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The Oporto Funicular - O Funicular dos Guindais
in Public Funiculars and Incline Railways
posted by: K!nder
location: Porto, Portugal
date approved: 6/4/2010
last visited: 12/30/2012
Elevador de Santa Luzia
The Elevador de Santa Luzia is a funicular in the city of Viana do Castelo, Portugal.
posted by: razalas
location: Viana do Castelo, Portugal
date approved: 5/16/2010
last visited: 12/10/2010
Angels Flight - Los Angeles, CA
The Los Angeles landmark is located close to the downtown area. The site is also on the NRHP.
posted by: saopaulo1
location: California
date approved: 3/19/2010
last visited: 6/14/2012
Funicular da Nazaré
This elevator provides a transport between Nazaré (low by the beach) and Sítio (high on the cliffs)
posted by: Paisagista
location: Leiria, Portugal
date approved: 2/4/2010
last visited: 4/27/2013
Stary Smokovec/Hrebienok - Stary Smokovec, Slovakia
posted by: crowak
location: Prešovský kraj, Slovakia
date approved: 9/30/2009
last visited: 2/20/2013
Braunwaldbahn, Braunwald - Switzerland
The Braunwaldbahn is a small, but modern Funicular in Canton Glarus, Switzerland.
posted by: superstein
location: Ostschweiz (SG/SH/TG/AI/AR/GL), Switzerland
date approved: 9/23/2009
last visited: never
Großglockner Gletscherbahn at the Kaiser Franz Josefs Höhe (Hohe Tauern National Park, Austria)
The Großglockner Gletscherbahn (Pasterze Glacier Railway) is one of touristic magnets of the Kaiser Franz Josefs Höhe in the middle of the Hohe Tauern National Park...
posted by: Dorcadion Team
location: Kärnten, Austria
date approved: 9/17/2009
last visited: 9/7/2012
Namsan Funicular - Seoul, Korea
This is a single car, single track automated funicular that connects a ground level street to the base station of the suspended cable car going up the side of Seoul's famed Namsan (South Mountain) and the Seoul N'Tower overlooking the city.
posted by: silverquill
location: Korea
date approved: 9/4/2009
last visited: 7/22/2012
Funicular of Old Quebec
This funicular connects the Upper and Lower parts of the Old City of Quebec.
posted by: sfwife
location: Quebec, Canada
date approved: 8/10/2009
last visited: 8/16/2014
Bom Jesus funicular - Braga, Portugal
The Bom Jesus funicular (Portuguese: Elevador do Bom Jesus) is a funicular located in Bom Jesus do Monte, city of Braga, Portugal.
posted by: FBBHaegar
location: Braga, Portugal
date approved: 7/17/2009
last visited: 4/5/2009
Duquesne Incline Railway - Pittsburgh, PA, USA
The Duquesne Incline Railway in Pittsburgh is the 3rd incline railway built in Pittsburgh and 2nd to survive, along with the Monongahela Incline Railway, and unlike the Monongahela, the passenger seating area is a single-level compartment.
posted by: NorStar
location: Pennsylvania
date approved: 6/6/2009
last visited: 1/31/2015
Funicular Lycabettus - Athens, Greece
Takes you to near the top of Lycavittos Hill. Have a drink at the cafe there and pay a visit to the chapel of St George dating from 1780. Co-ordinates are for the bottom.
posted by: Superted
location: Greece
date approved: 5/20/2009
last visited: 3/25/2007
Funicular de San Joan - Montserrat, Cataluña, Spain
This funicular railway gives visitors a spectacular panoramic view of Montserrat, 1,000 m above sea level.
posted by: manchanegra
location: Cataluña, Spain
date approved: 4/19/2009
last visited: 1/9/2014
Funicular de Santa Cova - Montserrat, Cataluña, Spain
Santa Cova funicular railway takes visitors from the sanctuary to the site near the cave where, according to tradition, the Mare de Déu de
Montserrat image was found.N 41° 35.535 E 001° 50.210
last visited: 9/1/2014
Elevador da Bica - Lisbon, Portugal
Elevador da Bica is the 3rd Lisbon Funicular: it opened in 1892 connecting Rua de São Paulo to Largo do Calhariz
location: Lisboa, Portugal
last visited: 3/23/2008
Petrin Funicular Train - Prague
Prague Funicular Train - Petrin Hill.
posted by: Dáin & Olík
location: Hlavni mesto Praha, Czech Republic
last visited: 2/11/2015
Elevador do Lavra - Lisbon, Portugal
First Lisbon Funicular conecting Largo da Anunciada with Travessa do Forno do Torel back in 1884.
date approved: 4/17/2009
Elevador da Glória - Lisbon, Portugal
The Glória funicular was opened in 1885 and it was the second of its kind in Lisbon.
Polybahn Zurich - Switzerland
The Polybahn is a short funicular in Zürich linking Central with Polyterasse.
location: Region Zuerich (ZH), Switzerland
date approved: 4/16/2009
last visited: 1/11/2014
Budavári Sikló (Budapest Castle Hill Funicular) - Budapest, Hungary
funicular in Budapest from the river bank of the Danube to Castle Hill
posted by: eikenboom
location: Hungary
date approved: 3/10/2009
last visited: 7/1/2015
Shadowbrook funicular - Capitola, CA
A nice funicular at the Shadowbrook restaurant.
date approved: 10/27/2008
last visited: 9/30/2013
Royal Gorge Incline Railway-Fremont County, Colorado
This incline railway is located at Royal Gorge in Colorado.
posted by: Team Min Dawg
location: Colorado
date approved: 10/23/2008
last visited: 9/12/2014
West Hill Lift Hastings, East Sussex
posted by: RocketRon47
location: United Kingdom
date approved: 10/15/2008
Wellington Cable Car. Wellington. New Zealand.
The Wellington Cable Car, running between Lambton Quay in the city and the top entrance to the Botanic Gardens, is one of Wellington's oldest and most popular tourist attractions and New Zealand's only remaining public cable car system.
posted by: Punga and Paua
location: New Zealand
date approved: 10/14/2008
last visited: 4/1/2015
Fishermans Walk Cliff Lift - Southbourne, Bournemouth, UK
This public lift is located in the seaside town of Bournemouth in the Southbourne area.
posted by: Dragontree
location: Southern England, United Kingdom
date approved: 9/20/2008
last visited: 8/30/2014
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Parker Police Arrest 9 As Part Of Nationwide Child Porn Sting
A nationwide operation to stop child pornography resulted in the arrests of nine people in Colorado.
Man Convicted Of Kidnapping Toddler, Producing Child Porn
A Colorado Springs man has been convicted of kidnapping a toddler in California and producing child pornography.
Man In Possession Of 35,000 Articles Of Child Porn Sentenced In Arapahoe County
An Arapahoe County man who pleaded guilty to having thousands of photos and videos of child pornography was sentenced to 4 years in prison on Monday.
Broomfield Nonprofit Director Pleads Guilty To Child Porn Possession
The director of a Broomfield non-profit has pleaded guilty to possessing child pornography.
Priest On Probation In Colorado Pleads Guilty In Michigan Porn Case
A Catholic priest who worked at a Detroit high school faces at least 10 years in prison after pleading guilty to a child pornography charge.
Priest On Probation In Colorado Faces Child Porn Crimes In Detroit
A Catholic priest accused of child pornography crimes will remain in custody, at least until he's transported to Detroit from Missouri.
Broomfield's 'Fish, Inc.' Director Accused Of Possessing Child Porn
The director of a Broomfield nonprofit has been charged with possession of child pornography.
Man Charged After Child Porn Found On Work Computer At DIA
A man accused of having pornographic images of children on his work computer for the City and County of Denver has been formally charged.
Naval Academy Students Facing Child Porn Charges
An AWOL naval academy student has been arrested on child pornography charges.
A child porn suspect has been convicted for possession of child pornography found in his home.

