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03 November, 2011
Tygana 11/2/2011
As many of you know, Tygana was diagnosed with CRF, high blood pressure and a heart murmur roughly 8 months ago. He began taking meds for his high blood pressure, calcitriol and receiving subcutaneous fluids for his CRF. He started out doing quite well and even gained a bit of weight as we began to gain control over his condition.
Tygana was receiving 75ml of lactated ringers every other day, a calcitriol pill and high blood pressure pill daily. In his bloodwork his numbers never got back to normal but we got close, which was good enough for us.
About 4 months later Tygana lost his appetite for his prescription food. He was an interesting eater because unlike most cats he would get tired of eating the same thing after so many months, to let you know he would not eat, but if you presented him with something new he would devour it. So I switched his wet food back to his old food but he continued to have prescription dry food, he never get tired of that cause he did not eat it often.
Over the next 4 months we would be switching his food often as he became quite the picky eater. 3 months later he began to lose weight again, I tried upping his intake to get him to gain but he just did not have that strong of an appetite.
Still fairly active and playing around with his brother I did not think way too much of it, just that he was incapable of eating too much cause it makes him uncomfortable or something.
This past week is where things got weird. It all happened so fast, he got even thinner, began to eat less, started taking naps in the bathtub, got less active. We scheduled him a vet appointment to get him checked up. The days before his appointment he completely stopped eating, barely drank and chose a room that he would not leave except to go sit in the bathtub or on the toilet. He stopped cleaning himself, had an awful smell. I wiped him with a damp cloth but the smell was coming from his mouth I looked inside and his teeth were fine, gums looked all right, his balance was starting to get thrown off.
I was terrified to take him to the vet, for fear they might say what I was thinking in the back of my head. What I really wanted was some kind of new suggestion, pill, suspension or injection that might bring my little guy back.
The vet looked him over...he was very dehydrated, his body couldn't hold on to any fluids including his lactated ringers it all went straight through him, his kidneys were done. The smell was toxins in his body his kidneys were no longer processing, they were coming out through his mouth. He didn't fight anything the vet did, he didn't have the energy his muscles had begun to atrophy as his body was eating his muscles to sustain his day to day life.
Of course I did not get the hopeful answers I was looking for, the vet suggested it was his time and gave me time alone with him to think it over and call someone if I needed to. I called his previous owner and let her come to say goodbye, she was holding him saying goodbye and in his last physical act jumped from her arms to my lap. I gave him some last cuddles before our final moments together. The decision was made to help Tygana to the rainbow bridge, I stayed with him petting his head and whispering in his ear. I stayed with him for a while afterwards and finally was able to pull myself away.
Pepper finally this morning realized that tygana is not around, he looked for him a bit but has relaxed. He will probably be off and on like this for a bit. Waking up this morning was terribly hard because tygana is usually right there waking me up, clawing me in the face to be exact. It's hard to look around and see all the stuff I got for him, the pictures of him on the wall.
I miss him terribly.
I know many of you miss him as well and I'm sorry we have not been around. Feel free to leave any messages for tygana here.
26 comments:
- Jan's Funny Farm said...
We were so very sorry to read about Tygana yesterday. Thank you for sharing the details. We send you a big hug, purrs and woofs.
- November 3, 2011 at 2:33 PM
- Fuzzy Tales said...
You absolutely did the kindest and most merciful thing, gave him a last and best gift--he's now free of suffering.
Sending you soft purrs and universal Light, wishing you peace in your heart.
-Mom Kim and the boys
- November 3, 2011 at 2:47 PM
- The Island Cats said...
We are so sad to hear about Tygana. We will miss him too. We send you purrs and headbutts to help comfort you during this sad time.
Wally, Ernie & Zoey
Having had a cat with CRF, I know exactly what you went through with Tygana...trying to get him to eat, the meds, etc. Hugs to you...I know the decision to set him free was not an easy one.
Island Cats' mom Sue
- November 3, 2011 at 5:16 PM
- d'Artagnan Rumblepurr said...
Oh no no no... poor sweet Tygana, I was so heartbroken to see he'd passed.
It was around this time last year that we went through the same thing with Inigo. I know they're together at the bridge, watching over us.
You're in my thoughts.
- November 3, 2011 at 5:37 PM
- Laura and Jet Dragon said...
So sorry for the loss of your beloved Tygana. I saw the notice on the CB, and came over to offer comforting hugs and purrs. The two cats I lost last year both had CRF (though they both died of something else). It is a terrrible disease. You made the choice out of love for him, and he knew he was loved. Hugs and purrs to you at this sad time.
Laura, Taffy, and (angels) Jet & Venus
- November 3, 2011 at 5:40 PM
- Old Kitty said...
Me and my cat Charlie came over from the CB. We are so sorry to hear that sweet handsome Tygana has run off to the rainbow bridge. He was surrounded by love right to the end. We are sending you all lots of purrs and hugs. Take care
- November 3, 2011 at 6:23 PM
- Ikaika said...
Oh dear, we are so sorry to hear that Tygana has made his way across the Bridge. You absolutely did the best thing for him but relieving his suffering. We send comforting thoughts and gentle purrs to you and Pepper.
Run free at the Bridge, handsome Tygana ...
- November 3, 2011 at 6:43 PM
- ABBY said...
We are so sorry to hear of your loss. We know that you are missing your baby. You gave him the most compassionate gift you could possible give. WE send you soft purrs and furry hugs.
- November 3, 2011 at 8:09 PM
- meowmeowmans said...
Oh no. We are so sorry to hear that Tygana had to run off to the Bridge. Thank you for loving him so much, and for making the courageous and compassionate decision you did.
We are purring and praying for you.
Your friends at Animal Shelter Volunteer Life
- November 3, 2011 at 10:02 PM
- The Lee County Clowder said...
We are so sorry to hear about Tygana. We never knew him, but it is clear he was much loved.
Sending comforting purrrrrrrss and gentle headbutttss to you all.
- November 3, 2011 at 11:33 PM
- Cory said...
We ran over here as soon as we heard the news of Tygana's crossing over The Bridge. He was a good cat and a good furriend. Sending you hugs and purrs.
Cory and family
pee ess, our Roger Ramjet ::bows head in honor:: has CRF and we know how hard it is.
- November 3, 2011 at 11:42 PM
- Karen Jo said...
I am so sorry that you had to help Tygana to the Rainbow Bridge. That was the best gift you could give him. We will all miss him, too.
- November 3, 2011 at 11:43 PM
- Fin said...
We are so sorry to hear of Tygana's passing. My purrs and Mom's hugs to ease your sadness.
Fin & Meg
- November 4, 2011 at 12:04 AM
- Samantha, Clementine and Maverick said...
Lots of purrrs and prayers for you!! We shall miss Tygana!! Till we meet again!!
Your TX furiends,
- November 4, 2011 at 1:21 AM
- Chesney Cats said...
We're so very sorry to hear that Tygana had to be helped to the Bridge. Sending hugs & purrs. You are in our hearts & prayers.
- November 4, 2011 at 2:14 AM
- Jacqueline said...
We are so sorry for your huge loss, but know you did the very best thing you could for your precious Tygana...Love is an energy that never dies and your sweet boy will be with you forever in your heart...Tygana was one of our first friends on the blog and we loved him too; we will never forget him...There are no words to express the courage and sorrow that you are experiencing, but know that we send big hugs and much love to you and your family...Big kisses to sweet Pepper=we know you guys will help each other through this difficult period...Wishing you all peace and comfort...J, Calle, Halle, Sukki
PS...I gave my Nikki sub q fluids for almost 2 years and understand the devotion you feel for Tygana= he knew how much you loved him...Always remembered, never forgotten, forever cherished...J
- November 4, 2011 at 7:06 AM
- 3 kats and a kwiltr said...
We just wanted to stop by and offer our snuggles and purrs on your loss. Often, it happens just this quickly and you gave him the freedom to run and play at the Bridge and not continue to suffer.
We will send purrs for his safe arrival and look forward to the day when we all meet at the Rainbow Bridge.
Taz, Runt and Charles in IL
- November 4, 2011 at 2:04 PM
- Grrreta said...
We are so very sorry to hear the sad news about sweet Tygana. We send you comforting purrs.
- November 4, 2011 at 9:16 PM
- Kimo and Sabi said...
We wish you a peaceful 2012.
- January 2, 2012 at 1:16 AM
- Jan's Funny Farm said...
Stopped by to say we're thinking of you.
- January 3, 2012 at 8:00 PM
- A few Good Cats said...
We saw a comment you left for us awhile ago and thought of you. We hope your grief is easing a little more every day. (Even though it never will completely go away. We feel the same way about Mr. Kelly.)
- January 29, 2012 at 6:32 PM
- meowmeowmans said...
We just stopped by to say hello, and wish you a happy birthday. We hope things are okay with you.
