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Daryl Temkin, Daryl Temkin
Ph.D., Licensed Marriage and Family Therapist
Psychotherapy or counseling is an essential tool to provide individuals, couples or family groups who may have been in conflict, discord or even crisis to a new level of resolve and ideally into a functioning working relationship with restored possibilities of effective communications and an integration of new responses and new relationship insight and responsibility. Counseling an psychotherapy are meant to help a person see themselves and the world around them in a manner which can provide them with valuable insights, awareness and useful life tools which will lead to effective and successful behaviors, personal contentment and greater possible happiness.
Dr. Carol Francis, Psy.D., MFT, CHypT,
Clinical Psychologist, Marriage, Family & Child, Hypnosis
Within Driving Distance of Palos Verdes Estates, CA
For 36 years, I have discovered the importance of having many psychotherapy techniques available to help people succeed in their lives. No one psychotherapy tool fits everyone and every life-event. Some work better with analytic, thinking and talking tools. Others grow faster with art, stress management even hypnotherapy or neurolinguistic programming. Emotion-based therapies can provide relief, caring healing and recovery. Nutritional and fitness counseling can be essential to alter emotional, mental and personal stress for some. Life Coaching and counseling can aim directly toward solutions and skills improvements. No one tool fits all. DrCarolFrancis.com 310-543-1824
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Filter Results:
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—A century-long controversy is over: The reals are denumerable. The failure of numbers with infinitely long precision to terminate in calculations precludes their membership in the field of reals. All other real numbers are denumerable. Leopold Kronecker was right, and Georg Cantor was wrong. The branch of mathematics heretofore known as Transfinite… (More)
- Brian Crissey, Dean Sanders
- ACM Conference on Computer Science
- 1985
The introductory computer science course often plays a dual role in the resource limited environment of a small liberal arts college. It must provide a firm foundation for the computer science major while providing a service function to the rest of the college. This paper describes such a course that is being developed at Linfield College. By emphasizing… (More)
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11:00PM- Well people, it all comes down to this...the girls just went to bed, and Steve is out scampering early...and back and forth he goes, from the bathroom, to the hall back to the bathroom, decies to take a shower i think. No wonder he is up so late every night, he is wide awake. he is looking for something i think to clean the shower.. has a brush in his hand, thought it was a shower cleaner brush but it might be his back scrub brush. not sure...into the shower he goes, the camera guy shows a a pic CoCo in the dark, and Vanessa with her nappy crappy red hat on, she did her hair and then put this old not washed hat on for about the 4th day in a row, yuk, its like not changing your underwear...double yuk!!
Steve is out of shower, girls still asleep in purple room, Liz fidgits, gets up, heads to bathroom, steve scampers to kitchen, back to bathroom, liz is in ehre and stands there waiting for liz to get out of toilet so he could get clothes he left in there, she goes back to bed,lights are out.


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An Unexpected Love
- United States
- Romance
- English
More informationProtected by loving parents, young, beautiful and happy, Lady Ravina Ashley has the world at her feet. Unused to harsh words, she is taken aback when a stranger at a ball in London takes her to task for her behaviour towards a clumsy suitor.
But Ravina hopes that one day she will fall madly passionately in love and refuses to think of marriage to anyone until then.With her parents away in the Balkans, Ravina leaves London to stay with her cousin, Dulcie, at Curbishley Hall, the Ashley estate in Dorset. She is travelling with Sir Michael Moore, who has begged a lift in her carriage to his home a few miles away from hers.To Ravina's surprise on the journey she once again meets the man who felt he had the right to criticise her behaviour -- Sir Richard Crawford!
Sir Michael's attentions, however, are far more complimentary and Ravina's belief in her own judgement of men cannot be shaken.
What will happen when Sir Richard is forced to ask Ravina for hospitality at Curbishley Hall?Why is he so anxious to spend so much time in her company and is he hiding some secret from her that could threaten her and her family?
What happens to Ravina, who she eventually falls in love with, and how she fights against the dangers that surround her is told in this romantic novel by BARBARA CARTLAND.
If you like Downton Abbey you will love Barbara Cartland .


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Sailor neptune
Eksploruj powiązane tematy
Sailor Neptune wand (with a little Uranus in the bow's heart). The colours look a little bit too Sailor Jupiter-y but they'll do. :)Background is transparent.Please don't re-post to other websites without asking permission or giving credit.
Sailor Neptune (#Michiru Kaiou #Sailor Neptune)
Sailor Neptune. Omg Michiru looks sooo beautiful!!! TToTT
Sailor Neptune More
Sailor Neptune graffiti assortment by ginkgo
moonlight's dreaming
Sailor Neptune (Crystal) by LadyHeinstein.deviantart.com on @DeviantArt
Hello, I'm Sailor Neptune(Michiru). I live in Japan and fight evil with my best friend, Sailor Uranus. When I am not a super hero I enjoy playing the violin. My girlfriend is Sailor Uranus. I am 17
Sailor Neptune Mirror Tutorial by yohlenyaoilover.deviantart.com on @deviantART
Sailor Neptune Crystal by ElynGontier.deviantart.com on @DeviantArt


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Filter Results:
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- Siva K Mulpuru, Cesare Saponieri
- Indian pacing and electrophysiology journal
- 2010
Question An 85 year old male presents to the emergency room with presyncopal episode associated with nausea and diaphoresis that lasted for 10 minutes. He has past medical history of hypertension and paroxysmal atrial fibrillation on anticoagulation. He also had complete AV block that necessitated the implantation of a dual chamber pacemaker (Medtronic… (More)
- Siva K Mulpuru, Ravi Diwan, Dayana Eslava Manchego, Cesare Saponieri, Balendu Vasavada
- Indian pacing and electrophysiology journal
- 2010
A 56 year old male with a past medical history of hypertension and dyslipidemia presented with recurrent dizziness. Routine EKG was performed, which suggested frequent junctional extra systoles with compensatory pauses. During telemetry periods of 2:1 block with effective ventricular rate of 34 bpm was observed. His bundle study suggested frequent His extra… (More)
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia that causes stroke affecting more than 2.3 million people in the US. Catheter ablation to terminate AF is successful for paroxysmal AF but suffers limitations with persistent AF patients as current mapping methods cannot identify AF active substrates outside of pulmonary vein region.… (More)
- Amit Noheria, Siva K. Mulpuru, Peter A. Noseworthy, Samuel J. Asirvatham
- Indian pacing and electrophysiology journal
- 2016
We present a case of incessant wide-complex tachycardia in a patient with left-ventricular assist device, and discuss the differential diagnosis with an in-depth analysis of the intracardiac tracings during the invasive electrophysiologic study, including interpretation of the relative timing of the fascicular signals during tachycardia and in sinus rhythm,… (More)
Catheter ablation is associated with limited success rates in patients with persistent atrial fibrillation (AF), which is mostly maintained by rotors that are located outside of pulmonary veins (PV) region. None of the currently available commercial mapping systems can accurately predict the rotor location outside of PV in patients with persistent AF.
- Siva K Mulpuru, Subha L Varahan, Navinder S Sawhney
- Indian pacing and electrophysiology journal
- 2011
A 72 year old male with past medical history of hypertension and dyslipidemia presented with a 10 year history of palpitations associated with dizziness. His physical exam was within normal limits. His LV function was 62% and left atrial size was within normal limits. He was euthyroid and a recent stress test was negative for inducible ischemia. During the… (More)
- Siva K Mulpuru, Cesare Saponieri
- Indian pacing and electrophysiology journal
- 2010
We thank Dr Bhargava for careful reading of our article [1]. As highlighted by Dr Bhargava, Non Competitive Atrial Pacing (NCAP) algorithm is designed to prevent atrial arrhythmias by preventing atrial pacing within 300msec after a sensed atrial event in the post ventricular atrial refractory period (PVARP). The varying AV delays and fixed interval of… (More)
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Main menu:
Mr. Pat Bunce's 5th Class, Room 19 exhibited their project "Energy Engineers" on Friday 13th January at the R.D.S. Primary Science Fair during the Young Scientist Exhibition 2012. The project was commended by the judges and the class received an award. The pupils worked with an engineer to prepare a C.E.R. (Certificate of Energy Rating) for the school. They worked in four groups;
Apprentice Engineers
Scientists and
Computer Experts
The project took into account all aspects of energy use and production in the school and with some maths they calculated the exact kw/h per m2 energy consumption of the building. They then went on to examine and experiment with ways to improve on this rating.
An excellent and fun day was had at the R.D.S. and we look forward to exhibiting there again in the future.


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My 30-year-old sitar has been placed for sale on Craigslist for the Tampa Bay Area, Florida. Photos in that ad.
Vintage Sitar: 30 years old, full size, 18 strings, double toomba, length 49.5", width 14", carving fine and deep, "Ravi Shankar style." Bought in Hyderabad/Secunderabad, India in the mid-1980's from the maker's workshop, needs new strings and tuning, well-cared for, single owner, excellent condition, and beautiful. No case. $700. Cash only.
sitar, vintage for sale in Florida, Tampa Bay
This is for general discussions of Indian music and dance that do not belong elsewhere. It is also for the announcement of workshops, lectures, and performances.
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Rankings For Best Internet Marketing Companies Under Different Categories
Dtec, B-Block Technohub, Ground Floor, Dubai Silicon Oasis Authority Dubai UAE 6009
RANKED #1 in UAE
Office # 209, Al Kazim Building, Hor Al Anz, Deira P. O. Box: 111306
RANKED #2 in UAE
Office 301, Hamsa Building, Khalid Bin Al Waleed Road
RANKED N/R in UAE
P.O.Box 235012
RANKED N/R in UAE
Bainuna Street 34, Al Bateen, PO Box 113100, Abu Dhabi, United Arab Emirates
RANKED N/R in UAE
Office 1713, Grosvenor Business Tower, P.O. Box: 123439, Tecom, Dubai, UAE
RANKED N/R in UAE
Al Sour Building, Al Sour Area, Behind Saudi Mosque, Opp.Gulf lights, Sharjah, United Arab Emirates.
RANKED N/R in UAE
1204, Fortune Executive Tower, Cluster T, Jumeirah Lake Towers, PO.Box: 336101, Dubai, UAE
RANKED N/R in UAE
Citadel Tower - 3506 , Business Bay Dubai, UAE
RANKED N/R in UAE
Downtown Dubai, Emaar Boulevard Plaza Tower 1, Level 14, P.O.Box 5000107, Dubai, UAE
RANKED N/R in UAE
If you are searching for best email marketing services then the search ends here. 10seos comes up with the list of best email marketing companies operating in the UAE. These firms were found imparting best email marketing services to a great client bases. 10seos takes the notice of genuity and quality in the services provided by the Email marketing companies. The highlighted companies on the top of the list provide email marketing solution to engage subscribers, target an audience, send responsive emails and track results. The process includes sending emails to current and previous customers.
10seos has got a big team of analysts who keep themselves updated of the trends running in the industry. It analyses the firms on the basis of their expertise in the same domain and the quality of services they have been bestowing to a number of businesses for years. Choose best Email marketing company from the list of high performers.
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HELP - (619) 798-6892 | Skype: virtuousreviews