subset: commoncrawl


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Electrical Sockets & Plugs
Electrical Sockets & Plugs
Electrical Connection Fuse Relocation Harness for Kawasaki KLR650A, '86-'07This "Plug & Play" bike-specific wiring harness replaces the fragile OEM glass fuses and puts all 3 in a conveniently accessible location that does not require you to peel the bike apart for access. Learn More$34.95
SAE Tankbag Wall Electrical Cable Pass-ThroughThis unit provides 12V Protective cap that is Water-Resistant to accommodate 12V wires for your Bags Connection system. For use with all Electrified Bags-Connection Quick-Lock tankbags. Electrical tank rings sold separately. Learn More$29.99
SW-MOTECH Adapter to convert SAE to Dual Cigarette SocketThis adapter allows a 12 V (volt) connection from SAE Tankbag to dual cigarette-style outlets via a 9.8 inch (25 cm) cable. Learn More$31.95
Powerlet Euro Socket SAE Battery Lead- 48 inchesThe Powerlet SAE battery lead allows you to power accessories and devices directly from your battery. Learn More$19.95
Replacement 5-pin relay (for Electrical Connection power distribution block, Stebel Air Horn or Denali SoundBomb Compact Dual-Tone Air Horn wiring kits)
Five pin relay for many automotive applications. Rated for 30-amps of 12-volt DC current. Offered as a replacement part for both the Electrical Connection Power Distribution Block and the Denali SoundBomb Compact Dual-Tone Air Horn.Learn More$7.99 $7.49
SW-MOTECH Handlebar Mounting Bracket for flush-mount 12-volt BMW/Euro-style socketThis universal fixing bracket allows you to attach a flush-mount 12-volt BMW/Euro-style socket to most handlebar mounting clamps for easy attachment of electrical accessories! Learn More$21.95
TAPP LITE USB ChargerThis compact USB Charger is the weatherproof answer to charging most cell phones, GPS units, and MP3 players. It mounts easily to your handlebars or any flat or curved surface using the included self-adhesive mount. A tethered seal cap protects the charger from dust and water. The included fused battery hookup harness is diode protected against reverse polarity. Learn More$32.95 $29.66
Gerbings panel mounted port kitGerbings Receiving port for Gerbing's coax power plug Learn More$15.95
Universal DIN Audio to 3.5mm Headset Adapter for Honda & Harley-Davidson Factory Audio SystemsThis adapter allows you to plug in a standard mini headphone or headset for audio listening. Works on both Honda and Harley Davidson factory audio systems. Learn More$24.95
SW-MOTECH Euro Socket with Wiring Harness and In-line FuseThe SW-MOTECH Powerlet-style Socket with Wiring Harness and In-line Fuse allows the use of external electronic devices. Learn More$36.95


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Letter - Pay Increase, W. E. Potts Director of Works to Katarina Pimenowa, 24 Jan 1952 Reg. No: HT 14883
- Summary:
- Letter from W E Potts, Director of Works, Department of Works and Housing, to Katarina Pimenowa dated 24 January 1952. The letter states that Katarina, a Temporary Mechanical Engineer F, was approved for an accelerated advancement of her salary from 14 December 1951, and will be eligible for incremental advancement of her salary from 14 December 1952.
Kateryna Caurs (nee Pimenow) was born on 7 July 1915 in Luzk, Poland. She grew up firstly in the Ukraine and then in Russia, where she studied mechanical engineering at the Moscow Technical Institute. From 1946 to 1949 Katerina worked with the United Nations Relief and Rehabilitation Administration (UNRRA) and later as a clerk for the International Refugee Organisation (IRO). In 1950 Kateryna and her mother migrated to Australia. Due to her degree and previous work in Russia and Germany, Kateryna was able to work as a mechanical engineer once in Australia. She married Latvian immigrant Alexander Caurs in 1959.
Alexander was born in Latvia on 12 July 1926, he migrated to Australia in 1948, arriving in Sydney aboard the 'Charlton Sovereign' on 29 October. Alexander worked as a fitter, and was living in Camberwell when he was naturalised in 1959. He married Kateryna Pimenow the same year on the 10th July. His parent's Peter and Nadeshda Caurs migrated to Australia in 1950, although they appear to have left in 1956. From 22 August 1966 to 21 August 1970 he worked as a storeman for the Commonwealth of Australia Department of Works.
- Description:
- Yellowing paper on Department of Works and Housing letterhead. Black typed text with blue pen signature.
- Statement Of Significance:
- The Caurs collection represents the experiences of wartime dislocation and post-war immigration of a family from three cultural backgrounds, Polish, Latvian and Ukrainian. The principle story represented in the collection is that of Kateryna Caurs (nee Pimenow) and is one not often told, that of a professional educated woman, a mechanical engineer, whose qualifications were recognised in Australia.
- Acquisition Information:
- Bequest from (Estate of) Mrs Kateryna Caurs
|20.20 cm (Width), 25.40 cm (Length)
More information
|Tagged with:
|immigration, settlement, polish communities, polish immigration, ukrainian immigration, russian immigration, identifications
|Themes this item is part of:
|Migration Collection
|Primary Classification:
|Secondary Classification:
|Settlement - Employment
|Tertiary Classification:
|Text: COMMONWEALTH OF AUSTRALIA/DEPARTMENT OF WORKS AND HOUSING/225 BOURKE STREET/MELBOURNE C.1./24th January, 1952./Miss K. Pimenowa,/Temporary Mechanical Engineer (F),/Grade 1,/Technical Division/Department of Works & Housing/MELBOURNE/(Forwarded through the Principal Engineer)/It is desired to advise that the Commonwealth Public/Service Inspector, Melbourne, has now given approval to the/accelerated advancement of your salary.
|Commonwealth of Australia Department of Works & Housing, Melbourne, Victoria, Australia, 24 Jan 1952
|Addressed To:
|Mrs Kateryna Caurs, Melbourne, Victoria, Australia, 24 Jan 1952
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Sales Hotline 1-877-778-8460
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Fitting Instructions
10 Years
Sleek and stylish the Hudson Reed Series 160 twin thermostatic shower valve with diverter is perfect for adding a hint of contemporary style to your bathroom. This durable shower valve will supply water to two separate outlets such as a fixed shower head and body jets.
Made from solid brass this high quality thermostatic shower valve features a built-in anti-scald device for a safer showering experience, while the ceramic disc technology ensures smooth and accurate control over the flow and temperature of the water. This shower valve has a chrome finish to blend in seamlessly with any decor.
Warranty: 10 years.


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Imagine 175+ ADV folks in the Mountains of Eastern TN for a long weekend, with some of the best riding in the east (dirt, gravel, twisties).... plus great company, a private resort (plenty of space indoors in case of rain), campfire, 3 great dinners and breakfasts, plenty of beer, and some bullshitting. What can go wrong?
Some random pics from last year: here - and here
Dinner on Thursday,
Breakfast and Dinner on Friday,
Breakfast and Dinner on Saturday,
Breakfast on Sunday,
about 18 kegs of beer and root-beer
a t-shirt, a mug and a sticker,
door-prizes and a huge indoor area and covered decks (in case of rain)
RDV fee $75
let us know if you plan to arrive on Wednesday!
The Eastern Rendezvous is the oldest annual ADV rally, and the only one in the south east. It started in 2002 as a small traveling gathering, and Rick aka Party Boss turned it into an annual event known as the Eastern Rendezvous. Sadly we lost Rick in 2012. Nobody will ever be able to be such a great and inviting host like he was, but we will keep his rally alive in honor of what he started. One for the Boss
This includes tents, hammocks, benches, chairs in front of the fire... basically if you spend the night and do not pay for a cabin, you gotta pay $23 for camping.
Please note: the camping area is for motorcycles and tents only - no cars or trailers please! We do have very limited parking for your rig next to the resort and can not guarantee a parking spot, also you will not be able to spend the night in your trailer.
Keyword: limited - if we are out of parking space, you may need to park at the AT-trailhead and carpool to the resort, or pay the neighbor for the use of his yard.
Shared Bunk-cabins for 4 people. Please bring a sleeping bag, since the cabins do not come with linens (a limited amount of linens will be available for rent). $35/person for 3 days.
Cabin rental starts Thursday - if you plan to arrive a day early, please book your assigned cabin with the resort.
Shared bunk-cabins for 4 people with mini-fridge (bigger then Creekside Cabins). Please bring a sleeping bag, since the cabins do not come with linens (a limited amount of linens will be available for rent). $45/person for 3 days.
Cabin rental starts Thursday - if you plan to arrive a day early, please book your assigned cabin with the resort.
We will bring basic tools, compressor, battery charger, tow straps, a pickup truck and ramps etc., plus a basic first aid kit, including braces, splints, bandages and painkillers for the mornings
Rides: There are no official rides for the Rick's Eastern Rendezvous. We have individuals who go on rides and welcome you to ride along. No part of your attendance fee has anything to do with any rides. All riders are responsible for their own actions. Above all, ride safe.
Bring your fishing gear! The stream in front of the resort is stocked weekly with trout (we accept bribes in front of cleaned trout ). TN fishing license required (details see below).
Pets: well behaved dogs are welcome - as long as you pick up after your pooch
Linens: Cabins do NOT come with linens. There are a limited sets of linens for the cabins available for rent - let us know if you need any.
Showers: the resort has at least 6 showers available and probably a few temporary ones as well.
Plates and cutlery: we will provide paper plates and plastic cutlery. Bring your own if you want to eat in style (and hate waste)
Fishing: for license information see post 1545
Parking: there is only very limited parking available for cars and trucks (and trailers). You may have to park in town and ride up to the resort, or pay the neighbor $5/night to park on his property.
1511 Dennis Cove Road - Hampton, TN 37658
do NOT use this address for your GPS - it will send you up the wrong road! (marked with a red X)
If you are using a GPS set it for 205 Dennis Cove Rd Hampton, Tn. That will take you into town and to the blacktop. Follow the road until you get to the resort. You can't miss it..
disclaimer: some of the Gravel may be a bit "bumpy"
We as organizer, provide only information regarding this event. You join all events voluntary and at your own risk. We are not responsible for anything that happens to you, or your gear. Neither at the event nor while traveling to or form the event. In case of an accident, damage or loss, you and the involved persons are fully responsible to each other. You accept this by registering for the rally!


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Obama lifts ban on Guantanamo transfers to Yemen
WASHINGTON President Barack Obama is lifting his self-imposed ban on transferring Guantanamo Bay detainees to Yemen, where a leadership upheaval has improved the country's security but not eliminated a terrorist organization trying to recruit jihadists.
