text:
- Take the Kidney Disease Quiz
- Kidney Stones Slideshow Pictures
- High Blood Pressure Slideshow Pictures
- Patient Comments: Dialysis - Experience
- Find a local Nephrologist in your town
When do patients require dialysis?
Patients usually require dialysis when the waste products in their body become so high that they start to become sick from them. The level of the waste products usually builds up slowly. Doctors measure several blood chemical levels to help decide when dialysis is necessary. The two major blood chemical levels that are measured are the "creatinine level" and the "blood urea nitrogen" (BUN) level. As these two levels rise, they are indicators of the decreasing ability of the kidneys to cleanse the body of waste products.
Doctors use a urine test, the "creatinine clearance," to measure the level of kidney function. The patient saves urine in a special container for one full day. The waste products in the urine and in the blood are estimated by measuring the creatinine. By comparing the blood and urine level of this substance, the doctor has an accurate idea of how well the kidneys are working. This result is called the creatinine clearance. Usually, when the creatinine clearance falls to 10-12 cc/minute, the patient needs dialysis.
The doctor also uses other indicators of the patient's status to decide about the need for dialysis. If the patient is experiencing a major inability to rid the body of excess water, or is complaining of problems with the heart, lungs, or stomach, or difficulties with taste or sensation in their legs, dialysis may be indicated even though the creatinine clearance has not fallen to the 10-12 cc/minute level.
What types of dialysis are there?
There are two main types of dialysis: "hemodialysis" and "peritoneal dialysis." Hemodialysis uses a special type of filter to remove excess waste products and water from the bblood. Peritoneal dialysis uses a fluid that is placed into the patient's abdominal cavity through a special plastic tube to remove excess waste products and fluid from the body.
During hemodialysis, blood passes from the patient's body through a filter in the dialysis machine, called a "dialysis membrane." For this procedure, the patient has a specialized plastic tube placed between an artery and a vein in the arm or leg (called a "gortex graft"). Sometimes, a direct connection is made between an artery and a vein in the arm. This procedure is called a "Cimino fistula." Needles are then placed in the graft or fistula, and blood passes to the dialysis machine, through the filter, and back to the patient. If the patient requires dialysis before a graft or a fistula is placed, a large diameter catheter is placed directly into a large vein in the neck or leg in order to perform dialysis. In the dialysis machine, a solution on the other side of the filter receives the waste products from the patient.
Peritoneal dialysis uses the patients own body tissues inside of the belly (abdominal cavity) to act as the filter. The abdominal cavity is lined with a special membrane, the peritoneal membrane. A plastic tube called a " peritoneal dialysis catheter" is placed through the abdominal wall into the abdominal cavity. A special fluid is then flushed into the abdominal cavity and washes around the intestines. The peritoneal membrane acts as a filter between this fluid and the blood stream. By using different types of solutions, waste products and excess water can be removed from the body through this process.


text:
T Is For...
T is for tiger, truck and two! Turn coloring time into a fun learning moment with alphabet coloring pages. Your child can practice T's letter sound and shape, and his memory recall by identifying objects as he colors.
Click to find similar content by grade or subject.

subset: commoncrawl


text:
GET FREE SHIPPING on every order over $100.
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Looking dreadful with those drowsy, tired, and puffy eyes? This Electric Pen will give you younger looking skin and eliminates fine lines, by allowing eye creams & serum penetrate deeper in the dermal layer. You have the right to feel good and look young with this amazing product!
- Designed to treat major eye concerns, dark circles, puffiness, and wrinkles
- Reduces appearance of fine lines around the eyes
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text:
"I think Shelby had a better holiday than us. Thanks so much for the updates. I. I'm happy to..."
"Lisa was truely fantastic, the dogs absolutly loved her. We came home to two very happy and healthy ..."
"Great experience! Zhenni sent us a message to let us know how our dog was settling in just one hour ..."
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"As always Lou Anne was just wonderful! "
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"Once again Nicole looked after Russell last minute and he loved her. Highly recommended "
"Kiaria was great with Zara. She sent me photos & I would definitely use her again & there was a..."
"Thank you very much for taking very good care of Tia! Khin sent me photos every night with a..."
"Taya was amazing, she looked after our pets so well, while we were away! We would highly recommend..."
"Michelle was amazing with Franco. Thanks for taking care of my naughty boy. I highly recommend her..."
"Terri and her beautiful family looked after lucky so well, we highly recommend them!"
"Frankie had the best stay with Stuart, I was worried she wouldn't want to come home. Stuart sent..."
"Diana took great care of Mango"


text:
Need a Thyroid Test in Grass Valley, CA? Simply order online 24/7 and get a fast, affordable Thyroid Test at a lab near you (Find More Locations):
What is a Thyroid Test?
A Thyroid Test consists of lab tests to check the thyroid. People in Grass Valley, CA get a Thyroid Test for general screening or at the request of a medical provider.
How much does a Thyroid Test cost?
Our Thyroid Test prices include the doctor's order that you need to get tested in Grass Valley, CA, all lab fees and taxes, and a pdf copy of your results. For current prices, please CLICK HERE.
What does a Thyroid Test lab report look like?
For a popular Thyroid Test sample report, please CLICK HERE.
We are delighted to offer the Thyroid Test in Grass Valley, CA.
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text:
Price was good, room was clean, futon couch was better than the last two foldout couches in much more expensive hotels. Bathroom is small, full kitchen but minimal utensils, etc. Beds were comfortable, (we had a two bedroom unit) and if you have to have a flat screen or more than one TV you're out of luck. Bonus was Whole Foods Market right next door. No workout center, but a three minute drive to the lake, take a swim or a trot on the paved walk around the lake. Really friendly and helpful front desk. For the price, we were pleased and would stay again.
- Reservation Options:
- TripAdvisor is proud to partner with Orbitz, Agoda, Travelocity, Hotwire, TripOnline SA, Cheap Tickets, Cancelon, HotelQuickly and Evoline ltd so you can book your Super 8 Penticton BC 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:
- Super 8 Motel Penticton Hotel Penticton
- Super 8 Penticton
- Super Eight Penticton
- Penticton Super 8
- Penticton Super Eight
- Super 8 Hotel Penticton