- March 4, 2012 at 10:37 AM
- KC and The Sherwood Bunch said...
We miss Tygana very much.
Stopped by to wish you a Happy Birthday.
Love & Purrs,
- March 26, 2012 at 6:57 AM
- Karen Jo said...
We all still miss Tygana. I just stopped by to wish you a happy birthday.
- March 26, 2012 at 8:01 PM
Miss you, Tygs...
- June 28, 2012 at 7:56 PM
- ra husky said...
We found your bloggie today and wanted to stop and paw our sympathy and offer soft husky woooos,
- September 4, 2013 at 3:54 PM


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Under an awning outside City Hall in Cambridge, Mass., as a street sweeper roared around midnight, Marcia Hams and Susan Shepherd wondered if someone would try to shoot them.
That night a decade ago, they were the first and only people in line to become the first same-sex couple to receive a marriage license in the United States. With no police around just yet, they worried about a protester targeting them.
Hams, now 66, and Shepherd, 62, ended up waiting without incident a total of 24 hours before they did indeed become the first of hundreds of couples to get their marriage licenses on May 17, 2004, in the first state to have legalized same-sex marriage.
"This is about so much more than us," Shepherd told the Los Angeles Times that day. "But it's about us, too."
In the decade since, court rulings and new laws have legalized same-sex marriages in more than 20 states. But as court appeals continue, parts of only 17 states and the District of Columbia were issuing same-sex marriage licenses, as of Saturday. Oregon could join the list as soon as Monday when a federal judge is expected to rule on the constitutionality of the state's ban on gay marriage.
Hams and Shepherd, who met 37 years ago as General Electric Co. machinists, recalled their experience from a decade ago during a radio show this week.
"It was so moving to actually have the whole community recognize our relationship," Hams told WBUR. "We could talk naturally about our relationship as heterosexual couples do and really have that mean something. It's constantly reinforced every time you say 'my wife Susan and I.'"
They received their marriage license after swearing on oath before a clerk.
Then they walked into a crowd of more than 1,000 supporters who celebrated with apple cider provided by the city and cake from a local bakery. City Hall's banisters had been decorated with bridal bunting, and a chorus was on hand for the festivities.
"I'm shaking so much," Hams said that early morning. "I'm really ready to faint."
The couple married the next weekend, before their regular church service, but didn't hold a large celebration until September.
They said they rushed to have a small ceremony because of fear that lawmakers would try to find a way to supersede the Massachusetts Supreme Court ruling that struck down a ban on gay marriage. Lawmakers, and others, did indeed try. And those efforts later failed.
Shepherd told WBUR that being able to marry had a "profound" effect on their now 34-year-old son, Peter.
"Peter came to us: … 'Are you going to adopt me now?'" Shepherd said. "Getting me on his birth certificate … now, he had a real family he could go to the world with. You forget how much the kids feel the brunt of this in the public. This was extremely liberating for all of our children."
The couple said local organizations recruited them to be the first in line because their family embodied professionalism and poise, and it was hoped they would refute the argument of critics that gay parents would have a deleterious effect on the upbringing of children.
"That's been important to the trajectory of gay marriage," Hams said. "Nothing was more persuasive than seeing us be married, and seeing nothing bad happen, only good things."
The couple said they were looking forward to their 10th wedding anniversary, though it was unclear if it would be as raucous as the original event.
"We couldn't stop people from coming," Shepherd said of their wedding.

subset: commoncrawl


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LEXINGTON, Va. — In what was billed as a major foreign policy address, Mitt Romney blasted President Obama's leadership in the Middle East on Monday, saying that a withering of American resolve had made the region a more dangerous place where the United States has less leverage.
"Hope is not a strategy,'' Romney said.
Romney sought to capitalize on the violence in Libya and Egypt that has made Obama vulnerable in the national security realm long seen as his strength. The Republican nominee vowed to "change course in the Middle East," including by taking a hard line on Iran and arming Syrian rebels.
Romney said he knows "the president hopes for a safer, freer, and a more prosperous Middle East allied with the United States. I share this hope."
But he added: "We cannot support our friends and defeat our enemies in the Middle East when our words are not backed up by deeds."
The address mostly repackaged things Romney has said before, sometimes with greater precision. The Republican offered few specific ways he would change the Obama administration's current approach.
Although he made broad critiques of Obama's "passivity," Romney did not call for any new armed intervention in any Mideast conflict.
"I believe that if America does not lead, others will," Romney said, "others who do not share our interests and our values."
Romney did say Obama failed reformist protesters in Iran in 2009, and is failing the anti-Assad forces in Syria now. The United States is "sitting on the sidelines," instead of working with other nations to arm Syrian rebels, Romney said.
Much of Romney's address focused on the complex threat posed by Iran, but he did not propose specific solutions that differ from the Obama administration's current policy of tightening sanctions and insisting that an Iranian nuclear bomb is intolerable.
Romney did not say whether he would continue the current international diplomatic effort to persuade Iran to back off the most worrisome elements of its nuclear program. Iran claims the program is aimed only at peaceful nuclear energy and medical uses.
Romney, speaking in confident and crisp tones before an audience of more than 400 cadets and invited guests at Virginia Military Institute, said it is Obama's "responsibility to use America's great power to shape history—not to lead from behind, leaving our destiny at the mercy of events."
Romney did not call for a new "red line" on Iran as Israel has said it wants, and he did not specifically say he would be open, in the future, to a U.S. attack on Iran to stop them from acquiring "nuclear capability" so Israel doesn't have to do it now. He did not mention the crippling effect sanctions are having now, and he didn't call for regime change in Iran.
The speech at VMI thrust foreign policy further into the center of a campaign that until recently had been almost entirely about the economy. The focus is expected to intensify as the two candidates debate foreign policy during their last one-on-one encounter, on Oct. 22.
Romney said he would support Israel, the nation presumably most at risk if Iran acquired nuclear weapons, and charged that Obama's poor relationship with Israeli Prime Minister Benjamin Netanyahu has help embolden Iran and other adversaries.
"I will reaffirm our historic ties to Israel and our abiding commitment to its security," Romney said. "The world must never see any daylight between our two nations."
That was a reference to a remark Obama reportedly made to "put some daylight" between the United States and Israel early in his administration. Obama has since pledged many times to support Israel and his administration claims ties between the two nations have never been stronger.
Romney said he would bulk up the U.S. naval presence around Iran, something the Obama administration has done occasionally on an ad hoc basis. He said he would add to the Navy's fleet, but did not say how he would pay for it.
Romney also promised new conditions on foreign aid, including to Egypt.
"I will make it clear to the recipients of our aid that in return for our material support, they must meet the responsibilities of every decent modern government," Romney said.
He said Obama has "no trade agenda to speak of," and has signed no new bilateral trade deals. That is technically true, since the deals he signed with South Korea, Panama and Colombia were begun under Republican President George W. Bush.
Free trade deals are often politically unpopular among key Democratic constituencies such as labor groups. Although Obama had used mild anti-free-trade rhetoric during the 2008 campaign, he has pointed to those three deals and another in the works with Asia as accomplishments.
Romney said Obama had failed to secure a deal to keep some troops in Iraq, and promised that he would manage the coming U.S. exit from Afghanistan with national security, not politics, as his guide.
The Obama campaign quickly criticized the speech as a patchwork of overheated rhetoric and outdated ideas.
"I just find him very shallow," former Secretary of State Madeleine Albright said in a conference call arranged by the Obama campaign. Romney's views on Russia, for example, seem rooted in the last century and infirmed by the most conservative of his circle of foreign policy advisers, Albright said.
"I'm beginning to think that Governor Romney just doesn't have the facts," Albright said.
Speaking to reporters aboard Air Force One campaign spokeswoman Jen Psaki called the address Romney's seventh attempt to reboot his foreign policy vision.
"This is somebody who leads with chest-pounding rhetoric. He's inexperienced. He's been clumsy of his handling of foreign policy," Psaki said.
Romney spoke in a small auditorium at the military school, behind a U.S. flag and several military flags. A group of several hundred white-uniformed cadets filled the seats, mixing with a few dozen invited guests. Patriotic and military music played in the background.
Romney stuck to his prepared text and did not ad lib.
The former CEO and Massachusetts governor, in his comfort zone when focused on the economy, has stumbled during his occasional forays into foreign policy.
It has been the unscripted or hurried moments that have caused Romney, who has little foreign policy experience, the most trouble.
Even many Republicans were critical after Romney slammed Obama's handling of the attacks on U.S. diplomatic missions in Egypt and Libya, even as the events were unfolding. The Sept. 11 assault in Libya killed U.S. Ambassador J. Christopher Stevens and three other Americans.
Romney has mounted a sustained attack on Obama's leadership ever since, as questions have mounted over the administration's shifting explanations of the attack and whether the U.S. post was properly secured.