Lifting the ban is a step toward Obama's goal of closing the Navy-run prison in Cuba since nearly 100 of the 166 terrorist suspects held there are from Yemen and have had nowhere to go even if they had been cleared for transfer. Obama wouldn't send them home and no other country was welcoming them, and their hopelessness after a decade or more of imprisonment had contributed to a hunger strike at the detention facility that helped reignite the long-stalled effort to close it.
But Obama's decision is not without risk - detainees who have been released to Yemen in the past have joined terrorist fighters in the Arab nation. The security concerns prompted Obama to suspend transfers to Yemen in January 2010 after a Nigerian man attempted to blow up a U.S.-bound flight on Christmas Day 2009 with explosives hidden in his underwear on instructions from al-Qaida operatives in Yemen.
Sen. Saxby Chambliss, R-Ga., was among those on Capitol Hill criticizing Obama's change in policy.
"Between December 2009 and today, has Yemen shown any indication that they are more capable of looking after those individuals? Absolutely not," Chambliss said. "And If we were to transfer those individuals to Yemen, it would be just like turning them loose."
Yemeni watchers in the U.S. say there is reason to hope security has improved since longtime authoritarian leader Ali Abdullah Saleh was ousted after mass uprisings last year. Al-Qaida had been on the upswing under Saleh, but his successor Abed Rabbo Mansour Hadi has made fighting terrorism a top goal and restored cooperation with the United States in the effort.
Obama announced that he was lifting the moratorium on Yemeni transfers in a speech Thursday at the National Defense University in which the president also defended targeted killings by U.S. aerial drones and pushed Congress anew to authorize Guantanamo's closure. The president did not explain his rationale behind the change in Yemen policy, but senior administration officials cited Hadi's leadership as an increasingly able partner to the U.S.
A Yemeni official told The Associated Press that a delegation, including the country's human rights minister, returned this week after a trip to Washington, where they agreed to set up of a rehabilitation center to help reintegrate detainees, with the support of the United States and other Arab nations.
Rageh Badi, an adviser to Yemen's prime minister, said in an interview that the transfer ban had cast a shadow on the relations with the United States. Badi said lifting the ban is a "welcome step, a progressive one that removes much of the ambiguity and confusion between the U.S. administration and the Yemeni government."
Yemeni authorities previously had a system to monitor returned detainees, but it ceased to function after massive anti-government protests swept most of the country, starting in early 2011. Of the estimated 30 Yemenis who returned from Guantanamo, only a handful had stayed in Sanaa, the capital, while the rest moved to remote areas where government authority is minimal, or nonexistent.


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Suitland, Maryland (PRWEB) August 14, 2014
Andrews Federal Credit Union recently joined several local businesses for Prince George's County District 9 Council Member Mel Franklin's Family and Friends Day at Showplace Arena.
In each of the past three years, over 1000 District 9 residents have attended this outstanding community event established to promote the local business community. Residents are treated to fun, food, and valuable information from over 100 District 9 businesses, nonprofits, and county government agencies.
"We are always happy to support this initiative as it aligns with our goal of giving back to the communities we serve," said Tameyka Whitney, Community Development Manager, Andrews Federal Credit Union.
About Andrews Federal Credit Union
Andrews Federal Credit Union was founded in 1948 to serve the needs of military and civilian personnel by providing a vast array of financial products and services. With over $1 billion in assets, Andrews Federal has grown to serve more than 100,000 members in the District of Columbia, Joint Base Andrews (MD), Joint Base McGuire-Dix-Lakehurst (NJ), and military installations in central Germany, Belgium, and the Netherlands. In addition, the Credit Union serves as a financial partner with many select employee groups in Maryland, the District of Columbia, and New Jersey.
To learn more about Andrews Federal Credit Union and its community involvement, or to become a member, call 800.487.5500 or visit http://www.andrewsfcu.org.


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Methods for enhancing the immune response to vaccination in animals, including humans, comprise administering interleukin-2 (IL-2) as part of the vaccination regimen, preferably for 5 to 14 days post-vaccination. In addition, compositions for enhancing the immune response of an animal to a vaccine employ IL-2 as an active ingredient, preferably human IL-2.
1. A composition for enhancing the immune response of an animal to a vaccine, which composition comprises interleukin-2 (IL-2) and said vaccine.
2. The composition of claim 1, wherein the IL-2 is human IL-2.
3. The composition of claim 2, wherein the human IL-2 is a water-soluble form of human IL-2.
4. The composition of claim 3, wherein the human IL-2 is PEGylated human IL-2.
5. The composition of claim 3, wherein the human IL-2 is succinylated human IL-2.
6. The composition of claim 2, wherein the human IL-2 is des-alanyl-rIL-2ser125.
7. The composition of claim 1, wherein the IL-2 is in the form of a continuous release formulation.
8. The composition of claim 1, wherein the IL-2 is in the form of a single sustained action formulation.
9. The composition of claim 1, wherein said vaccine is an Escherichia coli bacterin, a Pasteurella bacterin, a Vibrio fetus bacterin, a transmissible gastroenteritis vaccine, an equine influenza vaccine, a feline leukemia vaccine, or a pseudorabies vaccine.
10. The composition of claim 9, wherein said vaccine is an Escherichia coli bacterin.
11. The composition of claim 9, wherein said vaccine is a Pasteurella bacterin.
12. The composition of claim 9, wherein said vaccine is a Vibrio fetus bacterin.
13. The composition of claim 9, wherein said vaccine is a transmissible gastroenteritis vaccine.
14. The composition of claim 9, wherein said vaccine is an equine influenza vaccine.
15. The composition of claim 9, wherein said vaccine is a feline leukemia vaccine.
16. The composition of claim 9, wherein said vaccine is a pseudorabies vaccine.
This application is a continuation of U.S. Ser. No. 08/734,471 filed Oct. 17, 1996, now U.S. Pat. No. 5,800,810 which is a continuation of U.S. Ser. No. 08/448,884, filed May 24, 1995, now U.S. Pat. No. 5,643,565, which is a divisional of U.S. Ser. No. 07/314,975, filed Feb. 24, 1989, now U.S. Pat. No. 5,503,841, which is a continuation of Ser. No. 07/005,926, filed Jan. 22, 1987, now abandoned which is a continuation-in-part of U.S. Ser. No. 06/856,035, filed Apr. 25, 1986, abandoned; which is a continuation-in-part of U.S. Ser. No. 06/778,372, filed Sep. 20, 1985, abandoned.
The invention relates to enhancing the effect of vaccines in animals, such as domestic, sport, or pet species, and humans. More particularly, the invention relates to the use of interleukin-2 (IL-2) as an adjuvant with vaccines.
The use of vaccines to prevent diseases in humans, farm livestock, sports animals and household pets is a common practice, and considerable effort has been, and is being, made to extend this practice to cover a more extensive array of diseases to which these patients are subject. For example, the use of rabies vaccine in animals is by now commonplace, and efforts are being made to obtain suitable vaccines to immunize animals against other diseases.
One problem that frequently is encountered in the course of active immunization is that the antigens used in the vaccine are not sufficiently immunogenic to raise the antibody titer to sufficient levels to provide protection against subsequent challenge or to maintain the potential for mounting these levels over extended time periods. Another problem is that the vaccine may be deficient in inducing cell-mediated immunity which is a primary immune defense against bacterial and viral infection. Notorious among such "weak" animal vaccines are those constituted from inactivated Haemophilus pleuropneumoniae (Hpp) (which is associated with respiratory disease in pigs).
In order to obtain a stronger humoral and/or cellular response, it is common to administer the vaccine in a formulation containing an adjuvant (immunopotentiator), a material which enhances the immune response of the patient to the vaccine. The most commonly used adjuvants for vaccines are oil preparations and alum. The mechanisms by which such adjuvants function are not understood, and whether or not a particular adjuvant preparation will be sufficiently effective in a given instance is not predictable.
Accordingly, there is a need for additional effective adjuvant preparations which are suitable for potentiating vaccines for animals in general, including humans and other mammals. It has now been found that human IL-2 (hIL-2) is useful in this regard.
There is considerable background information available with respect to the biological activity of hIL-2. hIL-2 can be obtained from the supernatant of concanavalin-A (ConA) stimulated spleen cells or, presently, using recombinant technology, and has several measurable activities in vitro. First, it is a T-cell growth factor as measured by, for example, thymidine uptake when hIL-2 is added to cultures of cytotoxic or helper T-cell lines. It is mitogenic with respect to adult thymocytes, and stimulates a cytotoxic cell response (e.g., lymphokine-activated-killer (LAK) cell). It has also been shown to replace helper T-cells in athymic murine spleen cell cultures (Watson, J., et al., Immunological Rev. (1980) 51:257-278). Specifically, in the presence of IL-2 and antigen, specific T helper cells are generated which are able to contribute to antibody responses. Presumably this occurs because IL-2 is involved in the antigen-dependent maturation of helper T-cells in these nude mouse spleen cultures.
IL-2 has also been shown to directly affect B cells in vitro. Both proliferation and IgM and IgG secretion are enhanced by IL-2 in populations of purified, activated B cells (Mingari, M. C., et al., Nature (1984) 312:641; Mittler, R., et al., J. Immunol. (1985) 134:2393-2399; Muraguchi, A., et al., J. Exp. Med. (1985) 161:181-197).
