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Today, I just wanted to extend my thoughts and prayers to Sarah and other British MS friends. The attacks in London have brought back so many memories of the 9/11 attacks. Godspeed to all of you.
Welcome to the world's leading forum on Multiple Sclerosis research, support, and knowledge. For over 10 years, This is MS has provided an unbiased community dedicated to Multiple Sclerosis patients, caregivers, and affected loved ones.
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This elegant Signature C jacquard wallet is luxuriously framed with leather trim and finished by hand with an iconic dogleash clip and classic plaque logo. It comes ready to wrap in a signature gift box.
Currently, Coach product bought on Belk.com cannot be shipped to Hawaii, US Territories or APO/FPO addresses.
- Credit card and multifunction pockets; full-length billfold compartments
- Zip-top closure; wrist strap attached
- 7.75-in. (L) x 4.25-in. (H) x .75-in. (W)
- Packaged in a Coach gift box
- Style No: 48691B
- Signature fabric
COACH products cannot be shipped to Hawaii, APO/FPO addresses, the Virgin Islands or Guam.
Shipping & Returns
Shipping your purchase is easy on belk.com. Depending on the destination of your package, you can expect it to arrive within 4-7 business days. Shipping Information
Returns are easy on belk.com. Easy returns
Founded in a New York loft in 1941, Coach has grown into an iconic American luxury brand, bringing its New York heritage of tradition, innovation and quality craftsmanship to discerning customers from all over the globe. Whether it's handbags, men's bags, women's and men's small leather goods, weekend and travel accessories, footwear, watches, outerwear, scarves, sunwear, fragrance or jewelry, every precisely crafted piece is made with care, using premium leathers, handcrafted hardware and fabrics from the world's best mills. All are marked with the Coach logo to show the brand's continued dedication to excellence and modern design.
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subset: commoncrawl


text:
हेर्नुहोस भिडियो
It resembled they were imparting the solid power of profound devotion to each other, that when they give a solitary call anybody of them are prepared. They met much of the time and have intercourse with each different as they were upbeat and it resembles general timetable to meet each other and they were cheerful doing that.
One day the young lady call that kid, she was chatting on telephone with him and she says that nobody is at her home that day so she call him at home. Kid gets energized believing that he could invest some quality energy with young lady and he was so cheerful and he gets prepared and goes to her home and finds that it was bolted and he calls the young lady and she says nobody is at home so she requesting that he go to sustain her creatures.


text: Cowboys owner Jerry Jones on drafting Smith: 'I think our fans are sophisticated enough to know how important a really talented offensive lineman can be' http://cowboysblog.**************/archives/2011/04/cowboys-owner-jerry-jones-on-d.html ByRainer Sabin / Reporter rsabin@************** | Bio 11:23 PM on Thu., Apr. 28, 2011 | Permalink It didn't have the "wow" factor a showman like Jerry Jones may have wanted. But the Cowboys' owner seemed satisfied with the team's choice of USC offensive tackle Tyron Smith with the ninth overall pick of the NFL Draft on Thursday. "He was unique enough in his skills," Jones said. "And he's very athletic."


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Sullivan & Cromwell is a law firm with a long and storied history. Founded in 1879 by Algernon Sullivan and William Cromwell, the firm was on hand for the foundation of both General Electric in 1882 and United States Steel in 1901. Today, Sullivan & Cromwell has about 800 lawyers in four US and eight international offices. It focuses on advising companies – more... on mergers and acquisitions and on corporate law for industrial, commercial, and financial clients, more than half of which are located abroad. Sullivan & Cromwell's clients include industrial and commercial companies, financial services firms, private funds, governments, educational and charitable institutions, and individuals, estates and trusts.
Geographic Reach
Sullivan & Cromwell operates around the world through 12 offices in Beijing; Frankfurt; Hong Kong; London; Los Angeles; Melbourne; New York; Palo Alto, California; Paris; Sydney; Tokyo; and Washington, DC. – less


text:
The Mountains Next Door
€ 19,49
Besorgung - Lieferbarkeit unbestimmt
Juli 1991
BeschreibungThe Rincon Mountains east of Tucson are a small and seemingly undistinguished range; rounded and arid, they are more a site for foothill walks than serious exploring. Yet these unassuming mountains disclose many wonders and curiosities upon close inspection, as Janice Emily Bowers discovered while conducting a botanical study there. Over the course of two years she made 38 excursions into the Rincons some for two or three days at a time and garnered not only plant specimens but thoughts along the way. The Mountains Next Door is the first book to describe and celebrate the natural history of these mountains that even longtime Arizonans may often take for granted. "I watched the seasons march through the canyons," writes Bowers, "followed the wildflower parade from February through November, and throughout it all realized that I could travel in the Rincon Mountains forever and never learn all they contained." It is also a book of meditations, as Bowers reflects upon the meaning of nature, the similarities between the scientific and creative processes, the value of wilderness in the face of urban encroachment, and other ideas.
Participating in the long tradition of reflective natural history writing, she has produced a memorable book that depicts the delights and dilemmas of field botany as it explores the perennial struggle between science and mysticism that tugs at every naturalist's heart.
PortraitJanice Emily Bowers is a botanist with the U.S. Geological Survey in Tucson.
Untertitel: New. Sprache: Englisch.
Verlag: UNIV OF ARIZONA PR
Erscheinungsdatum: Juli 1991
Seitenanzahl: 147 Seiten
Format: gebunden


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by Jo
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text:
What do you think about Rhinoplasty using laser?
I recently heard about rhinoplasty using laser. What is the difference between conventional and laser nose surgery? is it applicable for septoplasty as well? and what about the healing process ( less bruises and swelling?) and the results using laser in comparison with the normal process? is it worth it? Thank you!
Doctor Answers 1
Rhinoplasty by Laser
Hi MikyFr,The advantage of laser is tp minimize the bleeding caused by small blood vessels, however, it will not work for bigger vessels, and it will never substitute cold-knife for skin incision. Laser will however be beneficial for subcutaneous and soft tissue resection, thus helping minimize bruising, but a meticulous conventional technique can also do the same.
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.