He offended his British hosts and Palestinian leaders during an overseas trip in July, failed to mention Afghanistan in his acceptance speech at the Republican National Convention, and was roundly criticized for the timing of his assault on Obama's handling of violence in Libya.
With increasing questions about the Obama administration's handling of the violence in Libya that killed four Americans — and with Romney gaining momentum from his widely praised performance in last week's first debate — some experts think the speech is well-timed.
Though Obama has consistently outpolled Romney on foreign affairs, that advantage has diminished. A Washington Post-ABC News poll conducted just before the first debate showed Obama with a five-point edge in who is more trusted to handle international concerns, down from the president's double-digit advantage earlier in the year.
"It's understandable why he's doing it now," said David Rothkopf, a former senior Clinton administration official who is chief executive of Foreign Policy magazine. "The administration, which two to three months ago seemed unassailable on foreign policy and national security issues, now looks much more vulnerable because of what happened in Libya, because the entire Middle East is a mess, because of tensions between Obama and Netanyahu."
In a series of speeches that began during the Republican primary campaign, Romney has proposed a more confrontational approach to China, Russia and other countries, and he accused Obama of failing to contain Iran's nuclear ambitions, offending Israel, and jeopardizing the U.S. military with budget cuts that Republican congressional leaders have supported.
Advised by veterans of the Reagan and both Bush administrations, Romney has also used blunt, sometimes swaggering language on the stump that has at times evoked the Cold War, including his pledge to "devote myself to an American century."
But Romney's description of Russia as America's "number one geopolitical foe" has drawn criticism, and his overseas trip in July, intended to showcase Romney as a world leader and potential commander in chief, was widely seen as plagued by missteps. Romney, in an interview, questioned Britain's readiness for the Olympic Games it was about to host, drawing rebukes from British leaders and a tabloid headline labeling him "Mitt the Twit.''
He then angered Palestinian leaders by suggesting that the Israeli economy has outpaced that of the Palestinian territories in part because of advantages of "culture,'' while also vastly misstating the difference in gross domestic product between Israel and Palestinian areas. Romney advisers argued at the time that the trip had been successful, pointing out the candidate's generally positive reception in Israel and an endorsement from former Polish president and pro-democracy icon Lech Walesa.
The Obama campaign, citing foreign policy achievements including the killing of Osama bin Laden and the U.S. military withdrawal from Iraq, is undeterred. Campaign officials have accused Romney of flip-flopping on the U.S. mission in Libya and troop withdrawals from Afghanistan, and have pointed out that the lack of new policy prescriptions. They also say most people don't vote based on foreign policy, though it may be seen more broadly as part of a leadership test.
The Obama campaign released a television ad Monday that blasted Romney's foreign policy credentials and said his "gaffe-filled" European tour in July showed his "reckless" and "amateurish" approach to international issues.
Gearan reported from Washington. Jon Cohen in Washington contributed to this report.


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Sending you very best wishes. I hope with all my heart you reach your target.
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Fingers crossed, you will make the goal. I wish I could get you closer to it! Thinking positive thoughts.
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Top respect to you for caring so much & doing what you can to help our fluffy little cuties. So much hope you get the funding you need.
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Really hoping that Plan A pulls through and the kitties get to stay with the 'Change One Life' Cat Rescue.
It's not much and I only wish I could give more. Thank you for all the hard work *you* do for our furry friends. God bless
The new Cat Sanctuary looks awesome!!! Please keep up the great work :D
Thank you for what you are doing for the strays, feral, and abandoned cats. I'm sorry it's not a bigger donation.
It seems so many who have less financially give the most to this heart work. THK U all for being Amazing Animal Angels!!! Hugs Peace & Love
Bless you for starting your own Sanctuary. The cats all look VERY happy and your cat rooms are gorgeous!
Keep doing your great work! We need more people like you in the world.
Thank you for looking after the cats. Good luck!
I found your page a couple of days ago and was so moved by your work, it's amazing what you're doing.
I think what you guys do is wonderful! I'm a huge animal lover and I think you guys are absolutely amazing with huge hearts. I wish I could donate tons of money to help you all out!
Thanks for taking the time to send a personal note. I wish the best for you & all the precious ones in your care.


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Pre-Occupational Therapy
Students who are service-oriented, compassionate , interested in health and human body issues, and academically competent can develop into skilled health care professionals.
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Occupational therapists work with individuals across their lifespan to enhance their health and well-being, job performance and quality of life. They assist people in setting goals and in designing interventions to successfully achieve those goals.
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Industries you may work within include health and wellness, mental health, productive aging, and rehabilitation disability.
Occupational graduate schools in Virginia
Recommended courses and minimum GPA
Two minors are highly recommended for future occupational therapists: biology and psychology.
Future occupational therapists should take a variety of undergraduate courses in biology, psychology, English, mathematics, and sociology or anthropology. Students interested in pursuing a graduate degree in occupational therapy should choose several possible graduate programs and keep the required and recommended courses in mind as they complete their undergraduate degree.
Most universities require students applying to a graduate program to have at least a 2.0 in prerequisite coursework with a minimum GPA of 2.8. To be competitive, though, a 3.0 is recommended.
Documented observation hours
Some graduate programs require a certain number of documented hours of observation of occupational therapy services. Undergraduate pre-occupational therapy students should spend volunteer time observing occupational therapy services. Be sure to check with the graduate programs to which you are applying for the number hours recommended or required for admission.
These volunteer experiences should be documented and put in your personal student file so your professors can reference them in letters of recommendation to graduate occupational therapy programs.
More info
For more info about occupational therapy, visit the American Occupational Therapy Association.


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pitbullmamaliz wrote:Such a handsome boy!
What's the tattoo?
call2arms wrote:Awe, poor Os boy, he looks so pitiful in that 1st photo!
And that hole punch looks painful... Anythinh sill draining from there? Cause otherwise it looks like there's not much of an accumulation in the area, or close to the tattoo.
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Rwanda: Women helping lead country's transformationJul 12, 2012
The people of Rwanda have been working tirelessly to put their country's tumultuous past behind them, paving the way towards a more promising future where peace and stability are helping transform the country into one of Africa's fastest growing economies.
Yet in this East African country – bordered by Uganda, Tanzania, Burundi and the Democratic Republic of the Congo – another tremendous shift has taken place: women are now at the forefront of national politics.
This advancement of women in Rwandan society has been documented in an inspiring documentary-style video produced by award-winning filmmaker Zak Mulligan, who lent his services pro-bono to the United Nations Development Programme (UNDP).
Unlike in the past, Rwanda's women now have a voice, and it is being heard across the nation. The country now ranks number one in the world in terms of highest participation of women in Parliament, with more than fifty percent representation.
"When men had the majority, we had trouble passing anything that had to do with gender issues. But now, with our numbers, we have a stronger voice than before," said Espérance Mwiza, a female member of Parliament.
Empowering women by making them true partners in development projects has been the focus of UNDP's work in the country, which aims to create opportunities for young people while promoting a culture of accountability, helping to build transparent institutions, and supporting peace consolidation.
Working through the Rwanda Women Parliamentary Forum, where female parliamentarians collaborate across party lines, UNDP has been training new female legislators on how the political process works. It is also working with the government to integrate gender dimensions into laws, policies, and budgets.
Though still widespread, poverty rates in Rwanda have dropped 12 percent over the past five years. Furthermore, 18 years after the 1994 genocide, the country has made huge strides towards achieving the Millennium Development Goals, particularly in the area of women's rights, as highlighted in Mulligan's film.
"The transformation from a war-ravaged society into a vibrant and dynamic nation is evident everywhere you go," said Auke Lootsma, UNDP's Country Director in Rwanda, now on his second tour of duty in the country. "The film shows how Rwanda has created a fast growing economy, lifted millions out of poverty, and healed a nation."
In 2010, Mulligan won the Excellence in Cinematography award at the international Sundance Film Festival, an annual event in the United States that showcases independent filmmaking.


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'The Mona Lisa' is New Music from Brad Paisley, and it's our Fresh Track of the Day!
Brad Paisley's 'Wheelhouse' CD has been a very different album for Brad, and some say an album that pushes the envelope, i.e. 'Accidental Racist' caused quite a bit of stir to which both Brad and rapper LL Cool J both quickly defended the song as nothing more than good music! Brad has already had two monster hits from the CD, 'Southern Comfort Zone' and 'Beat This Summer' both songs were Top 5 singles on the country charts, and today, Brad has another power hit with 'The Mona Lisa' it's our Fresh Track of the Day!
Click below to hear some of 'The Mona Lisa' from Brad Paisley
Check every day after the Q-106.5 Fresh Track of the Day at 11:45 am every weekday, and let us know what you think of that day's song. Thanks from Q-106.5!


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You are currently browsing the category archive for the 'holiday' category.
