (Fig. 3A, 3B).
Surrogate RSPO-mediated stimulation of intestinal organoid growth
The growth of primary human colon organoids is presumably driven by LGR5+ stem cells and requires the addition of exogenous RSPOs along with Wnt, EGF and Noggin8,9. To determine whether R5-IL2 or Z6-IL2 can substitute for RSPOs in human colon organoid culture, we performed an organoid growth assay using organoids that had been retrovirally transduced to express CD25. In this assay, CD25+ organoid cells were cultured in a basal medium of WNT3a, EGF and Noggin, supplemented with one of the following recombinant proteins: RSPO2, IL-2, R5 scFv, Z6 scFv, R5-IL2, Z6-IL2, or a 1:1 mixture of R5-IL2 and Z6-IL2, Subsequently, organoid growth was monitored by resazurin fluorescence in a cell viability assay. Although not as potent as RSPO2 (73-fold), addition of R5-IL2, Z6-IL2, or the mixture of R5-IL2 and Z6-IL2 each led to significant increases in organoid growth relative to the negative control protein, IL-2 (R5-IL2: 7.3-fold, Z6-IL2: 9.4-fold, mixture: 11-fold) (Fig. 4). However, addition of R5 scFv or Z6 scFv did not result in a significant increase. Importantly, neither R5-IL2 nor Z6-IL2 stimulated the growth of wild type organoids (Fig. 4), indicating that surrogate RSPOs specifically affect cells expressing CD25.
Figure 4. Surrogate RSPOs stimulate intestinal organoid growth.
Surrogate RSPOs were tested for their ability to stimulate the growth of LGR5+ human colon organoids that had been retrovirally transduced to express CD25. Basal media containing WNT3a, EGF and Noggin, but lacking RSPO2 was supplemented with 500nM concentrations of the indicated proteins, or with 25nM RSPO2. Microscopy was used to observe the appearance of spherical organoids in each condition (top) and growth was quantitated by resazurin fluorescence in a cell viability assay (bar graphs, bottom). The bar graph on the right is a zoomed panel of the colored region from the graph on the left. Error bars represent standard error of n=12.
The successful development of surrogate RSPOs indicates that a non-natural receptor, CD25, may be co-opted to selective amplification of Wnt signaling. The bispecific R5-IL2 and Z6-IL2 proteins do not include any components derived from natural RSPOs and do not recognize LGR receptors or HSPGs. The Wnt-potentiating activity of surrogate RSPOs is potentially driven by IL-2-mediated endocytosis of CD25, which would support the present model that RSPOs function by inducing membrane clearance of RNF43 and ZNRF3. However, it is also possible that surrogate RSPOs sequester RNF43 and ZNRF3 via an unknown mechanism that parallels the recently discovered HSPG-driven activity of RSPO2 and RSPO3. Regardless, the development of R5-IL2 and Z6-IL2 will open new avenues for the engineering surrogate RSPOs that act upon a broad spectrum of cell surface receptors. For example, tyrosine kinase receptors, G-protein coupled receptors (GPCRs), pattern recognition receptors and several other classes of receptors are internalized upon ligand-binding and may serve as alternatives for the targeting arms of surrogate RSPOs.
The selective amplification of Wnt signaling on CD25+ cells by R5-IL2 and Z6-IL2 has the potential to influence immune cell behavior for biomedical applications. CD25 is expressed predominantly on activated T cells, regulatory T cells (T regs), and natural killer cells (NK cells)20 and Wnt activation is known to modulate the behavior of several T cell subtypes. For example, Wnt signaling attenuates the suppressive activity of T regs by disrupting Foxp3 transcription activity21, and autocrine inhibition of Wnt signaling in NK cells mediates tumor immune evasion by downregulating the expression of activating ligands 22. Administration of CD25-targeted surrogate RSPOs alone or in combination with Wnt agonists may therefore augment the effectiveness of T cell- or NK-cell based cancer immunotherapies.
We designed R5-IL2 and Z6-IL2 such that they bind to RNF43 and ZNRF3, respectively, and neither surrogate RSPO is cross-reactive (Figs. 2D, 2E, S3). In our 293-based Wnt reporter assay, the highest levels of Wnt signal enhancement were achieved by co-administering R5-IL2 and Z6-IL2 (Fig. 3), suggesting that maximal activity requires the antagonism of both RNF43 and ZNRF3. Natural RSPOs, which are cross-reactive with both RNF43 and ZNRF3, were also more potent stimulators of colon organoid growth when compared to R5-IL2 and Z6-IL2 (Fig. 4). Based on these findings, we anticipate that second-generation surrogate RSPOs may be optimized through the incorporation of cross-reactive RNF43/ZNRF3 binding modules, such as the RSPO Fu1 domain8, in place of the scFv component. Additional optimization strategies may involve the use of scFvs that recognize different epitopes on the RNF43 or ZNRF3 ECDs, or the use of scFvs that bind to RNF43 or ZNRF3 with higher affinity. On the other hand, the ability of R5-IL2 and Z6-IL2 to target a given E3 ligase (RNF43 versus ZNRF3) confers an additional degree of selectivity that is not attainable using natural RSPOs, and this property may be advantageous for targeting cell types that express only one of the two E3 ligases. Collectively, our data provide proof-of-concept for surrogate RSPOs whose modular design will allow for the targeted enhancement of Wnt signaling on cells expressing RNF43, ZNRF3 or various other tissue-specific markers.