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You are currently using an unsupported web browser.
We support the latest versions of these browsers:
If you have any problems while attempting to download a browser, you should contact your organization's system administrator.
For any questions related to Cvent, feel free to contact our Customer Care team.
Anchana Resort and Spa - Pranburi is more like an enormous luxurious home than a tropical resort. Nestled in between majestically mountains and facing stunning tropical waters, Anchana Resort and Spa - Pranburi is one home you will never want to leave.
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(You save $113.52)
Free Shipping, No Tax
Daugava Rust Brown Floor Lamp - Tall, Primitive Style Base with a Mottled Rust Brown Finish and A Bronze Metal Mounting. Rectangular, Off-White Hardback Linen Shade. Houses 1) 150 Watt Bulb.
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Lampshade: Height: 11 - Top: 17W x 9D - Bottom: 18W x 10D - Rectangle Hardback
Bulb / Watt: 1) 150 Watt Bulb
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Type: Living Room Lamp
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Before You Purchase: 1) Check to make sure that the bottom width and depth of the shade is narrower than the table on which it sets. This is typically important on narrow surfaces such as buffet tables, dressers, or bedside tables. 2) Check the overall lamp height to make sure it is not too tall or too short.
Free Shipping to Lower 48 States: Satisfaction Guaranteed. We replace any items damaged in shipping at no cost. Please call for instructions. See Shipping & Returns Policy at bottom of page for details.
About Uttermost Lamps: Great Home Accessories: Innovative Design at Reasonable Prices.
Product: Uttermost, Daugava Rust Brown Floor Lamp


text:
When Will I Receive My Order?
Signature Almond Syrup
The rich and delicate flavor of almonds will enhance your beverage. With a unique blend of organic agave, maple and pure cane sugar, this delicious syrup works well in lattes, iced coffees, teas and so much more.
750 ml Glass Bottle
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The 750 ml syrup is sold in the same premium glass bottles used at your favorite cafe, restaurant or bar.
750 ml bottle
Pure cane sugar, water, organic agave syrup, maple syrup, natural flavors, citric acid.


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Located someone who looks right? Send them a word or two or just a wink and see what develops from there. With a little luck you'll be on your way to locating your suitable partner.
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Hospital Fernando Fonseca, Lisbon, Portugal
Correspondence to: Boban Thomas, MD, FCCP, Hospital Fernando Fonseca, Av Almirante Gago Coutinho, Lisbon 1700-029, Portugal; e-mail: firstname.lastname@example.com
In the excellent special report by Dr. Vincent on evidence-based medicine in the ICU, no mention was made about the beneficial effect of daily hemodialysis (DH) in patients with acute renal failure (ARF). Schiffl and colleagues1and Bonventre2 have demonstrated that a regime of DH was superior to alternate-day hemodialysis (ADH) in this cohort of patients who typically have a high mortality.1–2 Better uremic control, fewer hypotensive episodes, and more rapid resolution of ARF was noted in the DH group. Notably, among those patients with a normal urinary output at enrollment, 73% in the ADH group and only 21% in the DH group became oliguric. This could be related to the fewer hypotensive episodes in the DH group. Better uremic control and improved volume status could have contributed to the improved survival as well. This study, along with another study by Ronco and colleagues,3 call for intensive renal replacement therapy in the form of DH or continuous venovenous hemofiltration in all patients in the ICU with ARF.
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Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.


text:
Saving Grace
Three years ago the Guardian published an award-winning supplement featuring the story of Grace Mathanga, an ordinary African woman with HIV. To launch this year's Christmas appeal, which focuses on Aids in Africa, Sarah Boseley returns to Malawi to find out how Grace is doing now, and what her life can tell us about the future of the continent.
Doctor's act of kindness gives HIV-positive Grace a lifeline in stricken Malawi.
She is just 30 and has already lost her husband and child to HIV. The virus will slowly take her life too. But she could survive if she was given modern drugs.


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Category:Llambias House
This is a category about a place or building that is listed on the National Register of Historic Places in the United States of America. Its reference number is 70000846
English: Llambias House, a U.S. National Historic Landmark in St. Augustine, Florida on the U.S. National Register of Historic Places.
Media in category "Llambias House"
The following 10 files are in this category, out of 10 total.
- Fernandez Llambias House.JPG 4.41 MB
- St Aug NHL Llambias plaque01.jpg 1.99 MB
- St Aug NHL Llambias plaque02.jpg 2.59 MB
- St Aug NHL Llambias sign01.jpg 2.49 MB
- St Aug NHL Llambias01.jpg 2.14 MB
- St Aug NHL Llambias02.jpg 1.77 MB
- St Aug NHL Llambias03.jpg 1.35 MB


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"Add two functions to the contextual menu to copy and move files."
Add Copy To / Move To is a small utility, needing no installation, that lets you make some changes to the Windows contextual menu.
Add Copy To / Move To adds two new functions: one to be able to copy the selected file difrectly to a set folder, and the other to be able to move that file to a folder. It is interesting, above all, when you are continually copying/moving files from one place to another. When you need it no longer, you can delete, from the program itself, these two contextual menu options.
Add Copy To / Move To is completely free.


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Tote Bag
SF Against Stupidity* | Seaby Superfried
Our quality crafted Tote Bags are hand sewn in America using durable, yet lightweight, poly poplin fabric. All seams and stress points are double stitched for durability. Available in 13" x 13", 16" x 16" and 18" x 18" variations, the tote bags are washable, feature original artwork on both sides and a sturdy 1" wide cotton webbing strap for comfortably carrying over your shoulder.
After watching a documentary by Stephen Fry - Last Chance to see - we were alarmed by some of species extinction stats. This led to the inspiration for a series of designs to highlight the issue. We created a template and then developed a series of very different styles from the same starting point of a fluking whale. 50% of profit from this sale will be donated towards species conservation.


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Call our experts: 888.808.FINE
Shop Personalized StationeryCarlson Craft Wedding Invitations Customize any Address Stamp to match your style!
Select a quantity and printing method. Changes are easily made later.
This whimsical white invitation features a bride and groom accented by touches of sparkling glitter. Peach colored glittering bands accent the left and right sides of the card to complete the look. White envelopes with coordinating glitter accents are included.Our blank stock is compatible with most laser and ink jet printers. However, since each printer is different, we cannot promise that our products will be compatible. Read your printer's manual to determine whether or not blank stock will work for you. All blank stock sales are final.