How these in vitro activities translate into a specific in vivo mechanism for mounting an immune defense is not clear. However, with respect to such in vitro studies, cross-reactivity among species of various IL-2s has been studied. For example, Redelman, D., et al., J. Immunol. Meth. (1983) 56:359-370) show that hIL-2 supports activated T lymphocytes derived from rabbit and mouse to approximately the same extent as they are supported by the endogenous forms of IL-2. Ruscetti, F. W., et al., Blood (1981) 57:379-393 were the first to demonstrate the ability of hIL-2 to behave as a growth factor, not only for human T-cells, but also peripheral blood lymphocytes or splenocytes from other primates, horse, guinea pig, cat, rat, and mouse. Carter, J., et al., (Fed. Proc. (1985) 44:1290) disclose the ability of hIL-2 to enhance the development and maintenance of bovine cytotoxic lymphocytes in vitro.
Doyle, M. V., et al., J. Bio. Resp. Mod. (1985) 4:96-109 reports in vitro lymphocyte proliferation studies that compared the activities of native hIL-2 and a recombinant form of IL-2 on human and animal lymphocytes. The native IL-2 and recombinant IL-2 exhibited the same range of activity on animal cells.
Some in vivo data are also available. The activity of IL-2 in vivo has been shown to restore immunocompetence in nude mice in response to heterologous erythrocytes (Stotter, H., et al., Eur. J. Immunol. (1980) 10:719-722). There is information concerning cross-species reactivity, as well. Reed, S. G., et al., J. Immunol. (1984) 133:3333, disclosed the ability of hIL-2 to reconstitute spleen cell responses in mice infected with a parasitic protozoan, and Farrar, J. J., et al., Immunol. Rev. (1982) 63:158, showed that in vivo injection of IL-2 of human origin stimulates the splenic T-cells in nude mice. Fong et al., Vet. Immuno. & Immunopathol. (1986) 11:91-100 discloses the response of bovine and porcine peripheral blood mononuclear cells to human rIL-2. Stott et al., Vet. Immunol. and Immunopathol. (1986) 13:31-38 disclose that human rIL-2 augments in vitro the blastogenesis of bovine and porcine lymphocytes. Kawamura et al., J. of Exp. Med. (1985) 162:381-386 disclose that immunization with antigen and IL-2 in vivo overcomes Ir gene low responsiveness in mice. McFeeters and Nadler, Fed. Proc. 45(3) 633 (presented Apr. 13-18, 1986) disclose enhancement of antibody responses to protein antigens by administering rIL-2. Dr. Thompson at the University of Washington is investigating that IL-2 may boost vaccines (Gen. Tech. News, June 1986).
In summary, it is known that IL-2 behaves in some manner in vivo to mediate a successful immune response, including a response to a specific antigen, and in vitro studies have shown that cross-species reactivity of hIL-2 is very diverse (prior in vivo cross-species studies have involved only murine subjects for hIL-2). However, because the mechanism of involvement of hIL-2 in the immune response is not understood, it is not possible to predict the behavior of hIL-2 in boosting a protective immune response to an antigen administered as a vaccine to animals or humans. Accordingly, there is no suggestion in the art that hIL-2 could successfully be used as an adjuvant in vaccines. This is the contribution of the present invention.
IL-2 is a singularly effective adjuvant in connection with vaccines. Accordingly, in one aspect, the invention relates to a composition for enhancing the immune response of an animal to a vaccine, which composition comprises IL-2. In another aspect, the invention relates to a method of enhancing the immune response of an animal subject, including humans, to a vaccine, which comprises administering to the subject an effective amount of IL-2 as part of the vaccination regimen.
When used as a vaccine adjuvant, hIL-2 is effective on humans as well as animals. Accordingly, another aspect of the invention is a composition for enhancing the immune response of a human to a vaccine, which composition comprises hIL-2. In terms of a method, this aspect of the invention is a method for enhancing the immune response of a human to a vaccine, which method comprises administering hIL-2 to the human as part of the vaccination regimen.
FIG. 1 shows the amino acid sequence of hIL-2.
FIGS. 2A and 2B are dose-response curves showing the results of the lymphocyte proliferation tests described in section C.1 of the examples, infra.
FIG. 3 shows the effect of hIL-2 on blastogenesis of bovine and porcine T-lymphocytes.
A. Definitions
As used herein, "IL-2" refers to a polypeptide obtained from tissue cultures or by recombinant techniques exhibiting the spectrum of activities characterizing this protein. The word includes not only human IL-2 (hIL-2), but also other mammalian IL-2 such as, e.g., mouse, rat, rabbit, primate, pig and bovine IL-2. Bovine IL-2 is described by Cerretti et al., PNAS, 83:3223-3227 (1986). The term "IL-2" also refers to a protein that is capable of stimulating the proliferation of hIL-2 dependent cytolytic and helper T-cell lines, as set forth in the standard assays of Gillis, S., et al., J. Immunol. (1978) 120:2027-2032 and of Watson, J., J. Exp. Ned. (1979) 150:1510-1519. The amino acid sequence of native hIL-2 is shown in FIG. 1. This primary amino acid sequence may be obtained as the native protein from natural sources or may be recombinantly derived. The recombinant hIL-2 is preferred herein.
The term "recombinant interleukin-2," designated as IL-2, preferably human IL-2, refers to interleukin-2 having comparable biological activity to native IL-2 prepared by recombinant DNA techniques as described, e.g., by Taniguchi et al., Nature, 302:305-310 (1983) and Devos, Nucleic Acids Research, 11:4307-4323 (1983). In general, the gene coding for IL-2 is excised from its native plasmid and inserted into a cloning vector to be cloned and then into an expression vector, which is used to transform a host organism, preferably a microorganism, and most preferably E. coli. The host organism expresses the foreign gene to produce IL-2 under expression conditions.
More preferably the IL-2 is a mutein as described in U.S. Pat. No. 4,518,584, in which the cysteine normally occurring at position 125 of the wild-type or native molecular has been replaced by a neutral amino acid such as serine or alanine. Alternatively or conjunctively, the IL-2 mutein may be one as described in copending U.S. application Ser. No. 810,656 filed Dec. 17, 1985, the disclosure of which is incorporated herein by reference, in which the methionine normally occurring at position 104 of the wild-type or native molecule has been replaced by a neutral amino acid such as alanine. Finally, the IL-2 employed may have one or more of the first five N-terminal amino acids of the native IL-2 deleted.
Preferably, the IL-2 is a protein produced by a microorganism or by yeast which has been transformed with the human cDNA sequence of IL-2 which encodes a protein with an amino acid sequence at least substantially identical to the amino acid sequence of native human IL-2, including the disulfide bond of the cysteines at positions 58 and 105, and has biological activity which is common to native human IL-2. Substantial identity of amino acid sequences means the sequences are identical or differ by one or more amino acid alterations (additions, substitutions) which do not cause an adverse functional dissimilarity between the synthetic protein and native human IL-2. Examples of IL-2 proteins with such properties include those described by Taniguchi et al., supra; Devos, supra; European Patent Application Nos. 91,539 and 88,195; U.S. Pat. No. 4,518,584, supra, and copending U.S. application Ser. No. 810,656 filed Dec. 17, 1985, supra. Most preferably, the IL-2 is ser125 IL-2, des-ala104 ser125 IL-2, des-ala1 IL-2, des-ala1 ala104 IL-2, or des-ala1 ala104 ser125 Il-2, where "des-ala1 " indicates that the N-terminal alanyl residue of the IL-2 has been deleted.
The precise chemical structure of the IL-2 herein will depend on a number of factors. As ionizable amino and carboxyl groups are present in the molecule, a particular IL-2 may be obtained as an acidic or basic salt, or in neutral form. All such preparations which retain their bioactivity when placed in suitable environmental conditions are included in the definition of IL-2 herein. Further, the primary amino acid sequence of the IL-2 may be augmented by derivatization using sugar moieties (glycosylation) or by other supplementary molecules such as lipids, phosphate, acetyl groups and the like, more commonly by conjugation with saccharides. Certain aspects of such augmentation are accomplished through post-translational processing systems of the producing host; other such modifications may be introduced in vitro. In any event, such modifications are included in the definition of IL-2 herein so long as the bioactivity of the IL-2 is not destroyed. It is expected, of course, that such modifications may quantitatively or qualitatively affect the bioactivity by either enhancing or diminishing the activity of the IL-2 in the various assays.
As used herein, the term "adjuvant" has its conventional meaning, i.e., the ability to enhance the immune response to a particular antigen. Such ability is manifested by a significant increase in immune-mediated protection. Enhancement of humoral immunity is typically manifested by a significant increase (usually >10%) in the titer of antibody raised to the antigen.
B. General Method
Formulations containing IL-2 for adjuvant purposes are most conveniently administered by intramuscular or subcutaneous injections or as sustained release compositions although other methods of administration are possible. Specific formulations to prevent hydrolysis during digestion would be necessitated for oral formulation, and intravenous injections are generally uneconomic due to the skill level and care required in administration. Therefore, formulations suitable for intramuscular or subcutaneous injection, especially sustained release formulations, are preferred.