The ECDs of human RNF43 (amino acids 24-197) and ZNRF3 ECD (amino acids 56-219) were cloned into the pAcGp67A vector with a C-terminal biotin-acceptor peptide tag (GLNDIFEAQKIEW) followed by a hexahistidine tag. Unless otherwise specified, RNF43/ZNRF3 in the methods section will refer to their ECD only. Selected RNF43 and ZNRF3 high-affinity human antibody scFv fragments were cloned into pAcGp67A vector with a C-terminal hexahistidine tag. These human antibody scFv fragments were also cloned into pAcGp67A vector in frame with a (GS)5 linker and human interleukin-2 (amino acids 21-153) followed by a hexahistadine tag. All proteins were expressed in Hi-Five cells (Invitrogen) from Trichoplusia ni using Baculovirus and the cultures were harvested 60 hours after infection. Proteins were purified by nickel affinity chromatography followed by size exclusion chromatography in HBS buffer (10 mM HEPES pH 7.2, 150 mM sodium chloride). RNF43 and ZNRF3 were site-specifically biotinylated by BirA ligase at the C-terminal biotin-acceptor peptide prior to size-exclusion chromatography. All proteins were either used when freshly purified or snap frozen in liquid nitrogen with 20% glycerol and then thawed for use as necessary.
Selection of RNF43/ZNRF3-binding scFv fragments
The nonimmune yeast surface display library of human antibody scFv fragments was generously provided by the group of Prof. Dane Wittrup (MIT) 16. A sequential selection strategy involving a series of magnetic bead selections followed by flow-cytometric sorting was used as previously reported23. Round 1 of the selections was performed by mixing 250 µL magnetic streptavidin microbeads (Militenyi) with 400 nM biotinylated RNF43/ZNRF3. These microbeads were further mixed with 1 × 1010 yeast cells from the scFv library 16. Yeast were subsequently passed over a Magnetic-Activated cell sorting (MACS) LS separation column (Militenyi), the flow through was discarded and ZNRF3/RNF43 binders was isolated from the column elution. Round 2 was performed as Round 1 except 1 × 108 yeast cells from the recovered Round 1 sample were used for the selection. For Round 3, yeast cells incubated with 200 nM biotinylated RNF43 or ZNRF3 ECD, washed and then stained with streptavidin labeled with 50 nM Alexafluor-647 (SA-647). The ZNRF3/RNF43 binders were enriched by MACS using anti-647 microbeads (Militenyi). In Round 4, yeast cells were pre-incubated with 5 nM biotinylated RNF43 or 10 nM biotinylated ZNRF3, washed, and then double-stained with SA-647 and Alexa Fluor 488-conjugated antibody to the c-Myc epitope (Myc-488, Cell Signaling). High-affinity RNF43/ZNRF3 binders were isolated by fluorescence-activated cell sorting (FACS).
Plasmids from the final round of selection were isolated using the Zymoprep Yeast Plasmid Miniprep Kit (Zymo Research) and sequenced. These plasmids were electroporated into S. cerevisiae EBY100 yeast and recovered in SDCAA selection media, followed by induction in SGCAA induction media23. The individual scFv-transformed yeast was incubated with increasing concentrations of biotinylated RNF43 or ZNRF3 proteins. These were stained with SA-647 and Myc-488 and fluorescence was monitored by flow cytometry. The data were analyzed by GraphPad Prism 7 and the highest affinity clones encoding full scFv sequences (R5, Z6) were selected for use in subsequent experiments.
Binding of RNF43 and ZNRF3 to yeast surface displayed scFvs
Yeast cells expressing either the R5 or Z6 scFvs were stained with 1 µM recombinant biotinylated RNF43 or ZNR3 ECDs, respectively, in phosphate buffered saline (PBS) (Thermo Fisher Scientific) + 0.5% BSA + 2 mM EDTA at 4 °C for 2 hours with slow rotation. Cells were then washed, incubated with SA-647 and Myc-488 for 20 min, washed again, and then analyzed by flow cytometry.
All binding measurements were conducted using a BIAcore T100 instrument (GE Healthcare). Biotinylated RNF43, ZNRF3 and CD25 were coupled on a SA sensor chip (GE Healthcare) at low density. An unrelated biotinylated protein was captured at equivalent coupling density to the control flow cells. Increasing concentrations of R5-IL2 and Z6-IL2 were injected onto the chip in HBS-P (GE Healthcare) at 30µl/mL for 120 s or 300 s, respectively. Subsequently, the chip was regenerated with 0.5 M MgCl2 and 25% ethylene glycol in HBS-P buffer for 80 s after each injection. Resonance units were calculated by subtracting the resonance units observed in RNF43, ZNRF3, or CD25-containing flow cells from those of the control flow cell. Curves were fitted to a 1:1 binding model using the accompanying Biacore evaluation software (Biacore/GE Healthcare).