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Click here to view sale items.
Can't find the item you are looking for using the search and browse tools above? View our special order catalog.
Stan's 3.30HD 15mm Hub Kit makes Stan's 3.30HD front hubs 15mm through-axle compatible. Installation is easy—just pull the old ones off and put the new ones on.
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text:
Your favorite gear
View Single Post
[insert joke here]
Join Date: Sep 2008
Location: Washington, DC.
Posts: 10,625
vCash: 450
Originally Posted by
Yeah tried them this weekend. I have tremendously wide feet and they fit me (9EE). I had them on for an hour in the store and they didn't hurt. I was reluctant to spend that much on any equipment but I have never had skates that fit me that well. I took them out for a skate and had to get the edge of the toe caps punched out a tad, now they fit awesome. It is so frustrating buying skates when your feet are an awkward size. I went to 2 different stores in Calgary and they wouldn't even let me try on the X 60's, saying my feet were too wide. All the other skates the arches of my feet hurt within minutes. Finally the 3rd store I went to the salesman also had wide feet and told me to try the new X60's. So I tried them and they fit awesome. It is just ridiculous dealing with salespeople some times.
Well, the vapor line is traditionally quite narrow. You would not have fit in a vapor 40. I'm guessing they're not aware that Bauer changed the fit on the line yet.
Oh, and I forgot to mention my other favorite piece of gear: Tackla pro 5000 pants. The prefect pant. Really.
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Rheem powervent water heater gas leak
Just installed a new Rheem powervent water heater (40 gallon) and my wife smelled gas in the basement a week later. I checked the gas lines with soap and water and didn't find any leaks, but I put my nose by the gas valve on the water heater itself and I can smell gas. The gas company verified that there's a ".03" leak there. They didn't red flag it.
I then called Rheem and the technical support person said that a gas "leak" there is normal. Is that correct? He said that without a small vent (which is where the leak comes from) there would be vaporlock. I'd like to get your advice. Thanks!
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text:
ED Magedson – Founder
Ripoff Report
Karen Bircharddfw, Texas United States of America
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This report was posted on Ripoff Report on 10/11/2012 07:12 PM and is a permanent record located here: http://www.ripoffreport.com/reports/karen-birchard/dfw-texas-/karen-birchard-committing-child-support-fraud-dfw-texas-953940. The posting time indicated is Arizona local time. Arizona does not observe daylight savings so the post time may be Mountain or Pacific depending on the time of year.
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text:
Elizabeth, Thursday 2nd January 1851
Word count: 1,538
Thursday 2nd January
Lambert Place
Drawing Room
We hear a carriage outside the window. Throwing her embroidery to the ground, she drew the heavy, brown curtain aside. I looked up to see what the fuss was., before shaking my head and turning away. As I did so, a brown curl slid our of place and onto my forehead. I pushed it away.
The girl at the window peered through the darkness to get a better look at the man steping out of the cart. He's wearing a black suit, a hat and shoes with a reflection of the moon dancing on them.
"It's father!" the girl turns and runs out of the room, her long blonde hair flowing out over her shoulders as she trips over her blue dress. I set aside my sewing, pick up my red skirt and follow.
The tall man stepped into the house as the blonde girl ran and threw her arms around his neck.
"Abbie, my darling girl! How I've missed you!" Abigail released him from the hug.
"Eliabeth, dear." He held out his arms for an embrace.
A young maid hurried down the hall and picked up the suitcases that had been dumped behind him.
"Ah, Gennie, please put that one in the sitting room?" he pointed to the small trunk she had tucked under her arm. Gennie nodded and hurried away.
"Where's Esther?"
"She's at her harp lesson, Father." Abbie answered with the sweetest of smiles.
"Oh yes, good." he paused for a second. "Well let's not block the hallway. It's nearly tea-time and your Uncle Benjamin and Aunty Matilda are coming over for a New Year's dinner. Put on something nice!" as we hurried away, he called out again. "And Abigail, something your mother will approve of please?"
Abigail titles her head back and groaned as she waltzed away.
"How's that new chamber maid of yours Matilda? Was her name Clare?" Mother asked
"Oh yes, her she's doing rather well actually." Matilda nodded.
There was awkward silence at the table, except for the chinking of soup spoons against bowls. Cousin Frederick glared across the table at me with his icy blue eyes that he gets from my grandmother, my mother and Matilda's Mamma. Abbie was gazing out of the window at the rain, streaking across the glass panes.
"Aunty Matilda, did you see what Amelia wore to the Christmas doo at the church hall? What did you think?" Esther restarted the conversation.
"Oh no, the red did not go well with her blonder hair, and you could almost see her ankles!" Matilda cried.
"And red is such a common colour, no, she'd look better in blue. But that emerald dress was beautiful on Ellen. She made it quite exquisite!" mother chipped in.
"The straight neckline-across the shoulder thing is very Venecian. I think it'll be the next big look." I predicted.
"I wish I could have gone." Primrose whispered.
At eleven and thirteen, Primrose and Abbie aren't allowed to go to parties and events. It was a surprise to even hear her talk. Being sixteen, nearly seventeen, Esther and I have been allowed to go to two parties, but not a ball yet, that would wait until our full 'coming out.'
When the meal was over we relocated to the sitting room.
"So how was your New Year celebration with Lord Pengleton?" Benjamin asked my father.
"Oh do tell us father!" Abbie gasped.
Daddy told us about the lunch and dinner he'd had with a Lord up in Suffolk, being careful not to leave out a detail, he even told us the colour of Lord Pengleton's cravat - pale pink. He was observant like that. Most men don't remember things like that, but our father remembered everything, right down to the patterns on the cushions and how tall the candles were.
Lord Pengleton had a big manor house, bigger than ours, and a few acres in the countryside. he wasn't young, but not quite old, with a son who was married with a daughter of his own. He was a respected and much-loved figure. Every year one of the lords held a New Years party and it was somewhat tradition, this year had been Pengleton's turn.
Daddy pulled the suitcase he had asked to be left in here from under the settee and opened it.
"I've gotten you all a little something, of course." he explained.
He produced a little brass broach in the shape on a flower with three red gems in the centre and a green one on the stem. He passed it across the low table to Matilda, who promptly pinned it to her red dress. It worked perfectly with the colours and she kept smiling down at it throughout the evening.
Next, Daddy pulled out two pocket watches and passed the silver one to Benjamin and the bronze to Frederick. There was a butterfly hair clasp for Primrose and a white shawl for my mother, "hand-knitted by the local women" my father insisted, with a ruby pin to hold it together.
But the last three were the best by far. He lifted out an intricately craved glass bottle and gave it to Abbie. She opened it and sniffed it.
"Oh Daddy, it's simply gorgeous!" she squealed.
He presented some low topped, heeled, cream shoes with lace around the top and golden curls embroidered into the side and top to Esther. The heels seemed to sparkle from the inside. Esther thanked him politely and slipped off her old shoes to try them on. They fit perfectly.
Last, he pulled out a pile of dark purple fabric, decorated with silver swirls and flowers. Shaking it out, I could see that it was the most elegant dress I had ever seen. It curved in in all the right places and the skirt fell to create a hoop, so I wouldn't have to pick it up when I walk. The purple fabric was long at the back, so it trailed behind me, and came up to my knees at the front, revealing a silver taffeta petticoat, falling so it just covered my ankles. There were silver bands around the moderate neckline, sleeves and hem.
Everyone was silent, just staring at my dress.
"Oh Daddy..." I gasped, unsure of what else to say. "Thank you!"
It was truly stunning. I couldn't wait to try it on, but now was not the time.
"Abigail, would you care to show Frederick and Primrose our new and improved rose garden?" Abbie scowled at being called her full name, but regained her compsture and faked a smile as she led them away, chattering happily.
"Girls, I think now is a good time to discuss your coming out." Mother started.
"Matilda knows the most qualified stylists and Benjamin meets a lot of young men with his job." Daddy explained.
Uncle Benjamin was a schoolmaster at Saint James' college, so he knew a lot of young men who attended. But they weren't just young men, they were rich young men, with charm and manners, and if not that, at least they had a good education.
"But father, surely we're too young for suitors?" Esther exclaimed.
"Not too young to start meeting people though. No buts!" Mother shot as I made to protest. "You are going to your first ball in two weeks."
There was another silence.
"You'll be seventeen soon, old enough to be legally married! This'll give you a headstart." Matilda soothed. "It'll be fun! I remember when I started going to balls."
She told us how she was so jealous of mother because she was older and came out first, and when she danced around the room when she came home for the first time, they waltzed around together. Two years later she had met Benjamin and they had clicked instantly. At this point she looked over at her husband and smiled.
She told us about how whenever mother came home form her art college up north she told them about this terrible boy who annoyed her so much, picked on her art if she ever got it wrong, but then he saved her artwork from the rain one day and it all went uphill from there.
I took time to analyse my Aunt and Uncle. Bejamin was in his forties or fifties, with think dark hair, slightly thinner each time she saw him. He was an eccentric character, quite charming with all his odd little quirks. It seemed even odder that a person like Matilda would love someone like him, but behind all the prim and proper front, the strict 'Children should be seen and not heard' outer shell, she was soft and gentle, sweet and shy. I could only imgaine what she must have been like as a girl, in wonder at the new world she was entering. She and Benjamin were deeply in love and that's what their marriage was about. I respected them for that.
My parents were done discussing things, and Primrose was due to go and see a school in the morning, meaning they had to be up early, so Uncle Benjamin, Aunt Matilda and Cousin Frederick and Primrose departed, leaving me to contemplate the idea of coming out and marriage and children of my own.