text:
This is hardly a sleepy trip. Rather, this is the perfect 12-day adventure for sailing buffs that want to experience the blue waters of Australia, as well as off-road enthusiasts looking to explore via private 4x4s. Weve got a riverside camp to stay at in the gorgeous Noosa Everglades, and once weve left Airlie Beach, you'll learn about indigenous artisan crafts from local Aborigines, then check out the swimming holes of the Atherton Tablelands. While dreamtime is a mythology central to indigenous Australian society, were pretty sure youll want to be wide awake for this trip.
Arrive in Brisbane at any time. There are no planned activities during the day, so check into the hotel and explore the city.
If you arrive early enough, you'll have time to head into the city to visit City Hall, the Treasury Building or relax on Streets Beach.
Included Activities:
Arrival Day and Welcome Meeting
Once on the island, enjoy a 4x4 tour of Fraser Island, driving along over 100km of beach. Go for a swim in Lake McKenzie, and enjoy a rainforest walk along the way.
Additional Notes:
While on Fraser Island and the Noosa Everglades, main luggage will be stored in a secure storage facility. Each person will need to pack a bag for two nights with max weight of 5kg. This is due to luggage capacity restrictions in 4x4 vehicles and canoes. Your CEO will explain further details on arrival into Rainbow Beach.
Depending on the day of the week, some groups may swap the order of the Fraser Island and Noosa Everglades days. Some groups will first travel to the Noosa Everglades for a night before travelling on to Fraser Island. All inclusions will still be offered but just in a different order.
Private Vehicle (5.00 hour(s), 250km)
Enjoy a morning of exploring by 4x4 to hit the remainder of Fraser Island's highlights, then set off to the Noosa Everglades for an evening surrounded by stunning wilderness.
Included Activities:
4x4 Excursion
Noosa Everglades Overnight Excursion
Catch a train up the 'Capricorn Coast' which is well-known as 'Cattle Country'. Arrive at a remote farm and stay the night. The workers from the property are excellent hosts as they teach about the history of the farm, the cattle industry, and some of the challenges of raising cattle in such a harsh environment.
Train (6.00-8.00 hours)
After a traditional Outback-style breakfast, transfer to the town of Airlie Beach and embark on a maxi yacht which will be our home for the next three days. Set sail to a secluded cove in the Whitsunday Islands where you will drop anchor for the night.
Included Activities:
Whitsunday Islands Yolo Sailing Trip, Day 1
Maxi yacht
Private Vehicle (6.50-7.00 hours, 539km)
The sailing route today allows us to follow part of Captain Cook's route up through the Whitsunday Islands. There is the option for certified divers to scuba dive. Again we drop anchor in a secluded bay for the night.
Included Activities:
Whitsunday Islands Yolo Sailing Trip, Day 2
Maxi yacht
After three days at sea, we sail back to Airlie Beach for a night on land in a local beach hostel. Feel free to relax by the pool at the end of the day.
Included Activities:
Whitsunday Islands Yolo Sailing Trip, Day 3
Maxi yacht
Admire the scenery on the train north to Tully. Upon arrival, enjoy lunch and a tour of the G Adventures-supported Ingan Cultural Centre. Participate in a painting activity with traditional Jirrbal Aboriginal artists before continuing on to Cairns.
Additional Notes:
Get ready for an early morning wake-up today for the journey to Cairns. Make sure to stock up on snacks and bring personal entertainment – it may be one of the longer travel days on this trip, but it's worth it to reach The Gateway to the Great Barrier Reef!
Included Activities:
Ingan Cultural Centre & Jirrbal Aboriginal Art Demonstration
Train (6.50-7.00 hours, 482km)
Private Vehicle (2.00 hour(s), 140km)
Enjoy a free day to visit the Great Barrier Reef or get the adrenaline pumping by skydiving, whitewater rafting or bungee jumping. Cap it all off with a Big Night Out in Cairns.
Included Activities:
Big Night Out
Head north to Cape Tribulation. Stop en route to explore Mossman Gorge, take an interpretive walk through the Daintree Rainforest and swim in a remote waterfall within the Daintree NP.
Included Activities:
Aboriginal Interpretive Walk
Private Vehicle (3.00 hour(s), 140km)
Enjoy a free morning to further explore the rainforest or chill out poolside. Head towards Yungaburra in the Atherton Tablelands for the night, and enjoy additional free time to explore the area.
Private Vehicle (3.50 hour(s), 185km)
Stop at Lake Eacham, a volcanic crater lake, before continuing on to visit some of the waterfalls in the Atherton Tablelands, including the famous Millaa Millaa Falls. Later, go for a swim in the waters of Babinda Boulders before travelling back to Cairns where the tour ends upon arrival.
Additional Notes:
Ask your GCO about booking post night accommodation in Cairns, as this trip arrives back late in the evening.
Included Activities:
Lake Eacham Visit
Babinda Boulders Visit
Millaa Millaa Falls Visit
Departure Day (Activities)
Private Vehicle (2.00 hour(s), 70km)
Trusted by travellers since 1979
We guarantee to beat any price
Low deposits, Book now. Pay later.
24/7/365 Help on the road
Trip Name: Queensland Sand, Sailing & Dreamtime
Duration: 12 Days
From Price: 2609
Trip Code: 141293
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What is JotForm?
JotForm is a free online form builder which helps you create online forms without writing a single line of code. No sign-up required.
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hesabım devre dışı kalmış aktif etmek istiyorumAsked by satiye on May 23, 2016 at 06:37 PM
firstname.lastname@example.com mail adresim hesabım devre dışı bırakılmış tekrar aktif lütfen yardım edermisiniz
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Begin New Search
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Cemetery Lookup
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s in:
Glenwood Cemetery
Middlesex County
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CPT Ralph A. Sambuchi
Jun. 5, 1942
Erie County
New York, USA
May 18, 2010
Massachusetts, USA
Formerly of Lackawanna N.Y. Capt. Sambuchi died exactly 41 years to the date of being severely wounded in Vietnam.
Captain Ralph A. Sambuchi graduated from Lackawanna High School in 1960. He starred in football and held records in Track and Field., namely the triple jump and the long jump. He went on to play football at the University of Buffalo for one year before enlisting in the U.S. Army. He went to Officer Candidate School and became a commissioned officer.
On May 18, 1969 Captain Sambuchi's unit of 200 men of Husky Compound were ambushed by 1400 North Vietnamese and Viet Cong Troops. His unit fought bravely, sometimes hand to hand, and stemmed the enemy's onslaught. They suffered nearly 80 casualties that night, while killing or wounding almost 700 NVA/VC. Captain Sambuchi's body was riddled with bullets, shrapnel and fire. He was left for dead. Sambuchi was struck 14 times by shell fragments and bullets. A bullet from a Viet Cong rifle tore away his nose and right eye. Another severed his toes. His burning bunker caused second and third degree burns. And a ball of fire from a flamethrower, hit him in the forehead and shaved off his hair and ear.
He laid for hours until he was awakened by someone calling his name. Corporal Barker, Pfc. Indelicato and Sgt. Clark risked their lives trying to find him. He was evacuated by helicopter to Long Binh Hospital about 25 miles away. At the hospital he had two cardiac arrests.
During the next 41 years Captain Sambuchi had in excess of 200 operations and as many hospital stays to repair a shattered arm, lost nose, eye and ear, skin graphs to face, legs and chest, 8 missing toes and multiple other shrapnel wounds. He literally died on an operating table but was revived twice.
During this attack, Ralph was wearing a new Army issued flack jacket that actually prevented his lungs from collapsing after being shot twice in the chest. In the hospital, the only part of his body that was not riddled with shrapnel wounds and burns was the area protected by this flack jacket. After learning of Ralph's story, the Army made the new flack jacket standard issue, citing Ralph's experience and how it saved his life and would go on to save others.
The doctors believe that the heart problem that caused his death was due to the many "wooden" and "plastic" bullet heads that had been fired into him which could not be extracted.
A sports scholarship is being set up by his high school graduating class of 1960. Captain Ralph A. Sambuchi was awarded many medals and commendations which included the Silver Star and the Purple Heart.
Capt. Sambuchi was pre-deceased by his wife, Diane (Horskotte) and survived by a daughter Stephny (Aaron) Hallstad and a son Daniel (Consuela); he is also survived by his step-children, Toni, Terry, John and several grandchildren; also survived by brothers, Arthur (Theresa), Edward (Peggy), David (Nancy) and fiancee' Joan Quinn.
Capt. Sambuchi was awarded many medals and commendations which included the Silver Star and Purple Heart, he was a member of the VFW and American Legion in the Boston, MA. area.
Family links:
Sambuchi (1938 - 2002)
Glenwood Cemetery
Middlesex County
Massachusetts, USA
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Record added: Aug 07, 2010
Find A Grave Memorial# 56341254
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John Salmi
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text:
- any of certain bean plants having kidney-shaped seeds, esp the French bean and scarlet runner
- the seed of any of these beans
WordReference Random House Learner's Dictionary of American English © 2017
ˈkid•ney ˌbean, n. [countable]WordReference Random House Unabridged Dictionary of American English © 2017
Plant Biology, Fooda bean plant grown in many varieties for its seeds and pods which can be eaten.
Plant Biologyits mature seed, esp. the dark red, kidney-shaped seed of some varieties.
kid′ney bean′,
- Plant Biology, Fooda common bean, Phaseolus vulgaris, cultivated in many varieties for its edible seeds and pods.
- Plant Biology, Foodthe mature kidney-shaped seed of this plant.
- 1540–50
Collins Concise English Dictionary © HarperCollins Publishers::
kidney bean n
'kidney bean' also found in these entries:
borlotti bean - fagiolo - frijol - green bean - haricot - pea bean


text:
Skivate/Pripper is a fan-ship of Skipper and Private, as best friends, romantic or a father and son bond.
Private's hintsEdit
- I was a Penguin Zombie
When everyone thought that Skipper was dead, Kowalski slaps Private, probably on Private's request, and Private says Skipper's slap had more emotion in it; both disappointment and caring.
Skipper's hintsEdit
- Assault and Batteries
When Skipper called Private who was sleeping, Private just wiggles his tail in his sleep and Skipper calls it "cutest thing (I've ever seen)"
- When the Chips are Down
He was the most upset for Private's disappearance, and when he sees Private safe and sound he rushes to him, grabs him, swings him around and hugs him, nearly crying out of joy.
- Love hurts
Although at first mad that Private was faking his injuries so to see Shawna, he became tearful that Private found love, looking like a father expressing pride for a son, though he was against it, and he, Kowalski and Rico had tried to drag Private away.
- Antics on ice
Skipper was determined to have Private see the 'lunacorns on ice' play, believing if he didn't Private would become a hipster. Private did get to see the show but was jealous that Roy the rhinoceros and Bing the gorilla became tv stars for being forced into the play, and almost did become a hipster, but Skipper stops him.
- Penguins of Madagascar (movie)
Perhaps the most evident of Skipper's bond with Private, Skipper seems to view Private as a secretary and mascot, he had also came up with the idea to break into Fort Knox and get Private cheezy dibbles for Private's tenth birthday, he was also distraught after Private got kidnapped by Dave the octopus at Shanghai and for thinking Private died from Dave's medusa serum and constantly called Private cute throughout the entire movie.