Retrovirus production
Human full length CD25 was cloned into retroviral vector pMSCV-IRES-YFP (gift from Dr. Melissa McCracken, Stanford University). Retrovirus was packaged in HEK293T cells as described24. Briefly, HEK293T cells were plated the day before transfection. Cells were transfected with pMSCV-CD25-IRES-GFP and pCL-10A packaging vector using X-tremeGENE HP (Sigma-Aldrich). The supernatant was collected, filtered using sterile 0.45 um filter.
Luciferase signaling assays
HEK293T cells were stably transduced with Firefly Luciferase Reporter under the control of a concatemer of seven LEF/TCF binding sites and Renilla Luciferase Reporter by lentivirus as previously reported from the Garcia laboratory3. These cells were further stably infected with human CD25 by retrovirus co-expressing YFP. Transduced HEK293T cells were FACS sorted by YFP expression. CD25 surface expression were further confirmed by staining the transduced HEK293T cells with anti-CD25 Brilliant Violet 605 antibody (BioLegend, Clone BC96, #302632). Fluorescence was monitored by flow cytometry and was compared to non-transduced HEK293T cells (data not shown). The assays were conducted using the Dual Luciferase Assay kit (Promega) as instructed. Briefly, cells were plated at a density of 10,000 cells per well in a 96-well plate and incubated for 24 hours prior to stimulation. Following the plating step, cells were stimulated with 20% WNT3a conditioned media (derived from WNT3a L cells, ATCC) supplemented with RSPO2 Furin1 and Furin 2 domains (25 nM), R5 (500 nM), Z6 (500 nM), IL-2 (500 nM), R5-IL2 (5, 50, or 500 nM), Z6-IL2 (5, 50, or 500nM), or a 1:1 mixture of R5-IL2 and Z6-IL2 (5 nM, 50 nM, or 500 nM of each protein). Cells were cultured in the presence of signaling proteins for another 24 hours before being washed and lysed as suggested by the instructions in the Dual Luciferase Assay Kit (Promega) manual. Luminance signals were recorded using SpectraMax Paradigm and analyzed by GraphPad Prism 7. Statistical significance of WNT3a alone versus each condition was determined by using one-way ANOVA on log-transformed data.
Organoid growth assays
Fresh human colonic samples were collected at Stanford Hospital with informed consent and grown as primary organoids in Matrigel domes as described3. The culture was passaged several times in WENR media (WNT3a, R-spondin, EGF, Noggin) to confirm robust outgrowth of organoids. To evaluate surrogate activity, the organoids were transduced with retrovirus expressing CD25 and FACS sorted for YFP+ (YFP co-expression with CD25) to enrich CD25+ population. CD25+ cells were then subcultured in basal media containing WNT3a, EGF and Noggin but lacking RSPO2, and then supplemented with candidate surrogate R-spondins or RSPO2 as in Fig. 4. Organoid morphology was observed and phase contrast pictures were taken using Nikon TS100. To quantify cell growth, organoids were dissociated to single cells and plated at 10,000 cells per well in 96-well format. A fluorescence-based cell viability assay was performed 3 days after plating using AlamarBlue cell viability reagent (Thermo Fisher). Fluorescent signals were normalized to background signals from wells plated with Matrigel only.
Use of tissues from human participants
Primary human tissues were obtained through the Stanford Tissue Bank from patients undergoing surgical resection at Stanford University Medical Center (SUMC). All experiments utilizing human material were approved by the SUMC Institutional Review Board and performed under protocols #28908, #26213 and #17425. Written informed consent for research was obtained from adult donors prior to tissue acquisition.
V.C.L. and Y.M. generated surrogate RSPO constructs, purified the proteins, and conducted luciferase signaling assays. V.C.L. performed SPR binding assays. Y.M. performed yeast display scFv selections and generated stable cell lines. X.L. performed human colon organoid growth assays. M.J.H. provided IL-2 and CD25 proteins and CD25 retrovirus. V.C.L., Y.M., X.L., C.J.K. and K.C.G. interpreted the results. V.C.L., Y.M. and K.C.G. wrote the manuscript. V.C.L. and K.C.G. designed the study.
K.C.G. and C.J.K. are founders of Surrozen, Inc. K.C.G. and V.C.L. are inventors on a patent applied for by Stanford University describing surrogate RSPOs.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
We thank Lora Picton for edits and helpful comments. We thank Richard Reich from the Moffitt Cancer Center Biostatistics Core for advice with statistical analysis. This work was supported by a gift from the Mathers Fund, and the Ludwig Cancer Foundation (K.C.G.); the Howard Hughes Medical Institute (K.C.G.); NIH R01-DK115728(K.C.G. and C.J.K.) and NIH DK085527 (C.J.K).