text:
Clue: "The Three Sisters" sister
We have 2 answers for the clue "The Three Sisters" sister. See the results below.
Possible Answers:
Related Clues:
- Ballerina Spessivtseva
- One of Chekhov's "Three Sisters"
- Marathoner Markova
- Gymnast Korbut
- Actress Baclanova of old films
- "Eugene Onegin" sister
- One of Chekhov's Three Sisters
- "Eugene Onegin" mezzo-soprano
- First name in gymnastics
- Masha and Irina's sister, in Chekhov
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- LA Times - August 23, 2015
- LA Times - February 12, 2009
- New York Times - January 19, 1997
Found an answer for the clue "The Three Sisters" sister that we don't have? Then please submit it to us so we can make the clue database even better!


text:
Gift Premium Subscription To pandp
Join Date:06-01-2009
Last Activity:06-03-2009 1:27 PM
Posted in thread: Why I carry a Glock for CCW on 06-03-2009 at 12:13 PM
I've fired too many Glocks to count in my lifetime and owned 3. For a long time there wasn't
anything that could compete with Glock. I have two friends that will only own Glocks, but
they've never rea...
Posted in thread: Wife is pissed but I am happy on 06-01-2009 at 06:09 PM
Well, I have been researching various pistols for the past couple of weeks, mainly because I
would like to have another concealed carry option available to me. I currently have a Ruger
sp101 (.357 rev...


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Catching up again.
I follow the shape shifter, keeping up with her easily. We pass a small town and the faint scent of vampire reaches my nose. Not wanting to intrude on another vampire's turf, I speed up, over taking the shape shifter for a moment. She shouts at me to slow down, so the moment we're out of the town, I comply, falling back to her speed. I can smell the bus fumes, off in the distance. Well at least I know I can trust her directions now. She swoops down and flies next to me.
'Nearly there, it's a few miles off.' I nod and take an unprompted left through a hedgerow. There are a lot of them around. She follows. 'Where you going?'
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'What now?' the shape shifter asks, landing beside me. Her tone is exasperated.
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'Oh! Good question. I had an idea earlier, but it's kinda cruel...' she bites her lip gently and I grin.
'Cruel?' I ask. 'He can deal with it. I'm getting off soon anyway,' I look into her doubtful eyes. 'You can come with me too, if you want,' I add. She laughs and then smiles at me.
'Well my idea was this,' she explains it to me, and I feel my grin growing with every second. I see what she means about cruel, but at this point, I'm a little beyond morals.
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does any one have any other good quality sources on Large esb suit makers other than MOW he is out to? Arkady is backed up for months...Preferably here in the states
does any one have any other good quality sources on Large esb suit makers other than MOW he is out to? Arkady is backed up for months...Preferably here in the states
Last edited by tommyboy; Mar 31, 2016 at 6:00 AM.
I think you'll be waiting at least a few moths with anyone. But BobaMaker makes a really nice one.
i found a guy on ebay who has new WHITE jumpsuits L XL XXL for sale for $30 free delivery....i just ordered a suit should be here by monday 4-11 i will post results of quality. his ID is army.navy55
@Arkady ..one of the nicest and most affordable out there. Id recommend her work to ANYONE! The wait your speak of is well worth it, and unfortunately most quality makers will have a wait time. If your in a rush, Fett may not be the best choice of costume lol. Not trying to be a jerk or anything, just letting you know that quality work takes time, and the makers that are booked up for a bit are booked up for a reason, they are the best out there at what they do.
That said, that jumpsuit you mentioned you picked up is going to need ALOT of work to get it to Fett spec. Not impossible though of course. If you have good sewing skills or a good seamstress you may be able to pull it off pretty well. Looking forward to the final product.
I concur. Arkady is the flight suit that you need.
i agree with the both of you guys !! i was not blessed with patience...or how to sew lmao
I went with Clothears. Payment plan and great communication.
this post was really more about alternatives if your not able to get or have the best since they are more expensive and take much longer to acquire. there is no substitute for quality this i know ! I wanted this to be more about cheaper do it your self alternatives
- - - Updated - - -
thanks for the info
Attachment 98280here is a mando that i made .the flight suit can go in any direction - color style ect.
arkady and loanstar!
Do you have access to a sewing machine? If you are doing a custom mando you can always create a similar suit with minimal sewing knowledge. It probably won't be as nice as Arkady or some of the other makers if it is your first time, but I did mine over the course of a weekend.
well my mother in-law sews i just found out... I will be shipping out that helmet to you in the morning (priority) i will PM or text you the tracking info i wana say thanks again for all you build threads you do a great job on your FYI-DIYs
There is a mmcc get to gether this weekend so im going to ask some of them about their sewing skills haha
update; I just received the coveralls/jumpsuit and i think they are perfect as a starting point for a flight suit!! They are made in the USA light weight and are sturdy. here is a link
army.navy55 on eBay
now it all makes since..........................lmao