This weekend we took advantage of the Labour Day Holiday and went to stay on a farm for a few days. We were joined by another family who have 2 boys aged 7 and 5. It was really nice for Ruby to have Michael and Christopher to play with, even if she found all the noise and general excitement a bit overwhelming sometimes.
'Prestbury' is a working cattle farm in the Darling Downs area, 30 minutes West of Toowoomba. The owners, Rob and Sally Mcreath were very welcoming and took time out of their busy days to show us around the farm, we even found a homemade cake waiting for us in the fridge. Unfortunately, they have a cow who had a difficult birth and has been unwell so we were taken to visit her and her calf. The kids were able to pet the calf and feed her a bottle of milk since her mum has lost her milk.
We watched Rob bringing in a couple of loads of hay for their new Steers, for morning tea. They keep them penned in for a couple of weeks so that any nasty grass seeds they have in their bellies are 'planted' in these holding paddocks instead of out on the fields because a portion of their land is also cultivated.
We were taken on a 4×4 farm tour and the kids got to stand up and hang onto the back of the ute which, on a bumpy farm road was obviously wildly exciting! The farm covers 2500 acres and if you keep an eye out you can spot wallabies, koalas (we didn't), turtles, wild pigs and masses of birds. We surprised by a mob of wallabies bouncing across the road as we arrived at the farm on our first evening, thankfully they were heading away from us and not straight at our car!
Sally has 2 alpacas which she let us visit and the kids enjoyed the challenge of trying to feed them a bit of lucerne. They were a bit skittish and can be prone to spitting if they are upset. Thankfully they were well behaved and the children managed to reign in their excitement enough not to run at the poor darlings.
Rob and Sally have ducks and chickens and we were able to collect the hens eggs each morning for our breakfast. It was lovely being able to take the kids up to the farmhouse and see how many eggs had been laid that morning (instead of just reaching into the fridge). Ruby almost turned inside out when we disturbed a poor hen we hadn't noticed who then came 'flying' at her head screeching her little lungs out. I don't know who got the bigger fright, Ruby or the little black hen!
The house we stayed in was the original house that Rob and Sally lived in when they moved to the farm about 19 years ago while they renovated their current farmhouse. There is a queen room, a twin room and 2 singles. A large living room is separated from a dining area by a huge fireplace that would be wonderful in winter. The kitchen leads to a utility room with a washing machine and then on to a second shower and toilet. We enjoyed the big verandah and barbecue which caught the morning sun and led straight onto the enormous lawn which was perfect for the children to play.
Thankfully, we found a big box of toys that the kids enjoyed playing with during their down time.
How can I not include this face?
Final goodbyes, the boys before we left.
It was a very enjoyable stay at 'Prestbury' and was made even better by the welcome from Rob and Sally. It was good to get right away from it all (nearest supermarket 20km) and let the kids experience something completely different. I often forget that this is the life that my Mother lived – my maternal grandparents were cattle farmers. I remember wishing as a child that I'd grown up on a farm like my Mother. I'd love to do this again because I think Ruby will enjoy the experience in different ways as she gets older, so, you may see us again Rob and Sally!
If you'd like to check out 'Prestbury' the website is www.prestburyfarmstay.com and if you'd like more information you can email Sally Mcreath at email@example.com


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Tomorrow marks the beginning of the 103rd annual Drake Relays at Drake University, at which more than 8,000 athletes and spectators will gather to participate in the record 120 events at this year's competition. The Relays began in 1910 with 100 people both competing and cheering each other on. Now, the event is widely regarded at Iowa's premier sporting event. Better luck next year, competitive corn shuckers.
But more importantly than any heptathlon, decathlon, or dodecahedronathon was the Drake Relays preliminary event that took place yesterday as the official launch to the week – the 33rd annual Drake Relays Beautiful Bulldog Contest. Fifty bulldogs showed up for this year's poochstravaganza, and a bulldog named Tyson (above) was the ultimate good widdle boy. Joining Tyson's court were:
Runner-up – Charlie
Oldest bulldog – Max, 10-year-old
Best Dressed – Flethcher, dressed as Jethro's BBQ's famous "Emmenecker" sandwich
Mr. Congeniality – Vinny
Miss Congeniality — Heartstopping Ittybitty
Farthest from the Doghouse – Pork Chop, from Cambridge, Minnesota
(Via the Des Moines Register)
I've definitely added the Drake Relays to my sports bucket list, but not because I want to go see a few thousand people try to be the best at exercising – although finding the next Allison Stokke should be any sports blogger's greatest ambition. I just want to spend a whole day judging bulldogs for their costumes. Seriously, costumed bulldogs are the key to world peace, just look at the pictures after the jump and tell me you feel like doing anything other than rubbing a tummy or 50.
(All images via Flickr/Drake University.)


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Once again we have a spectacular number of fantastic soups and salads from fellow chefs. Since Jacqueline and I opened of up the event to vegetarian soups and salads rather than choose a particular theme, it has become more successful than ever. I warmly thank everyone who took the time to share a recipe with NCR.
Without further ado, pull up a chair and let's see what everyone is serving up in their kitchens around the world.
Recipe: Yet Another Side of Kale
Chef: Serendipity
Blog: Spicy Quirky Serendipitous
Location: USA
I think we all need more green in our diet and this lovely Kale Soup would certainly be welcomed on my table. It was a bit bitter the first time but the mighty potato came to the rescue. Not to hide the kale flavor but simply to subdue the somewhat strong flavor of the green. Throw in a bit of garlic, red chili flakes, cumin, chili powder and a bit of dried fenugreek and cozy up with this healthy bowl of goodness.
Super Speedy Sweetcorn Soup
Chef: Jane
Blog: The Hedge Combers
Location: Southwest England
This creamy sweetcorn soup we are told was on the table in 10 minutes. It's pretty, warming, including onion, garlic, paprika and of course sweetcorn. I certainly wouldn't mind if someone made up a bowl of this for me in return for a favor I did for them.
Tofu Salad
Chef: Mayuri
Blog: Mayuri's Jikoni
Location: Kenya
Next up we have a salad with tofu that certainly does absorbs flavors well. Mayuri marinates tofu with a dressing of sesame oil, ginger, garlic, soya sauce, rice vinegar and honey. Then grated carrot is tossed in, cucumber, spring onion and some lettuce leaves. Certainly a flavorful sounding Asian salad.
Butternut Squash Soup
Chef: Nayna
Blog: Citrus Spice and All Things Nice
Location: UK
One of the most comforting soups, especially in the winter months, is a thick and creamy squash soup. So pretty, this one includes not only butternut squash, but also granny smith apple, white onion and some seasoning. I adore heathy soups like this and it's low in calories too.
Parsnip and Leek Soup
Chef: Nanya
Blog: Simply Food
Location: UK
Parsnips are often an underrated vegetable but surely this soup will change your mind. Parsnips are featured here with carrots, potatoes, leeks and seasoning. Easy to make and low in fat. Warming and nourishing.
Hearty Potato Soup With Leeks, Garlic and Parsley
Chef: Letty
Blog: Letty's Kitchen
Location: USA
Looking to use up an excess of garlic, a whole bulb went into this soup. But not to worry about garlic breath we are told because cooking helps reduce the sharp bite of the garlic. In the soup they go with potatoes, leeks, parsley and garnish with an over easy egg and more parsley if you please. Certainly hearty and no doubt your taste buds would be smiling.
Taco Salad
Chef: Johanna
Blog: Green Gourmet Giraffe
Location: Australia
Johanna has been a long time supporter of NCR and this time she comes up with this colorful scrumptious Mexican-style salad. Black beans, corn, arugula, pumpkin, tomato, avocado and some corn chips are dressed with yogurt, soya milk, lime juice, garlic, paprika, cumin, oregano and a bit of cayenne. This intriguing salad we are told can be served in a variety of ways and a perfect summer salad. I'm jealous as the snow continues to pile up here in Canada.
Minestrone Soup
Chef: Mamta
Blog: Light Food Desires
Location: USA
To celebrate her new stainless steel soup pot, Mamta simmers up this tempting classic soup consisting of onion, garlic, carrot, celery, zucchini, green beans, tomatoes, cannellini beans, macaroni, herbs, a bit of spice and Parmesan cheese for garnish if desired. Certainly a successful way to break in her new pot. Filling and nourishing.
Roasted Broccoli and Quinoa Salad with Quick-Pickled Raisins
Chef: Janet
Blog: The Taste Space
Location: USA
Janet is another long time supporter of NCR and her recipes are always unique and tempting. I am sure this lovely dish was worth the effort. Stunned by the flavor of roasted broccoli, Janet features it here with curry powder, garlic, cherry tomatoes, carrot, quinoa, raw cashews, arugula leaves and interestingly, pickled raisins. What a fabulous and healthy blend of flavors. I would too double the recipe or maybe even quadruple it!
