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Adam says his peers will be surprised to hear his name in the same sentence with …author…...but once you've been published numerous times… it is a title you have to accept. Adam has a blog called Adam Parks is seeing some great success lately in a field that surprises him. http://www.ehc.edu/alumni-and-friends/alumni-news/2016/02/adam-parks-06-author/
Sue Thompson Hubble …E…H …69… just retired from a life of service to the United Methodist Church. On January 31… she was embraced by the congregation at Dublin United Methodist Church for almost 40 year Sue Thompson Hubble (E&H '69) retires from a career of serving the United Methodist Church -- and all the people beneath the steeple. http://www.ehc.edu/alumni-and-friends/alumni-news/2016/02/end-era/
If you live in or around Smyth or Washington County… Virginia… and you…ve gotten a ticket for a traffic violation… you may have found yourself sitting in front of Frank T-Bone Lewis (E&H '59) is the man with a defensive driving plan. http://www.ehc.edu/alumni-and-friends/alumni-news/2016/02/better-call-t-bone/
Greg Lowe …left… E…H …75… got together with his E…H college roommate recently. That may not be a big deal to some old roomies…but Greg hadn…t seen David Cox since 1972. David had a low number during the draft After 44 years, Greg Lowe ('72) and David Cox just had a great reunion. http://www.ehc.edu/alumni-and-friends/alumni-news/2016/01/reunited/
Charlie Sult …E…H …50… doesn…t let the candles on his birthday cake snuff out his enthusiasm for encouraging students t…o pursue their education plans. At the age of 92 Charlie Sult (E&H '50) is a champion for education, and he uses his good heart to encourage young people to achieve their dreams and goals. http://www.ehc.edu/alumni-and-friends/alumni-news/2016/01/compelled-help/
After almost 20 years as a teacher… Joseph Hicks knows a thing or two about kids. And it…'s that knowledge that led him to write …Paige and Sophie… Soccer Twins After almost 20 years as a teacher, Joseph Hicks knows a thing or two about kids. And it's that knowledge that led him to write "Paige and Sophie: Soccer Twins," a children's book about two soccer-playing sisters who are identical on the outside but very … http://www.ehc.edu/alumni-and-friends/alumni-news/2016/01/hicks-converts-love-soccer-childrens-book/
Three E…H students have spent the fall semester studying at Dublin City University… and in November… a group of E…H alumni… faculty… and staff members traveled to Ireland to visit them In November, 19 E&H alumni, faculty, and staff headed to Ireland to tour the country and meet E&H students studying in Dublin. http://www.ehc.edu/alumni-and-friends/alumni-news/2015/12/eh-goes-ireland/
Kelly Mae Kerlin …E…H '14… has a new job working at the American Society of Clinical Oncology as their Program Assoc…iate for their annual meeting in Chicago. The meeting draws 37 Kelly Mae Kerlin (E&H '14) has secured a great job for using her Mass Communications degree. http://www.ehc.edu/alumni-and-friends/alumni-news/2015/12/kerlin-finds-right-chemistry/
Ron Patterson …E…H '63… and Tom Corbin …W…M '65… have been very instrumental in securing historic designation for the community of Fairlin…gton… and now they have a website called Ron Patterson (E&H '63) and Tom Corbin can help you plan a meaningful trip to visit the community around Arlington and DC. http://www.ehc.edu/alumni-and-friends/alumni-news/2015/12/day-trippin/
Jo Marie Woodward Johnson been working for the past 5 years as a scientist and manager fo…r Washington River Protection Solutions …WRPS… at the U.S. Department of Energy Jo Marie Woodward ('87) is working to clean up radiation and make the world a bit safer. http://www.ehc.edu/alumni-and-friends/alumni-news/2015/12/cleaning/
Courtney Williams Park is the librarian for the International School of Tanganyika in Tan…zania. She recently was having dinner in Barcelona… Spain… with a group of other international school librarians when the accent of one of the parti Emory & Henry may be a small school, but alumni show up all over the world...including at random meetings in Spain. http://www.ehc.edu/alumni-and-friends/alumni-news/2015/12/small-world/
Emory … Henry had a large presence at this year…s Tobacco Science Research Conference… held from September 20…23 in Naples… FL. The Tobacco Science Research Conference is an annual conference which brings togethe Dr. Clarissa Tatum ('05) Chaired the 2015 Tobacco Science Research Conference in Orlando, Florida. And the headline speaker, was also an E&H alumnus, Dr. Mike Ogden ('80). http://www.ehc.edu/alumni-and-friends/alumni-news/2015/11/tatum-and-ogden-2015-tobacco-symposium-stars/
Revs. Brad Dulaney …'97… Patti Sufficool Money …'99… and Doug Forrester …'93… pose for a picture while serving food to the homeless at Dail Ministries in Seoul Three E&H pastors recently spent time together in Korea on a mission of compassion. http://www.ehc.edu/alumni-and-friends/alumni-news/2015/10/eh-alumni-korea/
Susan Matthis Johnson… '75… was recently featured on NPR for her work as a mentor for the PBS NewsHour Student Report…ing Labs. She and her students were interviewed by Scott Finn of West Virginia Public Bro Susan Mathis Johnson (E&H '75) was recently featured for her work with a student video project that sheds light on the opioid addition problem in West Virginia. http://www.ehc.edu/alumni-and-friends/alumni-news/2015/10/susan-mathis-johnson-featured-npr/
Beth Holding Hagan …E…H …83… admits that she has always been the …quarterback… … and switching to the position of …receiver… hasn…t been easy. But this …get…it Beth Holding Hagan (E&H '83) has been the recipient of a new heart...and so much more. http://www.ehc.edu/alumni-and-friends/alumni-news/2015/09/gracious-receiver/
Emory … Henry College recently celebrated the daughter of Fred W. and Eleanor Dean Jackson who… through her generosity… recently augmented the endowment of a scholarship in the name of her parents. Emory & Henry College recently celebrated the daughter of Fred W. and Eleanor Dean Jackson who, through her generosity, recently augmented the endowment of a scholarship in the name of her parents. http://www.ehc.edu/alumni-and-friends/alumni-news/2015/06/gift-enhances-jackson-memorial-scholarship/
Dr. Samir Saliba… who has served Emory … Henry for 51 years and whose leadership at the College helped shape its mission and many …of its most important programs Dr. Samir Saliba, who has served Emory & Henry for 51 years and whose leadership at the College helped shape its mission and many of its most important programs, provided a retrospective on the institution during his time at the institution at an event he… http://www.ehc.edu/alumni-and-friends/alumni-news/2015/05/dr-samir-saliba-presents-last-lecture/
Melvin …E…H …06… is a musician himself… and used to play at venues in the Emory area while a student to make a little extra money…. But as he got to know the industry Melvin Dillon (E&H '06) owns a record label -- but, unlike a lot of the big name record labels, Soul Step Records is all about the artists http://www.ehc.edu/alumni-and-friends/alumni-news/2015/04/vinyl-revival/
Emory … Henry College recently recognized an exemplary philanthropist whose generosity honors two… former teachers while supporting students planning careers in education. Wanda M. Faus Emory & Henry College recently recognized an exemplary philanthropist whose generosity honors two former teachers while supporting students planning careers in education. http://www.ehc.edu/alumni-and-friends/alumni-news/2015/04/gift-establishes-endowed-scholarship-support-future-teachers/
Renato Nascimento and Emory … Henry…s 140 Years of Missionary Service… By Dr. James Dawsey Former Emory … Henry College student Renato Nascimento spent five days during November 2014 on a mission Renato Nascimento is walking in the footsteps of Walter Lambuth and John Ransom. http://www.ehc.edu/alumni-and-friends/alumni-news/2015/03/story-140-years-making-james-dawsey/


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Does anyone have a recipe for salmon egg scramble? I made one but it was very dry.
By Onesummer
Well, I take a can of salmon and debone it. I then brown whatever veggies I have on hand ie onion, pepper, celery I have even used carrot that I shred. I brown all that in pan. Then add salmon and old bay seasoning to taste (I just shake until it is all pretty red. When the salmon is hot, I break up how many ever eggs will stretch it, then I eat it. Wonderful.
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text: Home Gallery Video Comedy Central Handicap House Comedy Central: Handicap House Published on Apr 02, 2003 Editor's Pick Rate this Ad You must be registered to rate the ad. Please Login or Register Now About CreditsDateApr 02, 2003Designer:Jennifer UngerCopywriter:Leslie KeeneClient:Comedy CentralAgency:In-house Latest Creativity News on Ad Age Ad Review: Skittles Makes the Play of the Week Snapchat's Mysterious 'Snap to Unlock' Ads Start to Pop Up Party Animals 'Illuminated by a Thousand Likes' Star in Bacardi's Latest Advertisement Ad Age Events Nov 02 Los Angeles, CA SummitAd Age Brand Summit The Ad Age Brand Summit in Los Angeles peels apart the layers of brand building with a carefully crafted roster of top marketing, technology, and creative leaders. Learn more Related work Comedy Central: Prison Guard Comedy Central: How Old Is Trevor Noah? Comedy Central: World Famous Animates Comedy Central's New Digital Series Want to see your work in our gallery? Submit now