Nusse, R. & Clevers, H. Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell 169, 985–999 (2017).
Hao, H. X. et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485, 195–200, (2012).
Janda, C. Y. et al. Surrogate Wnt agonists that phenocopy canonical Wnt and beta-catenin signalling. Nature 545, 234–237, (2017).
Koo, B. K. et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488, 665–669, (2012).
de Lau, W. et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476, 293–297, (2011).
Xie, Y. et al. Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin. Embo Reports 14, 1120–1126, (2013).
Wang, D. et al. Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes & development 27, 1339–1344 (2013).
Zebisch, M. et al. Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nature communications 4, 2787 (2013).
Lebensohn, A. M. & Rohatgi, R. R-spondins can potentiate WNT signaling without LGRs. eLife 7, 18, (2018).
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Zhou, W.-J., Geng, Z. H., Spence, J. R. & Geng, J.-G. Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection. Nature 501, 107–111 (2013).
Yan, K. S. et al. Non-equivalence of Wnt and R-spondin ligands during Lgr5(+) intestinal stem-cell self-renewal. Nature 545, 238–242, (2017).
Zhan, T., Rindtorff, N. & Boutros, M. Wnt signaling in cancer. Oncogene 36, 1461 (2017).
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Posted February 25, 2019.
You are going to email the following Surrogate R-spondins for tissue-specific potentiation of Wnt signaling
Vincent C. Luca, Yi Miao, Xingnan Li, Michael J. Hollander, Calvin J. Kuo, K. Christopher Garcia


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You are at: HomepageAbout usHistory
The Award was founded in 1956 by Prince Philip, the husband of Queen Elizabeth of the UK and Duke of Edinburgh, together with Kurt Hahn, a German educationalist and renowned promoter of experiential education, and Lord Hunt, leader of the first successful ascent of Mount Everest.
After the Second World War there was a growing concern about the development of boys, due to the gap between leaving school at 15 and entering National Service at 18. That is when HRH the Duke of Edinburgh got the idea of informal education programme that would empower young people and motivate them to actively use their leisure time.
He designed the programme together with Kurt Huhn on the basis of experiential education and introduced it in 1956 under the name "The Duke of Edinburgh's Award". Sir (later Lord) John Hunt was appointed the first programme's Director.
The word "international" was added to the programme's name in 1980 due to the fact that the programme had quickly spread throughout the world. Already in 1975 the number of participants reached one million, and in 1989 the limit of two million participants was exceeded.
Around the world in 140 countries, milions of young people participated in the Award. The Award was introduced in Slovakia by the British International School in Bratislava in 2007 and from the end of 2014 team of educators with strong support from business leaders is working on the opening of the National Office of the Award programme in Slovakia. The main goal of the National Office will be to spread the Award nation-wide in Slovakia.
The National Office of the Award in Slovakia, with the support of The Duke of Edinburgh's International Award Foundation in London, is piloting the Award at 10 organisations in Bratislava from June 2015 to June 2016. With 2 already existing organisations, the Award is offered at 12 organisations for 177 participants in total. The National Office has signed an Acredited Licence on the March 30th 2016 and from April we are working on growing the Award in other regions in Slovakia from September 2016.
Founders of the Award
The Duke of Edinburgh
Kurt Hahn
Educator and Politician
Lord Hunt
The first director
The Duke of Edinburgh's International Award was founded by HRH The Duke of Edinburgh KG KT, in 1956, in conjunction with Kurt Hahn, the German educationalist. Both were concerned that young people's development was lacking in certain key areas, and they resolved to create a programme that would be a 'do-it-yourself kit in the art of civilised living'.
The subsequent spread of the Award across the globe is testament to the universal appeal of the programme, and the vision of its founder. However, even HRH admits that this took him by surprise: "When the first trial of the Award was launched in 1956, no one had any idea quite what would happen. In the event it was an instant success, and the Award has been growing and expanding worldwide ever since."
HRH The Duke of Edinburgh has remained committed to the Award since its birth over 50 years ago. He continues to be involved, particularly in recognising the achievements of Award participants and the adults who support them. To find out more about HRH The Duke of Edinburgh, visit the official website of the British Monarchy.
This German educator and politician who left after 1930 Germany for UK because of his Jewish ethnicity. He contributed in particular to the development of experiential pedagogy, where he initiated schools and educational institutions based on its principles, and around the world. In addition to The Duke of Edinburgh's Inernational Awward it is especially international network of schools, United World Colleges and international adventure programme Outward Bound. As the founder and director of the school Gordonstoun in Scotland he also created a programme leading to a badge Morayshire, through which he met with Prince Philip. The desire to expand that program to other countries persuaded by Prince Philip and cooperation program remains similar - The Duke of Edinburgh's Award.