text:
Criminal Law
Criminal Law Questions? Ask a Criminal Lawyer.
I have a court date on Oct. 25. The last sentence was me being hopeful of that outcome. What i need help with is the process of how to go about proving my case that they can't adequately prove intent. I expect it'll be difficult to get out of the possession of stolen property at this point (right?). How can i view and then use the evidence so that i can start developing a more desirable resolve. Is a misd. plea deal realistically my best option? I'd like to hear a little more from you


text:
Late Registration
- Wake Up Mr. West (feat. Bernie Mac)
- Heard 'Em Say (feat. Adam Levine Of Maroon 5)
- Touch The Sky (feat. Lupe Fiasco)
- Gold Digger (feat. Jamie Foxx)
- Skit #1
- Drive Slow (feat. Paul Wall & GLC)
- My Way Home (feat. Common)
- Crack Music (feat. The Game)
- Crack Music (feat. Game)
- Roses
- Bring Me Down (feat. Brandy)
- Addiction
- Skit #2
- Diamonds From Sierra Leone (Remix) (feat. Jay-Z)
- We Major (feat. Nas & Really Doe)
- Skit #3
- Hey Mama
- Celebration
- Skit #4
- Gone (feat. Consequence & Cam'ron)
- Gone (feat. Consequence & Cam`Ron)
- Diamonds From Sierra Leone (bonus Track)
- Diamonds From Sierra Leone
- Late (hidden Track)
- Late
- Rádio interpreta
- Rok vydání: 2005
- Žánry: Hip hop, Hip Hop Workout, Inspirativní, Milénium hity, Olympijská, Rap
- Vydavatelství: Universal Music
- Text písničky
[Chorus: Kanye West]
I'll be late for that, baby I'll wait for that
If you had a taste of that, you'd probably pay for that
I'm comin in when I feel like
To turn this muh'fucker up only if it feels right
I'll be late for that, I can't wait for that
I think I was made for that
So I'm comin in when I feel like
To turn this muh'fucker up only if it feels right
[Kanye West]
Stop all your blood claat cryin, I was flyin
Made it to school with barely 'nuff time to sign in
Yeah I hear the alarm, yeah I hear you mom
Yeah yeah I don't wan' be broke when I'm 31
They said the best classes go to the fastest
Sorry Mr. West there's no good classes, and that's what yo' ass get
Not even electives? Not even prerequits?
You mean I missed my major by a couple of seconds?
Now I'm in the shop class or the basket weavin
With all the rest of the muh'fuckers underachievin
Man, this is a insult
I went to junior high with all of them and they been slow
If I can catch the beat then slow down the tempo
Just notice at the end if I'm too late for the intro
Will I make it from the student loans to a Benz-o?
Like old folks pissin, I guess it all (Depends), oh, oh
... Stop you're cryin baby
[Kanye West]
You know when you be late you miss all the lights
That's right (that's right) that's right (that's right)
And when you get back she gon' start up a fight
That night (that night) that night
Baby it's too late for that, lately I've been takin it slow
Try and make it to the party 'fore the guest list close
With the freshest hoes, the professors know
We about to get real unprofessional
Like them eskimos, what would you do for a Klondike?
Or two dykes that look Christina Milian like
Hmmm, I'll be on time for that
I ain't thought of no line that could rhyme with that
Yo, I'll be there in five minutes, five hours later
I'll be there in five minutes, go 'head ride with it
I'm so live with it, look how I did it
Been bullshittin but I finally arrived with it
I know it's late and I took all year but
You can stop complainin cause I'm finally here, yeah
"I'll be late for that" - [repeat 4X]
- Late (03:50)


text:
Clock Changes in Escuintla, Guatemala
Daylight Saving Time (DST) Not Observed in Year 2017
Escuintla currently observes Central Standard Time (CST) all year.
DST is no longer in use.
Clocks do not change in Escuintla, Guatemala.
The previous DST change in Escuintla was on September 30, 2006.
Try selecting a different year below.
Daylight Saving Time in Other Years
DST changes do not necessarily occur on the same date every year.
|DST Start (Clock Forward)
|DST End (Clock Backward)
|2010 — 2019
|DST not observed
|All times are local for Escuintla. Current year is highlighted.
Data for the years before 1970 is not available for Escuintla, however, we have earlier time zone history for Guatemala City available.


text:
[DEPRECATED]Unleash the Raptors
This quest is not available in game.
Sergeant Lukas at North Point Tower wants you to place the Raptor Bait near the windmill in Blackhoof Village.
- Raptors Released
- Raptor Bait (Provided)
Now that we've got our raptors, our next move is to "encourage" them to attack the Grimtotems at Blackhoof Village to the northwest.
I've got a leftover haunch of... well, it doesn't really matter what it is. It'll be your bait. Set it down on the ground in Blackhoof Village near the windmill in the center of the settlement. The raptors should take care of the rest, if their training took.
You will be able to choose one of the following items:
|Book of the Adept
|Crested Shoulderguard
|Pendant of Ferocity
You will also receive:


text:
3 Min Read
WASHINGTON (Reuters Life!) - Shopping lists are making a comeback.
A growing number of American women are returning to the lists to help them stick to family budgets, relying on a money-saving tactic once used broadly during the Great Depression, according to retail analyst Britt Beemer.
The popularity of shopping lists comes as government data released this week showed that American consumers are paying 4.5 percent more for food than they paid a year ago. And they are being hit twice, also paying record gasoline prices for their drives to the grocery store.
Beemer said in the eight years he has queried thousands of Americans about using shopping lists in a bimonthly survey, typically about one-third said they wrote out what they intended to buy.
Last October, though, the proportion began rising and now stands at 59 percent, Beemer said.
"They're literally saying: 'I can't afford more than this. I'm buying essentials. I'm not going to go overboard,'" Beemer told Reuters in a telephone interview from his Florida office.
Beemer's research focuses more on women because they tend to make their families' shopping decisions, but he said many men are also making lists, albeit shorter ones.
Nicole, who lives in Washington, said she started making grocery lists in September.
"I've recently started to do it and it's mostly to keep myself from going beserk," she said while standing in the meat section of a Safeway with a white sheaf of paper that had lines drawn through items she had already found.
Her boyfriend's mother had watched her in a store and, deciding "there was no rhyme or reason" to how she shopped, showed her how to draft lists. Nicole uses specials and sales advertised in the newspaper along with what is running low in the refrigerator to plan what she purchases.
Before, Nicole was more inclined to make impulse buys. Now, she said, "I stick to the list."
A shopper with a list will rarely buy more than two extra items, said Beemer, who is chairman of America's Research Group. Someone without a list will likely go to the checkout counter with many more items than she intended to purchase. And the current dominance of brand names on people's lists shows that shoppers are paying more attention to advertised discounts, he said.
There was an increase in shopping lists in the months following September 11, 2001, as survey respondents sought to cut their shopping time and increase their time at home, Beemer said. Typically, though, he said, list carriers had been single mothers, keeping watch on their cash and time, and women over 70 worried about forgetting items.
Now, the intent across the board is strictly to save money, mirroring the results of a Gallup poll Beemer found from the 1930's, during the country's legendary economic depression.
"We're not very far today from the mentality people had in the Great Depression," he said.