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Episode 220: Cat's Play
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|The Wubbulous World of Dr. Seuss
|Air Date
|December 28, 1997
|Written by
|Stephanie Simpson
|David Gumpel, Kathryn Mullen
In the Cat's Playhouse, everyone pretends to be pirates, and they imagine great adventures. In the Wubbulous World, Sarah imagines that she's a superhero, and Junior imagines what it would be like to be more special, with a super-long tail and antlers.
Video releases
- The Wubbulous World of Dr. Seuss: Volume 1 (1999)
- Fun with the Cat (2005)
|Previous episode:
|Next episode:
|The Cat in the Hat Helps a Friend


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Outstanding art, excellent food and extraordinary location......magical!
We had a wonderful time on Fire Mountain and enjoyed every minute. Thank you Mathew and Hiram for casting such a lovely spell upon us!
- Reservation Options:
- TripAdvisor is proud to partner with Expedia, Hotels.com and Travelocity so you can book your Fire Mountain Inn reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
- Also Known As:
- Fire Mountain Hotel Highlands


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Soléna Estate Winery was built with the future in mind, a place that would belong to Danielle and Laurent's daughter, Soléna. Soléna Estate is a place where biodynamic practices in the vineyard, French winemaking talent, and a sense of family all come together. Enjoy wine tasting at our home away from home and savor award-winning Pinot Noir and Chardonnay at our lakeside tasting room.
Location - 1700 N.E. Woodland Loop Road, Yamhill, OR 97148
Neighborhood - Wine Country
Categories - Wine Bars/Tasting, Winery
Pop out | Profile page | Powered by Visiting Media TrueTour™ Technology


text: I don't know the official chef's flavor analysis of this combination, but I had two items that perfectly complemented each other. I started with the pickled beets salad, which comes with goat cheese over arugula. That perked up my taste buds for PO's lobster corn chowder. I dined early in the dinner service, so the freshly made chowder wasn't as... More


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I spent some time with C.J. Williams the other week and came away from our chat thinking exactly what Dan Wiederer writes this morning in The Fayetteville Observer: Williams, just a sophomore, could emerge as a team leader this season.
Lowe now wants his sophomore shooting guard to showcase his heightened confidence to not only become a reliable playmaker but an energizing force for the whole team.
"C.J. knows the right things to say and the right things to do, there's no question about that" Lowe said. "Now will he emerge as a leader? I'm not sure yet. He absolutely knows the right way. But the other part about being a leader is you have to do it the right way every time. As a leader, I can't tell you not to take that bad shot if I'm taking bad shots. I can't tell you to stop turning it over if I'm turning it over. If you're going to talk the talk, you better walk the walk."
We'll have an article on Williams in the Winter issue of NC State magazine. h/t to Pack Pride poster rcaseyf.
(Photograph by Molly Renda)


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Ship your orders to your local dealer and pick up for free.
Return your orders to your local dealer for free.
Adds the convenience of a Retractable Tether to your Trike trunk door.
Fits '11-later Tri Glide™ models.
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text:
The Love Approach Test
Free to Love
All possible test results
Lone Ranger
You are content on your own. You aren't in a hurry to find love. Read more
Bring It
You aren't searching for romance right now. However you want satisfaction from life now not later. Read more
Tell It Like It Is
Forget romance. You just speak your mind. Read more
Speak Now
You want what you want. However you want it now. You're honest because you don't have time to waste. Read more
Pure Generosity
Even though you aren't the romantic type, you are a generous person. Don't forget to speak your mind. Read more
Generous Right Now
Generous as your heart maybe, you aren't about wasting time. Bring some romance into your life. Take the risk - say what's on your mind. Read more
Giving but Honest
Romance isn't your thing but that's okay. Your generosity makes up for the lack of romance. Although you care about others, you aren't afraid of what others might think. Read more
About Today & Giving
You never hold back and exude the qualities of a generous person. You aren't the type to slow dance through life. Take it up a notch, find your romantic side. Read more
The Romantic
You are a romantic. Luckily you aren't in a rush about love. Learn to give more and speak your mind. You will be that much happier. Read more
Quest for Love
If someone wants to win you over, red roses will earn your heart. Best thing you can do is slow things down when it comes to love. Perhaps you care too much about what others think. Read more
Truth is Romantic
You put your heart into love but you aren't afraid to be yourself. People should love you as is or not love you at all. You'll find more happiness you give. Read more
Free to Love
You're romantic almost to a fault. Don't forget to give to others. Consider slowing down. You may be scaring off potential lovers. Read more
Generous Heart
You're a romantic and generous person. You're only fault perhaps is not speaking your mind at risk of hurting others. Keep that kind heart! Read more
Long Stem Roses
You are a great person. You are generous and romantic. You're only fault may be your strong desire for love. Don't be afraid to speak what your heart feels. Read more
Great Catch
You have some great qualities. Not only are you generous but you are romantic. Even with romance you stay grounded though. Honesty is your language. Sign me up! Read more
Full of Love
You are an emotional, loving, generous person. You are in love with life and love. Read more
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"A harmonious composition with austere colours that introduces unexpected tonal rhythm. It look stupendous wherever you place it." 144x215 cm - 4'9"x6'9" 170x250 cm - 5'7"x8'3" 220x300 cm - 7'3"x9'10" Fibre composition: 100% wool. Total weight approx: 1'7 kg/m² - 0,35 lbs/ft² Total height approx: 6 mm. Reversible. Manufacturing technique: KILIM.
GAN is now GANDIABLASCO's indoor brand but it was really the starting point… José Gandía-Blasco, the company's chairman, reinvented the family firm at the end of the eighties after four decades in business.


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Brands event - ends Sunday
The Sanremo collection from Natuzzi is a masterpiece of clean, modern, modular style, in luxurious leather. Deep, sumptuous cushioning, roomy seats and wide cushioned arms invite you to relax. Take it even easier with optional inbuilt power recliners and power headrests. In a choice of beautiful colours, the modular units allow you to create your perfect seating arrangement.
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HollyFrontier (HFC), Holly Energy (HEP) Announce Woods Cross Refinery Units Dropdown; Holly Energy Enters $100M Equity Raise
- Record-setting rally pushes on as S&P ends week up 3 percent
- Trump's Cohn Pick Most Bullish Sign Yet for Banks - Cowen
- Unusual 11 Mid-Day Movers: (IDXG) (INVN) (EBS) Higher; (SCON) (DTEA) (DLTH) Lower (more...)
- 21st Century Fox (FOXA) offers to acquire Sky for GBP10.75/share
- Coca Cola (KO) Announces James Quincey to Succeed Muhtar Kent as CEO; Kent to Continue as Chairman
Get Alerts HFC Hot Sheet
Overall Analyst Rating:
NEUTRAL ( Up)
Dividend Yield: 4.7%
Revenue Growth %: -20.6%
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HollyFrontier Corporation (NYSE: HFC) and Holly Energy Partners, L.P. (NYSE: HEP) announced an agreement in principle for the acquisition by Holly Energy of a HollyFrontier subsidiary, which owns certain Woods Cross Refinery units constructed as part of the Woods Cross expansion for a total cash consideration of approximately $275.0 million, subject to the execution of definitive agreements and other customary closing conditions. The total transaction consideration represents an implied multiple of 8.5 times the 2017 expected EBITDA contribution. Holly Energy expects that the transaction will be immediately accretive to unitholders and contribute towards the achievement of HEP's 8% distribution growth target. The transaction is expected to close on or about October 1, 2016.
The assets to be acquired by Holly Energy include the newly constructed crude, fluid catalytic cracking and polymerization units at HollyFrontier's Woods Cross refinery. In connection with the closing of the proposed transaction, HollyFrontier and Holly Energy expect to enter into 15-year tolling agreements for each respective unit containing minimum quarterly throughput commitments from HollyFrontier.
In conjunction with the closing of the proposed transaction, Holly Energy has agreed to a private placement with certain clients of Tortoise Capital Advisors, L.L.C. for approximately $100 million of common equity. Holly Energy Partners does not anticipate any further equity financing needs for the remainder of 2016. The balance of the purchase price will be financed by borrowings under Holly Energy Partner's existing revolving credit agreement.n
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9/21/2016 to 9/23/2016
Your west coast RCI friends have hosted many conferences over the years and have a long history with RCI. Did you know Purdys Chocolatier joined RCI 50 years ago, and Charlie's Chocolate Factory has been a member for the past 40 years? Both companies have found a great deal of early successes, learning from fellow RCI members. We have always found great value at RCI conferences and are excited to be a part in building this event to provide many learning opportunities for each of you! As Candy Clinic is a favorite event of Charlie's, we want to encourage you to participate and share your ideas with others in the industry. To top off the week, during a tour of Charlie's Chocolate Factory you will experience Charlie's own chocolate river, and a visit to Purdys Chocolatier will sweeten your trip as you see manufacturing of creams, caramels, truffles and signature confections.
While in Vancouver, don't miss a chance to drive the Sea to Sky Highway to Whistler, a world-class, all-season resort. Enjoy a unique experience by riding the gondola up Grouse Mountain on a free evening and dine on top of the mountain overlooking some breathtaking views of the city twinkling below. From colorful downtown neighborhoods, to culturally diverse suburbs and mountainside districts, there is plenty to explore and something for everyone.
Charlie's Chocolate Factory & Purdys Chocolatier
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2/20/2017 » 2/23/2017Chocolate Boot Camp
6/12/2017 » 6/16/20172017 Annual Convention & Industry Expo
11/21/2016Clasen Quality Chocolate, Inc. Brings Chocolate to the Forefront of New Company Name
11/8/2016Davis Chocolate Creates New Chocolate for Sculptor Paul Joachim
2053 S Waverly Ste CSpringfield , MO 65804UNITED firstname.lastname@example.com


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4 Bedrooms Terraced House for sale
King Street, sheffield, South Yorkshire, S26
Housesimple is pleased to present this immaculately presented modern 4bedroom terraced house in sheffield.early viewing is advised to appreciate the size of the property, which benefits…
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Seventh Floor
Quay West at MediaCityUK, Trafford Wharf Road
Tel: See phone number 07746218088
Website: Go to Agent Website


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How Immigration Reform Could Impact U.S. Labor Market
President Obama's immigration reform could grant as many as 5 million with legal working status, which might ripple across the U.S. labor market.By Bram Sable-Smith | November 21, 2014
Jobless claims are down, more Americans are confident enough to quit their jobs and wages are slowly ticking up.
And right when it looked like the balance of the labor market was slowly tipping back toward a positive outlook for workers — a big announcement. (Video via CCTV)
"There are actions I have the legal authority to take as president," President Obama said.