More information at Wikipedia
John Hunt was a British Army officer, an experienced climber and instructor of special forces. He became famous as the leader of a successful expedition, whose members Edmund Hillary and Tenzing Norgay were the first people climbed between 1953 peak of Mont Everest. After returning to the UK he was ennobled for this achievement. In 1956 he became the first director of The Duke of Edinburgh's Award, a position he held for ten years. In 1966 he was awarded the baronial title for his merits in working with young people , which was awarded by Queen Elizabeth II.
Award stories
International Award website
Jump to intaward.org
Competition for Award holders from the pilot year in Slovakia - change
13.10.2016, News
Whole story
Contacts and units map
Searched term
The Duke of Edinburgh's International Award (or the Award) is the world's leading youth achievement award, bringing together practical experiences and skills to create committed global citizens and equipping young people for life.
About the AwardGet to know the philosophy, principles and levels
SectionsWhich activities you can take part in
HistoryOur programme has a rich, almost 60 year history
SignificanceThe importance and the benefits of the programme
Award storiesMeet the successful participants of the Award
RecognitionWhat awaits successful Award participants
Our teamWho we are, what we do and why we run this programme
Annual reportsWhat we have achieved in each year
The Award is a prestigious programme for anyone aged 14 to 24. You will develop your skills, pursue sports activities, take part in volunteering and plan and realize adventurous journey.
How to startWhat you will need to begin your Award
DofE Network SlovakiaWhat's next after achieving the Award
The Award is provided by schools and other educational institutions, which, thanks to their staff and volunteers, offer the Award to young people.
Diamantová cenaGet to know Diamond Award DofE
How to joinUseful information for potential providers
TrainingsWe train those who deliver the Award
The Duke of Edinburgh's International Award is the research-proven and globally recognized programme that allows young people to uncover their potential.
What to supportWhat makes this program unique and beneficial
How to support usYou can support us as a company or as an individual
Business partnershipsWhat long-term business partnership are we building
Our patrons and supportersWho is the founder, supporters and patrons
Our partnersWe thank these partners for their support
New ORB
All you need to know about ORB Next Gen.
ORB for participantsAll the information about new ORB
ORB for Award LeadersGet to know the new ORB
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Contribute to change
You too can help young people unreveal their potential and approach life with courage.
Find out how to help
Zostaň v obraze
Národná kancelária programu vás bude pravidelne informovať..
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Every 1st Wednesday of the month at 5:00 p.m.
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Committed to Listen • MLK Day 2022
Wildness and Spirituality for the Common Good
Eco Grief Circle
Lament with Earth
Spiritual Leadership for a Climate-Changed World
Research Collaborative
Leadership Commons
Pursuing Our Passions in a Climate-Changed World
Rooted & Rising
Creation's Wisdom
Part-time is Plenty
Earthbound Practices
Rev. Effie E. McAvoy
Rev. Effie E. McAvoy was ordained a Deacon in June of 1997 and an elder in full connection of the Western North Carolina Annual Conference of the United Methodist Church in June of 1999. After serving churches in North Carolina for 13 years, she moved to Oakland, Maine where she served Oakland-Sidney UMC for 7 years and was transferred in as an Elder in Full Connection to the New England Annual Conference. She earned her BA degree in Interdisciplinary Studies with a concentration in Women's Studies from Appalachian State University in 1994 and her MDiv from Boston University in 1997.
Currently Rev. McAvoy serves as the chair of the New England Conference of the United Methodist Church (NEAC UMC) Commission on Religion and Race (CoRR). The role of CoRR in every level of the UMC is to educate the body on issues of race, racism, implicit bias, eurocentrism, and xenophobia. In its mission, CoRR is also called to speak truth to power and hold leaders to accountability in regards to issues of race, culture, and ethnicity.
In addition to her role as chair of NEAC CoRR, she also is a member of the Connectional Table of NEAC which oversees the work of program ministries within the New England Annual Conference.
Reverend McAvoy has received certificates from Duke Divinity Preaching Institute, Disciple Bible Study, and the Maine Criminal Justice Academy in police chaplaincy.
In 2017 she was reassigned to the UMC York Ogunquit where she serves as pastor and is the chaplain for the York police department.
The BTS Center is pleased to welcome Rev. Ash Temin to its staff team, serving in the role of Communications Manager. Ash has been collaborating with The BTS Center over the past several weeks as a program consultant, assisting with some fall programming, and she officially assumes this new role effective October 25. Learn more …
If you attended Convocation 2021, you'll remember some really sacred moments as our Convocation music leader, Pax Ressler, shared their original song, "The Soil," commissioned by The BTS Center especially for this year's Convocation — "We Are God's Soil: Spiritual Leadership in a Climate-Changed World."
Several of you have asked for sheet music, and with special thanks to Pax, now it's available — and not only sheet music, but a lead sheet, a lyrics sheet, and an mp3 recording — all free for download here.