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Britain set for first new nuclear plant in 20 years as EDF board green lights Hinkley Point
After more than six years of negotiation, EDF grants final approval for the £18bn project, but in shock move government delays final decision on contract until autumn
EDF has formally approved plans to build an £18bn new nuclear plant in Somerset, moving the project a major step closer to the start of the full construction phase. However, in a shock twist to the...
More news
MPs call for national food waste target
Cross-party group of MPs wants to see supermarkets forced to publicly report annual food waste figures and put more 'wonky veg' on sale
UK investment under threat without EU chemical rules certainty, MPs warn
Parliament's Environmental Audit Committee urges government to provide certainty over future of EU chemicals regulations post-Brexit
EU backs stricter air quality standards designed to 'clean up or close down' dirtiest power plants
UK government backs tougher limits, which could prevent 20,000 premature deaths across the EU
Is employee activism on sustainability nearing a tipping point?
Most of those working for large US companies expect their CEO to be vocal about environmental and social issues, according to new research, and when it comes to the issues they care about most, renewable energy trumps immigration


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Designers were asked to submit a chic and modern design.
If you see a design that is not available for sale, please email us and we will help you purchase the design.
To link to this design on other websites, copy & paste this HTML.
This is a fresh, clean, and elegant invitation. It would be perfect for a spring wedding.
wedding invitations, Cosmos,
Gray, Fuscia, Pink, Purple, Lavender
Cursive Standard, MeMima
A7 Wedding Invitation
Nov 05 2010
perfect poppies!
Pretty flowers!
Send this design to a friend
Email sent to:
Your personal note (optional):
We uncover design genius through ongoing design competitions. At Minted, all that matters is good design. Designers submit, and the Minted community votes to tell us what to sell.
"Our purpose in life is to uncover exceptional design from all over the world and bring this to savvy consumers who won't accept anything else."
Copyright © 2017, MINTED LLC, all rights reserved


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Jason Shepherd – Learn Fingerstyle Guitar In 8 Weeks
Apr 21 2017
This step-by-step video can get you playing fingerstyle guitar in just 8 weeks. this is a realistic way to learn fingerstyle guitar a great gift that can last a lifetime. This video will help you learn to play fingerstyle and fingerpicking guitar without having any prior lessons or experience at all. Jason Shepherd has been an instructor in Phoenix, Arizona for many years years now and has seen what works and what doesn't. This DVD will guide you through 8 weeks of lessons designed to show you all the basics of beginning fingerstyle guitar. All it requires is that...Read More


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If you ever find yourself in need of Agency Bail Bonds, there is nothing to worry about! Many Agency bail bond companies can bail you (or another person) out anytime day or night in Agency. BailBondsNetwork.com makes it simple to find and get in touch with a licensed bail bond company in Agency, Iowa. At your request, many bail bonds companies will come pick you up discreetly. Payment plans are often available depending on case by case basis.
Upon arrest anywhere in Wapello county, a person must be processed at the Wapello county jail. To be released from Wapello jail, several steps must occur, including being booked into jail and posting bail. Once the bail bond amount is confirmed, a bail bond agent comes to post the bail bond at the local jail. Now the jail release procedure begins and typically takes anywhere from 1-2 hours to complete. Although cash bonds are allowed, it is normally not frequently done due to financial limitations.
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These velvet shams exceeded my expectations due to the fact that the back of the sham is the same fabric as the front--very beautiful texture, well made, simply lovely.
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Scatter Shots hack online now for free
Scatter Shot, online android casino game turned out to be very addictive but having enough resources to keep playing the game becomes a difficult job. At first the gems and coins seems enough to play through but then as the game proceeds the in-app purchases becomes really costly. The Scatter shot hack has free spins by which you can collect coins for free. To generate unlimited gems and unlimited coins follow the steps.
- Download the hack files
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var/Mobile/Applications/Scatter Slots/Documents/
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The Scatter shot hack – spin and win in casino slot machines works on both iOS and android smartphones. To generate the resources in game or online there are a few cheat codes.
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- rVHkZ4IVLT80UNU_Sm – VIP for a month
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Feb. 18, 2003 -- Here's a breakdown by position of the key defensive players who will be at the combine. We also are listing the top players at each position, and players you might not have heard of who might be a high draft pick.
Brandt's top 15 prospects - NFL.com - Gil Brandt
Feb. 18, 2003 -- It used to be that the top prospects never bothered to work out at the combine, for fear that a bad 40 time or shaky bench press would hurt their draft status. But these players are starting to learn that working out at the combine is one of the most important things they can do leading up to the draft.
Brandt's offensive pre-combine rankings - NFL.com - Gil Brandt
Feb. 17, 2003 -- Here's a breakdown by position of the key offensive players who will be at the combine. We also are listing the top players at each position, and players you might not have heard of who might be a high draft pick.
Combine still critical to evaluating talent - NFL.com - Vic Carucci
Feb. 18, 2003 -- Maybe it no longer is the one-stop-shopping experience it was originally meant to be. Maybe it doesn't provide a definitive answer to every critical question that NFL teams have about every player they view as a potential pick in April's draft.
Schedules more regimented at combine - NFL.com
Feb. 17, 2003 -- Bill Polian remembers the time Ryan Leaf missed his scheduled interview with the Indianapolis Colts. The explanation: Another team had corralled Leaf at the 1998 NFL scouting combine. Now it appears the league might have a solution to prevent similar conflicts.
List of possible salary cap cuts - ESPN.com- John Clayton
February 18, 2003 - Starting Thursday, teams can begin cutting veteran players to get under the salary cap. Though teams don't have to get under the cap until the beginning of March, the list of potential cuts could be better at certain positions than some positions on the list of unrestricted free agents.
Grossman anxious to throw at combine - ESPN.com- Len Pasquarelli
February 18, 2003 - While many of the 17 quarterbacks invited to the NFL combine workouts this week are still waffling over whether they will throw, there is no such mental debate for former University of Florida standout Rex Grossman, who is anxious to air it out for scouts.
Physical has become focus of combine - ESPN.com- Len Pasquarelli
February 18, 2003 - It remains a piece, and still a relatively significant chunk of the puzzle, in the ongoing process of evaluating NFL draft prospects. But as scouts continue to struggle convincing high-profile players to run the 40-yard dash, and sometimes must cajole even players projected as middle-round prospects to participate in on-field workouts, the annual NFL predraft combine has evolved into more of an interview than a full-blown audition.
Quarterbacks will garner plenty of attention at combine - ESPN.com- John Clayton
February 18, 2003 - The Super Bowl might be the NFL's annual celebration, but the scouting combine in Indianapolis is its annual convention. It's the only time during a year that the entire league assembles. Assistants usually don't go to owners meetings. Scouts don't head to the Super Bowl. Not all assistants make it to the Senior Bowl. But virtually everyone in football operations make it to Indianapolis in late February to see the college eligible players.
Upchurch urges fun for youths - Denver Post - Irv Moss
Wednesday, February 19, 2003 - Rick Upchurch delivered a stirring message Tuesday night in his induction speech into the Colorado Sports Hall of Fame.
Upchurch Becomes 19th Bronco in Colorado Sports Hall of Fame - DenverBroncos.com - Mike Sarro
Feb. 18, 2003 - In Rick Upchurch's first NFL game in 1975 he established a Denver Broncos franchise record. In a 37-33 victory over the Kansas City Chiefs, Upchurch amassed 284 all-purpose yards. He rushed for 13 yards, had 153 receiving, and gained 113 on returns. Denver took notice of their new rookie from the University of Minnesota and soon the rest of the league would as well.