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The recent trend shows that there is an increasing demand for talented people and that talent acquisition has become a huge problem. In the next few years, there is going to be a severe shortage of talented professionals compared to skilled workers. Hiring the best talent is going to be a tough job for the recruiters.
Importance of acquiring the best talents
It is important for an organization to have the best talent acquisition, retention and development strategies. Most of the organizations fail because of hiring people who fail to meet the standards of the organization. The situation is going to be worse in the case of companies which are not well established. Talent acquisition is the process of finding and involving the best-talents in an organization.
An organization can perform better in the industry only if it has a talented and skillful work-force. It is about putting in the right people, in the right place. Recruitment and talent acquisition are different.
Designing and Implementation of Talent Acquisition Strategy
It is important to understand the employer's choice before implementing a strategy. It also includes reviewing and utilizing talent acquisition tools and learning from best practices. Analyzing the performances like business impacts, financial strategies etc. It is also important to have a good knowledge about the recent trends and practices to acquire the best talent.
Talent Acquisition Strategies for the 21st century
It is important to become a good talent manager to pool in the best talents in an organization. It is also important to set high standards in a team and take necessary steps to strengthen the talent of a group. The manager is responsible for appraising his employees about their strengths, weakness and their performance levels. Strong performances must be posed with new challenges. The managers can also define sharp talent and performance differences among the employees.
An organization must place its emphasis on the development of people. Every employee can push the limits to certain level even if everyone cannot be a superstar. Leaders who can assess the talent factor get involved in hiring and making decisions.
People at that level may let their sub-ordinates know that they are capable of voicing their views and watching the performance and potential of his/her employees. Above all this, an effective talent review process is important to reap benefits.
A talent review process is to be carried out in a disciplined manner. Good companies have a stringent talent review programs and this helps them to grow faster. It is also a direct way to build the talent pool. Managers in the organization must be held responsible for accumulating and strengthening the talent factor in their respective divisions.
Also see