text:
If you would like to gift something towards a healing for someone who might need it but cannot afford it you can donate here. Thank you
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With Energy Healing Science you will receive help to restore your well being. At the same time it serves as a tool for awakening your consciousness and as a tool for personal transformation. It is my privilege to help you facilitate your healing journey, transforming the relationship you have with your Self and your life.
Pathways to the Self
Becoming a Healing Presence in the world


text: Investments in small-sized companies may involve greater risks than in those of larger, better known companies. Returns on investments in stocks of small companies could trail the returns on investments in stocks of larger companies.Although subject to the risks of common stocks, low volatility stocks are seen as having a lower risk profile than the overall markets. However, a portfolio comprised of low volatility stocks may not produce investment exposure that has lower variability to changes in such stocks' price levels. Risk associated with equity investing include stock values which may fluctuate in response to the activities of individual companies and general market and economic conditions. Non-diversified funds that focus on a relatively small number of securities tend to be more volatile than diversified funds and the market as a whole. The Fund invests by sampling the Index, holding a range of securities that, in the aggregate, approximates the full Index in terms of key risk factors and other characteristics which may cause the fund to experience tracking errors relative to performance of the Index. Returns on investments in stocks of large U.S. companies could trail the returns on investments in stocks of smaller and mid-sized companies. "SPDR" is a registered trademark of Standard & Poor Financial Services LLC ("S&P") and has been licensed for use by State Street Corporation. No financial product offered by State Street Corporation or its affiliates is sponsored, endorsed, sold or promoted by S&P or its Affiliates, and S&P and its affiliates make no representation, warranty or condition regarding the advisability of buying, selling or holding units/shares in such products. Further limitations and important information that could affect investors' rights are described in the prospectus for the applicable product. Russell Investments and Axioma, Inc. have entered into a strategic alliance with respect to the Russell-Axioma Factor Indexes, including the Russell 1000® and Russell 2000® Low Volatility Indexes. Russell and Axioma are the source and joint owners of the trademarks, service marks and copyrights related to the Russell-Axioma Factor Indexes. Russell is a trademark of Russell Investments. Axioma is the owner of all copyrights related to Axioma's optimized solutions. The SPDR products are not sponsored, endorsed, sold or promoted by Russell Investments or Axioma, Inc. and they make no representation regarding the advisability of investing in the SPDR products.


text:
Broncos fans enjoy big game, until the end
January 14, 2013
Bar stools remained filled at Randy's All American Grill in Greeley during the Denver Broncos' playoff loss to the Baltimore Ravens on Saturday night. Denver lost 38-35 in double overtime.
The game drwe about 70 fans the sports bar, 2118 35th Ave. When big plays happened during the action-packed game, the crowd exploded into cheers.
"We see a flux of people at playoff games," said Brett Daugherty, consulting manager at Randy's. "They post up, have a beer or two, and then vanish like tonight."
The crowd disappeared quickly and quietly after Baltimore's Justin Tucker hit the game-winning field goal.
Here's what some of the fans had to say about the game and the season.
"I'm very disappointed with the game. The Broncos were overly confident; I think they thought that they had it in the bag, and they clearly didn't."
— Elizabeth Vasquez, Greeley
"Other than offense, the game went our way. If Denver would have played defense, we would have gone all the way. You can't deny destiny."
— Casey Lauer, Greeley
"I think we should have gone for it in those last 31 seconds in regular time. With Manning, there's no reason not to try."
— Marco Moreno, Greeley
"At the end there, I think they took a chance (in overtime) that they shouldn't have, and it resulted in that interception, but it was still a good game to watch for how long it was."
— Jerry Beddo, Evans
"They're doing relatively good. We don't play football games in Peru, though, we just like to pass the ball around."
— Filippos Kazakos, 15, exchange student from Lima, Peru
"I'm a college student, so I'm here (at the sports bar) because I don't have cable. I was kind of nervous to wear my Packers shirt, but they turned out to be a good group of Broncos fans. I think they took it alright."
— Sadie Panzer, UNC student
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text: My goal as Admin is to log in and see any completely new threads that have been created since I last clicked that link to view new threads. We added a "new threads" link to the top of our forum, but it doesn't do what I expect it to do. For example: https://www.hairlosstalk.com/interact/find-new/threads?days=30 This is our "Latest Threads" link. But it shows me existing threads that have new posts in them. In fact it redirects upon click, to: https://www.hairlosstalk.com/interact/find-new/20218/posts 1) Why is it doing that? 2) I want to see only brand new, newly created threads. How can I see this?


text:
The leading Hospital in Maldives offering efficient and high quality patient-centered healthcare.!
IGMH will provide holistic and comprehensive health care service to the country where quality and safety of care are paramount; to serve and aspire to be the trusted leader and preferred provider of health care.!
- Patient Care: We deliver professional compassionate and committed care to every patient we serve.
- Teamwork: We build on the collective strength and cultural diversity of everyone, working with mutual respect and act without bias.
- Quality: We consistently strive to provide high quality safe patient care through a culture of learning and innovation.
- Responsibility: We will be accountable and accept ownership for everything we do.
- Integrity: We communicate openly and honestly, build trust and conduct ourselves according to highest moral and ethical standards.


text:
1 item from 2010
11 August 2010 9:07 AM, PDT | The Hollywood Reporter - Movie News | See recent The Hollywood Reporter - Movie News news »
David L. Wolper, the groundbreaking producer who made television history with the miniseries "Roots" as well as the opening and closing ceremonies of the 1984 Olympics, died at his home in Beverly Hills on Tuesday of congestive heart disease and complications of Parkinson's disease. He was 82.
Wolper won two Emmy Awards for 1977's "Roots" and its 1979 "Roots: The Next Generations," the two miniseries based on Alex Haley's novel about his African-American ancestors pioneered the docudrama genre. Broadcast in one-and-two hour segments over an eight-day period in early 1977, the first series won huge ratings, despite initial reservations that its focus on the history of African-Americans would not have wide appeal. It won a 44.9 Nielsen rating and garnered a 66% share of the national audience, becoming one of the most-watched programs in TV history.
Although he primarily turned out documentaries for TV and films, Wolper also produced several theatrical movies, including 1971's »
- By Duane Byrge
1 item from 2010
IMDb.com, Inc. takes no responsibility for the content or accuracy of the above news articles, Tweets, or blog posts. This content is published for the entertainment of our users only. The news articles, Tweets, and blog posts do not represent IMDb's opinions nor can we guarantee that the reporting therein is completely factual. Please visit the source responsible for the item in question to report any concerns you may have regarding content or accuracy.See our NewsDesk partners


text:
I feel my jaw line is to much in side profiles. No fat or double chin. Can bone be removed? What purcedure is it called when some of the jaw line bone is removed? What is the recovery time and what is the ball park figure in dollars?
Can Jawline Bone Be Removed and What Does It Cost?
Doctor Answers 1
Jawline bone removal.
{{ voteCount >= 0 ? '+' + (voteCount + 1) : (voteCount + 1) }}
{{ voteCount >= 0 ? '+' + (voteCount + 1) : (voteCount + 1) }}
If you are speaking of making the chin less prominent, this can be done by shaving the bone. See a surgeon who does this frequently. We do this for both male and female patients as well as gender reassignment patients.
These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship.


text:
Cambodian Health Professionals Association of America.
Promoting Health Through Service and Education
CHPAA is excited to invite everyone to our 2017 Spring Fundraising Dinner Party!
Thank you for helping CHPAA to provide free needed health care to the poor people of Cambodia and local community health education and screening.
If you wish to join the mission, please download below applications, fill out and send them back to us at firstname.lastname@example.com.