Orzo Salad with Chili – Maple Dressing
Chef: Gayathri
Blog: Spices Galore
Location: USA
Here we have another lovely salad, this one featuring Orzo. Though her kitchen was a mess due to renovations, Gayathri wanted to make a dish to say thank you to a teacher but it had to be easy. Surely this was one a hit. Orzo, refreshing mint, red onion, cucumber, sweet cranberries, crunchy almonds, tangy apples are dressed with red wine vinegar, maple syrup, chili flakes and olive oil. A perfect salad as we move into spring.
Tomato and Lentil Soupy Broth
Chef: Manjirichitnis
Blog: Slice of Me
Location: UK
If you need a delicious cleansing soup that also has the advantage of using up any tomatoes that are nearing the end of their shelf life, then this is the soup for you. Two types of lentils, tomatoes, onions, garlic, ginger and then a tarka of asafetida, coriander, cumin, red chili powder and cloves fill out the dish. Served with a nice crusty bread, you are in for a comforting lunch or light meal.
Roasted Sweet Potato Salad
Chef: Jennifer
Blog: A Girl Eats World
Location: USA
This pretty salad was taken to a family dinner and Jennifer was not allowed to leave with the leftovers and I can see why. Roasted sweet potatoes sprinkled with chili flakes are mixed with black beans, garlic, red pepper, fresh cilantro, red onion and lemon juice. How is that for a hearty and comforting dish.
Warm Potato and Pasta Salad in Sweet Onion Dressing
Chef: Pridhi
Blog: Drizzling Delicacies
Location: Unknown
Sweet and sour shine here in this gorgeous potato and pasta dish. Baby potatoes and fusilli pasta are dressed with garlic, red onions, cayenne, onion paste, lemon juice and then everything is garnished with fresh coriander and some freshly cracked black pepper. What a sunny dish to welcome the spring.
Cashew Fennel and Apple Soup
Chef: Vicki
Blog (FB page): Vicki's Kitchen Rocks
Location: USA
This savory seasonal soup has my mouth watering. Leeks, thyme, fennel, apples, turmeric and cashews served with maple syrup, crème fraîche, fennel fronds and chopped nuts. Served alongside a side dish of mixed kale, swiss chard and spinach stir fried with soba noodles, this would be one fine meal that surely would impress your dinner guests.
Butternut Squash and Red Pepper Soup
Chef: Louisa
Blog: Eat Your Veg
Location: UK
This soup was actually part of a lovely family photo shoot. The blended soup consists of butternut squash, onion, garlic, carrot, red pepper, smoked paprika and some Greek Yogurt. While her kids don't usually enjoy spice, Louisa added a bit of heat and the family loved it, especially when served along with some cheesy toast.
Pea, Asparagus and Pesto Soup
Chef: Antonia
Blog: A Little Bit Greedy
Location: UK
If you are considering giving up bread for lent, then this delightful green soup is just the choice for lunch. Think leeks, asparagus, peas and pesto. I'd gladly eat this for dinner too. Now I'm really craving asparagus season.
Creamy Butternut Squash and Hazelnut Soup
Chef: Vohn
Blog: Vohn's Vittles
Location: UK
Usually Vohn is quite on top of the vegetable situation, but a squash had slipped behind the bread box and when found, the natural solution was to turn it into a delicious soup. The nearly forgotten squash is simmered with onion, garlic, hazelnut milk, hazelnut meal and garnished with some fresh herbs. Nutty, creamy and vegan too, I'm glad this squash didn't end up in the bin.
Black Tea and Gingered Black-Eyed Peas
Chef: Lisa
Blog: Lisa's Kitchen
Location: Canada
This earthy dish is my contribution this month to NCR. I have only cooked with tea on a few occasions and I do believe this was the most successful attempt yet. Here black-eyed peas are simmered in black tea and seasoned with cumin and mustard seeds, ginger, garlic, chilies, cilantro, turmeric, mustard powder and fresh lime juice. Easy to prepare, smoky, tangy and slightly bitter, this is a new weekday favorite.
Fridge Lentil Soup
Chef: Jacqueline
Blog: Tinned Tomatoes
Location: UK
My best buddy Jac and co-host of NCR contributes this gorgeous and warming lentil based soup. As might be surmised from the title, this soup uses up leftovers from the fridge. Soup is indeed a very good way to use up vegetables and here lentils feature with onion, celery, garlic, carrots, red pepper and some cumin, ground coriander and some seasoning. Served with some crusty bread, your are in for a frugal but delicious meal.
Marbled Eggs
Chef: Galina
Blog: Chez Maximka
Location: UK
Though I don't eat eggs often, I have always wanted to try tea infused eggs and after seeing this stunning recipe, I must do so soon. The eggs are boiled and then "smacked" while in the shell. Then you place the eggs in a pan of cold water and add some tea, anise seed, a cinnamon stick, garlic cloves and ginger. The eggs are then boiled with the tea and simmered for about 3 hours. Galina added some other touches and served them in a noodle soup. How fancy is that?
That concludes the March 2014 edition of NCR. I am sure you will agree there are plenty of ideas here to keep you going for a good long time. Jacqueline will be hosting the April edition of NCR. Be sure to check in at the beginning of the month for the announcement.
No Croutons Required Vegetarian and Soup Roundup
Posted by Lisa Turner on Friday, March 28, 2014
Serve it up in No Croutons Required
Serve it up in No Croutons Required
5 comments:
- Johanna GGG said...
great round up lisa - nice to see that the new open season for the event is bringing in such delicious dishes - I am off bookmarking a few of these but could take a bowl of each really
- March 29, 2014 at 6:29 AM
- Light Food Desire said...
great salads and soups to try! thanks Lisa
- March 29, 2014 at 3:29 PM
- Kumudha said...
Yum! So many delicious vegan salads.
- March 30, 2014 at 12:48 AM
- Clevergirl said...
That Orzo Salad with Maple Syrup looks soooo yummy! I can't wait to try it. :-)
- March 30, 2014 at 8:54 AM
- Antonia said...
Delicious selection of recipes! Thank you for the great round-up.
- April 24, 2014 at 10:31 AM
Subscribe to: Post Comments (Atom)


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At a time when Roman Catholic bishops are waging political wars against contraception and same-sex marriage, one of the church's most hard-line generals was named Tuesday to head its historically important Baltimore archdiocese.
The Vatican appointed Bishop William E. Lori, 60, of Bridgeport, Conn., the next archbishop of Baltimore, a move that observers say could thrust the city, where American Catholicism was born, into the center of two hot-button issues.
"He's smart, he's articulate, he sticks to the party line," said the Rev. Thomas J. Reese, a Jesuit priest and senior research fellow at the Woodstock Theological Center at Georgetown University. "He can be very strong and forceful in articulating the church's position."
Lori chairs the U.S. Conference of Bishops' Ad Hoc Committee For Religious Liberty, created to lead the fight the Obama administration's mandate that health insurance plans offered to employees of Catholic schools, hospitals and charities include birth control and to defend traditional marriage.
Introduced at a news conference at the Basilica of the Assumption on Tuesday, Lori signaled he would continue his advocacy in Washington and now Annapolis from the seat of what he called "this great, historic archdiocese." He said he plans to jump into the fray over the Maryland law granting marriage rights to same-sex couples, which was signed into law by Gov. Martin O'Malley but is expected to go to voter referendum in November.
"The church has clearly and consistently taught the greatness of marriage between one man and one woman," Lori said at the news conference. "Certainly, I will continue that teaching as a bishop and will be working on this issue as the referendum unfolds."
O'Malley, who is Catholic, said in response through a spokeswoman that he too is "a defender of the one-man, one-woman concept — each man and each woman treated equally under the law."
"I congratulate him on his appointment, and welcome him back to the area," the governor said.
Lori, a native of Louisville, Ky., earned a master's degree from Mount Saint Mary's Seminary in Emmitsburg in 1977 and a doctorate from Catholic University in Washington in 1982. He was ordained to the priesthood in 1977 in Washington, given his first assignment at St. Joseph Parish in Landover and served several high-ranking posts under his mentor, Cardinal James Hickey, the late Washington archbishop. Lori took over the Bridgeport diocese in March 2001.
Most recently, Lori has been in the news for lobbying against the White House's contraception mandate. After a meeting last week with administration officials, he was quoted as saying it was "distressing" that the mandate appears "here to stay." He also wrote a rebuke, sarcastic at times, to an editorial in America magazine, a Jesuit publication. The editorial had taken the bishops conference to task for inflating a disagreement over policy into an infringement of religious freedom.
Already, an influential blogger on Catholicism is predicting that Lori's continued political activism, particularly in framing the contraception mandate as a religious-freedom issue, could become the signature endeavor of his time in Baltimore.