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This is a self-initiated tour poster I did for William Fitzsimmons.
I called it the 'Runnin' on Whiskey Tour'. You can see why if you check out the full thing here: http://tinyurl.com/bsslo6h
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CFTR chloride channels are encoded by the gene mutated in patients with cystic fibrosis. These channels belong to the superfamily of ABC transporter ATPases. ATP-driven conformational changes, which in other ABC proteins fuel uphill substrate transport across cellular membranes, in CFTR open and close a gate to allow transmembrane flow of anions down their electrochemical gradient. New structural and biochemical information from prokaryotic ABC proteins and functional information from CFTR channels has led to a unifying mechanism explaining those ATP-driven conformational changes.
The all-too-common deadly disease of young people, cystic fibrosis (CF), is caused by failure of a chloride-ion channel with the unwieldy name of CFTR, standing for cystic fibrosis transmembrane conductance regulator. Anion flow through this channel is needed for normal function of epithelia such as those that line airways and the intestinal tract and ducts in the pancreas, testes and sweat glands. Without anion flow, water movement slows, and dehydrated mucus clogs ducts and collects in the lung where it fosters ultimately lethal bacterial infections. The amino-acid sequence of CFTR immediately identified it as a member of the superfamily of ATP-binding cassette (ABC) transporter ATPases. Among the thousands of ABC family members, only CFTR is an ion channel. High-resolution electrophysiological studies of single CFTR channels therefore offer a unique window into mechanisms of ABC transporter function. And recent structural and biochemical advances in the study of bacterial ABC proteins have shed light on how opening and closing of the CFTR chloride channel are regulated.
Here we bring together the latest information on CFTR-channel function and on prokaryotic ABC-transporter structure to provide an up-to-the-minute view of what CFTR channels normally do, what a CFTR channel might look like and how its anion pathway is opened and closed. The gate that regulates chloride-ion flow through the membrane-spanning pore in CFTR is thought to be opened when ATP binds to CFTR's two cytoplasmic nucleotide-binding domains (NBD1 and NBD2) and, acting as molecular glue, holds them together. Hydrolysis of one of the ATPs disrupts the NBD1–NBD2 interaction and closes the channel gate, terminating anion flow. Kinase-mediated phosphorylation of a cytoplasmic regulatory domain in CFTR is needed for successful transmission of NBD events to the channel gate.
Evolutionary conservation of structural components of the NBD1–NBD2 interface makes it probable that a similar cycle of ATP binding and hydrolysis drives function in most ABC family members. Even so, important differences between NBD1 and NBD2 in CFTR seem to have evolved to allow only one of the bound ATPs to be hydrolysed while the other remains unaltered during numerous gating cycles. Similar differences in the NBDs are found in CFTR's closest relatives in the human genome. These are the multidrug-resistance-related proteins (MRPs), which are ATP-driven efflux pumps, and the sulphonylurea receptors (SURs), which associate with inward rectifier potassium-ion channels to form nucleotide-sensitive potassium conductance (see the review in this issue by Nichols, p. 470). So mechanisms inferred for CFTR are likely to apply also to MRP and SUR.
In 1989, when the gene mutated in CF patients was identified by positional cloning1,2, the expectation was that it would encode a chloride-ion channel. This was because CF epithelia behaved as though they were impermeable to chloride3, and chloride channels could be activated by cAMP-dependent protein kinase (PKA) in normal but not in CF airway epithelium4,5. So when the mutant gene was found to encode an ABC transporter homologue, with several consensus sites for phosphorylation by PKA, its product was suggested to regulate chloride channels by pumping out a cytoplasmic inhibitor: hence the name, CFTR2. But there were more surprises. CFTR itself was shown to be a chloride channel, directly activated by phosphorylation by PKA (Fig. 1). This channel allowed chloride ions to flow equally readily in either direction, though at modest rates (conductance ≤10 pS; for example, see ref. 6). However, the regulated channels previously studied in airway epithelia4,5 conducted chloride ions rapidly (conductance ≥30 pS) and preferentially into the cell, and so were not CFTR channels. How, and even whether, the function of these and other channels and transporters is modulated by interaction with CFTR is still unsettled7,8.
Although two-thirds of all CF disease cases can be attributed to a single mutation in CFTR, deletion of Phe 508 in NBD1, over 1,000 CF-disease-associated mutations of this 1,480-amino-acid protein have been logged (http://www.genet.sickkids.on.ca/cftr/). ΔF508-CFTR protein fails to mature properly and is tagged for degradation9. But cell incubation at room, rather than blood, temperature leads to maturation, trafficking and insertion of ΔF508 CFTR into the surface membrane, where it functions nearly as well as wild type. Much effort is therefore being directed to identifying small molecules that might chaperone ΔF508 to the cell surface in CF patients. Other CF-causing mutations lead to truncated protein or to full-length channels with reduced chloride-transport capacity because they either spend a smaller fraction of time open, or when open, conduct chloride ions more slowly than normal. Most disease-causing mutations have yet to be functionally characterized.
CF is a pleiotropic disease affecting all exocrine epithelia. Morbidity and mortality are largely due to chronic bacterial infection and inflammation in the lung. Inhaled DNase can ameliorate thickening of airway mucus by aggregated DNA from dead cells. Although the underlying pathophysiology of CF is still debated10, the simplest hypothesis is that impaired anion movement is the primary cause. In the handful of cases examined, severity of disease seemed related to impairment of channel function. Therapeutic efforts are therefore centred on restoring the activity of mutant CFTR or enhancing alternative pathways for anion flow. Gene therapy trials to introduce CFTR DNA into airway epithelial cells began over a decade ago, but difficulties with gene delivery and expression11 have led to refocusing of efforts to rescue ΔF508 CFTR.
As ABC proteins occupy up to 5% of each prokaryotic genome sequenced, there are thousands of examples of them, although few have been studied in any depth. They conform to a modular architecture, thought to comprise two transmembrane domains (TMDs), with typically six membrane-spanning α-helices each, and two cytoplasmic NBDs. Individual bacterial genes often encode single domains or fused pairs of domains (TMD–TMD, NBD–NBD or TMD–NBD), but three-quarters of the 48 human ABC genes (assigned to seven subfamilies) encode full-length ABC proteins12. In the case of CFTR, a unique regulatory (R) domain, the target of PKA phosphorylation, links two homologous halves, giving the overall domain organization TMD1–NBD1–R–TMD2–NBD2 (ref. 2).
A common assertion, rarely tested, is that a functional ABC protein contains two TMDs and two NBDs, as found in crystal structures of the bacterial ABC transporters MsbA13 and BtuCD14 and in a low-resolution structure of the multidrug transporter P-gp from two-dimensional (2D) cryo-electron crystallography15. For CFTR, this means a single polypeptide, and functional measurements have addressed this question. Two CFTR polypeptides can associate16, at least through their carboxy-terminal PDZ-domain-binding motifs17. However, co-expression of two kinds of CFTR channels with distinct functional characteristics produced no hybrid channels18, and cysteine-modification tests showed that a single introduced cysteine contributed only once to a CFTR pore19. So each CFTR channel seems to be constructed from just one CFTR polypeptide.
It seems that negatively charged ions, such as chloride, accumulate near positively charged regions at each end of the pore in CFTR's trans-membrane domain20,21 and flow through the pore after the opening of its gate by events initiated by ATP binding to the cytoplasmic NBDs (Figs 1, ,2;2; N-terminal NBD1, green; C-terminal NBD2, blue). Before events at CFTR's NBDs can trigger gating of the pore, the R domain must be phosphorylated by PKA22 (Fig. 1a). Once phosphorylated, CFTR channels need ATP to open normally; they close within 1 s of ATP withdrawal (Fig. 1a) and tend to stay shut until ATP is restored. A simple scheme linking these events to the pore gate (Fig. 1b) can account for most of the experimental evidence, although many details remain to be clarified. Once ATP binds to homologous nucleotide-interacting motifs in the two NBDs, these domains are thought to approach each other closely, sandwiching two ATPs in the NBD1–NBD2 interface. Upon this intramolecular heterodimer-like interaction, a signal would be transmitted through cytoplasmic-linking domains to open the gate in the transmembrane domain (Fig. 1b, grey). That channel-opening signal would be sustained until hydrolysis of one of the ATPs leads to disruption of the NBD1–NBD2 interface and separation of the NBDs. Loss of the signal allows the channel gate to close, terminating anion flow until ATP again binds to the NBDs.
High-resolution structures are not yet available for any full-length eukaryotic ABC protein but have been obtained not only for the prokaryotic MsbA and BtuCD entire transporters but also for several NBDs (for example, see refs 23–27). The NBD structures all reveal the same basic fold, with highly conserved sequence motifs positioned to interact with bound ATP (Fig. 2a).
In an ATP-bound NBD monomer23, the phosphate chain of the nucleotide is cradled by a canonical P-loop, or Walker28 A sequence (red, Fig. 2). This lies at the N terminus of a helix adjacent to a parallel β-sheet tipped by loops (one including the Walker B sequence (orange, Fig. 2), another including a 'switch' His (light green, Fig. 2)) that contact the γ phosphate of ATP in an F1-ATPase-like ATP-binding core. On the other side of that helix, an extended loop arising from the middle of an ABC-specific anti-parallel β-region contains an aromatic residue against which the nucleotide base stacks. Evident lack of nucleotide interaction with the conserved 'ABC signature' sequence (consensus LSGGQ; pink, Fig. 2), some 15 Å distant in the so-called α-helical domain (also containing Phe 508; Fig. 2b), was initially puzzling. The puzzle was solved by biochemical demonstration of nucleotide-induced dimerization of bacterial NBDs29, and by crystal structures that showed rotationally symmetric 'head-to-tail' NBD homodimers25–27 (compare with Fig. 2a). These nucleotide-bound NBD dimers enclosed two ATP molecules in interfacial composite sites, each comprising ATP-interacting motifs from the 'head' of one monomer and signature sequence residues from the 'tail' of the other (Fig. 2a, c).
Recent crystal structures30–32 of NBD1 of CFTR show that it, too, conforms to the established NBD architecture, although its ABC-specific β-sheet includes a long, inserted loop, not found in other NBDs, and whose shape and position are still unclear. Assuming that NBD1 and NBD2 in CFTR approach each other in the way that bacterial NBDs do in the homodimeric crystals (as illustrated in Fig. 2c, d) allows construction of speculative homology models of CFTR (Fig. 2a, b), based on the structures of prokaryotic NBD dimers and of MsbA. These structural diagrams serve to illustrate the relative positioning of the transmembrane domains, cytoplasmic linking segments and NBDs, and concur with a low-resolution map33 from cryo-electron crystallography of 2D crystals of CFTR. Much remains uncertain, however, including the precise structure of the TMDs, where homology between MsbA and CFTR is low. The structure and disposition of the R domain, lacking in other ABC proteins, is completely unknown and so is omitted from Fig. 2b (it must somehow connect the red spacefill residues, marked Rd).
A key distinction between homodimeric interactions seen so far in crystal structures of bacterial ABC proteins and the proposed NBD1–NBD2 interaction in CFTR is the asymmetry of the two expected interfacial nucleotide-binding sites, echoing the mere 27% identity between CFTR's NBD1 and NBD2. In contrast to the two essentially identical catalytic sites found in bacterial NBD homodimers24–27, each with its full complement of conserved consensus residues (Fig. 2c), the expected NBD1–NBD2 'heterodimeric' arrangement comprises only one consensus catalytic site (Fig. 2d). We call that site the 'NBD2 composite' site, as NBD2 contributes its nucleotide-binding residues of the Walker motifs, the residues that hold ATP in ATP-bound NBD monomers. The other interfacial site, the 'NBD1 composite' site, includes non-canonical residues from NBD1 Walker B (Ser instead of Glu) and switch (Ser instead of His) motifs, as well as from the NBD2 signature sequence (LSHGH instead of LSGGQ). Not surprisingly, as we will see below, evidence suggests that only the NBD2 composite site is catalytically competent.
Where is the pore in CFTR? Few systematic mutational studies have been attempted, making the residues that contribute to CFTR's anion pore uncertain. The focus of most attention has been the sixth putative membrane-spanning helix in TMD1 (gold helix, Fig. 2b), whose cytoplasmic extension connects TMD1 to NBD1. As befits a contributor to an anion-selective pore, transmembrane helix 6 is predicted to contain at least three basic residues, Arg 334 and Lys 335 (blue-green spacefill, Fig. 2b) towards the extracellular end and Arg 347 four helical turns closer to the cytoplasm. Although initially proposed to face the pore34, Arg 347 was subsequently shown35 to form a salt bridge to an Asp in transmembrane helix 8. A number of approaches have led to the conclusion that the positive charges at Arg 334 and Lys 335 promote entry of anions into an outer vestibule, and that the side chain of Thr338, one helical turn in, faces the pore. These include measurements of the ease of entering the pore and of passing through it, for a variety of monovalent anions, and measurements of the influence of covalent modification of introduced cysteines (reviewed in ref. 20).
Vast spans of the TMDs have not yet received attention (for example, helices 7 to 10), and effects on anion conduction of mutations at selected positions in helices 1 to 5 and 11 are not yet fully understood20,21. Although the symmetrical arrangement of membrane-spanning helices in the paired TMDs of homodimeric ABC proteins, such as MsbA and BtuCD, imbues CFTR models based on them with comparable twofold symmetry (see Fig. 2b), a lot more work is needed before the true disposition of transmembrane helices around CFTR's anion-selective pore can be specified.
Like most other chloride channels (see the review in this issue by Miller, p. 484), CFTR selects relatively poorly among small monovalent anions. Halide and pseudohalide anions larger than chloride, which escape their water shell more easily, also enter the channel more easily than chloride20. Their lower avidity for water also keeps larger anions in the pore longer, allowing them to impair chloride-ion flow by competition20. These characteristics imply a fairly featureless interior of the CFTR pore where no region makes very intimate contact with permeating chloride ions20. This contrasts with the close embrace of potassium ions by rings of backbone carbonyl oxygens in the selectivity filter of potassium channels. Whereas potassium channels need to discriminate between similarly sized sodium and potassium ions, CFTR channels face the simpler task of distinguishing chloride (and probably bicarbonate) from larger anions such as phosphate and sulphate. Loss of regulated conduction of bicarbonate10 by CFTR channels may contribute to both airway and pancreatic-duct disease in CF.
Gating of the CFTR channel is strictly dependent on R-domain phosphorylation by PKA. CFTR channel activity increases at least 100-fold upon phosphorylation36 (from an open probability of <0.003 for non-phosphorylated CFTR channels in saturating [ATP]). The R domain comprises the ~200 residues linking NBD1 to TMD2 and contains multiple consensus sites for phosphorylation by PKA; up to six have been found phosphorylated in cells37–39 and up to eight in isolated CFTR40. Among other kinases, both Ca2+-dependent and independent isoforms of protein kinase C (PKC) can phosphorylate R-domain sites22,38,41. Although CFTR phosphorylation by PKC itself causes only modest channel activation22,41, it potentiates22, and might even be a prerequisite for42,43, subsequent channel activation by PKA.