Standard formulations are either liquid injectables or solids which can be taken up in suitable liquids as suspensions or solutions for injection. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, and so forth. Nontoxic auxiliary substances, such as wetting agents, buffers, or emulsifiers may also be added. A particularly useful excipient comprises effective amounts of detergents, such as, for example, 0.05% sodium dodecyl sulfate (SDS), to assure solubility and bacteriostasis.
A variety of techniques are known in the art to effect long-term stability and slow release. For example, the stability and half life of IL-2 are enhanced by coupling it to a hydrophilic polymer such as polyethylene glycol (PEG) or a polyoxyethylated polyol as described in copending commonly owned U.S. patent application Ser. No. 866,459, filed May 21, 1986 and incorporated herein by reference. The PEG-hIL-2 complex, called "PEGylated" hIL-2, is particularly useful for administering a single sustained action dose of hIL-2.
Another useful IL-2 construct to effect long-term stability and slow release is a succinylated IL-2, as described in copending commonly owned U.S. patent application Ser. No. 903,668 filed Sep. 4, 1986 and incorporated herein by reference. Briefly, the succinylation reaction occurs by contacting the IL-2 with succinic anhydride, preferably at pH 5-9 at room temperature in an aqueous solution containing a buffer with a solubilizing agent such as sodium dodecyl sulfate.
Sustained and continuous release formulations are of considerable variety, as is understood by those skilled in the art. An exemplary composition for sustained release parenteral administration is an injectable microcapsule formulation that with a single injection will deliver recombinant hIL-2 or water soluble forms of hIL-2, such as PEGylated or succinylated hIL-2, at a controlled rate, in the range above about 103 and below about 106 units/kg/day, for a duration of 5 to 30 days post vaccination. (Pure hIL-2 has a specific activity of about 3-6�106 U/mg.) The microcapsule formulation is a free-flowing powder consisting of spherical particles 20 to 100 μm in diameter that can be resuspended in an appropriate vehicle and injected intramuscularly or subcutaneously with a conventional hypodermic needle. The microcapsules consist of 0.5% to 5% hIL-2 encapsulated in poly(DL-lactide-co-glycolide) (DL-PLG) excipient, a biodegradable, biocompatible polyester. Alternative standard formulations for sustained release are also usable.
The IL-2 will normally be administered separately from the vaccine, although it may, in some instances, especially in sustained or continuous release forms, be administered in combination with the vaccine. When IL-2 is combined with the vaccine, the composition administered contains an immunogen that is effective in eliciting a specific response to a given pathogen or antigen, a pharmaceutically acceptable vaccine carrier and an immunopotentiating amount of IL-2. A preferred regimen is to administer hIL-2 continuously until 5 to 30 days, preferably 5 to 14 days, post vaccination at levels above about 103 and below about 106 units/kg/day. The term "continuously" is intended to denote true continuous administration, such as is achieved via a sustained release dosage form as well as a multiplicity of intermittent administrations of hIL-2 (or enhanced half-life forms of hIL-2 such as PEGylated or succinylated hIL-2) that provide a pharmacokinetic pattern that mimics that achieved by true continuous administration. Data generated to date using daily intramuscular injections indicate a preferred dose is 104 to 105 units/kg/day. The vaccine will normally be administered per manufacturer's instructions. Other adjuvants may be administered either with the vaccine or together with the IL-2.
The IL-2 will typically be used to enhance the protection afforded by animal or human vaccines that are considered "weak" (i.e., provide diminished protection in terms of level, extent, and/or duration). Examples of such vaccines are bacterins such as Bordetella bacterin, Escherichia coli bacterins, Haemophilus bacterins, Leptospirosis vaccines, Moraxella bovis bacterin, Pasteurella bacterin and Vibrio fetus bacterin and attenuated live or killed virus products such as bovine respiratory disease vaccine (infectious bovine rhinotracheitis, parainfluenza-3, respiratory syncytial virus), bovine virus diarrhea vaccine, equine influenza vaccine, feline leukemia vaccine, feline respiratory disease vaccine (rhinotracheitis-calici-pneumonitis viruses), canine parvovirus vaccine, transmissible gastroenteritis vaccine, pseudorabies vaccine, and rabies vaccine.
C. Examples
The following examples are intended to further support or illustrate but not to limit the invention.
C.1 In Vitro Activity
In vitro activity with respect to bovine and porcine peripheral blood mononuclear cells (PBMC) has been shown for recombinant hIL-2 (Fong, Susan, et al., Vet. Immunol. and Immunopathol. (1986) 11:91-100, incorporated herein by reference). The hIL-2 used in this work is designated des-alanyl-rIL-2ser125, lacks an initial alanine and has a serine rather than a cysteine at position 125. It was shown to be mitogenic for unactivated bovine and porcine PBMC, and to be able to maintain the long-term growth of ConA-activated PBMC from both species. FIGS. 2A and 2B are curves of the dose-response of ConA-activated bovine (2A) and porcine (2B) PBMC to des-alanyl-rIL-2ser125. Also, bovine and porcine PBMC preincubated with des-alanyl-rIL-2ser125 for 1-5 days showed enhanced cell-mediated cytotoxicity against tumor cell targets.
In addition, Stott, J. L., et al., Vet. Immunol. and Immunopathol. (1986) 13:31-38 (incorporated herein by reference), have shown that bovine and porcine peripheral blood lymphocytes were responsive to human recombinant IL-2 in lymphocyte blastogenesis assays. Blastogenesis was determined by incorporation of 3 H-thymidine (18 hr. pulse) in 4-day lymphocyte cultures, and the results were expressed as the log10 of the geometric mean (Gx) of disintegrations per minute (DPM)/culture and plotted by nonlinear regression analysis as shown in FIG. 3. Mitogen dilution and concentration of hIL-2 in units are shown on the X-axis. These results show that the effect of hIL-2 on bovine and porcine cells is comparable to that shown by the plant lectins PHA and ConA, which are known to stimulate blastogenesis.
C.2 Effectiveness as an Adjuvant in Porcine Vaccine
Recombinant hIL-2 was shown to enhance the efficacy of an inactivated Hpp bacterin using 12 feeder pigs divided into 6 groups of 2 pigs each. Group 1 was an hIL-2 adjuvant control; group 2 was a bacterin control; group 3 received 103 units hIL-2/kg as a single injection on days 0 and 21; group 4 received 5 daily injections of 103 units/kg each following each vaccination; group 5 received 1 injection of 105 units/kg on days 0 and 21; and group 6 received 5 daily injections of 105 units/kg each following each vaccination.
The pigs in groups 2-6 were administered formalin-inactivated Hpp emulsified in an oil adjuvant intramuscularly in the neck muscles on days 0 and 21. The pigs in all groups were challenged on day 41 intranasally with serotype 1 Hpp and were killed on day 71 and autopsied. Lung area affected was determined visually with particular attention given to lung lesions. The pigs were weighed periodically during the 71 days with weight gain being an indication of general state of health. The results were as follows:
______________________________________ Autopsy Average Rate of Body (% Lung Area Affected) Weight Gain (lb/day)Group Pig 1 Pig 2 Days 41-71______________________________________1 24 57 0.67 2 6 100* * 3 25 58 0.59 4 12 12 1.89 5 13 19 0.86 6 0 0 1.93______________________________________ *pig died 5 days after challenge
As shown by these results the groups that received daily post-vaccination injections of hIL-2 (groups 4 and 6) exhibited substantially higher weight gain post-challenge than did the groups treated otherwise. These results also show a significant reduction of lung pathology in groups 4 and 6, indicating increased protection against challenge provided by the daily administration of hIL-2 in the vaccination regimen. All animals showed high antibody titers against Hpp after challenge.
A second study was carried out to confirm the ability of hIL-2 (des-alanyl-rIL-2ser125) to act as an adjuvant to Hpp vaccination. The protocol for the second study was similar to that of the first study described above: animals were vaccinated with/without hIL-2 treatment and subsequently challenged with virulent Hpp. Principal measures of efficacy included clinical signs following infection, weight gain following infection, and the extent of lung involvement at necropsy. The results of this second study are tabulated below.
______________________________________ Ave. Percent Ave. Daily Weight Gain Lung Affected (lbs/day) Group (N) At Necropsy Post-Challenge______________________________________Control (2) 34 0.68 Hpp Alone (3) 19 1.37 Hpp + IL-2 (3) 01 1.86 105 u/kg daily Hpp + IL-2 (2) 00 1.65 104 u/kg daily No Challenge (2) -- 1.82______________________________________
The data from the second study confirm the efficacy observed at 105 u/kg/day hIL-2 in the first study and extend these findings to the lower dose of 104 u/kg/day. Protection at an IL-2 dose of 104 u/kg/day was comparable to that observed at the higher dose.
C.3 Effectiveness as an Adjuvant in Dogs
Dogs were injected with keyhole limpet hemocyanin (KLH) at the time of initial hIL-2 treatment and 7 days subsequently at the start of 5 days of (daily) hIL-2 treatment. Enzyme-linked immunoabsorbent assays (ELISAs) were performed on sera taken from the dogs to measure antibody response to KLH. A significant, dose-dependent increase in IgG antibody against KLH was observed in the IL-2 treated dogs. The increase was specific to the KLH immunogen used.