"Lori has been and will continue to be a strong character with a strong voice. He really is the quarterback pushing a strident line on the freedom of religion," said Rocco Palmo, whose "Whispers in the Loggia" blog broke the news of Lori's impending appointment. "He will be heavily involved in the public debate, and that will be the golden thread of his tenure in Baltimore."
Reese said Lori's elevation to archbishop of Baltimore will heighten his visibility and that of his committee on religious freedom. He suspects that the new assignment also puts Lori in line to eventually become president of the U.S. bishops conference.
"It raises his profile as chair of [the religious freedom] committee. More people will take him seriously because he's an archbishop," Reese said. "Rank matters. Being in an important city matters. I think we're going to hear from a lot more from him in the future."
Lori was introduced at the Basilica by his predecessor, Cardinal Edwin F. O'Brien, who said the new archbishop would continue his efforts on "the preservation of marriage, religious liberty and the protection of children."
O'Brien vacated the archbishop post in August 2011 to become the Grand Master of the Equestrian Order of the Holy Sepulcher of Jerusalem, but will continue as apostolic administrator until Lori's installation on May 16.
In Bridgeport, Lori had to confront a problem that faces many dioceses, the sexual abuse of children by priests and other church employees. He apologized to victims in October 2003, and announced a $21 million settlement with 40 people who said they had been molested by priests, according to reports in The Hartford Courant.
The issue led Lori into a fight in which he again argued against government intrusion into religious affairs. The bishop battled to keep pretrial documents related to sex-abuse cases — which dated from before his tenure in Bridgeport — from being made public. Lori tried to appeal to the U.S. Supreme Court a Connecticut state court order that would open the records, but the high court declined a motion to seal them.
Advocates for sexual abuse victims point to such efforts when they criticize Lori's lack of transparency in handling the issue.
But Lori in the past has pointed to how he has helped the church become more proactive and vigilant about sexual abuse through his work on what has become known as the Dallas Charter. Lori was one of the bishops who in 2002 wrote what they call a "zero-tolerance" policy on dealing with priests who have sexually abused children, and got it approved by the Vatican.
But Beth McCabe, co-leader of the Connecticut chapter of the Survivors Network of those Abused by Priests, said Lori has been "unsympathetic to survivors" and has refused to deal with past events.
"He may have written the definitive charter on protecting children, but I question if he is following it," she said. "We find no empathy or compassion, only roadblocks."
Lori also has served as supreme chaplain of the Knights of Columbus, a Catholic fraternal organization, since 2005, and is "an excellent pastor and administrator," said Andrew Walther, the group's spokesman.
"He brings a calm, thoughtful solution to every situation," Walther said. "He is totally committed to the teachings of the church and is always a civil, resolute defender of the Catholic faith."
Lori said Tuesday he learned of the appointment on March 13 and has been getting a crash course on the archdiocese from O'Brien during the past week. He celebrated the noon Mass at the Basilica, and said he planned to visit parishes, schools and charities in the coming weeks.
He met with seminarians and parishioners who attended the press conference before the Mass, including Kelly Llobet and her five home-schooled children. Ranging in age from 2 to 11, they handed Lori a card welcoming him to town.
"He is a terrific, traditional Catholic," Llobet said. "This is history being made here today, and we are happy that he has come here to lead us."
During his remarks, Lori indeed proffered a conservative approach, decrying what he called "the erosion of religious liberty, by legislation, court decisions and the increasing secularity of culture."
Baltimore Auxiliary Bishop Mitchell T. Rozanski said he has worked closely with Lori in the last few years during the semi-annual bishops' conferences.
"He is a quick learner, a good listener and he has a great talent for processing information and acting on it."
Palmo, the blogger, said Lori will have to hit the ground running once he becomes the 16th head of the Baltimore archdiocese, which includes surrounding counties and has about 510,000 Catholics.
"Lori's steel grit will serve him well on the tough moral issues that he will face immediately," Palmo said. "Baltimore is one of the best-run dioceses in the country, but there are many looming crises. He won't have much of a honeymoon. He will take to the big city easily and I predict his tenure will be long."


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- Research article
- Open Access
Elucidating the mechanisms of cooperative calcium-calmodulin interactions: a structural systems biology approach
© Valeyev et al; licensee BioMed Central Ltd. 2008
- Received: 30 July 2007
- Accepted: 02 June 2008
- Published: 02 June 2008
Calmodulin is an important multifunctional molecule that regulates the activities of a large number of proteins in the cell. Calcium binding induces conformational transitions in calmodulin that make it specifically active to particular target proteins. The precise mechanisms underlying calcium binding to calmodulin are still, however, quite poorly understood.
In this study, we adopt a structural systems biology approach and develop a mathematical model to investigate various types of cooperative calcium-calmodulin interactions. We compare the predictions of our analysis with physiological dose-response curves taken from the literature, in order to provide a quantitative comparison of the effects of different mechanisms of cooperativity on calcium-calmodulin interactions. The results of our analysis reduce the gap between current understanding of intracellular calmodulin function at the structural level and physiological calcium-dependent calmodulin target activation experiments.
Our model predicts that the specificity and selectivity of CaM target regulation is likely to be due to the following factors: variations in the target-specific Ca2+ dissociation and cooperatively effected dissociation constants, and variations in the number of Ca2+ ions required to bind CaM for target activation.
- Dissociation Constant
- Equilibrium Dissociation Constant
- Multisite Protein
- Bind Ligand Molecule
- Skeletal Myosin Light Chain Kinase
Calmodulin (CaM) is a multisite and multifunctional protein that contains four EF-hand Ca2+ binding sites [1], and is involved in a wide variety of cellular functions [2]. For example, it regulates the concentration of intracellular cAMP concentration in a very complex manner by regulating activities of cAMP producing adenylate cyclases (AC) and cAMP hydrolysing enzyme phosphodiesterase (PDE). CaM also regulates a large number of kinases and phosphatases as well as other enzymes with opposing cellular effects. Despite a large number of experimental studies [3–15], the detailed mechanisms underlying CaM-dependent intracellular regulation of such a large variety of target proteins are still not fully understood.
Recent experimental studies have attempted to elucidate the mechanisms underlying Ca2+/CaM-dependent target regulation by measuring the kinetics and steady-state levels of CaM-target binding [3, 11, 31–33] as well as by analysing the mechanisms of Ca2+-CaM interactions [9, 12, 34–37]. Ca2+ ion binding to EF-hand sites was shown to lead to CaM conformational alterations [1, 38–41]. In the modified conformational state, CaM is likely to alter its affinity to different targets by increasing and decreasing its affinity to certain proteins. Ca2+ ion binding to CaM is also argued to positively modulate the affinity of other Ca2+ binding sites of the molecule. There is still, however, an ongoing debate about the existence, the mechanisms and the degree of cooperativity in Ca2+-CaM interactions. In some studies, Ca2+ binding to CaM has been reported to be independent [15, 37]. On the other hand, other studies have reported cooperative interactions between the neighbouring EF-hand binding sites [12, 35] or cooperativity linking all sites of the CaM molecule [9].
A number of previous studies have attempted to use mathematical modelling to obtain a quantitative understanding of the mechanisms involved in Ca2+-CaM interactions. Different mathematical models, including the well known Hill [42], Adair [43] and Monod-Wyman-Changeux (MWC) [44] models, have been used in the literature to describe the cooperativity of ligand binding to a multisite protein. The Hill equation is frequently used to qualitatively measure the degree of cooperativity in multisite binding. It describes the simultaneous binding of n ligand molecules to a protein where the parameter n can be interpreted as the number of bound molecules. The Adair model represents ligand-protein interactions in terms of successive binding steps. The MWC model is based on two conformations that are in equilibrium and have different affinities for a ligand. To date, the Hill and Adair models have been most frequently used to investigate Ca2+ binding to CaM [4, 9–12, 14, 33, 45]. While these studies have provided much useful information, the use of the classical models mentioned above also introduces some limitations in the analysis – see [46] for a full discussion of this issue. In particular, the detailed analysis of ligand-protein interactions which are unique to CaM requires the development of a model that captures multiple functionally important intermediate conformations of the protein. A steady-state solution to the cooperativity problem for Ca2+ binding has been analysed in [47]. In this paper, we develop a new model, based on the assumption that the specificity in CaM target regulation arises from the Ca2+-CaM complex specific target interactions with variable numbers of bound Ca2+ ions. In this approach, Ca2+ binding to each EF-hand sites causes conformational transitions in the CaM molecule leading to a model that has multiple conformational states in complex with variable numbers of Ca2+ ions. In the proposed model, CaM may regulate its targets with one, two or three Ca2+ ions as well as in the apo- or fully bound states. In particular, we address the Ca2+-CaM interaction in significant detail, although we do not incorporate detailed Ca2+-CaM species interactions with target proteins. This approach is in agreement with recent experimental evidence that the concentration-dependent profiles for several Ca2+-CaM-dependent protein targets exhibit quite a diverse range of behaviour. PMCA and PDE protein concentrations in the active state, for example, reveal "Hill-shape"-like curves, whereas the ACII isoform is inhibited by increasing Ca2+ concentration. The ACVI isoform exhibits inhibition with an interesting plateau feature on the Ca2+-dependent profile. Yet ACI isoforms have bell-shaped concentration-dependent profiles [48]. It has also been shown that CaMPKII [49] as well as the K+ channel from Paramecium [50] are activated by CaM with two bound Ca2+ ions.