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All meetings are held at Hartland Township Hall unless othewise noted. To stream meetings live, view archived meetings or review meeting agendas and packets, click here.
May 3, 2017, 7:00 PM
Board of Trustees – Regular Meeting
May 11, 2017, 6:30 PM
Board of Trustees & Planning Commission Joint Meeting – Special Meeting
May 11, 2017, 7:00 PM
Planning Commission – Regular Meeting
May 16, 2017, 7:00 PM
Board of Trustees – Regular Meeting
May 25, 2017, 7:00 PM
Planninig Commission – Regular Meeting
The Hartland Township Board of Trustees, after receiving recommendations from the Planning Commission, adopts ordinances to ensure that the character and aesthetics of the community are upheld.
View the Hartland Township Zoning Ordinance (Adopted Dec. 4, 2012; Effective Dec. 14, 2012; Last Amended March 19, 2015).
View the Hartland Township Zoning Map (Adopted Dec. 4, 2012; Effective Dec. 14, 2012).
The Township also adopts general ordinances for the protection of residents:
Ordinance No. 48, Dangerous Buildings
Ordinance No. 57, Land Division Ordinance
Ordinance No. 60, Liquor License
Ordinance No. 66, Outdoor Furnace Ordinance
Ordinance No. 69, Special Event Ordinance
Ordinance No. 74, Municipal Civil Infraction and Violations Bureau Ordinance
Ordinance No. 76, Zoning Ordinance
Ordinance No. 77, Fire Protection Ordinance
Ordinance No. 78, Blight and Nuisance
If you have any questions regarding any of the Township's ordinances, please contact the Planning Department.
If you would like to contact Hartland Township with questions or comments, our Staff Directory can be found here


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Franchisees asked, and Domino's is delivering
ANN ARBOR, Mich., May 16, 2016 – The launch of Domino's DXP delivery vehicles last year has franchisees asking for more, and more they will get. This summer, Domino's Pizza (NYSE: DPZ), the recognized world leader in pizza delivery, will roll out an additional 58 DXPs across 23 markets in the U.S., bringing the total number of DXPs to 155.
"The DXP demonstrates Domino's passion for pizza delivery," said Russell Weiner, president of Domino's USA. "The excitement around it has been incredible, which is why we have such a great demand for even more."
The DXP has a number of special features, including an innovative built-in warming oven, a reconfigured interior that holds up to 80 pizzas, and special compartments to hold side items and sodas. This first-of-its-kind pizza delivery vehicle allows drivers to deliver pizza with more ease and efficiency than ever before.
"The DXP has caught the eye of our customers and franchisee alike," said Weiner. "It's real, it's functionally superior, it's gorgeous and no other brand has anything like it. So when people ask, 'Did Domino's really build a car made just for pizza delivery?' I say, 'Oh yes we did.'"
To view a behind-the-scenes video on the making of the DXP, visit dominosdxp.com.
About Domino's Pizza®
Founded in 1960, Domino's Pizza is the recognized world leader in pizza delivery, with a significant business in carryout pizza. It ranks among the world's top public restaurant brands with a global enterprise of more than 12,600 stores in over 80 international markets. Domino's had global retail sales of over $9.9 billion in 2015, with more than $4.8 billion in the U.S. and nearly $5.1 billion internationally. In the first quarter of 2016, Domino's had global retail sales of over $2.3 billion, with over $1.1 billion in the U.S. and nearly $1.2 billion internationally. Its system is comprised of independent franchise owners who accounted for nearly 97% of Domino's stores as of the first quarter of 2016. Emphasis on technology innovation helped Domino's generate over 50% of U.S. sales from digital channels at the end of 2015, and an estimated $4.7 billion annually in global digital sales. Domino's features an ordering app lineup that covers nearly 95% of the U.S. smartphone market and recently introduced several innovative ordering platforms, including Ford SYNC®, Samsung Smart TV® Apple Watch and Amazon Echo, as well as Twitter and text message using a pizza emoji. In late 2015, Domino's announced the design and launch of the DXP®, a purpose-built pizza delivery vehicle, as well as its first digital customer loyalty program.
Order – dominos.com
AnyWare Ordering – anyware.dominos.com
Company Info – biz.dominos.com
Twitter – twitter.com/dominos
Facebook – facebook.com/dominos
Instagram – instagram.com/dominos
YouTube – youtube.com/dominos
More News
April 10, 2017 | Pizza Headlines
Firenza Pizza and Persona Wood Fired Pizzeria Announce Merger
Firenza Pizza & Persona Wood Fired Pizzeria – two restaurants known for their high quality and exceptional pizza product – are joining forces to become one! It's the best of both worlds as the two merge together under the Firenza Pizza name in Spring of 2017. Sarasota, Florida, April 4, 2017 (Newswire.com) – At Firenza,… Read More ›
April 7, 2017 | Videos
Cirque du Pizza — The Art of Pizza Acrobatics
Great Big Story has featured Tony Gemignani and the World Pizza Games at International Pizza Expo in Las Vegas. Watch the artistry of dough tossing. via Great Big Story Read More ›
April 1, 2017 | Pizza Headlines
Pizza & Pasta Northeast: The Cousins are Traveling to Atlantic City
I've got some exciting news to share with you regarding our Wednesday keynote address at Pizza & Pasta Northeast, which will be held October 17–18, 2017 at the Atlantic City Convention Center. Many have heard the call, but only two pizza makers have been chosen¬—at least by a national television network—to travel the country in… Read More ›


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Oris Chronoris Date
Our latest timepiece crush comes from Swiss watch manufacturer Oris. The stunning new Chronoris Date is a modern reinterpretation of the vintage watch, of the same name, released by Oris in the 70s. It features a 39mm brushed stainless steel tonneau-shaped case. The dial features several chapter rings in varying shades of silver, grey, and black wi...read more


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Posted by ESPN.com's Chris Low
Few teams in the country have been able to boast the kind of defensive line talent LSU has put on the field in recent years.
But this spring, there are more than a few question marks for the Tigers up front defensively. Gone are four seniors, including All-SEC defensive end Tyson Jackson, and junior tackle Ricky Jean-Francois, who left early for the NFL draft.
That doesn't mean the talent well has run dry. It's just that some new faces will get a shot up front, and that starts this spring.
In particular, first-year defensive coordinator John Chavis is anxious to get a look at the four defensive linemen the Tigers redshirted last season. One of those, Chancey Aghayere, was rated by Scouts Inc. as the No. 3 defensive end prospect in the country when he came out of Garland, Texas, last year.
The other three defensive linemen the Tigers redshirted last season were ends LaVar Edwards and Chase Clement and tackle Cordian Hagans.
"There are some young guys who haven't played yet, but they're very talented," Chavis said. "It's up to us to develop that talent."
This will also be a big spring for senior tackle Al Woods and junior tackle Drake Nevis. They need to prove that they can be consistent performers at this level. The Tigers got good news during the offseason when tackle Charles Alexander was granted a sixth year of eligibility, and they also return senior Rahim Alem at end. Alem was third in the SEC last season with eight sacks.


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The Studio Player's bring to the stage "Jake's Women," by Neil Simon and directed by E. Dale Smith-Gallo and Claudia Budris. The play tells the story of Jake, a novelist who has had more success with fiction than with his real life. Facing a marital crisis with his second wife, Jake begins to daydream about all of the women who have been part of his life. These comic and often moving flashbacks playing in his mind are continuously interrupted by real-life visits from the women in his life, including his revered first wife, his daughter, his sister, his analyst, his current wife who is leaving Jake for another man, and a prospective third wife.
"Jake's Women" will play March 24, 25, 26, 30, 3 and April 1, 2, 6, 7, 8; Thursdays, Fridays, and Saturdays at 8:00pm and Sundays at 3:00pm.
Tickets are $20 for adults and $17 for students/seniors. Opening night tickets are buy one, get one free.


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Dear Shoppers, We are undergoing a company-wide computer system upgrade, and the inventory levels listed on our website may not accurately reflect what is actually on our shelves. Please give us a call at 303-322-7727 and a bookseller will be happy to check stock for you. We apologize for the inconvenience.
Cracking the AP Environmental Science Exam (Paperback)
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• Engaging review activities to help you critically assess your progress
• Answer keys, explanations, and scoring worksheets for the practice tests


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Harvard Square Hotel
110 Mount Auburn Street
Cambridge, MA
Recently renovated, the Harvard Square Hotel now includes a Starbucks and modern, refined design in an old world building.
The hotel is situated within walking distance of Harvard Square attractions, such as the A.R.T. theater, Brattle Theater, and various pub and wine tours. The hotel is also within walking distance of the Harvard Square MBTA station, connecting you to Fenway Park, the Aquarium, the North End, and everything else Boston has to offer.
The Harvard Square Hotel holds 73 rooms, each featuring cozy beds and private baths. From the hotel's hip lobby, you can enjoy a distinct view of the lively square. Some amenities of the hotel include laundry service, self-parking, complimentary wireless internet access and a daily newspaper. You might even hear a Harvard game!
Located in the center of bustling Harvard Square, the Harvard Square Hotel is the perfect place to stay during your visit to Cambridge, MA.
Harvard Square Hotel Map & Directions
[pw_map address="110 Mount Auburn Street Cambridge, MA 02138″]


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Maybe it should be added to the Forum Rules:
Never ask for a release date of a new version of Space Engine !
ShockMaker wrote:Qr Bbpost I don't have any "RS" object in the Find Object window (F3)
Xiox wrote:Qr Bbpost (Also, any way to edit a post?)
Roswell wrote:Qr Bbpost Why I don't have HIP 1
Mosfet wrote:Qr Bbpost Also for the constellation name you need three, in your case "ZET Ret"
jasperhb wrote:Qr Bbpost How do I put the name of a star if it has a non-Latin or Cyrillic name? (Such as Zeta Reticuli)


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These numbers represent sheets of paper and trees saved by using Peachjar at your school.
There are 8,333 sheets of paper in a single tree.
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Medpages - The definitive contact database for healthcare in South Africa.
Learn about our flagship system, VASER Lipo. Includes system information, how it works, before and after photos, and testimonials.
A blog of surgical oncology aimed at residents in surgery
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With a 25% discount for students and teachers, plus plenty of tables and outlets to turn the shop into a mini study hall, Q Cafe attracts plenty of guests looking to get a little work done while also getting a caffeine jolt. Here are some other things to know about the café:


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|Publication number
|Publication type
|Application number
|Publication date
|Apr 25, 1989
|Filing date
|Apr 26, 1985
|Priority date
|Apr 26, 1985
|Fee status
|Also published as
|Publication number
|Otto Gansow
|Original Assignee
|The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (3), Non-Patent Citations (9), Referenced by (23), Classifications (33), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
This invention relates to metal chelate protein conjugates and to an improved method of forming metal chelate protein conjugates.
There has been a continuing interest in the art in metal chelate protein conjugates both for therapeutic and for diagnostic purposes. Representative type conjugates are disclosed, inter alia, in U.S. Pat. Nos. 4,454,106 and 4,472,509. One such type of conjugate is a metal chelate monoclonal antibody conjugate. Other proteins including, for example, polyclonal antibodies, antigens and blood proteins can also be employed in the formation of a metal chelate protein conjugate.
In general, the prior art has formed a conjugate of a chelate and protein and thereafter mixed that conjugate with the metal to be chelated. Such system is feasible as described in U.S. Pat. No. 4,472,509. In order to provide a conjugate in which substantially all the metal is contained in the chelate, however, several precautions are necessary. As a threshold matter, the protein to be used should be essentially free of metals which chelate because the presence of those metals with the protein may block the desired chelating sites. In addition, protein has an inherent ability to adventitiously bind metal along the protein molecule. Such metal may be either strongly or weakly bound depending upon the metal thereby presenting a significant challenge in removing the adventitiously bound metals from the protein. Some of the adventitiously bound metals may be (and often are) released in vivo and, particularly in the case of radioactive metals, may produce an undesirable concentration of the metal in bone marrow or the like. A process for processing metal chelate protein conjugates for the removal of adventitiously bound metals is disclosed in U.S. Pat. No. 4,472,509.
There continues to be a need for effective metal chelate protein conjugates as well as an effective method for forming a metal chelate protein conjugate that does not require substantial protein pre-purification and/or subsequent processing to remove adventitiously bound metals.
It is one object of this invention to provide a method for forming a metal chelate protein conjugate that does not require rigorous pre-purification of the protein.
It is a further object of this invention to provide a method for forming a metal chelate protein conjugate that does not result in adventitiously bound metals.
It is yet another object of this invention to provide a method for forming a radioactive metal chelate protein conjugate that does not require the use of carrier-free or no-carrier added radioactive nuclides.
It is still another object of this invention to provide an efficient method of forming a stable metal chelate protein conjugate.
It is yet a further object of this invention to provide a novel substituted diethylenetriamine as well as a novel bifunctional chelate.
It is still a further object of this invention to provide a novel metal chelate protein conjugate.
The present invention contemplates the method of forming a metal chelate protein conjugate which comprises:
contacting a metal in the absence of a protein with a bifunctional chelate having as a portion of its molecular structure a functional group attached to a carbon atom of the chelate backbone and which is stable in a dilute aqueous solution at a pH for metal chelation in the range of from about 1 to about 7 and which reacts directly with amino acid residues of a protein to form a stable covalent linkage at a conjugating pH in the range of from about 6 to about 11;
admixing said metal chelate with a protein in an aqueous solution having a pH of from about 6 to about 11 to form a stable metal chelate protein conjugate.
In another of its aspects this invention contemplates a particularly useful bifunctional metal chelate comprising a diethylenetriaminepentaacetic acid substituted on the carbon backbone with a side chain containing a nitro substituent. In still other aspects, the invention contemplates a diethylenetriaminepentaacetic acid substituted on the carbon backbone with a side chain containing an isothiocyanate substituent or an N-hydroxysuccinimide ester substituent and a metal chelate protein conjugate formed therefrom.
The practice of the method of this invention substantially eliminates adventitiously bound metal. By selection of proper functional groups on the chelate a rapid formation of the metal chelate protein conjugate is achieved. Such formation permits a variety of radioactive nuclides including those which have relatively short half lives to be effectively processed according to this invention. Moreover, since conjugates often are formed at somewhat basic pH's, a slow formation of the conjugate can result in unwanted side effects. Such side effects include hydrolysis of metals with the accompanying loss of metal from the chelate and precipitation of metal on protein surfaces as undesirable adventitiously bound metal. In addition, hydrolysis of metals can result in the formation of undesirable colloids which may be difficult to separate from the protein. Moreover, utilization of a rapid coupling reaction provides flexibility and makes a a kit practical thus expanding the types of laboratory locations at which the formation of metal chelate protein conjugates may be utilized.
A large number of reactive groups which have been indicated to be useful to couple chelates to proteins are not suitably efficient for this invention. Thus, disulfides or maleimides tend to dissociate in water at pH's that exist in vivo or in serum; nitrenes, sulfonamides, carbodiimides, sulfonyl chlorides, and anhydrides tend to be unstable in water at conjugation raction conditions; benzimidates, haloacetamides, hydrazides and diazotized amine groups tend to inefficiently conjugate; and azides and nitrenes must be coupled photolytically which can result in inefficiencies and require considerable equipment.
Yeh, Analytical Biochemistry, 100, 152-159 (1979) reported use of a side chain containing a COOH functional group attached to the carbon backbone of EDTA (1-(p-carboxymethoxybenzyl)-ethylenediaminetetraacetic acid). Yeh chelated both iron and indium before conjugation to protein by a carbodiimide coupling reaction. The iron and indium were employed to tie up the COOH groups of the EDTA portion of the molecule which was necessary because the coupling functional group was also a COOH group. This method requires a very large excess of bifunctional chelate and also results in some dimerization of protein. Yeh removed the iron after conjugation and then subsequently added the desirable metal ions. Yeh reported that the indium was not effective as a blocking agent for EDTA carboxylates thus resulting in an unstable metal chelate protein conjugate.
Prior art DTPA-containing protein conjugates have coupled the DTPA through a carboxylic acid group of the DTPA or through a functional group on a side chain attached to a nitrogen of the DTPA. The DTPA chelates of this invention are more stable than either or than DTPA itself.
Any of the organic chelating agents (called ligands) known in the art can be employed in the practice of this invention. Such organic ligands include, inter alia, the natural or synthetic amines, porphyrins, aminocarboxylic acids, iminocarboxylic acids, ethers, thiols, phenols, glycols and alcohols or the polyamines, polyaminocarboxylic acids, polyiminocarboxylic acids, aminopolycarbocxylic acids, iminopolycarboxylic acids, nitrilocarboxylic acids, dinitrilopolycarboxylic acids, polynitrilopolycarboxylic acids, ethylenediaminetetraacetates, diethylenetriaminepenta- or tetraacetates, polyethers, polythiols, cryptands, polyetherphenolates, polyetherthiols, ethers of thioglycols or alcohols, polyaminophenols, all either acyclic, macrocyclic, cyclic, macrobicylclic or polycyclic, or other similar ligands which produce highly stable metal chelates or cryptates. One summary of chelating agents is given in U.K. patent application No. 2,109,407. Obviously, the choice of the ligand depends upon the metal to be chelated and is within the skill of the art.
According to the practice of this invention, the bifunctional chelate has as a portion of its molecular structure a functional group attached to a carbon atom of the chelate backbone and which reacts directly with amino acid residues of a protein to form a covalent linkage. Such functional groups include isothiocyanate and the N-hydroxysuccinimide ester. The functional group, in accordance with this invention, may be attached directly to the chelate backbone or may be attached to the chelate backbone through any of a wide variety of side chains. Any of a wide variety of side chains may be employed and the choice of a particular one will be within the skill of the art. The side chain may contain carbon-to-carbon, ether or thioether linkages or the like. Hydrocarbon side chains are preferred. If there are heteroatoms present, for example in ether linkages, interrupting the carbon backbone, they may be counted as carbon atoms for the purpose of chain length determinations. Such structures include, without limitation, straight or branch chain alkyl groups having 1 to about 15 carbon atoms such as methylene, ethylene, propylene, butylene, isopropylene and the like; a straight or branch chain alkene group having 2 to about 15 carbon atoms including ethene, propene, butene and the like and isomers thereof; aryl groups including phenyl, diphenyl, napthyl and the like; and alkyl aryl groups having 1 to about 15 carbon atoms in one or more branched or straight chain alkyl groups, including benzyl, phenyl ethylene, phenyl propylene and the like. The essential purpose of the side chain is only to serve as a stable link between the chelate and the functional group. The side chain should be essentially free of reactive groups other than the desired functional groups as described above. Preferred side chains include straight chain alkanes, benzyl, and phenylethylene.
Chelates having the appropriate functional groups can be prepared employing methods known in the art. Those methods include, for example, that described in Analytical Biochemistry, 142, 68, (1984).
In one preferred aspect, this invention provides a diethylenetriaminepentacetic acid (DTPA) having a side chain attached to the carbon backbone of the DTPA and containing a functional group which is stable in a dilute aqueous solution at a pH for metal chelation in the range of from about 1 to about 7 and which reacts directly with amino acid residues of a protein to form a stable covalent linkage at conjugating pH's in the range of from about 6 to about 11. The preferred functional groups and hydrocarbon side chains are as described above.
In order to make the substituted DTPA, a precursor compound, a diethylenetriamine, is used. The most preferred such compounds contain a nitro group attached to the carbon backbone of the diethylenetriamine. Such attachment is provided via side chains containing carbon-to-carbon, ether, thioether linkages, or the like. Depending on the DTPA chelate described, the length of the side chain and composition thereof will vary as described above. Preferred side chains linking the nitro-group to the carbon backbone are straight chain alkyl, benzyl, and phenylethylene.
In one process for producing the substituted DTPA, nitrophenylalanine is converted to the methyl ester, for example, by reacting with methyl alcohol saturated with hydrochloric acid and the methyl ester is then reacted with ethylenediamine in the presence of triethylamine in an organic solvent to form the corresponding acid amide of ethylenediamine. The compound thus formed is subsequently reduced with diborane in tetrahydrofuran and the resulting boron hydride adduct is cleaved with hydrochloric acid in ethanol to form 2-(nitrobenzyl)diethylenetriamine trihydrochloride. The diethylenetriamine can then be converted to the pentaacetic acid employing techniques well-known in the art.
In an alternate method of providing the 2-(nitrobenzyl)diethylenetriamine, nitrophenylalanine may be reacted with the amine blocking group (BOC-ON, Aldrich Chemical Co.) and the blocked amino acid is then reacted with the acetic acid salt of glycinamide in the presence of triethylamine and 1-hydroxybenzotriazole. The primary amine is then "deprotected" from BOC by refluxing with HCl in dioxane to form the corresponding peptide salt. Reduction with diborane in tetrahydrofuran followed by cleavage of the boron hydride adduct with hydrochloric acid provides 2-(nitrobenzyl)diethylenetriamine trihydrochloride. Once again, this material may be converted to the nitro-substituted pentaacetic acid by reactions well-known in the art.
The nitro-substituted pentaacetic acid is readily converted to isothiocyanate-substituted pentaacetic acid by reduction of the nitro-group to an amine group, forming the corresponding amino-substituted pentaacetic acid which is then reacted with thiophosgene. The above amino-substituted compound can be used to form two particularly useful chelates: isothiocyanate-substituted DTPA and N-hydroxysuccinimide ester-substituted DTPA. To form the first such chelate a variety of methods, well-known in the art, may be used. To form the second compound, the amine-substituted DTPA is reacted with a di-N-hydroxysuccinimide ester of a dicarboxylic acid. Suitable esters include those of the alkyldicarboxylic acids, or aryl-dicarboxylic acids. Preferred esters are those of malonic, succinic and glutaric acid. Such reactions are generally performed by addition of the amine-substituted DTPA to solutions containing excess of the ester. Purification may be accomplished using reverse phase HPLC.