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Reduced modeling of signal transduction – a modular approach
Combinatorial complexity is a challenging problem in detailed and mechanistic mathematical modeling of signal transduction. This subject has been discussed intensively and a lot of progress has been made within the last few years. A software tool (BioNetGen) was developed which allows an automatic rule-based set-up of mechanistic model equations. In many cases these models can be reduced by an exact domain-oriented lumping technique. However, the resulting models can still consist of a very large number of differential equations.
We introduce a new reduction technique, which allows building modularized and highly reduced models. Compared to existing approaches further reduction of signal transduction networks is possible. The method also provides a new modularization criterion, which allows to dissect the model into smaller modules that are called layers and can be modeled independently. Hallmarks of the approach are conservation relations within each layer and connection of layers by signal flows instead of mass flows. The reduced model can be formulated directly without previous generation of detailed model equations. It can be understood and interpreted intuitively, as model variables are macroscopic quantities that are converted by rates following simple kinetics. The proposed technique is applicable without using complex mathematical tools and even without detailed knowledge of the mathematical background. However, we provide a detailed mathematical analysis to show performance and limitations of the method. For physiologically relevant parameter domains the transient as well as the stationary errors caused by the reduction are negligible.
The new layer based reduced modeling method allows building modularized and strongly reduced models of signal transduction networks. Reduced model equations can be directly formulated and are intuitively interpretable. Additionally, the method provides very good approximations especially for macroscopic variables. It can be combined with existing reduction methods without any difficulties.
Modeling of signaling pathways
Systems biology aims at a holistic understanding of cellular processes. Mathematical models that integrate the current state of knowledge are analyzed to understand system properties that are not apparent from the characteristics of their components.
Different approaches exist to model and analyze signal transduction systems. Qualitative modeling uses solely structural information about the network and performs no quantitative statements. Examples for qualitative modeling techniques applied to signal transduction pathways are Petri nets
Inside the cell, signals propagate in time and space. Therefore, partial differential equations should be used to describe them exactly. This continuous spatial behavior can often be modeled by assuming fast distribution of all species inside a cellular compartment and transport reactions between the compartments. This leads to model equations in the form of ordinary differential equations (ODEs). If processes are modeled on a molecular level mass action kinetics are a good description of the chemical processes and are frequently used. This view is the basis for the work presented here and also used by many others
The more information about the system is available, the more powerful quantitative modeling techniques become, as prediction accuracy of models grows.
Combinatorial variety
Modeling with ODEs is challenged by biological reality. In signal transduction, association and modification of a relatively small number of different molecules usually give rise to an enormous amount of possible protein complexes
Many deterministic models of large signaling networks that have been published within the last years neglect the combinatorial variety of protein complexes. Their focus is on small subsets of the occurring reactions and complexes
An alternative approach was suggested by Blinov et al.
The exact domain-oriented lumping technique proposed by Conzelmann et al.
Insulin signaling and combinatorial variety
The insulin signaling system is of high medical interest and therefore well studied
Defects in the insulin signaling system give rise to insulin resistance, obesity and type II diabetes mellitus
In a simplified form the insulin signaling system will serve as demonstration object for combinatorial complexity. The insulin receptor is a transmembrane protein that is constitutively dimerized
However, first we analyze complexity on a virtual monomer. The receptor monomer (which consists of an
Figure 1
Combinatorial complexity
Combinatorial complexity. The full combinatorial complexity of the described parts of insulin signaling is demonstrated. The insulin receptor can bind Insulin, Shc and IRS. IRS can bind four PI3K molecules, SHP2 and Grb2. Grb2 can bind SOS and phosphorylated SOS. This results in 35·5 = 1215 different complexes with IRS. For Shc and insulin binding to the receptor monomer there are seven and two possibilities, respectively. Altogether there are
Results and discussion
Introduction of the layer based approach
The two most important mathematical tools to tackle the enormous complexity of models describing biological reaction networks are model reduction and modularization techniques. Here, we introduce a new systematic approach which allows to create considerably reduced models of signaling networks and also provides a new modularization criterion. This new modularization criterion suggests to separate molecular processes (bindings and post-translational modifications) depending on the types of interactions between them.
The basic idea is that three different types of interactions between two processes in signal transduction networks exist. The first interaction type is called all-or-none interaction. In this case, there exists a causal relationship between the two processes, which means that one process must occur before the second process. Most frequently, this kind of interaction is between binding site phosphorylation and effector binding. These two processes can be divided into four molecular events (phosphorylation, dephosphorylation, binding, dissociation). The effector can only bind if the binding site is phosphorylated and dephosphorylation is only possible in the absence of effector. This means that phosphorylation is required for binding and dissociation is required for dephosphorylation.
The second interaction type is called graded interaction. There, two processes influence each other mutually, as it is the case for ligand binding and autophosphorylation of a receptor. This means that kinetic parameters for one process are influenced by the other process. Note that this allows unidirectional interactions, where the first process influences the second, while the second does not influence the first, and bidirectional interactions, where both processes influence each other.
The third type are non-interacting, independent processes. They do not influence each other directly. Therefore this type represents in fact no interaction. The concept of all-or-none interactions and graded interactions is demonstrated in Figure
Figure 2
Graded and all-or-none interactions
Graded and all-or-none interactions. A) The reaction cycle of ligand binding and phosphorylation consists of four species that are connected by four reactions. This is a general property of graded interactions. B) The processes are coupled via an all-or-none interaction. Therefore the species
According to our new modularization criterion, no graded interactions are allowed between different modules. Processes of different modules, which we call layers, interact only via all-or-none interactions. Interestingly, the so defined layers only exchange information. The number of molecules in each layer stays constant when no synthesis or degradation is considered. This is a main difference compared to metabolic pathways where mass flows occur and represents the characteristic signal flow within a signal transduction network. Considering the fact that in signaling an extra-cellular signaling molecule causes transmission of a signal to the nucleus of a cell without passing the cell membrane, this difference is most obvious. The signals that are exchanged between layers correspond to a very restricted number of macroscopic variables like levels of occupancy or phosphorylation as they are used by Borisov et al.
We also contribute a new aspect to the discussion about modularization of biological networks and the optimal criterion for modularization (see also