We are delighted to announce the six recipients of From What Is to What If Micro-Grants. Each of these grants will help a community of faith try something new, lay the groundwork for further innovation, and help to fire the imaginations of others. Learn more …
Learn more about our Research Collaborative program!
Introducing our new LEADERSHIP COMMONS: Welcome to The BTS Center's new Leadership Commons, a space where we are developing new content, and gathering materials adapted from past programs, to help equip faith leaders in the work of guiding communities of spiritual practice through the uncertainties of life on a changing planet.
The BTS Center@TheBTSCenter·
Join us today at 12:15 pm ET for a public reading of the Rev. Dr. Martin Luther King, Jr.'s sermon "Remaining Awake Through a Great Revolution." We hope to see you there.
Details at https://thebtscenter.org/committed-to-listen-2022/
Join us one week from today, when we host our second annual Committed to Listen event for MLK Day, in collaboration with the Maine Council of Churches and @AtlanticBlckBx. For more information and to register: https://thebtscenter.org/committed-to-listen-2022/
There is still time to register for our Wildness and Spirituality Course which starts January 15th! Taught by our very own Director of Partnerships and Formation, Aram Mitchell, in collaboration with the School of Global Citizenry. Find more info here: https://thebtscenter.org/wildness-and-spirituality-for-the-common-good/
Bangor Theological Seminary Transcript Requests
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The NG Systems PoE/Data Splitter (XPS1) is an installation device which allows PoE power to be delivered to a camera whilst allowing a direct connection to a laptop or other device (e.g. Pinger). This significantly simplifies camera configuration or lens focusing and shortens installation time.
Simply connect the PoE-carrying network cable, laptop/Pinger and camera into the XPS1. The eliminates the need for a local power supply for the camera and also allows precise focusing/angling adjustments of the IP camera at its final installation site. A high-intensity LED lights up on the XPS1 once a PoE-camera is attached and has started to draw power enabling rapid troubleshooting of an installation.


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Healthy Driven Blogs
Stories and Insights to Move Your Health Forward
Back to Healthy Driven Blog Home
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Collaboration leads to successful weight loss
December 04, 2019 | by Edward-Elmhurst Health
Categories: Healthy Driven Heroes
At 67 years old, Rick Buscemi had spent most of his adult life overweight. During regular checkups over the years, doctors would share test results that included rising blood pressure and blood sugar levels, but he never felt inspired to make the necessary changes that would allow him to lose weight and take control of his health.
Until he did.
Buscemi weighed 421 pounds in December 2017 when he met with Omar Shamsi, M.D., a physician who specializes in bariatric and obesity medicine.
"When Mr. Buscemi came to me, he was diagnosed as prediabetic and I could see in his eyes that he was ready to focus on his health," says Dr. Shamsi. "He wasn't interested in surgery, instead he wanted to make diet and lifestyle changes."
Dr. Shamsi felt Buscemi would be a great candidate for the Jumpstart your Health program to get the support he needed to develop and maintain healthy changes.
Jumpstart your Health is a yearlong diabetes prevention program based on a Centers for Disease Control and Prevention-approved curriculum. Working with a lifestyle coach for guidance and encouragement, participants learn the information and skills needed to lose weight, be more active, manage stress and prevent the onset of type 2 diabetes. Sixteen weekly group classes are followed by six monthly sessions to help participants maintain new lifestyle changes.
Before Buscemi could secure a spot in the class, on the day after Christmas he was admitted to the hospital with weight-related heath issues that warranted a five-day stay. When he left the hospital, Buscemi was 100 percent committed to getting healthy.
Once he officially began the program in spring 2018, Buscemi says everything just clicked. "It was kind of simple, I just never really looked at things like calories and fat grams before," he says. "The program taught me why and how to do it, and once I started, I lost weight week after week."
After one year in the program, Buscemi lost more than 150 pounds. He has graduated, but still participates in group sessions every other month to help him stay on track.
Buscemi's story is a bit more unique than just counting calories and fat grams, however. He lost his weight while also eating out at fast food restaurants for nearly every meal.
"At his starting weight, the odds were against Rick to lose the weight with diet and exercise," says Julie Sanfilippo, RD, LDN, a registered dietitian who leads the Jumpstart program and worked directly with Buscemi. "In addition, Rick shared early on that he didn't cook at home or plan to, that he keeps very little food at home and eats at restaurants several times a day."
Sanfilippo admits she had concerns about whether successful weight loss could be achieved this way, but supported Buscemi in his plan to be diligent with calories and fat grams while still eating out.
"I said to myself, 'I'm going to work on this, but I have to do it in a way that fits into my lifestyle,'" says Buscemi, who describes his pre-program fast food breakfasts as more than 1,000 calories.
Once committed, he diligently researched calories and fat grams to learn what he could eat while staying within target calorie and fat goals. Although he loves eating at fancier restaurants, he learned that the detailed nutritional information fast food restaurants provide made it easy to plan his daily allotment of fat and calories, which now includes fast food breakfasts around 250 calories.