The 2-(nitrobenzyl)diethylenetriamine is a valuable intermediate since the nitro group can readily be converted employing reactions well-known in the art, to an amine, as well as other groups. Diethylenetriamine salts produced by many of the above techniques can, of course, be salts of acids other than hydrochloric such as hydrobromic acid, acetic acid and the like. These salts can be converted to the free amine by neutralization with, for example, triethylamine or other base and extraction into ether.
Any suitable metal can be employed in the chelate including metals which exhibit paramagnetism, metals which are fluorescent and metals which are radioactive. Representative paramagnetic metals include gadolinium and iron, fluorescent metals include several metals of the lanthanide series such as terbium and europium; and radioactive metals include radionuclides of bismuth, indium, yttrium and scandium.
Metal chelation is carried out in an aqueous solution, preferably in a dilute acid medium having a pH of about 1 to about 7 and most preferably at a pH of from about 4 to about 6. Ambient temperatures or below (to just above freezing) readily can be employed for the metal chelation. Any appropriate metal salt, either in solid form or in solution, is contacted with the chelate in solution in order to form the chelated metal. The amount of metal employed may be from tracer amounts to amounts equimolar with the chelate. A wide variety of metal salts may be employed including, for example, nitrates, iodides, chlorides, citrates, acetates and the the like. The choice of an appropriate metal salt for any given metal as well as the choice of a particularly appropriate chelate for any given metal is within the skill of the art. It will be apparent that the practice of this invention permits the processing of rather small quantities of metal and protein to form metal chelate and metal chelate protein conjugates.
The chelated metal is then mixed in aqueous solution with the desired protein at a pH of from about 6 to about 11, most preferably at a pH of from about 7 to about 9.5. Desirably, the pH is adjusted with buffered solutions such as a bicarbonate buffered solution. Once again, the choice of an appropriate buffer is within the skill of the art. The temperature of the solution can range from just above freezing to the temperature at which the chelate becomes unstable or the protein denatures. Often temperatures above 37� C. tend to denature proteins.
The choice of a protein for use in the metal chelate protein conjugate is not critical. Any desirable protein may be employed to form the conjugate. Monoclonal antibodies, of course, are often chosen as the protein for the formation of metal chelate protein conjugate both for diagnostic and for therapeutic purposes. Other suitable proteins include polyclonal antibodies, antigens and blood proteins generally. Generally, chelate and protein are mixed in a molar ratio of greater than 1:1 and generally less than about 10:1. Ratios of about 2:1 to about 4:1 are often preferred.
When either an N-hydroxysuccinimide ester or an isothiocyanate is employed in the practice of this invention, no catalyst is necessary in order to form the conjugate and pH's of from about 6 to about 9.5 are desirable. The presence of a catalyst, while not necessary, may speed the conjugation reaction by a factor of 3 or 4 or more. Suitable catalysts are general base catalysts and include triethylamine, N,N-dimethylaminopyridine, and the like.
The metal chelate protein conjugate of this invention may be used as such with appropriate pH adjustment, if needed. Alternatively, if it is desired to purify the conjugate from unconjugated chelate or products of any side reactions, the product may be purified. A variety of purification techniques known in the art may be used including column chromatography such as that described in U.S. Pat. No. 4,472,509. High-pressure liquid chromatography (HPLC) can also be used.
The invention contemplates as in vivo therapeutic procedure in which radiometal chelate conjugated monoclonal antibodies are introduced into the body and allowed to to concentrate in the target region. There are a wide variety of radiometal isotopes which form stable DTPA complexes and emit cytotoxic beta particles, Auger electrons and alpha particles. Useful beta particle emitting isotopes include Sc-46, Sc-47, Sc-48, Ga-72 and Ga-73. Bi-212 is a useful alpha emitter. The therapeutic effect occurs when the conjugates are near or in contact with and bind to the targeted cells. Cell death, it is believed, is a direct or indirect result of the radiation event of the radiometal which is positioned in close proximity to the cell.
The benefits of this aspect of the invention are several. First, the high specificity of the conjugated monoclonal antibody minimizes the total radiation dosage. Only enough radiation for the target cells need be employed. In addition, radiometal chelates generally are cleared rapidly from the body should the conjugated antibody be disrupted. The isotope can be short-lived and the affinity constant by which the isotope is retained in the DTPA chelate is very high resulting in a stably bound metal. Finally, since the amount of radiometal employed is minimized, the radiation hazard to persons preparing the administering the radiometal chelate conjugated antibody is significantly reduced.
Because of the properties of the DTPA radiometal chelate conjugated monoclonal antibody employed by the present invention, tissue damage or whole body dose during therapy are markedly reduced as compared to that from presently employed methods of radiation therapy such as isotope implants, external radiation therapy, and immunoradiotherapy employing iodine-131 labeled polyclonal or autologus antibodies. Additionally, both biological and physical half-lives of the targeting radiobiological may now be controlled, minimizing whole body radiation effects. Since radiation is targeted specifically to cell types (e.g., neoplastic cells) a therapeutic dose is delivered specifically to malignant cells, either localized or metastasized. The ability of radiometal chelate conjugatged monoclonal antibody to provide an effective dose of therapeutic radiation specifically to metastasized cells is also unique and singularly useful for cancer therapy.
In another embodiment, the present invention contemplates an in vivo diagnostic procedure which comprises introducing a metal chelate conjugated monoclonal antibody into the body, allowing sufficient time for the conjugate to localize and identifying the degree and location of localization, if any. The present invention also contemplates in vivo analytical procedures employing a chelate conjugated monoclonal antibody. The conjugated antibody of the present invention is substantially free of adventitiously or weakly chelated metal. The chelate conjugated to the antibody in the present invention is a derivative of diethylenetriaminepentaacetic acid (DTPA).
Other diagnostic and therapeutic techniques are described in U.S. Pat. No. 4,454,106, which is incorporated here by reference.
The following examples are to be used for illustrative purposes only are and not to be limited by the scope of this invention.
Preparation of 1-(p-isothiocyanatobenzyl)ethylene diaminetetracetic acid.
Synthesis of methyl p-nitrophenylalanine hydrochloride 1: Dry methanol (200 ml) was saturated with HCl by bubbling in a three-necked round bottom flask and cooled to -10� C. p-Nitrophenylalanine (10.0 g, 47.6 mmol) was added in one portion and left to stir for two hours, then resaturated with HCl. The reaction flask was stoppered with a drying tube and left to stir at room temperature for 18 hours. The solution was evaporated to near dryness on a rotary evaporator and the precipitated product collected in a Buchner funnel. After drying under vacuum at 50� C., the yield of 1 was 10.97 grams (88.3%). A TLC of the free amino ester run in CHCl3 :MeOH (4:1) revealed an Rf =0.85-0.88. 1 H NMR (220 MHz, D2 O, pH 1.5) δ 8.20 (d, 2, J=10.0), 7.53 (d, 2, J=10.0), 4.55 (t, 1, J=11.0), 3.84 (s, 3), 3.43 (m, 2); CI-MS 225 ((M+1)/z).
Synthesis of p-nitrophenylalanine amide 2: A slurry of 1 (10.97 g, 42.1 mmol) in dry methanol (5 ml) was treated with triethylamine (6.45 ml). After clearing, anhydrous ether (200 ml) was added to the solution and cooled to -10� C. for one hour. Precipitated triethylamine hydrochloride was removed by filtration and the filtrate concentrated to a limpid yellow oil. The oil was added to dry methanol (250 ml) previously saturated with NH3 (g) at -10� C., tightly stoppered and left at -10� C. for 42 hours. The precipitated product was collected and dried under vacuum. The liquid filtrate was spotted on a TLC plate and developed with CHCl3 :MeOH (4:1) which revealed one spot at Rf =0.50, identical to that of the collected precipitate. The filtrate was therefore stripped to dryness and the remaining solid 2 combined with the precipitate (8.12 g, 92.3%): mp 160�-162� C.; 1 H NMR (220 MHz, DMSO-d6), δ 8.07 (d, 2, J32 8.0), 7.5 (d, 2, J=8.0), 7.41 (s, 1), 7.00 (s, 1), 3.50 (t, 1, J=6.0), 3.09 (dd, 1, J=6.0, 16.0); 2.81 (dd, 1, J=6.0, 16.0) CI-MS 210 ((M+1)/z).
Synthesis of 1-(p-nitrobenzyl)ethylenediamine dihydrochloride 3: A one liter three-neck round bottom flask was fitted with a reflux condenser, septum, argon inlet and bubbler exit, then flame dried. 2 (8.12 g, 38.9 mmol) was washed into the reaction flask with dry THF (150 ml) and cooled to -10� C. Next, 1M BH3.THF solution (200 ml) was added with a syringe. The reaction solution was stirred one hour at -10� C., then raised to a gentle reflux for 18 hours, after which it was cooled to -10� C. and dry methanol (25 ml) was injected. The reaction was allowed to warm to room temperature before stripping the solvent to near dryness. Methanol (25 ml) again was added and evaporated to near dryness. The residue was taken up in dry ethanol (100 ml), saturated with HCl(g) and heated to reflux for two hours. The reaction was then tightly stoppered and left at 0� C. for 18 hours. The precipitated product 3 (8.86 g, 85.1%) was collected and dried under vacuum. 1 H NMR (500 MHz, D2 O, pH 1.0) δ 8.234 (d, 2, J=8.0), 7.634 (d, 2, J=8.0), 4.125 (m, 1), 3.543 (dd, 1, J=6.5, 18.0), 3.467 (dd, 1, J=6.5, 18.0), 3.391 (dd, 1, J=7.0, 14.0) 3,260 (dd, 1, J=7.0, 14.0); (500 MHz, D2 O, pH 11.5) and 8.046 (d, 2, J=8.5), 7.423 (d, 2, J=8.5), 3.061 (m, 1), 2.926 (dd, 1, J=10.0, 13.5) 2.730 (dd, 1, J=10.0, 13.5), 2.665 (dd, 1, J=16.0, 13.5), 2.592 (dd, 1, J=16.0, 13.5); CI-MS 196 ((M+1)/z).
Synthesis of 1-(p-nitrobenzyl)ethylenediaminetetraacetic acid 4: A 50 ml three-neck round bottom flask was fitted with the addition tube from an autoburette, a glass electrode, a stirring bar and a stopper. The reaction flask was charged with 3 (2.0 g, 7.465 mmol) in H2 O (6 ml) and heated in a temperature controlled oil bath at 45� C. Bromoacetic acid (4.198 g, 30.2 mmol) was added in four equal portions over 4 hours while the reaction mixture was maintained at pH 10.8 by the controlled dropwise addition of 7M KOH. After the final addition, the reaction was allowed to continue for 18 hours before filtration through a medium glass frit, acidification with concentrated HBr to pH 1.8, and evaporated to dryness. A substantial amount of salt was removed by triturating with hot 100% formic acid followed by filtration on a medium frit. The filtrate was evaporated and the residue taken up in 1M formic acid and loaded onto an ion exchange column made up of a 2.6�30 cm bed of AG1�8, 200-400 mesh, anion exchange resin, formate form (Bio-Rad Corp.). The column was jacketed and maintained at 40� C. by a water bath. The product was eluted from the column with a 1M to 7M gradient of formic acid at a flow rate of 2 ml/min., monitoring at 370 nm, with a 6.5 ml fraction size. Fractions 155-206 which contained precipitated product 4 were collected by filtration and the eluant in fractions 135-237 was combined with the filtrate and stripped to dryness (2.234 g, 70.0%).
TLC of the product was performed in 1-butanol:H2 O acetic acid (4:1:1) with an Rf =0.20 and in Methanol:10% aqueous ammonium acetate (1:1) with an Rf =0.80-0.83.
1 H NMR (500 MHz, D2 O, pH 4.5) δ 8.176 (d, 2, J=8.0), 7.577 (d, 2, J=8.0), 3.928 (d, 2, J=17.0), 3,839 (q, r, J=17.0), 3,685 (d, 2, J=17.0), 3,581 (t, 1, J=12.0) 3,388 (m, 2), 3,006 (t, 1, J=10.0); (500 MHz, D2 O, pH 11.5) δ 8.098 (d, 2, J=7.5), 7.398 (d, 2, J=7.5, 3,40-3.00 (m, 7), 2.888 (t, 1, J=10.5), 2.720 (d, 2, J=16.0), 2,562 (t, 1, J=13.0), 2,462 (t, 1, J=12.0), 2,152 (d, 1, J=14.0); EI-MS--sample was prepared by reacting with excess bis(trimethylsilyl)trifluoroacetamide in acetonitrile; m/z (M+) 715, 700, 598, 579, 425, 920.