The unphosphorylated R domain exerts an inhibitory influence on CFTR channel gating that can be relieved by phosphorylating it, or deleting it44,45. Thus, at saturating [ATP], the open probability of CFTR channels cut in half and lacking the R domain is ~60% of that of fully phosphorylated CFTR channels similarly cut in half but retaining the entire CFTR sequence, including the R domain45 (which all testifies to the nature of CFTR's modular ABC-protein architecture). So loss of inhibition by the unphosphorylated R domain can account for over half of the more than two orders of magnitude increase in open probability of intact wild-type CFTR channels upon phosphorylation36. Any additional stimulatory effect of the phosphorylated R domain46 is therefore probably small (less than twofold).
Just how R-domain phosphorylation controls channel gating is not clear. No other ABC protein contains an R domain, and its sequence, though conserved across species47, shows no homology to other proteins. Its shape and location in the CFTR channel are therefore unknown. CFTR-channel activity changes gradually as increasing numbers of target serines are mutated37,48 or as increasing PKA concentrations incrementally phosphorylate wild-type CFTR39,43. Results like these have fostered notions of redundancy among serines in a structureless R domain, and of action by accumulated negative charge37,49. But this is unlikely to be the whole story. For instance, purified R-domain protein undergoes discernible conformational changes upon phosphorylation39,50. In addition, two of the most readily phosphorylated serines inhibit channel activity when phosphorylated, despite undoubted introduction of negative charge39,51. Although direct introduction of negative charge by substituting aspartate52 or glutamate53 for six to eight serines does result in partly active channels, their maximal activity is 2–3-fold lower than that of phosphorylated wild-type CFTR. And circular dichroism spectra of the purified R domain indicated that the introduced acidic residues imperfectly mimic phosphoserines54. Also, a role for a conformational change of the R domain is suggested by the finding that the prolyl-isomerase cyclophilin A stimulated wild-type CFTR channel activity, but not that of mutants lacking three conserved R-domain prolines55.
The R domain does not seem to prevent ATP from binding at the NBDs or hydrolysis, because phosphorylation is reported not to alter photolabelling by 8-azido-ATP56–58. Nor can inhibition of gating in the unphosphorylated channel be attributed to the serine-containing nonconserved structural elements in and around CFTR's NBD130–32, say by preventing NBD1–NBD2 interaction. This is because excision of neither segment vitiated the strict dependence of channel gating on phosphorylation by PKA36.
By contrast, simply severing CFTR where the R domain connects to TMD2 partly disrupts inhibition of gating in unphosphorylated channels45,59. So the closed conformation of the pore might be stabilized (relative to the open conformation) by an action on the TMDs of the unphosphorylated R domain that requires its covalent attachment to transmembrane helix 7? That interaction could be relieved by R-domain phosphorylation — perhaps through its association with some other part of the channel — and the free energy difference between open- and closed-state conformations thereby lowered sufficiently to enable ATP-mediated closed-to-open transitions. Physical association of the R domain with CFTR's N terminus might be required for channel activation by PKA60 and might be promoted by R-domain phosphorylation61.
The location of the gate that prevents ion flow through closed CFTR channels is not known. But the machinery attached to the strings that pull the gate open and closed has recently come into view. Opening and closing of the CFTR pore are now believed to be linked to formation and disruption of a tight NBD1–NBD2 complex, driven by ATP binding and hydrolysis events (Fig. 1b). Phosphorylated CFTR channels can be opened by a broad range of nucleoside triphosphates, including ATP, GTP, ITP, UTP, CTP, AMP-CPP62 and 8-azido-ATP58. But they are opened only inefficiently by millimolar concentrations of poorly hydrolysable analogues such as AMP-PNP, AMP-PCP or ATP-γS53,62–64, and not at all by ADP62. The frequency of CFTR-channel opening increases with ATP concentration along a Michaelis curve and is half maximal at about 50 μM ATP (Fig. 3a). At saturating concentrations of ATP, a channel waits in the closed state for a second or so (depending on the temperature) before opening. This means that binding of ATP limits channel opening at low concentrations, but at saturating ATP concentrations some other slow step controls how quickly the channel can open once ATP has bound.
Where does this rate-limiting binding of ATP occur? Mutagenesis experiments (Fig. 3) to alter the Walker motifs that contact the bound ATP in NBD crystals (Fig. 2a) confirm that, as expected, the ATP acts at CFTR's NBDs. The fact that neutralization of the Walker A Lys at either the NBD1 or the NBD2 composite site severely impairs channel opening at low ATP concentrations (Fig. 3, but compare it with ref. 65) implies that ATP binding at either site can be made rate limiting. This suggests that ATP normally occupies both sites before a channel opens64,66 (but compare with ref. 67).
Photolabelling of CFTR with 8-azido nucleotide, followed by separation of NBD1- and NBD2-containing fragments, confirmed binding to both NBD1 and NBD2. But only 8-azido nucleotide at NBD1 could survive washes at 0 °C before crosslinking the nucleotide with UV irradiation57,58,68. NBD1 was photolabelled to a similar extent with 8-azido-[α-32P]-ATP or 8-azido-[γ-32P]ATP57,58, even after prolonged washes at 30° C before UV irradiation58, whereas, even without washing, NBD2 could never be photolabelled with 8-azido-[γ32P]ATP57. This all suggests that hydrolysis of 8-azido-ATP is rapid at the NBD2 composite catalytic site57 but negligibly slow at the NBD1 composite site, even at 30 °C58. As loss of 8-azido-ATP from NBD1 at 30 °C before photolabel-ling takes minutes, but opening and closing of CFTR channels in ATP takes seconds (Fig. 1a; also in 8-azido-ATP58), nucleotide-dependent gating would seem to be controlled predominantly by events at the NBD2 composite catalytic site58.
But how are nucleotide comings and goings at the NBD2 composite site linked to channel opening and closing? The principal consequence of mutations at the key catalytic NBD2 Walker A Lys and Walker B Asp and Glu residues (K1250, D1370 and E1371 in Fig. 2d), at saturating concentrations of ATP, is a marked increase in the time for which channels remain open (Fig. 4b). This is most easily seen from the markedly delayed step-like closure of individual mutant channels after sudden withdrawal of ATP (Fig. 4b) compared with the rapid closure of wild-type CFTR channels (Figs 1a, ,4a).4a). As biochemical measurements confirm that homologous mutations abrogate ATP hydrolysis in other ABC proteins (reviewed in refs 69, 70), and mutation K1250A has been shown to abolish ATPase activity of CFTR71, the implication is that hydrolysis of the ATP bound at the NBD2 composite catalytic site occurs before normal rapid channel closure64,72,73. The idea that ATP hydrolysis sets the timing of normal CFTR-channel closure is further supported by the strong dependence of channel closing rate on Mg2+ concentration74 and on temperature (activation enthalpy, ~70 kJ mol−1)45,75. It is also supported by the finding that closure is markedly delayed in the presence of ATP plus the poorly hydrolysable analogue AMP-PNP63,76 or of ATP plus the inorganic phosphate analogue orthovanadate58,76,77, which forms a stable complex with the hydrolysis product ADP after dissociation of the γ-phosphate (for example, see ref. 78).
So if hydrolysis of the NBD2-site ATP controls the timing of channel closing, what normally triggers its opening? The slow step that limits the speed of channel opening at saturating nucleotide concentration is sensitive to the structure around the γ-phosphate and, for AMP-PNP, AMP-PCP or ATP-γS, that step occurs at ~4% of the maximal rate seen with ATP64. The step is also dependent on Mg2+ and, at saturating ATP concentrations, in the absence of Mg2+ ions, occurs at only <2% of the maximal rate seen in their presence74. The slow opening step is also highly temperature sensitive (activation enthalpy ≥100 kJ mol−1)75,79. These characteristics suggested that the process that usually opens CFTR channels is likely to be formation of an ATP-driven tight NBD1–NBD2 heterodimeric interaction80 (Figs 1b and and2d),2d), which is analogous to the homodimeric interaction (Figs 2a, c, 5a) found in biochemical and structural studies of bacterial NBDs21–24,29,69,70,81.
One clue that the CFTR-channel open state corresponds to the heterodimerized NBD1–NBD2 conformation comes from the ~1,000-fold stabilization of the open state (Fig. 4b) caused by the mutation E1371Q of the Walker B Glu (the possible catalytic base29,81). The homologous Gluto-Gln mutation in bacterial NBDs was required to produce the highly stable ATP-bound homodimers needed for crystallization25,29. Even with that hydrolysis-impairing mutation, stable dimers were not obtained with ADP29, which is consistent with a cycle of ATP-induced NBD dimerization and hydrolysis-induced dimer disruption24. Opening of a CFTR channel can then be viewed as being triggered by a pincer-like drawing together of ATP-bound NBD1 and ATP-bound NBD2, as inferred from the relative positions of dimerized bacterial NBDs in the presence and absence of ATP26,69 (Fig. 5a, b). Channel closing would follow hydrolysis of the ATP at the NBD2 composite site, loss of the liberated phosphate and subsequent disruption of the heterodimeric NBD1–NBD2 interaction, as illustrated in Fig. 1b.
Direct evidence for a head-to-tail NBD1–NBD2 interaction in functioning CFTR channels comes from two sources. First, target cysteines introduced in pairs, one in NBD1 and the other in NBD2, can be crosslinked by short bifunctional thiol-specific reagents only when, for example, one cysteine is in a Walker motif and the other is in a signature sequence, and not when both are in Walker motifs or both are in signature sequences82. Second, measurements of the energetics of channel gating revealed that a residue near the NBD1 signature sequence and another in the NBD2 Walker A motif make an energetically favourable interaction when the channels are open, or in the transition state (Fig. 1b) between closed and open states. But these residues do not interact when the channels are closed, either before or after (states C1 and C2, Fig. 1b) binding the second ATP, which is thought to trigger channel opening80. The sign and magnitude of that coupling energy are consistent with formation of a hydrogen bond between these interacting residues as the channel opens. The corresponding two residues (labelled 'R555 equivalent' and 'T1246 equivalent' in Fig. 5b) in bacterial NBD homodimers are indeed linked by a hydrogen bond in the ATP-bound, tightly dimerized conformation25–27 (Fig. 5a) but not in the nucleotide-free, 'open dimer' conformation26 (Fig. 5b). This strongly supports a cyclic, dynamic restructuring of the NBD1–NBD2 heterodimeric interface during the CFTR-channel gating cycle.
A bonus of the large complement of ABC-protein genes in prokaryotic genomes is that over 20,000 NBD sequences are available (http://www.sanger.ac.uk/cgi-bin/Pfam/getacc?PF00005). Statistical analysis83 of these sequences suggests that the two residues that hydrogen bond across the ATP-bound NBD dimer interface (that is, the 'R555 equivalent' and 'T1246 equivalent' residues) were subject to evolutionary pressure as a pair, rather than individually. They seem to have co-evolved to retain the ability to form a hydrogen bond that precisely spaces their a-carbon atoms in the dimer (as in Fig. 5a). Analysis of the distributions of potential hydrogen-bond donor (R555 equivalent) and acceptor (T1246 equivalent) side chains shows that the two positions have changed in concert so that a shorter acceptor is more frequently paired with a longer donor and vice versa80. The broad conservation of NBD-sequence motifs throughout prokaryotic and eukaryotic ABC proteins, and specific conservation of the structural underpinnings of the hydrogen bond found to undergo dynamic changes during the gating cycle of CFTR channels, implies that such NBD dimerization is crucial to the function of most ABC proteins.
Although progress is being made, much remains to be learned about CFTR, including the structures and locations of the anion pore in the transmembrane domain, of its gate and of the R domain. It would also be good to know how graded R-domain phosphorylation controls communication between the NBDs and the gate. The transduction pathway by which conformational rearrangements at the NBDs are transmitted through the protein to the transmembrane domains is not known for any ABC protein. This question could be addressed by further examination of the extensive evolutionary record for ABC proteins. Statistical analysis of sequence alignments may reveal sets of positions at which amino-acid distributions are correlated. Thermodynamic mutant-cycle analysis in CFTR80 could then be used to test whether statistical coupling reflects conservation of a network of energetically coupled residues that mediates transmission of allosteric signals. It may be possible to follow how energetic coupling between side-chain pairs changes, both as a function of their location in the protein and as a function of time during CFTR's channel-gating cycle.
Sequence analysis suggests that CFTR's asymmetric catalytic interface, with one active and one dead composite site, may be characteristic of all ABC-C subfamily members (CFTR, MRPs and SURs) but not of ABC proteins in general. The structural and mechanistic detail relevant to ABC-C proteins that can be gleaned from studies of symmetric, homodimeric ABC proteins is therefore limited. Determination of the structure of any comparably asymmetric ABC protein would greatly advance our understanding of how the ABC-C proteins CFTR, MRP and SUR work.
Much also remains to be learned about the physiological roles and functions of CFTR — for example, the identities of other proteins with which CFTR interacts (reviewed in refs 7, 8), whether CFTR functions as an ATP-driven transporter84 and whether, and under what conditions, CFTR behaves like an adenylate kinase85,86.
Present treatment of cystic fibrosis is essentially symptomatic, and although average life expectancy for CF patients is now just over 30 years, there is as yet no cure. Development of procedures for delivery of wild-type CFTR-encoding DNA using viral and non-viral (such as liposome or nanoparticle) agents or of functional CFTR protein (by means of liposomes) to affected cells continues apace11. Because of the many hurdles to be overcome, parallel efforts to harness high-throughput methods to find small molecules that would allow maturation of ΔF508 CFTR or enhance activity of other mutant CFTR channels are important. Because of the continuous turnover of epithelia, repetition of all these treatments will be required. On the other side of the coin, small molecule inhibitors87 will be used in the near future against CFTR channels in the intestinal tract to combat excessive fluid loss, not least in travellers' diarrhoea.
This review and our research on CFTR were supported by grants from the NIH and Fogarty International Center (to D.C.G). We dedicate this review to our late colleague Benjamin Angel, MA, MB BS (3rd December 1978 to 2nd October 2005), whose courage and grace in the face of CF continue to inspire us.
Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Herschel Supply Co. NovelSKU: #7995669
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- Anonymous - customer
- February 11, 2014
I travel for work a ton, and have flown with this bag countless times. It's been tossed around, and been all over the country with me and the bag is still in great condition. Size is great, easy for a carry on, and easy to bring with you for any occasion. I recommend this duffel if you're looking for something functional and stylish.
Runs Small
Runs Large
Felt true to size
- Trevor - customer
- from Austin, Tx
- November 21, 2016