text:
select a format
Recent Viewed Reports
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This is an on-demand report and will be delivered within 2 working days (excluding weekends) of the purchase.
Executive Summary
PTC Therapeutics Inc (PTC) is healthcare products provider that offers therapies. The company discovers, develops, and commercializes orally active small molecule therapeutics that target post transcriptional control. Its pipeline products include an orally administered small-molecule targeted at genetic disorders due to a nonsense mutation; an orally active small molecule to reduce the function, activity and amount of BMI1; and an investigational oral therapeutic used for the treatment of spinal muscular atrophy. PTC's ataluren is in clinical development for the treatment of nonsense mutation duchenne muscular dystrophy and nonsense mutation cystic fibrosis.The company serves in the areas of genetic disorders and oncology. It operates through biotechnology and pharmaceutical companies for improvement of its pipeline candidates. PTC is headquartered in South Plainfield, New Jersey, the US.
PTC Therapeutics Inc Key Recent Developments
May 08,2017: PTC Therapeutics Reports First Quarter 2017 Financial Results and Provides Corporate Update
Apr 10,2017: PTC Therapeutics Announces Departure of Chief Financial Officer, Shane Kovacs
Mar 16,2017: PTC Therapeutics Reports Fourth Quarter and Full Year 2016 Financial Results and Provides Corporate Update
Feb 08,2017: PTC Therapeutics Announces Third Annual STRIVE Grant Award Program for Duchenne Muscular Dystrophy
Jan 09,2017: PTC Therapeutics Provides Corporate Update and Outlines 2017 Strategic Priorities to Maximize the Global Value of Translarna and Advance its Innovative Pipeline
This comprehensive SWOT profile of PTC Therapeutics Inc provides you an in-depth strategic analysis of the company's businesses and operations. The profile has been compiled by GlobalData to bring to you a clear and an unbiased view of the company's key strengths and weaknesses and the potential opportunities and threats. The profile helps you formulate strategies that augment your business by enabling you to understand your partners, customers and competitors better.
This company report forms part of GlobalData's 'Profile on Demand' service, covering over 50,000 of the world's leading companies. Once purchased, GlobalData's highly qualified team of company analysts will comprehensively research and author a full financial and strategic analysis of PTC Therapeutics Inc including a detailed SWOT analysis, and deliver this direct to you in pdf format within two business days. (excluding weekends).
The profile contains critical company information including*,
Business description-A detailed description of the company's operations and business divisions.
Corporate strategy-Analyst's summarization of the company's business strategy.
SWOT Analysis-A detailed analysis of the company's strengths, weakness, opportunities and threats.
Company history-Progression of key events associated with the company.
Major products and services-A list of major products, services and brands of the company.
Key competitors-A list of key competitors to the company.
Key employees-A list of the key executives of the company.
Executive biographies-A brief summary of the executives' employment history.
Key operational heads-A list of personnel heading key departments/functions.
Important locations and subsidiaries-A list and contact details of key locations and subsidiaries of the company.
Key manufacturing facilities-A list of key manufacturing facilities of the company.
Detailed financial ratios for the past five years-The latest financial ratios derived from the annual financial statements published by the company with 5 years history.
Interim ratios for the last five interim periods-The latest financial ratios derived from the quarterly/semi-annual financial statements published by the company for 5 interims history.
Note*: Some sections may be missing if data is unavailable for the company.
Key benefits of buying this profile include,
You get detailed information about the company and its operations to identify potential customers and suppliers.
The profile analyzes the company's business structure, operations, major products and services, prospects, locations and subsidiaries, key executives and their biographies and key competitors.
Understand and respond to your competitors' business structure and strategies, and capitalize on their weaknesses. Stay up to date on the major developments affecting the company.
The company's core strengths and weaknesses and areas of development or decline are analyzed and presented in the profile objectively. Recent developments in the company covered in the profile help you track important events.
Equip yourself with information that enables you to sharpen your strategies and transform your operations profitably.
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Scout for potential investments and acquisition targets, with detailed insight into the companies' strategic, financial and operational performance.
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Gain key insights into the company for academic or business research.
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Table of Contents
Section 1-About the Company
PTC Therapeutics Inc-Key Information
PTC Therapeutics Inc-Overview
PTC Therapeutics Inc-Key Employees
PTC Therapeutics Inc-Key Employee Biographies
PTC Therapeutics Inc-Key Operational Heads
PTC Therapeutics Inc-Major Products and Services
PTC Therapeutics Inc-History
PTC Therapeutics Inc-Company Statement
PTC Therapeutics Inc-Locations And Subsidiaries
PTC Therapeutics Inc-Key Manufacturing facilities
Head Office
Other Locations & Subsidiaries
Section 2-Company Analysis
PTC Therapeutics Inc-Business Description
PTC Therapeutics Inc-Corporate Strategy
PTC Therapeutics Inc-SWOT Analysis
SWOT Analysis-Overview
PTC Therapeutics Inc-Strengths
PTC Therapeutics Inc-Weaknesses
PTC Therapeutics Inc-Opportunities
PTC Therapeutics Inc-Threats
PTC Therapeutics Inc-Key Competitors
Section 3-Company Financial Performance Charts
PTC Therapeutics Inc-Financial Ratios
Financial Ratios-Capital Market Ratios
Financial Ratios-Annual Ratios
Financial Ratios-Interim Ratios
Financial Ratios-Ratio Charts
Section 4-Appendix
Ratio Definitions
About GlobalData
Contact Us
Note*: Some sections may be missing if data is unavailable for the company
List of Figures
PTC Therapeutics Inc, Performance Chart
PTC Therapeutics Inc, Ratio Charts
List of Tables
PTC Therapeutics Inc, Key Information
PTC Therapeutics Inc, Key Ratios
PTC Therapeutics Inc, Share Data
PTC Therapeutics Inc, Major Products and Services
PTC Therapeutics Inc, History
PTC Therapeutics Inc, Key Employees
PTC Therapeutics Inc, Key Employee Biographies
PTC Therapeutics Inc, Key Operational Heads
PTC Therapeutics Inc, Other Locations
PTC Therapeutics Inc, Subsidiaries
PTC Therapeutics Inc, Key Manufacturing facilities
PTC Therapeutics Inc, Key Competitors
PTC Therapeutics Inc, SWOT Analysis
PTC Therapeutics Inc, Ratios based on current share price
PTC Therapeutics Inc, Annual Ratios
PTC Therapeutics Inc, Interim Ratios
Currency Codes
Capital Market Ratios
Equity Ratios
Profitability Ratios
Cost Ratios
Liquidity Ratios
Leverage Ratios
Efficiency Ratios
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PTC Therapeutics Inc, SWOT analysis, SWOT, Strengths, Weaknesses, Opportunities, Threats, Corporate Strategy, Key Ratios, Share Data, Performance, Financial Performance, Overview, Business Description, Major Product, Brands, History, Key Employees, Key Operational Heads, Strategy, Key Competitors, Company Statement, Capital Market Ratios, Financial Ratios, Annual Ratios, Interim Ratios, Ratio Charts
Company Brochure


text:
|Single Status
Single Statusme cry.. who will accept me for who I am. Please appear soon
Ok let me get this straight, you are relying on me being a gentlemen .. lmao you idiot!!
Oh well looks like mr jack dainels will be my date along with mr sambuca who will get me drunk and mr red bull will fly me home safely
OK Christmas time is here now where is the hot guy and the mistletoe :D
No, I am not single. I am in a long distance relationship because my boyfriend lives in the future.
No one can tell me what to do, how to do it, or when to do it. I'm single, I can do what the hell I like now and it's great
Met Mr. wrong, Mr. jerk, Mr. cheater, Mr. liar, Mr. horn-dog. Where's my Mr. right? Have you seen (him/her)?
Looking for that boy who deserves the key to my heart
Life's a bitch then you die or marry one...hm it both is death one way or another just one is less painful!!!
Just because my status says I'm single, does NOT mean I'm looking! My eyes will remain closed until that special someone is brave enough to try to open them!~
It's not that I can't stop being single, it's that I haven't found anyone that's been up to the challenge.
In NEED of a F..bad.. buddy ;)
If you're single, focus on being a better you instead of looking for someone better than your ex. A better you will attract a better next.
I'm tired of hearing 'There are plenty of fish in the sea'! Who wants a fish?? They're slimy and they smell!!
I'm single. You're single. You like me. I like you. Am I missing something?
I'm single but if you would like to change that like this status. :)
I'm single because i am saving myself for someone who deserves me.
I'm only single because out of all the men out there I just haven't met one brave enough to take me on or who can handle me, but you are welcome to try.
I'm not single. . . I'm riding solo and loving it!
I'm not single because I don't pray for love. I'm single because I don't play around with love.
I'm not picky, I just have standards.