Synthesis of 1-(p-aminobenzyl)ethylenediaminetetraacetic acid 5: A water-jacketed three-necked flask (50 ml) was charged with 10% Pd/C (43 mg), H2 O (5 ml) and a stirring bar. The center neck was attached to an atmospheric hydrogenation apparatus, one side neck was fitted with an injection valve, and the remaining neck firmly stoppered. The assembled hydrogenation apparatus was evacuated and flushed with hydrogen while the reaction flask was cooled to 4� C. 4 (427 mg, 1 mmol) was dissolved in H2 O (10 ml) and 5M NaOH was added to bring the pH to 10.0. The solution was injected into the reaction flask and hydrogen uptake monitored. After 67.5 ml of gas had been consumed, the flask was disconnected from the system and the contents filtered through a fine frit coated with celite 535. The filtrate was acidified to pH 2.0, stripped to near dryness and the residual solution loaded onto an ion exchange column, 2,6�30 cm, charged with AG50W� 8, 200-400 mesh, H+ form, and eluted with 0.5M ammonia. The fractions containing product, as determined by TLC, were evaporated to a solid and dried under vacuum for 18 hours (390 mg, 98.0%). The TLC of the product had an Rr =0.10 in 1-butanol:H2 O:acetic acid (4:1:1).
1 H NMR (500 MHz, D2 O, pH 1.5) δ 7.468 (m, 4), 4.109 (d, 2, J=16.0), 4.020 (d, 2, J=16.0), 3,768 (d, 2, J=17.5), 3,640 (d, 2, J=15.0), 3.887 (m, 2), 3,193 (d, 1, J=13.0), 2,798 (d, 1, J13.0), one proton obscured by doublet at 3.640; (500 MHz, D2 O, pH 6.0) δ 7.173 (d, 2, J=7.0), 6.959 (d, 2, J=7.0), 3.832 (d, 2, J=16.5), 3,699 (d, 2, J=16.5), 3,624 (d, 2, J=16.5) 3.568 (d, 2, J=16.5), 3,346 (t, 1, J=9.5), 3,233 (d, 1, J=14.0), 3,131 (d, 1, J=9.5), 2,679 (t, 1, J=13.0) one proton obscured by doublet at 3.624; (500 MHz, D2 O, pH 11.5) δ 7.033 (d, 2, J=7.0), 6.805 (d, 2, J=7.0), 3.40-3.00 (m, 4), 3,0069 (d, 2, J=16.5), 2,841 (d, 1, J=13.0) 2.725 (t, 1, J=12.0), 2.659 (d, 2, J=16.5), 2,429 (t, 1, J=12.0), 2,171 (d, 1, J=13.0), 2.096 (t, 1, J=12.0); EI-MS sample was prepared by reacting with excess bis(trimethylsilyl)trifluoroacetamide in acetonitrile; for the free amine, m/z (M+) 685, 670, 579, 396; for the silated amine, m/z (M+ -15) 742 468).
Synthesis of 1-(p-isothiocyanatobenzyl)ethylenediaminetetraacetic acid 6: The precursor 5 (0.33 mmol) was taken up in H2 O (10 ml) and stirred rapidly in a 10 ml round bottom flask fitted with an addition funnel. The pH was adjusted to 8.5 with solid NaHCO3 and thiophosgene (42 mg, 0.365 mmol) in CHCl3 (10 ml) was added dropwise. Stirring was continued until the solution tested negative for amine by the fluorescamine method. The aqueous layer was taken to dryness. Purification was done by column chromatography on a 1�30 cm Florisil™ column eluted with acetonitrile:water (30:8). The product eluted from the column cleanly as determined by TLC and was stored in a dessicator in a freezer and re-purified immediately prior to use.
The Rf of the product, determined by TLC, was 0.45 in acetonitrile:water (30:8) and 0.60 in ethanol:water:acetic acid (70:25:5). The IR spectra showed an absorption at 2100 cm-1 in Nujol™. 1 H NMR (500 MHz, D2 O, pH 5.3) δ 7.273 (q, 4, J=8.5), 3.471 (d, 1, J=17.0), 3.313 (broad singlet, 2), 3.118 (d, 1, J=14.0), 3.05-2.70 (m, 6), 2.547 (t, 1, J=13.5), 2.447 (t, 1, J=13.0), 2,257 (d, 1, J=14.0).
Preparation of 1-(p-isothiocyanatobenzyl)diethylenetriaminepentaacetic acid.
Synthesis of N-(2-aminoethyl)p-nitrophenylalanine amide 7: In a manner identical to the preparation of 2, 1 (4.4 g, 17.9 mmol) was treated with triethylamine (2.78 ml, 20.0 mmol) to generate the free amino ester. After removal of the solvents, the ester was taken up in methanol (5 ml) and added dropwise to ethylenediamine (35 ml) at room temperature with vigorous stirring. While TLC revealed that the reaction was essentially completed in less than one hour, the reaction was allowed to stir for 18 hours. The reaction flask was fitted with a vacuum take-off adaptor and attached to a vacuum pump with a liquid nitrogen trap in line. Removal of the solvent left a brownish solid which was dried at 50� C. under vacuum for 6 hours, and 24 hours at room temperature (4.42 g, 87.5%). TLC of the product showed an Rf =0.10-0.12 in chloroform:methanol (4:1).
1 H NMR (220 MHz, D2 O, pH 1.0) δ 8.23 (d, 2, J=8.0), 7.54 (d, 2, J=8.0), 4.36 (t, 1, J=7.0), 3.62 (m, 1), 3.41 (m, 3), 3.12 (m, 2); CI-MS 253 (M+I)/z).
Synthesis of p-nitrobenzyldiethylenetriamine-trihydrochloride 8: 7 (5.38 g, 21.3 mmol) was reduced with 1M BH3.THF (125 ml) in a manner identical to that employed in the preparation of 3 (6.05 g, 82.3%).
1 H NMR (500 MHz, D2 O, pH 11.5) δ 8.285 (d, 2, J=9.0), 7.605 (d, 2, J=9.0), 4.118 (m, 1), 3.68-3.57 (m, 2), 3,538 (t, 2, J=7.0), 3,458 (t, 2, J=7.0), 3,378 (dd, 1, J=9, 12.5) 3,213 (dd, 1, J=9, 12.5); CI-MS 239 ((M+1)/z).
Synthesis of BOC-p-nitrophenylalanine 12 (Alternative synthetic pathway to 8 for verification purposes): p-Nitrophenylalanine (7.94 g, 37.8 mmol) was dissolved in 50% aqueous dioxane solution (60 ml) and triethylamine (0.9 ml, 56.7 mmol) added. BOC-ON (10.24 g, 41.6 mmol) (Aldrich Chemical Co.) was added and the solution stirred for two hours. Ethyl acetate (100 ml) and H2 O (50 ml) were next added and the contents poured into a separatory funnel. The aqueous layer was retained and extracted twice with ethyl acetate (100 ml). The aqueous layer was cooled to 0� C. and the pH was adjusted to 2.0 with 3N HCl, whereupon a precipitate formed which was collected and dried under vacuum. The filtrate was extracted with ethyl acetate twice (100 ml), dried (MgSO4) and stripped to dryness. The two fractions provided to be identical and were combined (11.0 g, 94.0%). The melting point of the compound was 165� C.
1 H NMR (220 MHz, DMSO-d6) δ 8.036 (d, 2, J=8.0), 7.29 (d, 2, J=8.0), 5.38 (d, 1, J=8.0), 4.44 (m, 1), 3.25 (dd, 1, J=6, 13.0), 3.05 (dd, 1, J=6, 13.0), 1.39 (s, 9); CI-MS 311 ((M+1)/z).
Synthesis of 1-(p-nitrobenzyl)diethylenetriamine trihydrochloride 8: Glycineamide, acetate salt (432 mg, 3.23 mmol) was dissolved in ethyl acetate (50 ml) and cooled to 0� C. Triethylamine (326 mg, 3.23 mmol) 12 (1.0 g, 3.23 mmol) and 1-hydroxybenzotriazole (383 mg, 2.84 mmol) were added in succession. Dicyclohexylcarbodiimide (731 mg, 3.55 mmol) in ethyl acetate (5 ml) was then added. The flask was stoppered with a drying tube, allowed to come to room temperature, and stirred for 48 hours. Three drops of acetic acid were then added and, after 10 minutes, the reaction mixture was filtered. The filtrate was retained and washed three times with 0.5N HCl (50 ml), then with saturated NaCl (50 ml), three times with 5% NaHCO3 (50 ml) and again with saturated NaCl (50 ml). The wet organic phase was dried (MgSO4) and evaporated to a solid which was dried under vacuum for 18 hours; CI-MS 367 ((M+1)/z). The product 13 (765 mg, 2.09 mmol) was deprotected by stirring for 4 hours in dioxane (40 ml) to which was added 3N HCl (65 ml). The solution was evaporated to dryness, taken up in methanol (25 ml) and again evaporated to a solid which was dried under vacuum for 18 hours; CI-MS 267 ((M+1)/z) to form 14 (1.0 g, 3.7 mmol) which was reduced by 1M BH3.THF (15 ml) in a manner identical to the preparation of 3. The isolated solid (897 mg, 3.077 mmol) was identical in all respects to that from the reduction of 7.
Synthesis of 1-(p-nitrobenzyl)diethylenetriaminepentaacetic acid 9, the corresponding amine 10, the corresponding thiocyanate 11: These compounds were synthesized by methods analogous to those for compounds 4, 5 and 6 and similarly characterized by nmr and mass spectroscopy.
An aqueous solution of 5 millicuries of 111 InCl3 in 0.1 ml of 0.2 molar HCl was neutralized to pH 4.5 with a 3.0 molar solution of sodium acetate. To this was added the isothiocyanate chelate of Example 1 in an amount equal to 3 times the molar equivalent of the protein to be labeled. This procedure quantitatively complexed the indium as demonstrated by silica gel plate chromatography with elution in 50:50 solution of methanol:10% aqueous ammonium acetate.
The procedure of Example 3 was repeated with the the isothiocyanate chelate of Example 2. Quantitative complexation was again demonstrated.
|Cited Patent
|Filing date
|Publication date
|Jun 7, 1982
|Jun 12, 1984
|Gansow Otto A
|Use of metal chelate conjugated monoclonal antibodies
|Jun 7, 1982
|Sep 18, 1984
|Gansow Otto A
|Metal chelate conjugated monoclonal antibodies
|Title not available
|Biological Abstract, vol. 80, No. 3, 1985, Lauffer et al., "Preparation and Water Relaxation Properties of Proteins Labeled with Paramagnetic Metal Chelates", 11-16.
|Biological Abstract, vol. 80, No. 3, 1985, Lauffer et al., Preparation and Water Relaxation Properties of Proteins Labeled with Paramagnetic Metal Chelates , 11 16.
|Chemical Abstracts, vol. 83, No. 8, 1975, Sundberg et al., "Chelating Agents for the Binding of Metal Ions to Macromolecules", 587-8.
|Chemical Abstracts, vol. 83, No. 8, 1975, Sundberg et al., Chelating Agents for the Binding of Metal Ions to Macromolecules , 587 8.
|International PCT Search Report.
|Meares et al, "Metal Chelates as Probes of Biological Systems," Acc. Chem. Res., 17, 202-209 (1984).
|Meares et al, Metal Chelates as Probes of Biological Systems, Acc. Chem. Res., 17, 202 209 (1984).
|Yeh et al, "A New Route to `Bifunctional` Chelating Agents: Conversion of Amino Acids to Analogs of Ethylenedinitrilotetraacetic Acid," Analytical Biochemistry, 100, 152-159 (1979).
|Yeh et al, A New Route to Bifunctional Chelating Agents: Conversion of Amino Acids to Analogs of Ethylenedinitrilotetraacetic Acid, Analytical Biochemistry, 100, 152 159 (1979).
|Citing Patent
|Filing date
|Publication date
|Apr 29, 1988
|Oct 22, 1991
|Neorx Corporation
|Minimal derivatization of proteins
|Mar 26, 1990
|Jun 23, 1992
|The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services
|Bifunctional dtpa-type ligand
|May 28, 1991
|Jul 13, 1993
|Abbott Laboratories
|Bifunctional chelating agents
|May 11, 1992
|Feb 15, 1994
|The United States Of America As Represented By The Department Of Health And Human Services
|Antibody DTPA-type ligand conjugates
|Jan 17, 1992
|Apr 4, 1995
|University Of Utah Research Foundation
|Method for oral decorporation of metals
|Nov 4, 1993
|Jul 18, 1995
|The United States Of America As Represented By The Department Of Health And Human Services
|Bifunctional DTPA-type ligand
|Apr 3, 1995
|Feb 27, 1996
|University Of Utah Research Foundation
|Methods for oral decorporation of metals
|Jul 18, 1994
|Nov 11, 1997
|Novartis Ag
|Polypeptide derivatives
|Nov 30, 1994
|Dec 9, 1997
|Schering Aktiengesellschaft
|Derivatized DTPA complexes, pharmaceutical agents containing these compounds, their use, and processes for their production
|Nov 30, 1995
|May 5, 1998
|Schering Aktiengesellschaft
|DTPA derivatives substituted in a novel way, their metal complexes, and their use in diagnosis and therapy
|Jun 5, 1995
|Aug 25, 1998
|Schering Aktiengesellschaft
|Derivatized DTPA complexes pharmaceutical agents containing these compounds, their use, and processes for their production
|Nov 30, 1995
|Dec 29, 1998
|Schering Aktiengesellschaft
|Use of tetra azacycle complexes as x-ray diagnostic agents for the liver and gallbladder
|Nov 30, 1995
|Mar 23, 1999
|Schering Aktiengesellschaft
|Multiply substituted DTPA derivatives and their metal complexes, and their metal complexes, pharmaceutical agents that contain these complexes, their use in diagnosis and therapy, as well as process for the production of pharmaceutical agents
|Oct 6, 1994
|Mar 21, 2000
|Schering Aktiengesellschaft
|Derivatized DTPA complexes, pharmaceutical agents containing these compounds, their use, and processes for their production
|Jul 7, 1999
|May 25, 2004
|Smithkline Beecham Corporation
|Fluorescent lanthanide chelates
|Jul 28, 2000
|Feb 7, 2006
|Biogen Idec Inc.
|Kit for radiolabeling ligands with yttrium-90
|Jan 12, 2005
|Oct 27, 2009
|Rit Oncology, Llc
|Radiolabeling method
|Jun 8, 2007
|Nov 17, 2009
|Rit Oncology, Llc
|Method for radiolabeling antibodies with yttrium-90
|Mar 1, 1999
|Aug 1, 2002
|Paul Chinn
|Radiolabeling kit and binding assay
|Feb 24, 2003
|Oct 23, 2003
|Rainer Albert
|Polypeptide derivatives
|Jun 8, 2007
|Dec 27, 2007
|Paul Chinn
|Method for Radiolabeling Antibodies With Yttrium-90
|Dec 1, 2004
|Jan 6, 2016
|Immunomedics Inc.
|Improved method for preparing conjugates of proteins and chelating agents
|Mar 28, 1988
|Oct 6, 1988
|Schering Aktiengesellschaft
|Substituted complex-forming substances, complexes and complex salts, process for manufacture thereof and pharmaceutical agents which contain them
|U.S. Classification
|558/17, 548/547, 562/553
|International Classification
|Cooperative Classification
|European Classification
|Jan 7, 1986
Owner name: UNITED STATES OF AMERICA AS REPRESENTED BY SECRETA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:GANSOW, OTTO A.;REEL/FRAME:004493/0291
Effective date: 19851211
|Sep 30, 1992
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|Sep 30, 1996
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|Oct 24, 2000
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Title: Best Efforts: World Class Runners and Races
Publisher: Doubleday
Publication Date: 1982
Binding: Hard Cover
Book Condition: Very Good +
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First edition, stated. Quarterbound in dark brown paper-covered boards with a red cloth, gold-lettered spine. Book is square and unmarked; corners sharp, spine ends bumped. The dust jacket is not price-clipped (original price $15.95); edgewear at spine ends and corners; a one-inch closed tear to top of back panel. Brodart protected. Bookseller Inventory # 004194
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Now you can save a draft of your blog. Saving a draft means you can tell MindSay to save your blog without actually posting it This makes it easier if you decide you want to finish an entry later.
The best part is, MindSay will auto-save your entry every 2 minutes, so if you are typing a long entry and your computer crashes -- you don't lose much!