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MANDY Moore sees herself as a 60-year-old woman rather than a 32-year-old.
GIGI Hadid is working hard to try and "take the pressure off" herself this year and accept herself for who she is.
There's something so down-to-earth and genuine about the man that comes through on the screen.
HOLLYWOOD heavyweights helm serious reboot of beloved action franchise.
At 67 a veteran is still committed to music and social justice


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The Hamilton Bulldogs defeated the Toronto Marlies 3-1 on Sunday (Nov.21) at Ricoh Coliseum. Gabriel Dumont scored the game-winning goal in the third period while Curtis Sanford stopped 28 of 29 shots to earn the American Hockey League victory.
Hamilton sits in first place in the Western Conference's North Division.
After a scoreless first period, Hamilton opened the scoring 31 seconds into the second stanza. Neil Petruic dished the puck to Max Pacioretty, who carried it into the Marlies' zone before firing a shot over the glove of goaltender Jussi Rynnas.
The Marlies tied the game at 10:50 of the final frame. Danny Richmond received the puck from Marcel Mueller before sending the puck to Brayden Irwin, who was positioned at the right side of the net. Irwin wired a shot that beat Sanford over the shoulder.
The 'Dogs regained their lead at 18:52 of the period. Ben Maxwell streaked down the left side boards before firing a shot on goal that bounced off Rynnas' glove. Dumont scooped up the loose puck before burying it past the goaltender and into the net. J.T. Wyman provided an empty net goal at 19:39 to seal the win for Hamilton.
Hamilton was outshot, 29-24 before 5,624 fans.
Hamilton continues its six-game road trip with a game in Glens Falls, N.Y., to battle the Adirondack Phantoms Wednesday, Nov. 24 at 7 p.m. All regular season Hamilton Bulldogs broadcasts on AM 820 CHAM will begin with a pre-game show 30 minutes prior to the scheduled start time. All pre-game shows during 'Dogs home games will be broadcast live from the main concourse at Copps Coliseum.


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On-the-go summer snack ideas
Accredited Practising Dietitan Simone Austin shares her top healthy food choices that are easy to prep and eat on summer travels.
• A handful (30 g) of nuts.
• A bread roll with a banana thrown in.
• Rice cakes or corn thins with a nut spread or avocado and tomato.
• Air popped popcorn, with a sprinkle of chilli flakes or cinnamon.
• Canned fish with dry biscuits and, if you have room for fresh ingredients, some rocket/salad.
• Thermos flask with soup (yes, even in hot weather this can be nice!).
• Fresh or canned fruit (remember a spoon!)
• Kangaroo sausages or lean burgers for the lunch stop to put on the barbeque in a park.
• Fruit bun or fruit scone – pick up one from a local bakery.
• Punnet of cherry tomatoes, strawberries, blueberries to snack on the way.
• Breakfast cereal and long life milk for the early morning breakfast stop or for in your hotel.
Remember to think about food hygiene issues if food is going to be unrefrigerated for long periods, or pack with a frozen ice block in a cooler bag. Keeping up your water intake and including fresh fruits, vegetables and wholegrain cereals for dietary fibre can be important while travelling. Making room for your favourite breakfast cereal in the suitcase can be a good option, even for a high fibre snack!
|Interesting Informative Useful
|Food Lifestyle Travel Summer


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Regions Bank Teller - Part Time (20 hour) - Birmingham Main Branch in Birmingham, Alabama
As a Regions Bank Teller, you will be the initial contact to our valued customers. You will greet our branch visitors with a welcoming smile and perform all the duties of other paying / receiving Tellers, including providing information regarding customers accounts and bank service recommendations. It is essential that you enjoy working with the public.
Primary Responsibilities
While running an inside or drive-through teller window, provide paying and receiving transaction services to customers with accuracy, professionalism and a high level of service
Answer basic customer inquiries regarding products while complying with disclosure requirements, regulations and consumer privacy policies
Identify customer's potential product and services needs and support delivery of appropriate bank services by referring clients to the platform team for further consultation
Balance cash items, teller over/short report, traveler's checks, savings bonds, etc and adhere to all branch procedural controls
Answer incoming telephone calls in a friendly and professional manner
This position is incentive eligible. Required Qualifications
- High school diploma or GED
Skills and Competencies
Basic computer skills
Excellent communication skills
Stellar customer service skills
Ability to work with money transactions with high degree of accuracy
Preferences Regions is looking for candidates committed to helping customers reach their financial goals by understanding and meeting customer needs.
Previous sales and/or cash handling experience
*20 hours per week based on branch needs.
*This position is included in the Saturday rotation.
This position is eligible for paid time off benefits, but not medical benefits. You will be expected to report to work each week for the days and times of the schedule listed above. We do not make scheduling accommodations.
Job Branch/Consumer Banking
Title: Teller - Part Time (20 hour) - Birmingham Main Branch
Location: Alabama-Birmingham
Requisition ID: 1615279


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Our attorneys are known for their excellence in achieving solutions for clients. Focused efforts to cultivate highly skilled practice groups have paved the way for growth in our clientele even in a challenging regional climate.
The firm is built upon a long history of capable and ethical service by its attorneys who, jointly, have over 30 years of experience partnering with our clients to face and solve challenging legal issues.
We partner with each client, ranging from the individual to large multi-national corporations, to successfully navigate legal issues surrounding:
- Business acquisitions
- Conflict negotiation and mediation
- Contract negotiations
- Day to day company operations
- Employment and personnel law
- Estate and Tax Planning
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- Large school districts
- Probate and Estate Administration
- Public utilities
- Real estate transactions and development
- Technological development
- Workers' compensation
Clients who work with Gregory, Doyle, Calhoun & Rogers, LLC benefit from our proactive legal counsel and guiding principals:
- Our clients' best interest always come first.
- We seek to invest in our clients by building intimate, meaningful relationships over the long term.
- We leverage our collective experience and intellectual property for the benefit of our clients.
We are a firm large and experienced enough to take on and resolve our clients' most challenging business issues, yet small enough to deliver on our commitment to value, loyalty, integrity and collaboration that define our relationships.