text:
Conversations, Collaboration, and Community Change with Paul Born
NorthSky Nonprofit Network
Wednesday, April 9, 2014 from 9:00 AM to 12:00 PM (EDT)
Who's Going
San Francisco, California
London, United Kingdom
Florence, Italy
Event Details
Please join us as we explore how we can work together to achieve more! Rotary Charities and the NorthSky Nonprofit Network will be hosting Paul Born from the Tamarack Institute on Wednesday April 9 from 9 a.m. to 12 p.m. We will build on our recent collective impact training, explore the collaboration continuum and move our networks forward to achieve even better outcomes.
Paul Born is the President and cofounder of the Tamarack Institute, which since 2001 has provided leadership in Canada on issues of citizen engagement, collaborative leadership and community innovation. Prior to Tamarack, Paul was the Executive Director and co-founder of the Community Opportunities Development Association one of Canada's leading community economic development organizations that was recognized by the United Nations as one of the top 40 projects in the world. An author of four books, Paul is a motivational speaker who loves the power of stories.
Questions? Please contact Mo Stych via email or call (231) 941-4010.
When & Where
Traverse City Civic Center
1213 W Civic Center Dr
Traverse City,
Wednesday, April 9, 2014 from 9:00 AM to 12:00 PM (EDT)
Add to my calendar
NorthSky Nonprofit Network
NorthSky Nonprofit Network is the capacity building program of Rotary Charities of Traverse City providing the region's nonprofits, government and social enterprises with consulting, professional development, coaching services and tools to help build their capacity and support sustainability. NorthSky also serves as a conduit for new resources, securing state and national support and partnerships to bring technical and financial resources home to nonprofits and social enterprises in this region. As part of Rotary Charities' mission, NorthSky also serves in leadership roles, participating and facilitating regional initiatives.


text:
Learn more about CROCKFORD PARK PROPERTIES LIMITED. Check the company's details for free and view the Companies House information, company documents and list of directors.
Know about every new company document that is added!
Take advantage of our watch this company feature free of charge and have notifications sent directly to your inbox. Whenever a new document appears on this website, or if their particulars change, you will be immediately informed about such changes. To monitor these changes, all you need to do is click on watch this company.
|Tangible Fixed Assets
|£ 20
|Current Assets
|£ 797,464
|£ 61,870
|Shareholder Funds
|£ 8,371,623
|Profit Loss Account Reserve
|£ 4,376,075
|Revaluation Reserve
|£ 3,792,548
|Called Up Share Capital
|£ 132,000
|Total Assets Less Current Liabilities
|£ 8,371,623
|Net Current Assets Liabilities
|£ 1,366,482
|Creditors Due Within One Year
|£ 2,163,946
|Cash Bank In Hand
|£ 735,594
|Share Capital Allotted Called Up Paid
|£ 132,000
|Number Shares Allotted
|132000 Ordinary shares of £1 each
Information about the Private Limited Company CROCKFORD PARK PROPERTIES LIMITED has been prepared for information purposes only. It is not intended to be nor does it constitute legal advice. This is public information provided by the official company register.


text:
This product contains 3d Cartoon Monkey
Render: Vray and mental ray
-High quality polygonal model.
-Detailed enough for close-up renders. For high-res rendering!
-Hand and legs are separate from body
You can convert it in Low poly model (select Mesh> Attribute editor > Select poly Smooth Face TAB> SET 0 division level)
- For EYE Lattice Tool is Attached with Character eyes. For Aim Constrain of eyes Select LT & RT_eye_ball Group (Monkey->LT_eyes->LT_eye_ball) as a Child. Eye Lid are also Available in group LT & RT_eye_lid (Monkey-> LT_eyes-> LT_eye_lid)
Polygon Count - Division Level 1 – 13,994 Division Level 0 – 9,368
File Formats Available: .mb(maya 2011 binary) .ma(maya 2011 asci) .Fbx
The model is provided with high resolution textures in JPG
textures (2048×2048) bump (2048×2048)
Best For: Animation Project Game Project E-Learning
Please rate when you buy,


text:
Spicer approves agreement with new administrator
SPICER -- Leslie Valiant will begin duties as the new city administrator and finance director for the city of Spicer on April 13.
City council members unanimously approved an agreement with Valiant during a special meeting on Saturday, Spicer Mayor Denny Baker said.
Valiant, who is from Litchfield, is currently working for the city of St. Joseph.
She has more than 20 years of experience in municipal government and is currently completing a degree in municipal financial management, according to the mayor.
Valiant emerged as the favored candidate from a field of 56.
Baker said her experience and background in municipal finances makes her both qualified and ready to step right into her new role. She is already familiar with the accounting and utilities billing systems used by the city.
The mayor said the city has been fortunate to have interim administrator Wayne Thompson assist while the search for a new administrator was underway.
Thompson will work alongside Valiant to help with the transition period, he added.
Valiant succeeds former administrator Andrea Aukrust.
Aukrust and the city of Spicer recently finalized a severance agreement; Spicer and the League of Minnesota Cities will pay Aukrust $25,000. The former administrator had threatened litigation against the city since mid-November for reasons never stated publicly.


text:
Welcome to Gillthwaite Rigg, Heathwaite Manor.
Lake District bed and breakfast
Gillthwaite Rigg
Gillthwaite Rigg is the central portion of Heathwaite Manor, an Arts and Crafts house built in 1904.
Come here to enjoy the architectural delights of the Arts and Crafts movement, and complete peace and quiet. 12 acres of private woodland to wander in, with red and roe deer, our badger set, and a wide variety of birds including nesting ravens and buzzards
Explore the entire Lake District from here, and even have a day out in the Yorkshire Dales.
Close to home we have:-
And while you're here why not visit Crosthwaite, Cumbria Village of the Year for