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Ella homes are delighted to introduce to the market this lovely 4 bedroom home. Set on a quiet country road in the sought after village of Akeley, this lovely home has a lot to offer. Bright and airy living space and a beautiful dining space for entertaining family and friends opening onto the re...
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Property for saleStowe, Buckinghamshire
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Моя проблема
My iPhone 5 battery would lose a 100% charge in 15 minutes, I ordered a replacement battery kit and the install maybe took 10 minutes and battery is back to normal.
Моё решение
Мой совет
You can do it!
Note: Lithium ion battery shipping regulations limit the shipping methods for orders containing batteries. Domestic orders may only be shipped via Standard shipping. iFixit is not able to ship batteries internationally or outside the contiguous US at this time. iFixit Customer Support will contact you if your order needs to be modified after it is placed.
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- 10.03.2017
My battery was shot. I lasted less than a day but even more problematic it was unreliable below 50%. It would just randomly shut down with apparently lots of battery left.
It went well.
I would offer that the steps more thoroughly cover the steps of putting it back together. Both the video and the . . .
- 06.03.2017
My iPhone 5 was beginning to need multiple charges to get through the day - and I am not one to have my phone in hand constantly. I did some traveling, and the fear of getting lost in a strange city with a dead phone was enough to make me think it was time for a new battery.
Good! I paused the video . . .
- 04.03.2017
Battery replacement for two phones.
Awesome!! I'm a gear and tool junkie and love taking apart and fixing things but have never gotten into small electronics before. The instructions for the various devices are very thorough and accurate, you know precisely what to expect when that case pops open. I . . .
- 16.03.2017
battery would die from 100% to completely off with 2 minute video without light on!
fairly easy other than the scary part of separating the screen from the case with the suction cup, the force needed worried me, but otherwise went off without a hitch.
Super easy and affordable kit and the video suppor . . .
- 12.04.2017
My battery had malfunctioned to the point that it was expanding within the case and was beginning to separate the display from the body of the phone. In addition, the home button had stopped working.
Disassembly was a piece of cake. However, the reassembly was a bit more challenging. This was mainly . . .
- 20.04.2017
Bad old battery. It already had bulges when I took it off.
Replacing the old battery with the new one supplied by I fix it went very well.
Just follow the video instructions. Pause it when you need to, don't be in a hurry, relax and take your time. The screws are so so tiny, and the ribbon connectors . . .
- 13.04.2017
Battery not holding a charge.
The repair was nice and easy. Simply follow the the repair guide and you cannot go wrong.
When you are removing the battery remember that they are held in place with sticky tape. It is difficult to pull up on the plastic tab to remove the battery. Pull hard and keep the p . . .
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text:
The Docklands scheme - Matrix South Quay sponsored by Matrix-Securities - will become the largest enterprise zone project if it goes through, as planned, at the start of next month. However, the attractions of the scheme, which offers a 20.6 per cent return on investment within six months, hinge initially on its eligibility for tax relief.
Matrix-Securities was given clearance for the scheme's tax reliefs several weeks ago by the local tax inspector dealing with it. However, last week it received a fax from the Inland Revenue head office. In a letter subsequently sent out to potential investors, Matrix said: 'This fax states that, on the facts provided to the Revenue, the accuracy of which is not in question, the clearance previously and unequivocally given to us should not have been given and that the Board of the Inland Revenue 'cannot undertake not to challenge certain aspects of the scheme'.'
Matrix says it is confident it will win the day on Tuesday. In their letter to investors, the Matrix directors go on to say: 'We have been advised by leading tax counsel that the points raised by the Revenue in their fax are wrong and moreover, the facts concerning these points were put to and previously agreed by the Revenue in their clearance application. Counsel has further advised that in any event the Revenue is not entitled to withdraw its clearance as that would be unfair and an abuse of power.'
Matrix says that investors' cheques will not be presented to the bank 'until this problem with the Revenue has been resolved'.
Commentaries on the scheme are available from specialist advisers Allenbridge Group (071- 409 1111) and BESt Investment (071-936 2037).
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Product Description
- Giant Abacus Counting Frame, sturdy and very popular
- This 100 bead, 10 bar giant wooden abacus helps the development of children's counting in a massive playful way!
- Suitable for nurseries, infant schools etc.
- Dimensions: 70 x 91 x 30cm (width x height x depth).
- Size of beads is 1.5in/4cm in diameter
- Free UK Mainland Shipping!
Not always always available direct from stock, delivery may take up to 5 working days. Next Day Delivery NOT available
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Get Involved Go Current Vacancies
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English Conversation Project Outreach Assistant
Location: Global
Here is an opportunity to use your English language skills to share the gospel and equip others with a valuable skill using a unique format. You can assist the English Conversation Project Coordinator in all administrative /clerical duties to help promote outreach of ministry partners using an audio programme and English clubs in the new media emphasis of Reach Beyond.
You will work with English Conversation Clubs to:
Develop conversation starters and basic activities for programmes taking into account the cultural, language, political and religious diversity
Develop relationships at a club while using the English conversation club materials you helped develop
Develop and upload material to websites used for English-learner follow-up and delivery of material to club volunteers
Interact with English learners and club coordinators as necessary
Prepare, execute and follow-up club coordinator training, engagement, encouragement, updates and relationship-building
EFL/ESL training helpful. TOEFL certification desired. This is a full-time missionary, working visitor, or volunteer position working 40 hours per week. For more information about Reach Beyond's English Conversation Project click here.
The successful applicant is required to raise their support or have the capacity to be self-funded and must be able to sign the Reach Beyond Statement of Faith.
English Conversation Clubs Development Volunteer
Location: Bradford
Reach Beyond is looking for a volunteer worker to support and promote English Conversation Clubs in the UK. Five days a week, a 15 minute radio programme which uses a special English method of broadcasting, called Specialised English, is broadcast. It is Reach Beyond's international radio programme which has a holistic Christian worldview, specially designed for people who are learning English as a foreign language. English Conversation Clubs are a spin-off ministry of the programme. They provide a way for churches to use programme resources to reach out and serve their local or immigrant communities. As the English Conversation Clubs Development Officer you would be responsible for encouraging churches and Christian groups within the UK to run their own English Conversation Clubs.
The hours of work are by negotiation and are flexible. Work will be from Reach Beyond's offices in Bradford although some work from home is possible.
This is an unsalaried position.
Radio Trainer
Location: Asia Pacific Region
Are you a radio producer or presenter who loves to train others? Would you be excited by the opportunity to equip people on the mission field to be more effective in reaching those who have never heard about Jesus Christ? We are looking for a person to train and equip nationals and others in the Asia Pacific region to manage and run Christian radio stations.
A degree in communications, broadcasting or related field
1 year of broadcasting/media experience
1 year of teaching or training experience
An interest to work with a cross-cultural team on the mission field and coordinate projects and training programmes
The availability to serve at least 3 years in this role
Excellent verbal and written communication skills
The successful applicant is required to raise a portion of their financial support but a significant bursary is available to assist with this process. Details are available upon application. A full job description is available upon request. Applicants must be able to sign the Reach Beyond statement of faith.
Associate Radio Producers
Location: UK, flexible
Associate Producers with Whistling Frog Productions work under our name for specific projects with their local commercial radio station. We will make the initial approach to the station, and then liaise with the Associate Producer throughout the production process. If you're interested in being an Associate Producer send us your CV (by post or email), telling us which station you have in mind and why you want to be part of Whistling Frog Productions.
Reach Beyond needs broadcast engineers, information systems technicians, doctors, nurses, teachers, managers, graphic artists, writers, secretaries and many other skills. We work in five regions: Latin America, Euro-Asia, North Africa/Middle East, Sub-Saharan Africa and Asia/Pacific and we have offices and ministries on every continent.
Contact us to see how you could be part of the Reach Beyond team.
For more information about applying for non-salaried posts, read our Basic Requirements for Service and the Steps in the Application Process.
If you are interested in any of these non-salaried positions above, please complete the on-line Preliminary Information Form or contact us for more information.