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Spark Toys doing War Within Megatron!
Forum Moderator at Allspark.com
Tony has been with the allspark since 2001 and a forum moderator since 2011.He's been a fan of Transformer since the mid 80's and is an obsessive troop builder.
Latest posts by Tony (see all)
- New Gallery of Titans Return Sixshot! - November 21, 2016
- New Box Art Image of Takara Tomy Baldigus - November 16, 2016
- Takara Tomy MP-36 Masterpiece Megatron Up For Preorder! - November 9, 2016
Luna Toy Store took to their Facebook page to sneak us a picture of an upcoming release from Spark Toys. They are calling it ST-02, but no other name associated with it; however, we all know it to be War Within Megatron! This is on the heals of the company revealing their version of War Within Optimus Prime. Join in […]Continue reading »


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Vila Ruffle Detail Swing Cami Top
Regrettably this item is unavailable to order.
Our love affair with Vila is never ending and we are head over heels for this ruffle detail swing top. Featuring a subtle V neck shape and crochet detailing across the front, this top is the ideal piece to release your inner fashionista!
Washing instructions: 30 degree wash.
100% Viscose


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Harbor inn Santa Cruz: "Nice "Good Old Times" inn in nice neighborhood" Santa Cruz Hotel Tip by flyer31
Santa Cruz Hotels: 31 reviews and 38 photos
Harbor inn Santa Cruz is a very nice inn with very individually stuffed rooms (antique furniture, but all very clean and in good shape, wonderful sleep in a good bed), 3-4 blocks from the beach in the calmer south part of Santa Cruz. The environment is nice, very calm at night - I heard some animals crying from far during the night - maybe seals? Very nice place to hang off from the busy city of San Francisco/ San Jose.
Unique Qualities: Great place + great "good-old-time" stuffed rooms, but including such things as microwave, fridge.
Address: 645 Seventh Ave., Santa Cruz, California 95062
Price Comparison: less expensive than average
Directions: about 4 blocks from the beach, calm and nice neighborhood
Phone: 831-479-9731
Price: US$40-80
Theme: Inn
Website: http://www.harborinnsantacruz.com/
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Gender: Girl
Meaning: Ocean
Origin: Hawaiian
Moana is a Girl name, meaning of the name is Ocean and origin of the name is Hawaiian. This name is mostly used in
If you select the name Moana for your baby, Congratulations! But if you don't like Moana then please continue searching our site.
External References
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Desert Snake Cool Racerback and Moody Mirage Power Y
Harbour Blue/Space Stripe Wild Tank
Hmmm, the Moody Mirage print CRB may be worth trying on...not sure i'm digging all this new camo print though...What happened to the coat striped inspires? Do you think US will see those uploaded today? :-DReplyDelete
sorry COAL striped inspires, not *coatDelete


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Performances by the U.S. Air Force Service Band, Lynn Cooper and the Nadas will highlight another full schedule of entertainment at this year's Tulip Time festival.
Keywords: 2010 Tulip Time, 75th Annual Tulip Time, Lynn Cooper, pella, The Nadas, TT 2010, Tulip Time, Tulip Toren, U.S. Air Force Heartland of America Band
Will Lt. Governor Kim Reynolds be a good governor?
View Results
call: (641) 842-3161 | (641) 628-8672


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Just Say "NO"
07 Aug 2008
Posted by: VAR in: Uncategorized
OK, ready? Repeat after me… "NO"
Try it again…"NO"
That's what you should be saying firmly when the bank/lender says or "demands" that you lower your commission on your short-sale listing.
That's also what you should be saying firmly when the listing agent says that the bank "demands" that the commission be lowered and that you, as the buyer's agent, have to "split the difference".
Too many agents are letting banks get the best of them. I've said "no" several times and have never had a problem. There are plenty of other agents that have also said "no" and have not had a problem either.
Can you actually say "no"?
Yes, you can! And you should. If you haven't already, check out Lem Marshall's presentation on short-sales which covers what's required and what's not and what's legal and ethical.
Will the bank kill the deal if you say "no"?
I've yet to hear of a bank not approving a short-sale over 1 percent worth of commission. If someone has, please let me know and I will stand corrected.
So next time the bank tells you that you have to cut your commission to almost nothing, just say "no" and move on to the next subject. You'd be surprised at how well that works…
Tips on Short Sales, New Economic Development, Help on Helping Sellers
23 Apr 2008
Posted by: Andrew Kantor in: Uncategorized
Tips on short sales, getting the VAR publications you need in a click, new economic development in Virginia, and help on helping sellers in Todays market; these are just a few reasons to check out the April edition of Commonwealth Online. Check your mailbox for your customized version or view it online to see it all. Either way, don't miss this chance to tap into the relevant information you need as your business starts to heat up.
View Commonwealth Online
What Realtors REALLY Need To Know About Short-Sales…
18 Apr 2008
Posted by: VAR in: Uncategorized
Lem Marshall, Special Counsel for the Virginia Association of Realtors gave a presentation this morning called "Advanced Short-Sales". It proved to be an excellent presentation that probably should have been called "What Realtors REALLY need to know about short-sales to successfully deal with one".
Some of the things in the presentation that Lem covered were:
- The history of economics and lending in America, how credit markets work and why we're in this mess.
- Prices may not be at the bottom yet. It may take another 12 to 18 months to get there.
- Knowledge is the key. Make sure you get everything out on the table regarding the seller's financial and personal situation. You can not properly help them without knowing all the facts and their overall situation – past, current and future.
- Make sure you get the borrower's permission, in writing, in order to publicize the fact that it's a short-sale. You must have the seller's permission to disclose personal and financial information about them, which is what you're doing by publishing that it's a "short-sale" or stating "subject to third party/lender approval".
- Make sure that you correctly word the "subject to third party approval"/bank contingency. How you word this will directly affect whether you face potential issues in the future or not.
- If the bank says that they want the commission lowered from what you've agreed upon with your client, don't give in so easily. Many Realtors in attendance said that they said "no" to the bank's request and that the bank was okay with it.
- If the bank insists on lowering your commission, try asking them to counter at a higher price that covers both your and the Selling Broker's commission.
- Remind the Selling Agent (Buyer's Agent) that the process of approval by the bank can take 60 to 90 days, if not longer. This will help alleviate an upset agent and buyer down the line.
- Short-sales can be messy. Be prepared to do much more work than a traditional resale or even a foreclosure.
There were many other great points that Lem made that Realtors can use on a daily basis when dealing with short-sales. I recommend watching the video of Lem's presentation once it's up on the Dulles Area Association of Realtors' web site sometime next week. I'll publish a quick post when it's up to alert everyone so you can go check it out.


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W-A+©2011-2015 InfiniteSweeps.com. All rights reserved.Mobile - Desktop
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Far West NSW faces drug 'epidemic'
The illegal use of methamphetamine or 'ice' has penetrated almost every town in Far West NSW according to a mental health expert who warns a lack of resources will contribute to a losing battle against drugs.
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Dr Andrew Howie, a visiting psychiatrist to Broken Hill and Clinical Director of the Western NSW Local Health District, has painted a grim picture claiming; "there will always be a need" for a re-hab facility in the region.
"(As well as Broken Hill) I don't think there is any town that has been exempt from 'ice' use," Dr Howie told Andrew Schmidt, host of ABC999 Broken Hill's Morning Program Outback Outlook.
"Wilcannia, Menindee, Tibooburra, White Cliffs, Ivanhoe, Dareton ... those are the ones I am specifically aware of.
"It is a wide spread problem in the Far West."
Dr Howie's concerns have been echoed by a recovering drug addict who claims the problem is already an "epidemic" that authorities may never regain control of.
"Something has to be done about it and every day that we miss out on helping someone is a day that we have lost to save a life," the man, who wished to remain anonymous, said.
"It's an epidemic that has hit and they're never going to get rid of it unless the government steps up to the plate.
"We've had six deaths in Mildura in the last three months and two at Lake Cargelligo where they were hanging and stabbing themselves," the man continued.
During an interview for Outback Outlook the man revealed he had been "clean" for three months and was keen to use his own experience to deter others.
"We're losing too many kids and if I can be any help with all the background I have with 30 years of being an addict - but now being sober (clean from drugs) - I'm quite happy to put my 110 per cent in to get these kids on track," the man explained.
"I know kids who are 11 and 12 who are on it (ice) ... it's all over Australia."
Dr Howie - who was prompted to speak with ABH Broken Hill after hearing the heart-wrenching story from the mother of a 15-year-old Broken Hill boy suspected of being addicted to ice - reported that the drug presented many challenges for authorities.
"It can induce psychosis - where the person loses touch with reality and may believe things that aren't true - it can make them angry and violent ... the impact is horrible," Dr Howie revealed.
"It's very difficult to make a firm diagnosis of a person having amphetamine in their system.
"A person's urine test - which is the best test - can be clear (of the drug) within 24 to 72 hours," Dr Howie added.
Latest videos
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- Vic guards call for crackdown after youth detention riot
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- Hamilton Stock Agents Association president Craig Pertzel says the Government's consultation with industry about electronic sheep tags was "a bloody j
- Victorian Agriculture Minister Jaala Pulford says ongoing protests against mandatory electronic sheep tags is futile.
- ALPAA chief executive Andy Madigan says there is no evidence to suggest electronic tags would improve biosecurity in Victoria.