C.4 Effectiveness as an Adjuvant in Mice
The SAD strain of attenuated live rabies virus adapted to PK-2A cells was inactivated using binary ethylenimine in a final concentration of 0.01 M solution to obtain a rabies vaccine. Sixteen Swiss white mice per group were each vaccinated intraperitoneally with 0.5 ml of undiluted, 1:5 diluted, 1:25 diluted or 1:125 diluted concentrations of the rabies vaccine in minimal Eagle's medium (a standard cell culture salt solution). Two doses of vaccine were given to each mouse one week apart.
Each vaccinated mouse was injected subcutaneously with 1 μg hIL-2 diluted with phosphate buffered saline per gram of mouse two times daily for five days starting on the day the mice were vaccinated. The IL-2 injections were also repeated two times daily for five days following the second vaccination.
One week after the second vaccination all the vaccinated mice were challenged by intracranial (IC) inoculation of a CVS strain virulent rabies virus propagated in BHK-21 cells using a dilution that would approximate 20 to 30 mouse LD-50 of virus in 0.03 ml. As a further step to determine more precisely the actual challenge dose, a group of 16 mice were inoculated with the challenge pool. Groups of 10 mice each were also inoculated with a 1:10 and 1:100 dilution of this pool. All inoculations were IC using 0.03 ml inoculums.
All mice were observed daily and signs of rabies or death were recorded. Deaths within 24 hours were discarded as not significant. Observations were made for 12 days post-challenge.
Evaluation of the results of challenge of the vaccinated mice was accomplished using a modification of the volumetric method described in NIH Test for Potency, "Laboratory Techniques in Rabies", Ch. 33, WH0 (1973). The simultaneous titration of the CVS rabies challenge virus showed that the vaccinated animals were challenged with 35 mouse LD-50 of virus.
The results of the rabies challenge on the vaccinated mice are summarized below:
______________________________________ Vaccine Only Vaccine + IL-2 Dilution of No. Deaths/ No. Deaths/No. Vaccine No. Vacc. Vacc. & Treated______________________________________Undiluted 16/16 0/15* 1:5 15/16 5/16 1:25 15/15* 13/14* 1:125 16/16 16/16______________________________________ *While 16 mice were vaccinated in each group, the difference reflects 24hour postchallenge deaths.
As can be seen from the table, despite the poor potency of the rabies vaccine employed, mice receiving the IL-2 plus the lowest dilutions of vaccine showed significant resistance to CVS rabies challenge. This indicates that IL-2 can modify the immune response to allow for production of antibodies against even poor antigens if adequate vaccine is present. Moreover, the effect observed is not due to the IL-2 alone, because at the highest vaccine dilutions of 1:25 and 1:125, the same amount of IL-2 was administered as with the lowest dilutions.
Modifications of the above described modes of carrying out the invention that are obvious to those of skill in the fields of medicine, immunology, pharmacology, and related fields are intended to be within the scope of the following claims.
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Employers are wondering whether browsing public social media sites to learn more about a job applicant is worth the potential risks. A CareerBuilder survey found that 39% of employers use social networking sites to research job candidates, but do the other 61% have good reasons to stay away? Continue reading
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West Virginia 24/48 in MSN United States Land Value Ranking
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P&G Announces Next Step in North American Supply Chain Re-Design
CINCINNATI--(BUSINESS WIRE)--The Procter & Gamble Company (NYSE:PG) will build a multi-category manufacturing facility in Berkeley County, West Virginia, in the Eastern Panhandle of the state near the town of Tabler Station. When the plant opens in 2017, it will be one of the most advanced and sustainable plants among P&G's global manufacturing and supply-chain operations.Click Here to read more
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Final Score: Northern Illinois 45, Bowling Green 36
Bowling Green, OH (SportsNetwork.com) - Travon Baker led all scorers with 13 points, as the Northern Illinois Huskies won a low-scoring affair over the Bowling Green Falcons, 45-36, in Mid-American Conference action at the Stroh Center.
Baker shot 4-of-9 from the field and 4-of-6 from the free-throw line for NIU (7-7, 1-1 MAC), which has won two of three. Darrell Bowie and Jordan Threloff both hauled in eight rebounds for the visitors.
For BGSU (6-9, 0-2), losers of four straight, Richaun Holmes tallied 12 points, eight boards and six blocks.
NIU shot just 39.1 percent from the field in the first half, but BGSU was even worse at 25 percent, as the Huskies took a 26-18 lead into the break.
The Falcons stormed back in the second half and even led by one with just over three minutes to play, but the Huskies finished the contest on an 11-1 run to pull away.
NIU won the rebounding battle, 40-29.


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The Kraft Foods stub, which will change its name to Mondelez International Inc. and its ticker symbol to MDLZ, will remain in the S&P 100 & 500. Alpha Natural Resources and Korn/Ferry have market capitalizations that are more representative of the mid cap and small cap market spaces, respectively. Pulse Electronics is ranked #600 in the S&P SmallCap 600 and is no longer appropriate for inclusion in that index. InterDigital Inc. (NASD:IDCC) will replace Quest Software Inc. (NASD:QSFT) in the S&P MidCap 400 after the close of trading on Friday, September 28. S&P 100 & 500 constituent Dell Inc. (NASD:DELL) is acquiring Quest Software in a deal expected to be completed soon, pending final approvals. Genesee & Wyoming Inc. (NYSE:GWR) will replace Collective Brands Inc. (NYSE:PSS) in the S&P MidCap 400 after the close of trading on Monday, October 1. A group that includes S&P SmallCap 600 constituent Wolverine World Wide Inc. (NYSE:WWW) is acquiring Collective Brands in a deal expected to be completed soon, pending final approvals.Kraft Foods Group is a consumer packaged food and beverage company. Headquartered in Northfield, Illinois, the company will be added to the S&P 500 GICS (Global Industry Classification Standard) Packaged Foods & Meats Sub-Industry index. Alpha Natural Resources produces, processes, and sells steam and metallurgical coal. Headquartered in Abingdon, VA, the company will be added to the S&P MidCap 400 Coal & Consumable Fuels Sub-Industry index.Korn/Ferry International provides talent management solutions. Headquartered in Los Angeles, CA, the company will be added to the S&P SmallCap 600 Human Resources & Employment Services Sub-Industry index.InterDigital develops technology for advanced digital wireless telecommunications applications. Headquartered in King of Prussia, PA, the company will be added to the S&P MidCap 400 Communications Equipment Sub-Industry index.Genesee & Wyoming owns and operates short line and regional freight railroads, and provides railcar switching services. Headquartered in Greenwich, CT, the company will be added to the S&P MidCap 400 Railroads Sub-Industry index.Following is a summary of the changes:S&P 400 INDEX ? September 28, 2012COMPANYGICS ECONOMIC SECTORGICS SUB-INDUSTRYADDEDInterDigitalInformation TechnologyCommunications EquipmentDELETEDQuest SoftwareInformation TechnologyApplication Software S&P 500 INDEX ? October 1, 2012COMPANYGICS ECONOMIC SECTORGICS SUB-INDUSTRYADDEDKraft Foods GroupConsumer StaplesPackaged Foods & MeatsDELETEDAlpha Natural ResourcesEnergyCoal & Consumable Fuels S&P MIDCAP 400 INDEX ? October 1, 2012COMPANYGICS ECONOMIC SECTORGICS SUB-INDUSTRYADDEDAlpha Natural ResourcesEnergyCoal & Consumable FuelsGenesee & WyomingIndustrialsRailroadsDELETEDKorn/FerryIndustrialsHuman Resources & Employment ServicesCollective BrandsConsumer DiscretionaryApparel Retail S&P SMALLCAP 600 INDEX ? October 1, 2012COMPANYGICS ECONOMIC SECTORGICS SUB-INDUSTRYADDEDKorn/FerryIndustrialsHuman Resources & Employment ServicesDELETEDPulse ElectronicsInformation TechnologyElectronic Manufacturing ServicesAdditions to and deletions from S&P Dow Jones Indices do not in any way reflect an opinion on the investment merits of the companies involved.About S&P Dow Jones IndicesS&P Dow Jones Indices LLC, a subsidiary of The McGraw-Hill Companies is the world's largest, global resource for index-based concepts, data and research. Home to iconic financial market indicators, such as the S&P 500® and the Dow Jones Industrial AverageSM, S&P Dow Jones Indices LLC has over 115 years of experience constructing innovative and transparent solutions that fulfill the needs of institutional and retail investors. More assets are invested in products based upon our indices than any other provider in the world. With over 830,000 indices covering a wide range of assets classes across the globe, S&P Dow Jones Indices LLC defines the way investors measure and trade the markets. To learn more about our company, please visit www.spdji.com. It is not possible to invest directly in an index. 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"Dow Jones" is a registered trademark of Dow Jones Trademark Holdings LLC ("Dow Jones").SOURCE S&P Dow Jones IndicesFor further information: Dave Guarino, Communications, S&P Dow Jones Indices, firstname.lastname@example.com, +1-212-438-1471; David Blitzer, Managing Director and Chairman of the Index Committee, S&P Dow Jones Indices, email@example.com, +1-212-438-3907


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Paint Body
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Remember Me
The AmericanaramA tour rolled on to Tampa tonight for performances by Grateful Dead /
Furthur guitarist Bob Weir, and
tour headliners My Morning Jacket
, Wilco
and Bob Dylan
. AmericanaramA's visit to Tampa's Live Nation Amphitheatre comes after last night's
opening show in West Palm Beach, which was highlighted by a Weir sit-in with Wilco. Well Bobby continues to be the story as tonight
he guested with My Morning Jacket and Wilco.