text:
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text:
Discrete diffusion models to study the effects of
The ISIBM International Joint Conferences on Bioinformatics, Systems Biology and Intelligent Computing (IJCBS)
The ISIBM International Joint Conference on Bioinformatics, Systems Biology and Intelligent Computing (IJCBS)
The challenge today is to develop a modeling and simulation paradigm that integrates structural, molecular and genetic data for a quantitative understanding of physiology and behavior of biological processes at multiple scales. This modeling method requires techniques that maintain a reasonable accuracy of the biological process and also reduces the computational overhead. This objective motivates the use of new methods that can transform the problem from energy and affinity based modeling to information theory based modeling. To achieve this, we transform all dynamics within the cell into a random event time, which is specified through an information domain measure like probability distribution. This allows us to use the "in silico" stochastic event based modeling approach to find the molecular dynamics of the system.
In this paper, we present the discrete event simulation concept using the example of the signal transduction cascade triggered by extra-cellular
Our results illustrate the accuracy of the proposed diffusion models in explaining the molecular/ionic transport processes inside the cell. Also, the proposed simulation framework can incorporate the stochasticity in cellular environments to a certain degree of accuracy. We expect that this scalable simulation platform will be able to model more complex biological systems with reasonable accuracy to understand their temporal dynamics.
Advancement in high-throughput biological experiments has generated huge amounts of empirical data on the molecular foundations of biological structures and functions that require computer models for analysis. The next challenge is to understand the complex interactions of biological processes and functions creating the intelligence of life. The complexity increases manifold as we move into higher scales: interaction of large ensemble of cells in a tissue or interaction of tissues in an organ. Thus, we need to develop a comprehensive model integrating molecular and genetic data for quantitative studies of physiology and behavior of biological processes at multiple scales
Existing models used in the understanding of biological processes can be divided into three main classes. Quantum Mechanics based models (femtosecond-picosecond;
Recently, it was shown that gene expression type interactions create a stochastic resonance
The rest of the paper is organized as follows. We briefly present an overview on the different modeling and simulation paradigms in Section Modeling and Simulation landscape. Next, we introduce the discrete event based simulation framework in Section Discrete Event Simulation Technique. In Section PhoPQ Biological System Model, we present the concept of event abstraction of biological pathways using the PhoPQ biological system in Salmonella. We introduce the analytical models for the molecular transport mechanisms in Section Analytical Models for Molecular Transport. In Section Numerical Results for the Molecular Transport Models, we present the performance results and validation of the molecular transport models. Section Simulation Results of the PhoPQ system presents some in silico results from the discrete event simulation of the PhoPQ system, to validate the performance of the simulation engine and also provides some examples of in silico hypothesis tests. Finally, we conclude in Section Conclusion and provide some directions for future work. A short version of this paper appeared in
Modeling and simulation landscape
The inherent complexity involved in the molecular processes governing life has motivated the development of computational modeling and simulation techniques to decipher their ensemble dynamics. In this section, we provide an overview of the wide spectrum of in silico modeling and simulation methodologies available for system-wide study of biological processes.
Mathematical models have being extensively used for intracellular molecular networks like kinase cascades and metabolic pathways, gene regulatory networks and protein interaction networks. A large section of the work in computational models of biological systems is based on classical chemical kinetic (CCK) formalism based on a set of ordinary differential equations (ODE), also known as reaction rate equations or mass action kinetics
While continuous-deterministic reaction models are capable of capturing behavioral dynamics for spatially homogeneous systems with large number of molecular species, the inherent stochasticity observed in many biological processes (gene expression and protein synthesis) have proven the limitation of CCK in accurately representing biological processes. In a recent article
Another technique in building abstract computational models for biosimulation has been developed based on Petri nets
Other simulation methodologies, based on object oriented and agent based (ABM) paradigms have also been studied for in silico modeling of complex bio-processes by Uhramacher et.al
The overarching theme, guiding the development of in silico modeling and simulation tools, is developing models based on continuous-deterministic ODEs or using stochastic simulation algorithms (SSA) for approximating the chemical master equation, which capture the temporal evolution of the biological process dynamics. Most of these techniques focus on molecular pathways, which are represented in graphical and mathematical formalisms, treat spatial dynamics in terms of well-defined cellular compartments, and abstract the complexity in terms of estimated parameters and rate constants. In the next section, we briefly outline our modeling and simulation technique, based on a discrete event system specification, where the molecular events (representing reactions, molecular/ionic transport etc) are mechanistically modeled depending on their biophysical characteristics to compute the probability distribution of their execution times. A discrete event simulation system then links the biological processes to simulate the behavior emerging from the interaction of the events in time.
Discrete event simulation technique
In a discrete-event based approach, the dynamics of the system are captured by discrete time-space state variables, where an event is a combined process of large number of state transitions between a set of state variables accomplished within event execution time. The underlying assumption is that it is possible to segregate the complete state-space into such disjoint sets of independent events which can execute simultaneously without any interaction.
We consider a biological process as a system of resources (typically the various molecules, ions, ribosome-chromosome operon etc involved in the system) that periodically change between one of the following four states (Figure
Figure 1
State transition diagram of an enzyme during its life cycle.
State transition diagram of an enzyme during its life cycle A biological process is visualized as a system of resources periodically changing between one of the following four states based on the underlying resource usage algorithms: (i) 'used' (e.g, an enzyme is busy in a reaction), (ii) 'idle'(e.g, an enzyme is free to enter a new reaction), (iii) 'created' (e.g, a molecule is created by a reaction) and (iv) 'decayed' (e.g, a molecule is in the process of disintegration at the end of its life-cycle). The state transitions are governed by transition flow rates of the dynamic functions involved in it. The process is initiated by a set of input signal(s) from the external world to the system. These input signals initiate the creation of dynamic events which drive the simulation across in time domain, capturing how the system resources change states.
Two types of event models are required for this: (1) event execution time, and (2) probability of next event type. Figure
Figure 2
Modeling scheme for pathway abstraction
Modeling scheme for pathway abstraction Schematic representation of the two types of event models required in our simulation approach: (1) event execution time, and (2) probability of next event type. The figure shows a section of the reaction pathway in a biological process with these two types of events.
To illustrate the concept, we present the discrete event modeling of the PhoP/PhoQ two component regulatory system which controls the expression of essential virulence traits in Salmonella Typhimurium depending on the concentration of extra-cellular magnesium
Figure 3
Biological processes involved in the PhoPQ process in Salmonella
Biological processes involved in the PhoPQ process in Salmonella functional event diagram of the PhoP/PhoQ two component regulatory system with the list of discrete events included in the simulation based on the available knowledge of the system.
PhoPQ biological system model
In Salmonella, virulence is produced by the two-component PhoPQ system that is activated by
Mg2+ receptor Signaling Process
Normally a biological process is defined by a pathway (experimentally determined by biologists) that shows the cascade of biological functions in time. Currently, many pathway databases have been established maintaining this record for different species which we use to understand this process. With the departure of a
Thus we can identify the following discrete events from the PhoPQ pathway: with the departure of a
Thus we can identify many different biological functions and separate models are required to estimate their characteristics. The models for cytoplasmic reactions
Analytical models for molecular transport
From the PhoPQ system, we find that an important process that we have to model is the movement of molecules (
Model 1: the diffusion model
The actual diffusion model of
Figure 4
A simplified illustration of bacterial cell membrane with ion channels
A simplified illustration of bacterial cell membrane with ion channels Schematic for the actual diffusion process of
where, for convenience, we assume that the capillary is infinitely long. Here,
Because the solute bath in which the capillary sits is large, it is reasonable to assume that the chemical concentration at the tip is fixed at
The solution of this problem is given by
Theorem 1
Proof 1
It is also possible to determine the diffusion coefficient by solving Eqn 4 for
Also, from Eqn 2 it can be observed that
Table 1
Estimates of diffusion times for typical cellular structures, computed from the relation
10 nm
100 ns
thickness of cell membrane
1 ms
size of mitochondrion
100 ms
radius of small mammalian cell
60 s
radius of squid giant axon
1 mm
16.7 min
half-thickness of frog sartorius muscle
2 mm
1.1 h
half-thickness of lens in the eye
5 mm
6.9 h
radius of mature ovarian follicle
2 cm
2.6 d
thickness of ventricular myocardium
31.7 yrs
length of a nerve axon
These diffusion times have been estimated from Model 1.
Model 2: diffusion model considering the ion flux
For better analysis of the diffusion process, we need to consider the ion flux through the membrane of width
If the process is in steady state so that the ion flux everywhere in the channel is the same constant, then the total flux,
Theorem 2
Proof 2
Thus we get the time domain analysis for the concentration of
Theorem 3
Proof 3
The third diffusion model basically characterizes reaction-diffusion systems and can be simply computed by convoluting the event time distributions (which are random variables) of a reaction model and any of the above diffusion models.
Numerical results for the molecular transport models
Here we present the numerical results for our diffusion models and Table
Table 2
Parameter Estimation for the numerical plots
Salmonella cell
Diameter of an ion-channel (d)
10 × 10–10
Cross-sectional area of ion-channel (
Number of ion-channels (
List of parameters used to generate the numerical results on the two diffusion models reported in the paper.
Figure 5
Inter-arrival time vs number of molecules for diffusion model 1
Inter-arrival time vs number of molecules for diffusion model 1 Inter-arrival time of diffused molecules for molecular concentrations ≃ 10–9, 10–6, 10–5, 10–4 moles respectively governed by Model 1. This model as stated earlier is suitable for diffusion of uncharged molecules. The figure shows that the inter-arrival time increases with increasing number of molecules diffused in. This is because the concentration gradient reduces with more molecules diffusing in, resulting in larger time required for the molecules to move in. Also, it is observed that larger the initial concentration, the lesser is the inter-arrival time. This is expected due to a higher concentration gradient. This inter-arrival time distribution can be easily fitted to an exponential distribution.
Figure 6
Inter-arrival time against number of molecules for diffusion model 2