With consistent effort, the pounds came off week after week. The more success he experienced, the more motivated Buscemi felt. While the majority of his meals continue to come from fast food, he has started to keep some healthy foods at home and incorporate regular exercise, prioritizing 75 minutes of cardiovascular exercise a day, six days a week.
Throughout Buscemi's weight loss, Dr. Shamsi and Sanfilippo have closely collaborated on his progress, making changes where needed and celebrating his ongoing success. They regularly work together to help patients prevent the onset of type 2 diabetes, hypertension, sleep apnea or other weight-related diagnoses.
Dr. Shamsi says his patients typically deal with one or more issues related to struggles with weight loss: stomach hunger, where a patient feels hungry all the time; brain hunger, where patients overeat for emotional reasons and/or a lack of physical activity.
"Sometimes people don't fall into just one category and need to fine tune their lifestyle in many ways," says Dr. Shamsi. "In collaboration with the Jumpstart program, we may use a combination of medications, behavior health therapy and increased physical activity to help our patients achieve success."
Today, Buscemi has achieved all of his initial weight loss goals, but has one more on the horizon. He is 9 pounds away from his lightest adult weight and less than 50 pounds away from his high school weight. He fully intends to get there.
"There's a right time and a right place for everything," says Buscemi. "For me, this was it."
Endeavor Health® Weight Management at Edward-Elmhurst Health offers both surgical and non-surgical options to help you achieve permanent weight loss and the healthy, active life you were meant to live.
How cutting 300 calories a day could help your heart
A recent study suggests that even healthy, slim adults can improve their heart health by cutting a few calories each d...
Buscemi weighed 421 pounds in December 2017 when he met with Omar Shamsi, M.D., a physician who specializes in bariatr...
How to keep holiday weight gain at bay
Don't let holiday celebrations give you the gift of a couple extra pounds this season.
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Edward-Elmhurst Health
Healthy Driven Stories with Mary Lou Mastro
Our very own President & CEO Mary Lou Mastro will post about what our patients want to know, from the latest buzz in our hospitals to what's new in health care.
Healthy Driven Life
We've got fresh new ideas about how to lead a healthier life! Our physicians and other experts will post about exercise and fitness, recipes, wellness advice and more.
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Our stories about patients who bravely and proactively improved their health, and the caregivers who helped them along the way, are sure to motivate and inspire.
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Our physicians and other experts will post about issues that matter most to people affected by cancer.
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Our physicians and other experts will post about the latest treatments and more for living a heart healthy life.
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Our physicians and other experts will post about the steps you can take today to stay healthy and fit for years to come.
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Here Comes the Workforce of Tomorrow
By James Glave|June 12th, 2020|In The News|
Big changes lie ahead for British Columbia's $22 billion construction sector. But what will the shift mean for the people on the ground?
Between today and 2032, recent and forthcoming energy and climate regulations will fundamentally change the way we build, heat, cool, plumb, and connect new buildings in this province. As of that year, every new condo tower, hospital, retail centre, university building—you name it—will need to meet the highest attainable level of energy-efficiency performance.
By the late 2020s, the majority of these new projects will emit no climate pollution whatsoever.
While we know a fair bit about the likely inner workings of these next-generation buildings, we don't know nearly as much about what lies in store for the people who excavate, assemble, pour, lift, hammer, bolt, and weld them together.
That's why the Vancouver Regional Construction Association is kicking off The Construction Workforce of Tomorrow. The research project aims to view the shift to high-performance buildings through the polycarbonate glasses of the workers who will put them together. Along the way we'll ask:
Which skilled construction trades will be in high demand in the zero-carbon world?
Which will need retraining?
When will the needed changes start to accelerate?
Who will be impacted first?
They're big questions, for sure. And In the coming months, with your help, we're going to get the answers — and share them with you as they come into focus.
Here's How You Can Help
Let us know what the future looks like from your vantage point! What do you see as the exciting opportunities? What keeps you up at night? Contact our research team directly via [email protected]
Note: We want to hear from everyone, but especially general and trade contracting companies that work across the Lower Mainland.
Future labour skills: utilizing machines to address dwindling labour
Future tools (Lifting arm)


text:
Federal internet wiretapping rule challenged
Tuesday 25 October 2005 at 7:27 PM ET
by Katerina Ossenova
[JURIST] A recent Federal Communications Commission [official website] ruling that would allow wiretapping of Internet calls [FCC press release, PDF] was challenged Tuesday by privacy and technology groups in federal appeals court in Washington. The ruling makes it easier for law enforcement officials to tap Internet phone calls by mandating standards that would allow the wiretaps to be made. Internet call providers are already contesting the order, saying it would require them to rewire their networks at high costs. The Center for Democracy and Technology [advocacy website] along with other privacy groups and Sun Microsystems have petitioned the US Court of Appeals for the DC Circuit to review the FCC ruling. The American Council on Education [association website], representing about 2,000 colleges and universities, also filed its own appeal[press release] of the ruling Monday in federal court. The education group voiced concerns about the costs colleges and universities would incur if required to rewire their networks to comply. AP has more.
default-domestic domestic


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Q: Google translate pages does not translate whole page I am asking this question again, as no one was able to answer it before. I am including some updates.