Following Weir's opening set, which included takes on "Me & My Uncle," "Black-Throated
Wind" and "Walking Blues," Bobby came out during My Morning Jacket's set for a cover of
"Dear Prudence" by The Beatles. While Weir last performed "Dear Prudence" last night,
tonight's version was the first for My Morning Jacket. Bobby and Jim James shared vocals
on the cover. MMJ showed off the depth of their catalog by only repeating one song,
"Circuital," from Wednesday night's set.
Wilco also has shown their propensity
to mix it up by playing a number of songs they didn't play last night such as "War On
War," "I Am Trying To Break Your Heart" and "Sunken Treasure." The Weir guest spots
weren't over, as Bobby re-emerged ten songs into the Chicago-based band's set for a pair
of covers. First up was "Dead Flowers" by The Rolling Stones, which Wilco performed last
Friday night during the "All-Request Set" at the Solid Sound Festival. Then, Weir sat in
with Jeff Tweedy and Co. on "Friend Of The Devil." Tonight was the Wilco debut of the
treasured Grateful Dead song.
Meanwhile, on Thursday night Bob Dylan stuck to a similar script as he did at the tour
opener. Dylan did swap in classics "A Hard Rain's A-Gonna Fall" and "Blind Willie McTell,"
which weren't performed in West Palm Palm.
Here's the My Morning Jacket setlist from tonight:
Check out Wilco's setlist from this evening's AmericanaramA tour stop:
Bob Dylan's setlist will be found here once he finishes his set...
Watch Bobby sit-in on "Dear Prudence" with My Morning Jacket...
Check out this brief clip of "Friend Of The Devil" as shared by Ari4324...


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Why does my ex contact me when she is seeing someone else?
OK I don't think it is because she wants me back but would like to know what her reasons are. It is often general conversation and catching up. She... Show More
Most Helpful Opinion
Well it really depends on the kind of guy you are. For me personally, I feel that I am a big kid (lol) and there is no need for sugar coating or beating around the bush. That being said, if I were in your position (which I have been before) I would flat out say: 'Look, I still have feelings for you but we broke up and shortly after, you got a new boyfriend. There is no reason for us to be talking the way we do when the feelings here are not mutual. I am not here for whatever HE is lacking. Sorry but we can not be friends.' end of story. do not be spiteful or try to hurt her feelings. be honest, if she gets pissed off then oh well, she did this to herself by trying to have you both at once. birthday party is a no go, that will just further cause problems. OH and clearly her boyfriend is either an idiot or she is lying to him if she can get away with talking to you as much/as often as she does. Kinda raises a few red flags, yes?
This is what's all so confusing. I wouldn't like her talking to me if I were her boyfriend either but we have known each other for a couple of years before we started going out so their was a friendship. But I know I can't be friends right now. I just want to make sure I'm making the right call!
What Girls Said 3
If you two are meant to be together, it will happen. No need on killing yourself (not litterly) over this friendship. It is being masochistic, you are knowingly continuing on with this friendship while it is killing you inside. end it, even if you do miss her, it will not be as painful and will give her the wake up call that despite the fact that you still have feelings for her, you will not be around while she dates others. this could be the motivating factor for her to stop being stupid and either a- break up with the guy or b- come find you later on and maybe then the situation will be reversed.
She knows you are not over her. She is using you to talk to since she cannot say this stuff to her current boyfriend. Maybe he is not giving her all the attention she needs and she knows you still care so she turns to you. Either way, being friends with an ex is normally (about 80%) going to turn out badly. Someone gets hurt and it will be you, she already has a fall back. She can not have you both, and having you on the side like this is unfair to you. Cut ties and move on, she has.
Thanks! It's messing with my head, she has even invited me to her birthday which would be too awkward! So you think I should tell her why I am cutting ties? If (like you suggest) she already knows how I feel then their is no need to explain right?
What Guys Said 0
Be the first guy to share an opinion and earn 1 extra Xper Point!
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Originally written on Fox Sports North | Last updated 10/9/12
EDEN PRAIRIE, Minn. Rookie wide receiver Greg Childs walked through the Minnesota Vikings' locker room Monday, flashing a big smile and showing no limp or the slightest sign of the potentially career-threatening knee injuries he suffered early in training camp in August.Childs, a fourth-round draft pick by Minnesota in April, ruptured the patellar tendon in both of his knees during the team's annual evening passing scrimmage in front of fans in Mankato, Minn. during training camp. Childs hadn't been around the portion of the team's facilities open to reporters very often since the injury, but has been in the building doing the rehab necessary to work his way back from the injury."I've been walking for a while," Childs said, speaking to reporters Monday for the first time since the injury. "No braces, no nothing, coming in every day, getting the leg stronger, range of motion, working out, lifting weights, all that. It's a long process, but you've just got to be prepared for it, get ...
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All quotes tagged Coupled
(4189 quotes found)
"A state of coupleness is attained when two people each feels that her/his number one priority is the happiness and contentment of the other"
"Up to a third of bundling couples found themselves presented with a permanent souvenir of the occasion"
Contributed by: Andy James
"I've done a fair share of stupid things in my life, a couple of which should have put me in the grave. But here I am, typing away as if I had a brain."
"I put quite a few trees in last autumn. A lot of silver birch and a couple of native trees - just generally doing gardening, putting plants in and hedges in. It takes quite a lot of time and I love it."
"I have made my thoughts on it (sledging) well known over the last couple of years. We are more than happy to be talking to opposition players in the field so long as it is not personal or abusive."
"We took a couple of penalties that we didn't need to take. Hockey is a game of mistakes and in order for us to be successful we just have to limit those."
"I'm sad to announce that I've called off my engagement. Over the last couple months I've realized that this is the right decision for me. We remain best of friends, and I'll always love him."
"The Cubs, the last couple of times I've pitched against them, have taken a good approach on me and gotten the better of me. I don't know if it's just them now or what."


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So I gave birth to my second baby boy on Nov 16th. For the first two weeks, he as extremely mellow and a quiet sleeper. He has now began the grunting and straining phase of his life - haha. I say this because my first son did the SAME thing. He is quiet and sleeps great during his naps but as soon as 9:00pm comes around he begins a cycle of grunting, straining and sometimes crying that doesn't end until around 6:00am. He sometimes sleeps through it but I get hardly any sleep...he will also sometimes wake up. I do give him gripe water, mylicon, and sometimes Hyland's colic tablets to help ease his tummy but it doesn't really seem to help consistently.
I know from my first son that really the only "cure" for this is time and they do outgrow it. I just cannot remember around when that time is?? Any second time moms out there who can refresh my memory? When do they outgrow the grunt phase? I can't wait!


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40 comments
On Thursday, NFL Network draft analyst Mike Mayock held a two-hour pre draft conference call with the media and during it he gave his thoughts on which direction he thinks the Pittsburgh Steelers should go in the first round with the 15th overall selection.
"I think that the way Pittsburgh historically approaches the draft, it's the best player at the position of need," started Mayock. "Defensively they're No. 14 in points allowed, offensively No. 16. So basically, I think as they get close to No. 15 here, I think first and foremost they've got to see if a corner matches up with what they want to do on defense.
"Ike Taylor is going to be 34 years-old, making $7 million dollars. William Gay is probably better as a nickel. Are any of those other guys ready to step up and play? I think they need a corner and I think at 15 they can get one. Whether it's (Kyle) Fuller, (Darqueze) Dennard, (Justin) Gilbert or (Bradley) Roby, it just depends really on what Dick LeBeau wants and how Kevin Colbert lines them up.
"My perspective is, I think they got to get a corner there. I don't think the tight end Eric Ebron will be there. If he was, I think he'd be a heavy consideration also."
It's hard to argue with Mayock suggesting the Steelers go cornerback in the first round and he once again shared his thoughts on why he believes Virginia Tech's Kyle Fuller is the best one in this year's draft class.
"I think that Fuller – he's my No. 1 corner – he's a first-round corner," said Mayock. "He's got it in his DNA and you do know what you're getting day one. He can play on, he can play off, he can play man, he can play zone."
Mayock is usually right on with what he says. If one of the top CB's are there at #15 Steelers need to take him.
Maybe. I still think Aaron Donald fits best. Look at what Mike Daniels has done in Green Bay's 3-4, same size not nearly as violent or as fast of the line.
we have to go corner we got burnt last year well ike did but still we need a corner to shut down one side of the field
We're definitely due a top notch corner. My vote is for Dennard or Fuller with No. 15 if either player is still on the board.
Our corners got burnt last year not entirely but do in part to NO pass rush on the right side…answer Aaron Donald.