In detailed modeling binding or modification events are represented by a huge number of reactions, since the involved proteins can exist in a high number of feasible configurations. The sum of a certain subset of these reaction rates defines a gross reaction rate of binding or modification. The sum of a certain subset of species corresponds to macroscopic quantities as degrees of phosphorylation or occupancy. In the following we show that in most frequent biological scenarios gross rate kinetics can be formulated using macroscopic variables and have a quite simple structure. Mathematical analysis of detailed and reduced models shows that the dynamics of essential macroscopic quantities is highly preserved in most cases. We give qualitative and also some quantitative information about the approximation quality for varying kinetic parameters. A basic advantageous feature of models that are created with the layer based approach presented here is intuitive interpretability. Additionally, preceding generation of detailed model equations is not necessary, as reduced models can be built directly by an intuitive procedure, for which a step by step procedure is given. There exists also a mathematical formalism to derive the reduced model equations. Thus, one can access model generation intuitively or by a mathematical formalism. Since both approaches are equivalent, understanding of the mathematical part is not necessary to create reduced models.
The approach combines qualitative and quantitative system descriptions. The first, qualitative step identifies processes and their interactions to define modules. Inside these modules, processes are described highly reduced using quantitative techniques. All methods of quantitative system analysis then can be applied to the model.
A general problem in modeling of signal transduction is availability of experimental data. Especially kinetic data is difficult to measure. Obviously, the layer based approach has also to face this problem. However, the same kinetic parameters can be taken for the macroscopic quantities that are states of the model as in detailed mechanistic modeling. Therefore, the problem does not become worse when using the reduced modeling technique.
The layer based method can also be combined with the exact domain-oriented lumping technique
Table 1
Necessary equations for modeling the insulin signaling system
Detailed modeling
Exact lumping
Layer based reduction
145 156 468
145 156 468
145 156 468
In two scenarios layer based reduction, domain-oriented lumping and their combination are compared with respect to the number of necessary differential equations. The insulin signaling system is used as example system. Insulin concentration is assumed to be constant. The two binding sites on the receptor for Shc and IRS in each case are assumed to be equivalent. 1): All binding site phosphorylations and corresponding bindings are all-or-none interactions. All binding sites on the same molecule can perform graded interactions. 2): All binding site phosphorylations and corresponding bindings are all-or-none interactions. The phosphorylation state of binding sites does not influence phosphorylation of other binding sites on the same molecule. See Additional files
The approach does not have to be used rigorously throughout the model. Subsystems can also be modeled in the detailed formalism, which simplifies integration of existing models.
A simple example system
In the following the reduction method is presented by introducing general principles, which are exemplified considering a strongly simplified model of insulin receptor signaling (see Figure
Figure 3
Visualization of the detailed kinetic model
Visualization of the detailed kinetic model. All possible reactions of the detailed model for the small example system are shown. The model equations are shown in Equation 1.
a) Molecules and complexes
In order to provide a complete and general description of our method, we introduce a formal nomenclature. Due to its generality this nomenclature might appear cumbersome. A simplified nomenclature can be used in most cases because many examples only comprise a small subset of all formally possible cases. In our examples we consistently use a simplified denotation.
Consider a general signaling protein
The general rule for representation of complexes is as follows. All molecules within a complex are listed comma separated within curly brackets. On each occupied binding site the name of the binding partner is indicated.
Since our method often works with lumped states comprising a number of molecular species, we introduce the symbol 'X', which is a replacement character for each possible state of a binding site. An 'X' within the site definitions of the molecules indicates all possible modifications on one site. A sequence of three dots following 'X' or before 'X' indicates that there may be additional sites and abbreviates a sequence of 'X'. A sequence of dots between site configurations other than 'X' indicates other sites with distinct configurations (not 'X').
b) Rules and reactions
According to Blinov et al.
and a binding reaction as
These rules shall be interpreted as a set of elementary reactions, which all can be modeled using the mass action law. If we consider the simple example defined above a possible reaction rule is
which defines all three elementary reactions describing
are equivalent, since both describe the reactions
Our goal is to formulate reduced order models in terms of macroscopic chemical species (denoted by a leading R) and macroscopic gross reactions (denoted by r) converting them. The phosphorylation of a binding site may be described in a reduced manner by the gross reaction
with the rate
The corresponding submodel consists of the two ODEs for the macroscopic variables
c) Different types of interactions
As introduced earlier, there exist three structurally different types of interactions. Now we discuss the three types by means of our example (Figure
We start considering the special case of non-interacting processes. If the kinetic parameters describing the reactions
A structurally different type of interaction is given if there is a causal relationship between the two processes, which means that one processes must occur before the second process. In many cases this probably will only be an approximation to the real interaction. However, it allows to strongly simplify the model. One can assume that receptor phosphorylation only occurs if ligand is bound to the receptor and the species
d) Modularization: layers
We define that all binding and modification events coupled by graded interactions form a module which we call a layer. Note that the definition of layers is according to interactions of processes and not according to molecules. Roughly speaking, a layer contains processes, not molecules. However, layers are often dominated by the reactions of a single molecule.
Diffierent layers are only coupled by all-or-none interactions. The definition of layers and resulting modularization is demonstrated for two example systems in Figure
Figure 4
Interactions define layers
Interactions define layers. Processes (white boxes) are coupled by graded (red lines) and all-or-non interactions (green lines). All processes that are coupled by graded interactions are merged into the same module, which is called layer (blue boxes). Therefore, layers are only connected by all-or-none interactions. A) A small example system that is discussed in detail. Occurring processes are ligand binding, binding site phosphorylation and effector binding. The reaction scheme is shown in Figure 5. B) A larger example system that is discussed in Additional file
An important feature of this modularization is that it only depends on the definition of interactions. The introduction of additional graded interactions between processes of different layers leads to disruption of the modular structure. In most cases these layers now form one larger common layer.
The terminus 'layer' results from the typical structure of the modules. As described, usually binding of a signaling molecule and its modifications (usually phosphorylation) form a layer. There is also the possibility that a layer comprises only one process, typically a binding process, as can be seen for
The layers are interconnected by signal flows. This means that information about macroscopic quantities of a layer is exchanged with other layers (signal flow). No mass flows cross layer boundaries. This means, that no reaction exists that transports substance from one layer to the other. Therefore, in the absence of protein synthesis or degradation, the sum of concentrations of all species for each molecule remains constant within the layers. Within layers there are mass flows defined by reaction equations and corresponding rates as in detailed modeling.