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: News : Division One : Season 2016/17 : Ginner joins Dronfield : Printable Version
New Dronfield Town manager Chris Millington has completed his backroom staff with the appointment of Chris Bullock as coach of the Toolstation NCEL Division One side.
Bullock, also known as Ginner, has previously worked with Chris at both Clipstone and Shirebrook Town, and joins Nick Siddons as part of the managerial team.
Millington commented on the appointment: Ive worked with Ginner for a number of years now and he will bring a wealth of experience with him to Town.


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Job Description
This UK business is looking for an individually with a proven sale experience to effectively manage & develop the sales export division within this wholesale business.
Reporting into the Food & Beverage Sales Director you will oversee the development & take responsibility for delivering the company's export strategy. The primary purpose of this role is to develop and manage long-term strategic partnerships including distributors, customers & partnerships to grow the business globally.
In this position you responsibilities include:
- To deliver on the global sales and income plan against the cost regarding the exports sales business
- Responsible for assessing potential international partnership and business proposals.
- Responsible for implementation, monitoring and evaluation of the international strategy alongside the Sales Director.
- Responsible for liaising with other Departments in order to achieve Financial, Technical and Operational objectives & review and develop Marketing & sales strategies in each country.
- To monitor distributors and partners, to ensure that they deliver against targets
- To develop and maintain links with Chamber of Commerce, Embassies including the UK Trade & Investment.
- Responsible for all contract negotiations and legalities in setting up strategic partnerships abroad - this will include negotiating business plans, targets and royalties.
- Liaison with Stakeholder & Board Directors
To be successful in the position you must have -
- Experience in food retail or wholesale B2B Export sales
- A skilled negotiator
- Track record of success establishing partnerships, & distributors within international businesses and worked with different markets and territories.
- Ideally from a food service, retail, wholesale, R supplier or hospitality background.
- Commercially focused, capable of delivering results in a cost effective manner
- Strong organisational and planning skills
- Strong management and leadership skills managing a team of export sales executives.
In return you will work for a business with a great national presence with over £200 million in sales. This position comes generous benefits including pension and generous bonus potential.
This is a business where leadership and behavioural competencies are essential for the fit of the business! If you feel that this opportunity sounds like you please send your cv quoting the reference Q99913.
We request that candidates send their CV as a Microsoft Word document where possible.
Quest Search and Selection is acting as an Employment Agency in relation to this vacancy.