My vote is they trade down, get an extra pick and select Fuller. And then with a bit of luck we get K. Alphonse Benjamin (lol) in round 2. Stranger things have happened
Aaron Donald is a square peg in a round hole for the Steelers D. He is a great player but an absolutely horrible fit.
Gilbert/ dennard/fuller pleeease then another in rd 2/3/or four
Him saying Ebron in the first surprised me! I just don't think we're attracted to a TE that can't block? I'd rather have KBenjamin than Ebron!
And I'm starting to think Fuller won't last til the 2nd. Maybe not even pick 20, so 15 seems fine with me if we want him!
Shazier seems like the only one to trade down for? Maybe Tuitt, too?
I'm not in love with none of these corners. No matter which 1 they pick they not starting. U got decent value 2nd & 4th rounds with Baptiste, Philip r E.J. Gaines, Mcgill, Desir & Cockrell. We need to get a pass rush so I'm on the Hageman bandwagon. Good coaching & we set for a minute on the DL. Question who is starting opposite 97…please no Keisel??
I like Baptiste. If they don;t go CB in the 1st, I am all for Baptiste and later Aaron Colvin in the 5th or 6th. I don;t care if he's not ready until 2015, the CB situation would have a chance to be great by then.
Mayock was asked about Colvin on the conference call and he said he believes Colvin will be taken in round 4.
Yea, thats what Packer fan's said about 6'1 300 pound 3-4 DE Mike Daniels. Dude is an edge setter and gets after the QB (6.5 sacks).
Double dip in the Middle rounds definitely would work. BTW im a huge Colvin fan, sucks he got hurt. A good pass rush and the Db's will b okay
Pay attention Mayock. Ike's not making even close to 7 million..
Crap. That's too bad as I have heard many others say rounds 5 or 6 for Colvin. I was hoping later. There's always teams out there willing to gamble just like SF did with RB Lattimore last year. Imagine if he makes it all the way back. That guy looked scary good until the scary injury.
I wouldn't mind seeing them go safety deon buccannon and leave shmarko in current role
If and thats a big IF we go dl i would hope they go tuitt instead of hageman if hes still on the board and for all those that like benjamin at 1/15 he didn't even get picked in rd 1 of the mock draft special that was on total access where there were 8 or 9 wr selected in rd 1 why is that
Do they have many College games on over there in the fall/winter?
i like Mayock and his thoughts on the draft i agree that they should go cb and draft a WR in round 2 from a deep draft
Pretty sure he meant counts $7,692,404 against the cap. Mayock focuses on draft, not salaries.
How does this sound, I think it`s possible Browns want to trade up with their second first round pick, I propuse this, steelers give ther first round and second round (15 and 47 overall), Browns give the (26,35,79 and 164 overall) first round+second+therd (the third from Shamarko trade) and a 6. Steelers could select probably one of the top 4 cbs with their first, and with their secondu a reciver like Benjamin or the Ole miss wr, also they coul trade that second and get a later second and another therd round, with that second you can selec Tuitt or the other Clemson Wr, and now you have 3 medium-late their round
Mike Mayock is like the Nostradamus of draft experts. Is it just be or is he batting .800 at the draft when he actually calls the teams pick before they pick. He has a true passion for being completely informed on all teams needs. It shows also that when he talks about the Steelers, he speaks with passion. Even though they cut him after drafting him he still shows love. Mayock is my favorite of them all. Mel Kiper is too worried about his hair his choices for the Steelers have been all over the place. I like Todd McShay but he seems to be more passionate about disputing what Kiper says. Once he begins to focus, he is like Obie Wan Kenobi, Mayock is Yoda and Kiper is Aniken (soon to be Darth Vader), lol.
If we could walk away with Dennard or Barr in the first, Nix, Tuitt, or Hagemen in the 2nd, a WR or a TE like Seferian-Jenkins in the third, I'd call that a good draft. We will probably draft 2 corners, 2 wr's, a RB, an outside linebacker, a d-lineman and an o-lineman–in no specific order.
Thank you S-P M. Just because CB is our biggest "need" doesn't mean we should draft one with our first pick. You must look at value.
If I'm drafting a CB at 1.15, he better look like a pro bowler. He better be very very quick, with very good technique and ball skills.
When I look at Dennard and Fuller I see good solid bottom of the 1st round CB's. I don't think either of them look elite (like some of the top CB's in years past).
When you draft a guy earlier than you should because you need that position it's called REACHING. Not drafting the best available player.
Having said that, it may be difficult to find a player at 1.15 who rates higher (top ten for example). Most of those guys are ranked bottom of the 1st round talent/grade. Including my favorite (Kelvin Alphonse* Benjamin).
There are flaws with all of them. That's WHY they're not ranked in the top 10. But if I'm picking flaws in a CB, I'd prefer a guy who runs in the 4.3's who needs technique work. Not short slow CB's who tackle well.
It would be hard to argue with a Dennard-Tuitt-ASJ draft. That is a pretty nice threesome. And even though I personally would go about it differently, I bet the Steeler front office is thinking a little more along your lines than mine.
It really depends on who's sitting there in round 1… How would you approach it? I'm curious.
I like Tuitt, I just like Hagelman better ya know. That body type @ 6'6, upside is ridiculous.
Is there a CB you would sprint to the podium for in round 1??? I feel you on good tackling thing. Who ever they pick I hope they can cover & make plays on the ball over anything.
Tuitt and Hagemann are virtually the same sized frame. Hagemann is "inconsistent" and 24; Tuitt played through injuries and is 20. All things considered, Tuitt, IMO.
Love those picks, but no way ASJ falls to the third. Especially after running a 4.56 the other day for the Jets. Only if we trade back will we have a shot. Jordan Matthews is one of my favs if we decide to go WR. Shaizer is someone that I hope they are considering a first round option.
Coming out of Iowa, Daniels probably only had half the talent of Aaron Donald (at best). I completely agree with you and I'll throw a huge party if he's the pick..
Okay, I'll throw a party either way
I agree.
Kyle Fuller, as Mike Tomlin would say PEDIGREE
I listened to the Ike Taylor show and he said Louis Nix because it all starts upfront,the foundation. Then we can move McLendon to DE and double dip a cb later in the draft. He also said Odell Beckham was special. I have to say I agree with his logic but I really want a top CB. I'm ok with trading back to pickup an extra 2nd or Cleveland's two 3rds.
I think The Jets will give up a 3rd to move up but they might want Kyle Fuller.
Did he really run a 4.58? I heard earlier in the draft season he had to have surgery and wouldn't be able to workout at the combine or pro day or privately. He's certainly worth trading back into the 3rd to nab and we have extra picks in the later rounds so I can see use being mobile on day 2 and 3. What do you think? Will he go in the 2nd?
Gotcha. He's making about $2.75m but his cap number is still way up there because of the dead $$.
I would trade down under almost any scenario. Even if the offer was minimal (like a 3rd round pick).
I would draft Kelvin Benjamin in the bottom of the 1st round. Then use the new 3rd rounder + our 2nd rounder to trade up for Stephon Tuitt. And then draft two CBs in the 3rd and 4th round where the true value is.
My thinking is that even if we draft a CB in the 1st round he's probably not gonna play much this year. So if he's sitting and learning anyway, why not draft two solid CB's in the 3rd and 4th and let them sit and learn this year. And which ever one develops faster can start in 2015 along side Cortez.
If we draft Tuitt, our CB's don't have to be "shut down' type guys because Tuitt-Heyward-Worilds-Jones will produce a nice pass rush without blitzing.
The reason I go Benjamin in round one is because I know he can catch TD passes. That directly affects points, which directly affects wins. If you have a shut down CB you only affect one receiver. A good QB will just throw to the other guy. (See Aaron Rodgers/Jordy Nelson. SB 43).
I wouldn't mind trading down to recoup some picks either. I just don't like Benjamin, unless we intend to use him as a TE, and even then I'd like him a lot better in round 2.
I get your argument about corner. It's solid logic; however, I just think Dennard can start this season, which is probably the only prospective defender at any position we can say that about, except maybe nix–who incidentally, I wouldn't be surprised to see fall to the bottom of the second. It's usually a safe bet that whoever we draft on defense is going to take time to develop. If he can develop into a great player, we should take him early and have him ready for 2015. Later round players might not have as high of a ceiling.
I honestly think we could address the red zone problem with a solid TE selection or another of the taller receivers a little later in the draft. There's going to be a ton of talent left on the board at least into the 4th. I wouldn't complain about Allen Robinson in the 3rd or Lattimer on the second and someone like Scott Crichton in the 3rd–I hear he's incredibly strong and could add some bulk and become a high quality 5-technique.
Its a tough call. There's so many ways to go and it really depends on what the other teams ahead of us do in round 1. That'll set the tone for the rest of our draft. For all I know they could end up trading back to the bottom of the first and getting Tuitt there, then we'd have Anne extra high round picks to play around with.
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Covert Action: Adaptation, Challenges, and Advances
Thursday, February 7, 2013 at 9:30am to 6:00pm
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The Center for Security Studies is hosting an all-day conference on the most-hyped and least-understood intelligence function: covert action. Scholarly, practitioner, and policymaker perspectives will be offered and debated, with the goal of increasing understanding and charting a path toward a more informed discourse and policy process.
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