The structural systems biology approach, [51], employed in this paper provides new insights into the Ca2+-CaM-target binding dose-response curves which have been derived experimentally, and allows us to advance testable hypotheses about the nature of cooperative mechanisms unique to calcium-CaM interactions. The resulting analysis further bridges the gap between our understanding of CaM structural properties and intracellular Ca2+-CaM-dependent target regulation.
Multisite binding of cooperatively linked binding centres
In order to investigate the dependence of one Ca2+ binding site on another in both the N- and C-terminal domains, we assumed the alteration of a dissociation constant when a neighboring site is occupied as illustrated schematically in Figure 3 (compare the Model 1 and Model 2 descriptions in the Materials and Methods section). This approximation allows the derivation of a model that has an analytical solution in the form of conditional probabilities (Equation 12). It provides a quantitative comparison of the concentration of Ca2+ bound to CaM in the presence and absence of Ca2+ binding site cooperative interactions (Equations 13–14). Figure 5A shows the model predictions in the case where CaM is assumed to have two pairs of independent EF-hand globular domains. Within these domains, one Ca2+ binding site influences the other. In the N-terminal domain, the affinity of the second site depends on the state of the first and changes from K2 = 0.9 to = 0.2 (μM l-1) when a Ca2+ ion occupies the first centre. In the C-terminal, the affinity of the fourth site depends on the state of the third and changes from K4 = 0.8 to = 0.1 (μM l-1) when a Ca2+ ion occupies the third centre. The model (Model 2 in Materials and Methods) predicts that such changes will mainly influence the "amplitudes" of the intermediate conformations of the concentration-dependent profiles while leaving the ligand concentrations that produce their maximum values largely unchanged. Figure 5B shows the difference in the total amount of bound ligand with and without the type of cooperativity described above. Since the amount of bound Ca2+ is frequently measured in Ca2+-CaM or other ligand-multisite protein interaction experiments, these results allow a direct quantitative comparison to be made of the binding reactions with and without the presence of cooperative binding.
N- and C-terminal domains reveal unique cooperative properties
A more realistic description for EF-hand Ca2+ binding sites would involve the incorporation of the influence of both Ca2+ binding sites on each other within the CaM globular domains as schematically illustrated on Figure 5 (Model 3 in Materials and Methods). The resulting system of differential equations describing the Ca2+-CaM interactions is given by (Equation 15) in Materials and Methods. The model based on these assumptions leads to some interesting predictions regarding Ca2+-dependent CaM interactions with various CaM target protein peptides [33, 49] and reveals a complex story of specificity in CaM regulation. While it is well established that Ca2+ ions are required to modulate the CaM-target protein interactions, the mechanism of Ca2+-induced CaM conformational transitions that allow selective interactions with a particular target protein is still unclear. The presented model for Ca2+ binding to CaM provides new insights into how the cooperative interactions between EF-hand binding sites contribute to the mechanism of selective target regulation by CaM, as described below.
Calmodulin-target interactions reveal target-specific cooperativity in Ca2+ binding
The results of the present study, when combined with previous experimental data from the literature, suggest that CaM interacts with phosphorylase kinase, CaATPase and skMLCK in the apo state, but activates these proteins only when Ca2+ ions bind to a CaM-target protein complex. CaMKII kinase, on the other hand, binds to the Ca2+-CaM complex rather than apo-CaM. Each kinase has a unique combination of K1 and K2 dissociation constants. The half length peptides of CaATPase and skMLCK appear to have an even more complex mechanism of binding. As mentioned earlier, each Ca2+-CaM complex (with variable numbers of Ca2+ ions bound) may have a unique set of K1 and K2 constants for a target protein or peptide. For simplicity, all possible CaM species were divided into two groups: i) those with less than 3 Ca2+ ions bound and ii) those with three and four Ca2+ ions bound to CaM. A comparison of the model predictions with the Ca2+-CaM-parts of skMLCK and CaATPase peptide binding data (Figure 7B and 7C) suggests that both the K1 and the cooperatively influenced K2 dissociation constants are different when peptides are bound to CaM species with less than 3 Ca2+ ions or to CaM species with 3 or 4 ions. The conclusion from this observation is that the specificity in Ca2+-CaM-dependent regulation arises from a combination of the target specific affinity between Ca2+ and CaM, target specific cooperative constants, the order of the Ca2+-CaM-target complex assembly, as well as the number of Ca2+ ions bound to CaM. All these factors contribute to the mechanism of selective Ca2+-CaM dependent regulation in addition to the diversity of CaM-target interfaces [39].
pH dependence of cooperative Ca2+ binding to CaM
Ca2+-CaM dissociation constants derived by the different mathematical models.
present model
K1 = 1, Kc1 = 1, K2 = 1, Kc2 = 1
K1 = 0.04, Kc1 = 0.02, K2 = 0.04, Kc2 = 0.02
K1 = 0.06, Kc1 = 0.02, K2 = 0.06, Kc2 = 0.02
K1 = 0.15, Kc1 = 0.05, K2 = 0.15, Kc2 = 0.05
K1 = 2, Kc1 = 1, K2 = 2, Kc2 = 1
K1 = 0.4, Kc1 = 0.2 K2 = 2, Kc2 = 1
K1 = 0.5, Kc1 = 0.5, K2 = 0.5, Kc2 = 0.5
K1 = 5, Kc1 = 5, K2 = 5, Kc2 = 5
CaM pH = 7.2
K1 = 17, Kc1 = 7, K2 = 20, Kc2 = 0.5
K1 = 17, Kc1 = 7, K2 = 17, Kc2 = 7
K1 = 20, Kc1 = 0.5, K2 = 20, Kc2 = 0.5
CaM pH = 6
K1 = 10, Kc1 = 5, K2 = 10, Kc2 = 5
CaM pH = 10.1
K1 = 2, Kc1 = 1.8, K2 = 2, Kc2 = 1.8
In this paper a structural model of CaM interactions with and without cooperativity has been used to elucidate the mechanisms of Ca2+-CaM-target complex assembly. The differences seen in dose-response curves for proteins activated by Ca2+-CaM pairs were explained in terms of cooperative interactions between the EF-hand pairs [38, 40, 41] in both CaM domains. This study predicts that the specific interaction interface between CaM and CaM-regulated proteins [8, 10, 39] is complemented by a number of additional factors influencing the Ca2+-CaM-target complex assembly. By comparing our model predictions with experimentally measured dose-response curves from the literature, we propose that some proteins bind CaM without Ca2+ ions and only become activated when Ca2+ ions interact with the CaM-target complex, whereas others are activated by CaM molecules with already bound Ca2+ ions. The Ca2+-CaM interaction properties are tuned by the target proteins and characterized not only by the macroscopic dissociation constant set for Ca2+ sites, but also by the macroscopic cooperatively altered dissociation constants that are also unique to the CaM binding proteins. In other words, the order of Ca2+-CaM-target complex assembly, the number of bound Ca2+ ions, target specific Ca2+-CaM cooperative affinities, in addition to unique CaM-target interaction interfaces, all allow CaM to achieve its highly versatile intracellular multifunctionality. This proposition also explains the effects of pH on the considered dose-response curves by allowing for the modulation of the cooperatively effected dissociation constants. We would also like to point out that while we addressed the Ca2+-CaM interactions in great detail, the model could still be developed further by incorporating detailed dissociation constants between the intermediate Ca2+-CaM complexes and target proteins in a similar way to how it has been done for the Ca2+-CaM interactions.
Although the presented model predicts similar curves to the ones already used to approximate the experimental Ca2+-CaM-target dose-response data using the Hill and Adair models, it allows a far more detailed interpretation of the Ca2+-CaM dependent interactions involved. In particular, it distinguishes the structure-dependent properties of CaM molecules and suggests potential scenarios for Ca2+-CaM-target complex assembly. Importantly, it reveals the CaM specific type of cooperativity involved in this process and helps to explain the contribution of cooperativity in the specificity of CaM-dependent regulation.
- (1)
Mathematical models for protein interactions are usually derived according to a number of assumptions which will inevitably be more or less applicable to each particular protein. The structure of CaM suggests that this molecule is very likely to have non-sequential Ca2+ access to EF-hand binding sites. The results of our analysis support the theory of non-sequential cooperative access of Ca2+ to CaM binding sites, and also allow the derivation of cooperatively effected dissociation constants, thus providing a more realistic tool for fitting experimental dose-response curves.