Inter-arrival time against number of molecules for diffusion model 2 Inter-arrival times for diffusion model 2 where the potential gradient is considered. We assume a constant potential gradient of 60mV for the molecules to overcome for diffusion to take place. The inter-arrival times are higher than the first model because the molecules have to overcome the potential gradient as well in order to diffuse. Here, the exponential increase in the inter-arrival times can be observed more clearly. This scenario is best depicted by the curve for concentration 10–9
Note that model 1 is standard and we estimated the inter-arrival times of
Simulation results of the PhoPQ system
As the arrival/departure of
The simulation framework also uses the holding time estimates of other elementary biological processes such as cytoplasmic reactions
Modeling validation and performance measurement
The efficacy of an in silico modeling and simulation approach is governed by
(a) validation of the model against existing wet-lab experimental results,
(b) effective calibration and sensitivity analysis of the key parameters governing the biological model and
(c) hypothesis testing of different conditions on the biological system which can give further insights for novel experiments in the future.
In this section, we employ the discrete event based stochastic simulation framework to model the dynamics of single cell dynamics, specifically, the effect of the PhoPQ two-component signal transduction pathway on the expression of virulence genes involved in bacterial pathogenesis of the gram-negative bacteria Salmonella Typhimurium. While the simulation system can be used to model the temporal dynamics of different regulatory pathways in a bacterial cell, we focus on the particular system in this work as it provides,
1. Existing wet-lab experimental setup and results
2. The system involves the interaction of signal transduction with subsequent expression of genes governed by the upstream signals
3. The gene regulation pathway as built based on existing literature on the two-component system provides various regulatory mechanisms including up and down regulation of genes, and positive feedback effects which can serve to test different hypothesis in silico.
4. As the system involves complex biological functions like gene regulation and protein expression, whose exact molecular mechanisms are not always well known, it provides a platform to test the efficacy of granular model abstraction based on available knowledge, on the behavior at a systems level.
In the rest of the section, we start with a brief description of the wet lab experimental system, moving on to present the detailed results of in silico analysis. We show how the discrete event simulation framework can be used for hypothesis-driven analysis of different conditions in silico for the PhoPQ system.
In-silico model validation with wet lab experimental system
The experimental setup, explained in details in
In the experimental system, low
Figure 7
Effect of
Effect of
Figure 8
Effect of low
Effect of low
Figure 9
Effect on the system output when toggled from high to low
Effect on the system output when toggled from high to low
Also, the platform provides flexibility in changing these conditions and resources to generate synthetic, hypothetical results for a better understanding of the test system. In the next subsection, we outline the system and simulation parameters and present the results of the in silico experiment.
Figure 10
Experimental results: concentration of phoPp molecules with time with
Experimental results: concentration of phoPp molecules with time with
Simulation setup
Next, we setup the 'dry-lab' experimental system for the signal transduction and subsequent gene regulation pathway involved in the test-bed. The in silico experiment is initialized with the system molecular resources and biological parameters associated with the probability distribution functions of the different event holding time modules. In this experiment, we focused on parameters associated with the Salmonella bacterial cell based on the CCDB database
Table 3
System model and simulation parameters
Biological Parameters
Length of Genome
Number of Genes
Rate of transcription
40 nucleotides/sec
Rate of translation
18 residues/sec
Area of cell
6 × 10–12
Volume of cell
Diffusion coefficient of
Diffusion coefficient of protein molecule
7.7 × 10–6
Average mass of a protein molecule
25 kDa
Average diameter of a protein molecule
5 nm
List of parameters used to generate the complete discrete event based simulation results
We used comprehensive knowledge extraction from PubMed database
Figure 11
PhoPQ gene regulatory pathway
PhoPQ gene regulatory pathway Manually-curated comprehensive gene regulatory pathway network for the phoPQ system. The two component pathway involves transcriptional regulation of 44 genes, 5 of which are involved in another cascading two component system (pmrBA). A positive feedback loop exists in this pathway, in the form of up regulation of phoPQ gene by the system. The figure shows the complete pathway, with the positive feedback loop marked in dark color. The pathways have been constructed using the Cell Designer 3.0 software which presents a structured (Extensible Markup Language (XML)) format data that can be easily rendered into the discrete event simulation framework. The process involved 112 experimental reports of this system extracted from PubMed
For the current system, the simulation focused on tracing the effects of signaling events (
In order to simulate similar conditions "in silico", the simulation was configured to run with low
Figure 12
Effect of low
Effect of low
In another simulation experiment, the system was started with high
Figure 13
In silico system output when
In silico system output when
Figure 14
Simulation results: concentration of phoPp molecules with time with
Simulation results: concentration of phoPp molecules with time with
Also, the condition of no resource starvation shows relative smoothness in output as obtained from continuous system models since the effect of low copy number of molecules on stochasticity
In silico hypothesis testing
The in-silico simulation allows the modeler to test the system under various synthetic conditions, in terms of system resource states, initial conditions and different combinations of environmental cues driving the systems (for example, the diffusion of
In order to capture the effects of varying the rate of diffusion of
Figure 15
Change in conc. of membrane phoQ
Change in conc. of membrane phoQ In order to capture the effects of varying the rate of diffusion of
Figure 16
Change in conc. of membrane phoP
Change in conc. of membrane phoP Simulation plot capturing the effects of varying diffusion rates on phoP. An interesting observation, not captured in the wet-test lab results, is the orchestration of the positive feedback loop of phoP, as identified in the knowledge extraction phase. As seen in this figure, the concentration of phoP in the system decreases initially; but once the expression of genes is triggered by phoPp (phosphorylated phoP), phoP starts appearing in the system. The corresponding effect on phoPp, which increases in concentration when
The in silico results on the test-bed pathway demonstrate the efficacy of the modeling and simulation approach for studying single cell dynamics. Particularly, the flexibility in event scheduling and resource state specifications allows a modeler to validate the effects of high and low copy number of molecules on different parts of the biological system. Moreover, the flexibility allows the simulation to be computationally efficient depending on the required granularity of the biological model and the resource state space considered
We have proposed a new "in silico" modeling technique capturing the temporal dynamics of biological systems at multiple scales that can be simulated by the discrete event technique. For this, we need the transformation of biological functions into information theory based measure like probability distributions of event time. We have presented one example of the transformation of a biological function (i.e., molecular transport time) driven by concentration and potential gradients in this paper. We also validated the molecular transport models and put together a discrete event simulation for the PhoPQ system to validate the system level dynamics based results with experimental estimates. We also used this molecular transport model to generate some in-silico hypothesis testing results on the PhoPQ system.
The proposed stochastic models meet the accuracy and computational speed requirements for modeling complex biological processes. These models are parametric and can be used for different cases of molecular transport. Once the complete set of mathematical models for the different biological functions are in place, it should be possible to reuse these models to construct other biological process models with marginal changes. The models provide for both speed of computation and flexibility that is required to model the dynamics of an entire cell. We envisage the development of an efficient tool for understanding the dynamics of complex biological systems that can model the multi-scale biological process at a coarse grain accuracy.
Competing interests
The authors declare that they have no competing interests.
Authors contributions
PG helped with the development of the model and simulation and generating the results. PG, SG, KB, SKD and CZ helped with conceptualizing the whole project and writing the paper. All authors have read and approved the paper.
The authors would like to acknowledge the National Science Foundation (NSF) and the University of Southern Mississippi for providing generous funds to accomplish this project. The authors also thank Dr. Simon Daefler's lab at the University of Texas, Southwestern Medical Center for providing the experimental results on the PhoPQ system. Publication of this supplement was made possible with support from the International Society of Intelligent Biological Medicine (ISIBM).
This article has been published as part of
Computational Systems Biology
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ECell: Software environment for whole cell simulation
Continuous System Modeling
Dizzy: Stochastic simulation of large scale genetic regulatory networks
StochSim: modeling of stochastic biomolecular processes
Accommodating space, time and randomness in network simulation
DimSim: A Discrete Event Simulator of Metabolic Networks
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Translating the Noise
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iSimBioSys: A Discrete Event Simulation Platform for 'in silico' Study of Biological Systems
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Deviant effects in molecular reaction pathways
Modular modeling of cellular systems with ProMoT/Diva
STODE automatic stochastic simulation of systems described by differential equations [abstract]
A general method for numerically simulating the stochastic time evolution of coupled chemical reactions
Concerning the validity of the stochastic approach of chemical kinetics
Efficient Exact Stochastic Simulation of Chemical Systems with Many Species and Many Channels
Approximate accelerated stochastic simulation of chemically reacting systems
Binomial leap methods for simulating stochastic chemical kinetics
Time accelerated Monte Carlo simulations of biological networks using the binomial tau-leap method
Stochastic petri nets: Modelling, stability, simulation
Quantitative modeling of stochastic systems in molecular biology by using stochastic Petri nets
Hybrid Petri net representation of gene regulatory networks
Modelling the influence of RKIP on the ERK signalling pathway using the stochastic process algebra PEPA
Theory of Modeling and Simulation
Discrete event systems specification in systems biology - a discussion of stochastic pi calculus and DEVS
Concepts of Object and Agent Oriented Simulation
Modeling and Simulation of Mobile Agents
A component based simulation layer for JAMES
AgentCell: A Digital Single-Cell Assay for Bacterial Chemotaxis
Implementation of a discrete event simulator for biological self-assembly systems
The Pleitropic Two-Component Regulatory System PhoP-PhoQ
Unravelling the mysteries of virulence gene regulation in Salmonella Typhimurium
An Analytical Model to Estimate the time taken for Cytoplasmic Reactions for Stochastic Simulation of Complex Biological Systems
Stochastic Modeling of Cytoplasmic Reactions in Complex Biological Systems
Holding Time Estimation for Reactions in Stochastic Event-based Simulation of Complex Biological Systems
A Markov Model based Analysis of Stochastic Biochemical Systems
Modeling protein-DNA binding time in Stochastic Discrete Event Simulation of Biological Processes
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Ion channels, or stochastic networks with charged customers [abstract]
Computational Cell Biology
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Probing Gene Expression in Live Cells, One Protein Molecule at a Time
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