Web-page - http://jewelryfashionstyle.com/sv/
In the right top corner there is google translate thingy. It translates the whole page correctly from any language but Swedish. In Swedish version, the main menu and some other items do not get translated. The "from" language is set correctly.
I tried everything, even removed all tags from menu (only the menu item words remained) but for some reason it does not translate the menu. I tried placing the menu in different place, tried to remove the javascript that animates it - no luck.
Does anyone have any idea what could the problem be? Please, help. I've been looking for the solution for a week already :)

A: The problem doesn't come from google translate, the problem comes from the personn that makes the page, the website does not use google translate to translate the page.
if you insert your page in google translate website, you will have the exactly the same elements that are translated in russian and swedish


I have a method set up to go through all of the stations in my model looking at specific attributes and using the attributes.
The problem is that not every object has the specified attributes. Because of that, when the for loop hits an object missing the attributes it creates an error. I tried to avoid this using an If statement and a not equal to, but it hasn't worked. As you can see I tried not equal to unknown, and I originally tried not equal to void. Neither worked. Is there a way to move on if an attribute/identifier is unknown?
You can test if your station has an attribute called "Efficiency" !
Luckily only the Worker (which is never a node of a Frame) has the internal attribute 'Efficiency', so you can use the simpler (and faster) check.
Thank you both for your solutions! Took a little bit to get the code working, (I'm not very good with Simtalk 1.0), but I got it adapted for my purposes.
Works perfectly, had no idea I could look at every object in the whole simulation in that way.


A part from the day we were born this must be the biggest event so far in our lives ... Marina put a pen up and cut open the box so we ventured outside ... that was so scary at first for some of us ... actually Loma (light blue) and Laîme (red) stayed in the box - for quite a while - fast asleep and oblivious to this momentous experience... and when they woke up they just sauntered out to the bar!
There are lots of photos uploaded so you can see our new world!
We also SAW and smelt Mum eat a piece of chicken and we all thought that looked and smelt delicious - we cannot wait to try!
Then Marina decided that she wanted to use a different pen - so Freddy was delegated to go get them at the bottom of the garden and hose them down wash them etc... then came the taking away and putting in with Alex' help this afternoon... but all went smoothly and we are all 6 still here in one piece.
Now will you look at these teeth? poor Mum! we think Marina is going to start us on meat pretty soon..
There are lots of photos uploaded - you will see we have started playing for "real" not only with each other but with the toys Marina has given us!
After a little while we woke up and Mum came in to open the bar and the lovely young man came to sit with us - when we had finished eating he gently played with us and cuddled us and we just climbed all over him - his toes were good to eat!!
well Marina did give us some more meat .... it is just sooooo good ... and just to show you how much we loved it here are 2 photos of Lymm ... do we think she overdid it?
Well today was another experience - Marina put the meat in this gynormous bowl (Michou who has our grandmother Cash very kindly lent it to Marina) and we just surrounded it and licked away - she did this 3 times today and it was just sooo good - we thought it was already Easter - cause no choccy eggs for us dogs - it is "poison" to us.
We are really starting to be able to focus much better and some of us can even follow and catch a ball!
It was a beautiful sunny day so the door to the terrace was open and the other dogs came visiting a few times - Marina managed to get a photo of Lâme having a "conversation" with Purdey.. the others came in as well but Marina was not ready with camera ... maybe tomorrow ..
Today we had Rachel and Brent come visit - they sometimes come and dog sit when Marina goes away for a few days - so they know Mum and the rest of the pack very well - Rachel had a really soft spot for Lucie ...not that she does not like puppies too of course ... specially us as we are sooooo cute..
We started hearing strange noises today... there is normally what Marina calls classical music playing but today there were these noises (very faint but we did hear some..) the noises apparently come from a special CD to start us getting used to all sorts of different sounds.. as they were still very faint we are not sure what they all were ... so it will be a surprise when they become louder.
Marina has put newspaper down and we are trying to pee and poo just there but not very good at that yet but we do not soil our box at all!
One of us decided we needed peace and quiet and she took herself off with little "hedgehog" into the box - bliss!
Look at our tails - Mum had been away for sooooo long ... starvation had set in... even though we are getting some 800grs of meat between us every day now we still like Mum's milk!!
Monday we had lots of visits - Freddy came to puppy sit in the morning and then we had Joe and Dan come calling - and then Agnieszka who like Cousin Judy has one of there "pro" cameras came by with Johan (we are still waiting for the photos ... she is never happy with them!) so that you can see them but we are sure they will be terrific!!
And after that a young couple came by to meet us as well ... so lots of new faces and smells and voices...!