Altogether, layer based reduced modeling and modularization results in a highly structured reduced model that is characterized by mass conservation within layers and signal flow between layers.
Description of the reduction method
First, we consider the more academic case that all processes within a reaction network either do not interact with each other or provide an all-or-none interaction. Afterwards we will consider general networks also including graded interactions. General considerations are illustrated using the simple example defined above.
a) Networks without graded interactions
General considerations: We assume that within a reaction network all occurring processes do not interact, except domain phosphorylation and subsequent effector bindings that are characterized by all-or-none interactions. Phosphorylation usually can be considered as an essential precondition for binding an effector protein. The reverse modification (dephosphorylation) is prevented by binding of this molecule. Both conditions have to hold, otherwise the interaction between phosphorylation and binding will be graded.
We dissect the pathway into layers as defined above. Since the whole network does not contain any graded interaction, each process can be described in a separate layer. Interestingly, the network has another nice property. All rates
Obviously, the same considerations can be made concerning modification processes. So, it is only necessary to balance capital letter species.
Gross rates of bindings as well as modifications can be formulated using the mass action formalism, as the parameters of all single elementary processes are equal. This is also discussed by Borisov et al.
Example: The example (Figure
Two binding layers describing ligand and effector binding, and one modification layer describing receptor phosphorylation. Ligand binding can be described by the reaction rule
which can be expanded to the reaction rates
with the gross reaction rate
The gross reaction
describes binding site phosphorylation and corresponds to the reaction rule
which can be expanded to the reaction rates
The corresponding gross reaction rate is given by
in which the lowercase letter concentration
The gross reaction
describes effector binding and corresponds to the rule
which can be expanded to the reaction rates
Note that
Note that instead of
b) Networks including all kind of interactions
To introduce the general reduced modeling concept, where all kinds of interactions are allowed, we start with an example to illustrate the main features.
Example: Again we consider the simplified insulin model introduced above. Now, we assume that ligand binding unidirectionally influences receptor phosphorylation which in turn is an essential precondition for effector binding. Ligand binding and effector binding do not interact directly. From this it follows that the reaction rates
In the reduced model there are two layers. The receptor layer describes ligand binding and receptor phosphorylation, the effector layer effector binding (Figures
Figure 5
Visualization of the reduced kinetic model
Visualization of the reduced kinetic model. In this small example system the left module is the receptor layer which includes ligand binding and phosphorylation of the binding site on the receptor. The right module is the effector layer, where binding of
Observe, that these six equations are linearly dependent.
The connection between the two layers, i.e. the information exchange, is given by
If we compare the reactions of the reduced model (Figure
As already mentioned, the reaction rates that are merged together (
Our model shall provide equations for all variables that are given in Equation 22. Hence, all the
The approximation bases on the assumption that ligand and effector binding are completely independent.
Accordingly, the calculus of probability suggests that the ratio equation
is fulfilled
Hence, it is possible to reconstruct all micro-states of the detailed model. The accuracy of this reconstruction highly depends on the validity of the ratio equation (Equation 27). Observe, that an erroneous ratio equation may not have similar strong impact on the accuracy of the reduced model states, like e.g.
Table 2
Kinetic parameters and initial conditions for the small example system
Literature value
Initial conditions were 40
Figure 6
Simulation results: comparison reduced and detailed model
Simulation results: comparison reduced and detailed model. For parameter values from literature (Table 2), the deviations of the lumped states from the corresponding sums of states of the detailed model (Equation 22) are negligible. Reconstitution of states of the detailed model is possible with high accuracy. The axis of abscissae is given in
Summary: Only one variable has actually been eliminated by model reduction, but the example serves to illustrate the main elements of the method. These are:
• Two kinds of real interactions between two processes exist: all-or-none interactions and graded interactions. The third possibility is that these two processes do not interact.
• Modularization is achieved by analyzing interactions between processes. No graded interactions are allowed between modules which are called layers. Layers are only connected by all-or-none interactions.
• Each layer is modeled independently of the others. Gross reactions are formulated that correspond to reactions of macrostates.
• Dephosphorylation reactions of binding sites need special attention, as approximation of lowercase species is necessary. All other reactions can be formulated as in detailed mechanistic modeling, however, using also macroscopic species.
• Concentrations of macroscopic species (or sums of them) are transfered between the layers. Between layers there is only signal flow, but no mass flow.
• Combinatorial complexity is decreased, as all-or-none interactions between layers reduce the number of binding events and bound species by introducing a macroscopic description of the processes.
• Reduced model equations can be obtained directly without previous generation of detailed mechanistic model equations.
• Model equations can be understood and interpreted intuitively. Model variables are macroscopic quantities that are converted by rates following simple kinetics.
General considerations: In reaction networks including graded interactions the formulation of gross reaction rates as defined above becomes more difficult than only with all-or-none interactions. We again start by dissecting the whole network into layers. Processes coupled by graded interactions are merged into one layer. All binding and modification processes within a layer must be directly or indirectly linked by graded interactions, while the different layers are only coupled by all-or-none interactions. The coupled layers only exchange information about macroscopic variables, like phosphorylation degrees and levels of occupancy.
Now we assume that the processes of each layer form an isolated network and formulate a detailed kinetic model of solely these processes. Since processes from other layers are neglected in these considerations combinatorial variety is highly reduced. Each state of the submodel can be interpreted as a sum of states of the complete model, and each single reaction in the submodel represents a number of reactions in the complete network. Interestingly, all reactions of the complete network corresponding to a certain reaction in the subnetwork are parameterized by the same kinetic parameters. The reason for this can be found in the definition of layers. Since there are no graded interactions between layers, alterations in other layers do not change the kinetic properties inside the considered layer.
Observe, that we define the reactions of the isolated partial network as gross reactions. We stated earlier that if all reactions forming a gross reaction have the same kinetic parameters it can be formulated using the law of mass action. However, one has to accommodate these rates by including mass conservation relations to eliminate lowercase species from the description (as in Equation 9). As processes within a layer can be modeled separately each layer has to fulfill certain conservation relations. The receptor layer e.g. is characterized by a conservation relation for
It is assumed that this fraction is identical for all species
Consistent initial values
When comparing the reduced and detailed models the initial conditions have to be chosen that transformation equations hold for the starting point. This is guaranteed for the example system (Figure
Another aspect of choosing proper initial conditions arises from approximation of lowercase species (Equation 29). As there is division by