- (2)
Our model suggests that the structural data alone cannot provide the required level of information and comparisons with the dose-response data are required. Predictions from the mathematical model used in this study were compared with the dose-response curves for Ca2+ binding to CaM and Ca2+-CaM-target peptides. This analysis allowed us to distinguish between (a) proteins that form a complex with CaM in its Ca2+ free state and then interact with Ca2+ ions and (b) other proteins which interact with Ca2+ bound CaM with variable numbers of Ca2+ ions. However, the transient kinetics has not been addressed in this study.
- (3)
In addition to the diversity of interaction interfaces, the specificity and selectivity of CaM target activation may be achieved by variations in the target-specific dissociation and cooperatively effected dissociation constants, the order of Ca2+-CaM-target complex assembly and the number of Ca2+ ions required to bind CaM for target activation.
A structural mathematical model for Ca2+-CaM activation
Here, we present the mathematical equations used to describe Ca2+-CaM interactions in our study. To clarify how various factors contribute to the CaM-dependent regulation, we describe three models for CaM starting from a very basic approximation of completely independent Ca2+ binding sites and gradually progressing to more realistic models that take account of cooperativity mechanisms and the Ca2+-CaM-target peptide complex assembly.
Model 1. CaM with independent Ca2+ binding sites
where cm 0 is the total concentration of CaM, u is normalised Ca2+ concentration, is the probability of binding site i not being occupied and is the probability of binding site i being bound. c i equals 1 if a binding site is occupied and 0 if it is not. The probability of CaM being in a particular bound state is equal to the product of the probabilities of each individual binding site.
where the K and u are the microscopic equilibrium dissociation constant and the ligand concentration, respectively. Effectively these are Michaelis-Menten equations for a protein in a complex with and without a ligand molecule, but normalized by the total protein concentration.
where the K and u are the equilibrium dissociation constant and the ligand concentration, respectively.
A complete mathematical description of the relationship between macroscopic constants derived from the Adair equation and the proposed model is provided in the Supplementary Materials Section (Additional File 1).
where L 0 is the total protein concentration and L i is the concentration of conformation i, K j are the equilibrium dissociation constants of each binding site, and u is the ligand concentration.
The conformations L1(u), ..., Ln-1(u) of a multisite protein are all bell-shaped curves, the conformation L0(u) is the apo state of a multisite protein, whereas the L n (u) is the fully bound multisite protein. If equation (5) is divided by L 0, then instead of predicting protein concentrations in specific ligand-bound conformations, it predicts the probability of a particular conformation to be in that state as a function of ligand concentration.
where cm i (u) is substituted from equation 5, and Kd is the dissociation constant for CaM-target interactions, N 0 is the total concentration of target protein.
Model 2. Cooperative Ca2+-CaM interactions
While the previous model provides predictions for the number of Ca2+-CaM complexes as a function of Ca2+ concentration with a reasonable accuracy, it does not capture the effects of the cooperative influence of Ca2+ binding sites. There are several possible ways to incorporate these cooperative mechanisms into the model. In order to derive a model that illustrates what contribution cooperativity makes to the distribution of concentration profiles of Ca2+-CaM complexes, we assume that in the N-terminal domain, the first centre is cooperatively bound to the second, and in the C-terminal, the third is cooperatively bound to the fourth. In this case, we will define the dissociation constants as K1, K2, , K3, K4, , where and are the cooperatively influenced dissociation constants for the second and fourth centres when the ligand is bound to the first and third binding sites, correspondingly.
where K1 and u are the equilibrium dissociation constant for the first centre and the ligand concentration, respectively.
where is the probability for both the first and the second centres to be free, is the probability for the first site to be free and the second to be occupied, is the probability for the first site to be bound and the second to be free, and is the probability for both sites to be ligand bound. K2 and are the dissociation and the cooperatively modified dissociation constants for the second Ca2+ binding site.
where K3 is a dissociation of the third binding site.
where is the probability for both the third and the fourth centres to be free, is the probability for the third site to be free and the fourth to be occupied, is the probability for the third site to be bound and the fourth to be free, and is the probability for both sites to be ligand bound. K4 and are the dissociation and the cooperatively modified dissociation constants for the second Ca2+ binding site.
where ki = 0, if the binding site i is not occupied and ki = 1 if the centre i is occupied by a ligand molecule.
The distribution of intermediate Ca2+-CaM complexes with 1, 2 and 3 Ca2+ ions with and without cooperativity is shown in Figure 5A.
Figure 5B shows the total amount of ligand bound to CaM in the presence (1) and absence (2) of cooperative binding. The line (3) shows the difference in the level of bound ligand between the two types of binding mechanisms.
Model 3. The Ca2+-CaM-target protein complex assembly
where cm00, cm01, cm10, cm11 are CaM molecules without Ca2+ ions, with one Ca2+ ion bound to the N-terminal domain, with one Ca2+ ion bound to the N-terminal domain, and CaM species with two bound Ca2+ ions at each terminal domain, respectively. k1 and k2 are the association constants and kc1 and kc2 are the cooperatively modified association constants for the N- terminal binding sites of CaM, respectively. Similarly, d1, d2, dc1, dc2 are the dissociation and cooperatively modified dissociation constants for the N- and terminal binding sites, respectively. Note that a similar system of differential equations can be developed for the C-terminal.
The conservation law gives:
cm00 +cm10 + cm01 + cm11 = 1
In steady-state, the matrix for the system (15) with the last equation substituted by (16) is given by:
where , . k1 = k2 = kc1 = kc2 is a simplifying assumption that allows analytical solution of the current system.
where N00, N01, N10 and N11 correspond to the N-terminal domain without any Ca2+ ions bound, with one Ca2+ ion bound to one or another binding site and to the fully bound state, respectively.
where is the probability for the N-terminal to be in a Ca2+ state, and describe the probabilities for a complex with one Ca2+ ion, and is the probability function for the N-terminal to be occupied by Ca2+.
where is the probability for the N-terminal to be in a Ca2+ state, and describe the probabilities for a complex with one Ca2+ ion, and is the probability function for the N-terminal occupied by Ca2+.
where are CaM species in apo state, is fully bound CaM, and and are CaM species with fully bound N- and C-terminals, respectively. and are CaM species with one Ca2+ ion bound to N- and C-terminals, respectively. Comparison of numerical solutions of this system with the available experimental data [9, 15, 33] allows us to propose that CaM molecules can be represented as a pair of two independent N- and C-terminal globular domains, each containing two symmetrical and cooperatively bound EF-hand Ca2+ binding sites.
The equations (28) are specific to Ca2+-CaM interactions and incorporate the pairwise cooperative interactions between the EF-hand binding sites within the N- and C-terminals, whereas the N- and C-terminal domains are considered to be independent of each other. Note that the equations developed here for the Ca2+-CaM complexes are essentially different from the Michelis-Menten, Hill and Adair models, and also differ from models with independent binding sites (5) or with limited amounts of cooperativity (11) and (12).
where T 0 is the total concentration of a target protein or a peptide, K d is the equilibrium dissociation constant between CaM and a target protein, and is a single Ca2+ complex or the sum of several CaM complexes.
The combinations of Ca2+-CaM complexes have been varied simultaneously with the dissociation constants to fit the experimental data. This analysis allows us to predict the Ca2+-CaM complexes required for activation of specific protein targets. The fitting of dissociation constants of Ca2+ binding sites on CaM molecules to the experimental dose-response curves reveals the impact of the target protein on the Ca2+-CaM interactions. The dissociation constants calculated based on the cooperative Model 3, which also takes into account the impact of target proteins, are compared with the dissociation constants calculated using the Hill and modified Adair equation in the original experimental publications for the same data in Table 1.
This work was carried out under EPSRC platform grant (EP/D029937/1), BBSRC grant (BB/D015340/1) and by RFBR grant.
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Colin Kaepernick Leads 49ers 32-7 Rout of Bears
Colin Kaepernick threw for 243 yards and two touchdowns in his first NFL start, and the San Francisco 49ers beat the Chicago Bears, 32-7, in San Francisco on Monday night.
Starting for an injured Alex Smith, Kaepernick completed 12 of 15 first-half pass attempts — including a 3-yard touchdown to Vernon Davis — as San Francisco (7-2-1) built a 20-0 halftime lead on the vaunted Bears' defense. Kaepernick tossed a 10-yard scoring pass to Michael Crabtree on the 49ers' first drive of the second half to make it 27-0 San Francisco.
Jason Campbell, who started for injured Bears' quarterback Jay Cutler, tossed a 13-yard touchdown pass to Brandon Marshall in the third quarter for Chicago (7-3). Campbell threw two interceptions and was sacked six times, including five-and-a-half by 49ers' linebacker Aldon Smith. The Bears managed just 143 total yards on offense.
[Via NFL.com]