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Hundreds of energy experts sent a letter to Donald Trump, urging him to admit that climate change is real.
William Rivers Pitt of Truthout: Imagining Donald Trump with the power to impose martial law makes me want to burn a flag.
Robert Naiman is policy director at Just Foreign Policy and president of Truthout's board of directors.


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Experienced Shipping Receiving 1st Shift
at Nesco Resource
Jeffersonville, IN
Posted on Oct. 14, 2016
Sorry, this job has expired.
See similar jobs below or start a new search.
Registered Nurses - RNs DupontThe Brook Hospitals Dupont – Louisville, KY – Full Time
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PickingNesco Resource – Jeffersonville, IN – Full Time
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Fulfillment ClerkNesco Resource – Jeffersonville, IN – Full Time
Full Time
EXPERIENCED SHIPPING/RECEIVING/1ST SHIFT - Wages range from $10.00/hour to $15.00/hour - Jeffersonville, IN
Nesco Resource is currently recruiting for additional OPENINGS in Louisville and Shepherdsville, KY
Bring 2 forms of ID with you.
Drug and Criminal Background Checks Required
Nesco Looks Forward To Starting You On Your Career Path!
For contact and location information go to the 'Quick Apply' button located at the Top Right.


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What's On TV Tonight? – 'The Biggest Loser' Finale, 'The X Files' Finale on Monday
A winner is crowned LIVE on The Biggest Loser finale! But what else is on TV tonight? Here are the TV listings for Monday 02/22/2016:
The Bachelor – Ben faces friction from the families of the remaining women when he travels with the girls to visit their hometowns. (ABC)
Supergirl ("Truth, Justice and the American Way") – Supergirl battles with Master Jailer (Jeff Branson), who is tracking and killing escaped Fort Rozz prisoners; Cat hires an additional assistant (Italia Ricci), who tries to one-up Kara; James and Kara don't agree on the DEO's methods. (CBS)
The Fosters ("Minor Offenses") – Stef and Lena become concerned when Callie wants to film an endorsement for a new foster care reform bill; Nick asks Jesus for advice on planning the perfect first date with Mariana; Stef recovers from surgery. (Freeform)
WWE Monday Night RAW [LIVE] – Fastlane PPV results. Who is going to WrestleMania: Brock Lesnar, Dean Ambrose or Roman Reigns? (USA Network)
Love & Hip Hop – An all-new episode of the reality TV series. (VH1)
Superstore [SEASON FINALE] ("Labor") – When Amy calls corporate to talk about maternity leave for employees, Ben sends everyone into a frenzy by mentioning unions. (NBC)
The X-Files [SEASON FINALE] ("My Struggle II") – The investigation that Mulder and Scully began with Internet show host Tad O'Malley (Joel McHale) seems to have created powerful enemies; Scully searches for a cure when people all over the country become gravely ill; a figure from the past emerges. (FOX)
Crazy Ex-Girlfriend ("Josh and I Work on a Case!") – Rebecca hopes to redeem herself by working on a case that she thinks will bring her closer to Josh; Darryl struggles with his feelings for White Josh; Greg searches for Rebecca's true motives for taking on the case. (The CW)
Telenovela [SEASON FINALE] ("The Stalker") – When Xavi invites Ana to have coffee, but doesn't show up, Ana worries that he has been abducted; cast members try to impress Isaac as he works on a script for the next year's telenovela. (NBC)
NICK'S PICK: The Biggest Loser [LIVE FINALE] ("Live Finale") – All 16 contestants reunite for one last weigh-in; eliminated contestants compete for the $100,000 "at home" prize; one of the three finalists wins the $250,000 grand prize. (NBC)
Scorpion ("Adaptation") – Team Scorpion must stop an influx of drugs that are being smuggled into the country via drones; an ultimatum is issued. (CBS)
Jane the Virgin ("Chapter Thirty-Four") – Jane asks Xo for advice about her relationship with Jonathan, and throws Petra a baby shower; not everything is as it seems when Luisa is in a terrible car accident; Michael needs to share something with Jane. (The CW)
Lucifer ("Sweet Kicks") – Lucifer wants Chloe to investigate a shooting at a fashion show, which resulted in a young woman's death; Amenadiel targets Dr. Linda Martin. (FOX)
Recovery Road ("My Loose Thread") – Charlotte begins to resent Cynthia's role in Maddie's life; Maddie helps Les break his grandmother out of her nursing home for the afternoon; Trish has a rough start at her new job; Ellie and Nyla have questions about Maddie. (Freeform)
The Magicians ("Impractical Applications") – The first-year students are put through The Trials, a series of unconventional tests that must be passed to stay at Brakebills. (Syfy)
Major Crimes ("Hindsight Part 2") – The team rushes to capitalize on a shocking discovery made in a church; Stephanie and Sanchez's connection grows; Rusty learns that his biological mother's ex is a fugitive; Tao's former partner pushes him too far. (TNT)
Castle ("The Blame Game") – Castle is abducted and forced to solve deranged puzzles and mind games with strangers; Beckett and the 12th precinct race to save Castle. (ABC)
NCIS: Los Angeles ("Matryoshka, Part 2") – While in Russia, Callen, Sam and Anna try to break Anna's father and a CIA agent out of prison; Callen makes a discovery; Eric goes on an assignment with Kensi and Deeks. (CBS)
Better Call Saul ("Cobbler") – Mike brokers a deal in order to keep a potentially messy situation intact; Jimmy tries to exonerate an eccentric client. (AMC)
The Graham Norton Show – Actor Tom Hanks; actor Peter Capaldi; actor David Walliams; Duran Duran performs. (BBC America)
Teen Mom ("Taking Chances; Walk Away") – Farrah and Simon take their relationship to the next level; Taylor's t-shirt business; Cate discovers she has postpartum depression; Amber and Gary work out custody; Farrah refuses to film. (MTV)
Lost Girl ("Judgement Fae") – Bo tracks down an old foe. (Syfy)
Hit the Floor ("Lockout") – Ahsha, Derek, German, Zero, Jude and Pete face the consequences of their actions; Sloane must revisit her past; Jelena and Terrence are blindsided. (VH1)
Bitten ("Our Own Blood") – Elena struggles to deal with a mysterious werewolf claiming to be her father; Clay readies Stonehaven for a possible attack from the Spanish. (Syfy)
The Graham Norton Show – Actor Matthew Perry; actress Gemma Arterton; actress Miriam Margolyes; Jack Savoretti performs. (BBC America)
E! News – Entertainment news. (E!)
The Wendy Williams Show ("Hot Topics") – Hot Topics; Ask Wendy; movie critic Ben Lyons previews the Oscars; the latest news from Hollywood; a viewer plays for a chance to win a trip to Jamaica. (BET)
At Midnight With Chris Hardwick – Paul Rust; Gillian Jacobs; Claudia O'Doherty. (Comedy Central)
The Daily Show With Trevor Noah is joined by Sen. Cory Booker. (11:00 PM, Comedy Central)
Conan welcomes Rob Lowe; Gina Rodriguez; Leonard Ouzts. (11:00 PM, TBS)
The Nightly Show With Larry Wilmore features Journalist Jose Antonio Vargas. (11:30 PM, Comedy Central)
The Tonight Show Starring Jimmy Fallon has Actors Hugh Jackman and Taron Egerton; actress Audra McDonald; Hall & Oates perform. (11:35 PM, NBC)
Late Show With Stephen Colbert is joined by Actor Casey Affleck; actor Richard Dreyfuss; interview and performance with Mavis Staples. (11:35 PM, CBS)
Jimmy Kimmel Live features Actor Aaron Paul; actress Rachel Bloom; Mashup Monday: KCee-Lo & The Sunshine Band (Cee-Lo and KC and the Sunshine Band). (11:35 PM, ABC)
Late Night With Seth Meyers welcomes Actor Anthony Mackie; actress Renée Elise Goldsberry; comic Neal Brennan. (12:35 AM, NBC)
The Late Late Show With James Corden has Television personality Dr. Phil; actor Shad Moss; actress Cristin Milioti; AWOLNATION performs. (12:35 AM, CBS)
Last Call With Carson Daly is joined by Actors Jay & Mark Duplass; Wolf Alice performs; actress Anya Taylor-joy; director Robert Eggers. (1:35 AM, NBC)
What, if anything, do you plan on watching on TV tonight? Sound off in the comments!
And for more TV updates, follow me on Twitter: @NickRomanTV