Mathematical background
In this section we analyze the presented reduced modeling method from a mathematical point of view. First, we introduce some general mathematical considerations about model reduction. Afterwards we will show that the layer based reduction method also fits into this general procedure. This will help us to evaluate the method and make statements about approximation errors.
General considerations
The layer based approach allows to directly generate reduced model equations, a step by step procedure for this is given after the mathematical background. However, in common model reduction techniques the starting point is a detailed mechanistic model of the form
The relevant states
Now, we show that the layer based reduction method fits into the previously introduced general pattern of model reduction. Hence, we first have to define the two set of states
If we consider the example shown in Figure
which transforms the states
In the transformed system the structure of the ODEs for
However, the transformed algebraic equations now also have a different form:
If one now replaces
Approximation of neglected states
After having defined the new coordinates
Borisov et al. showed that if this equation is fulfilled at a point of time
which is equivalent to the ratio Equation 27.
In both the examples here and in Figure
The assumption of rapid equilibrium
Approximation quality
In order to mathematically analyze approximation of these ratio equations, we consider a reaction cycle with four different influxes
Figure 7
Typical reaction cycle with input fluxes
Typical reaction cycle with input fluxes. The in-fluxes
Interestingly, this error function fulfills the linear differential equation
where the rates
It is apparent that the error will completely vanish if
and the dynamic error as
In order to provide at least a rough estimation of the maximal error we assume that
These equations show that both the steady state error as well as the maximal dynamic error decrease for increasing values of
Additional file 1
Transformation and stationary error
Click here for file
Additional file 2
Transformation and stationary error
Click here for file
The modeling procedure – step by step
The following procedure provides a guide to build reduced models step by step. This procedure is used to generate a large model of insulin signaling that covers all processes discussed in the introduction (Additional file
Additional file 3
Layer based reduced modeling of insulin signaling
Click here for file
1. Identify all processes (Figure
2. Define layers: all processes that are coupled by graded interactions are within the same layer. Layers are coupled by all-or-none interactions or do not interact (Figure
3. Model each layer individually.
(a) Define all sums of phosphorylated binding sites
(b) Define the concentrations of all unoccupied phosphorylated binding sites that are needed as binding partners within the considered layer (e.g.
(c) Define rules and reactions (including dephosphorylation of binding sites) as if there were no other layers and in particular as if there was no binding of effectors (see Figure
(d) Translate each reaction into the corresponding rate by using the desired kinetic law. This step is analogous to detailed mechanistic modeling. For dephosphorylation reactions of binding sites multiply the expression describing dephosphorylation with (
(e) Optional: for each molecule that is not degraded or synthesized a conservation relation can be formulated (e.g.
(f) Construct ODEs as a sum of rates for each species that is used in this layer and not defined by an algebraic equation (see Equation 26c).
4. Additional information transfer between layers is allowed, as long as no additional graded interactions are introduced (e.g.
Additional file 4
Documentation and analysis of the larger example system
Click here for file
This procedure also outlines how automation of the modeling procedure can be achieved. Steps 1) to 3c) most probably will be performed by the user, whereas expansion of rules and generation of rates and ODEs could be automated. The modeling procedure then remains in close similarity to automated rule based building of detailed mechanistic models by BioNetGen
A larger example system
To demonstrate the method on a more realistic example we study an extended subsystem of insulin signaling. This subsystem was also employed to demonstrate the modularization criterion (Figure
Additional file 5
Layer based reduced model of the larger example system
Click here for file
Figure 8
Layer based modularization of the larger example system
Layer based modularization of the larger example system. In the larger example system the left module describes the receptor layer. The output of this layer is the sum of all species which are phosphorylated on the binding site for
Figure 9
Simulation results: comparison reduced and detailed model, larger example system
Simulation results: comparison reduced and detailed model, larger example system. For parameter values from literature (Additional file
Optimization study of the larger example system
An optimization study was performed to analyze the worst case scenario within physiologic parameter ranges. Measures for reduction quality are the errors in
Synthesis, degradation and transport of proteins
Up to now it was assumed that there is no protein synthesis or degradation. However, synthesis and degradation of free unmodified proteins is easy to handle. The rate of synthesis or degradation just has to be included in the differential equation for the free species. Degradation or synthesis of complexes is also possible though often not being as easy to realize. If a scaffold protein or even the receptor is to be degraded one has to observe that there exist lumped states in several layers that correspond to complexes with this effector or the receptor. In this case, the rate of degradation or synthesis has to be considered in different layers to guarantee consistency. Now more communication between the layers is necessary. The same rates that are modified by different correction terms to reflect complex composition occur in distinct layers. Transport between different compartments can be handled as degradation in one compartment and synthesis of the same complex in the other. Therefore, synthesis, degradation and transport of complexes is possible with the layer based formalism. Concise modular structure of the model with a minimum of information transfer between the layers is yielded when these processes are limited to free protein species.
Outline: application on insulin signaling
A model for the insulin signaling system which includes all events that were mentioned in the introduction can be built with 64 + 128 + 4 + 11 + 5 + 2 = 214 differential equations instead of 1.5·108 in the detailed case. The 214 equations for the reduced model are composed as follows. 26 = 64 equations in the receptor layer describe binding of two insulin molecules and phosphorylation of four binding sites (two for Shc and two for IRS). The 27 = 128 equations of the IRS- layer derive from six binding sites, each of them can be phosphorylated and unphosphorylated. IRS can be bound to the receptor and unbound. 4 equations are needed for the Shc layer (Shc binding to the receptor and becoming phosphorylated). SOS and Grb2 are merged into one layer. This allows SOS binding to Grb2 influencing Grb2 binding to IRS and Shc. The corresponding layer is described by 11 equations (six equation describing binding of complexes of Grb2 and SOS to IRS and Shc, five equations for free species, remember that SOS can be phosphorylated). The PI3K layer contains 5 differential equations (binding to four binding sites) and the SHP2 layer 2 (binding to IRS). Free species are considered. The two binding sites on the receptor for Shc and IRS in each case are assumed to be equivalent. Other underlying assumptions are specified in Table
Reduction ratios and combination with domain-oriented lumping
As shown above for insulin signaling combinatorial complexity increases as the effector is subject of additional modification and binding events. The reduction potential of the layer based reduced modeling method strongly increases with increasing combinatorial complexity. For the small example system the number of equations is reduced by 20%, for the larger example system by 48%. The fraction of necessary equations for the signaling system as described in the introduction is reduced by 99.9999 %. This illustrates that even large systems can be described with a number of equations that can be handled by manual modeling. However, molecules with many binding sites or regulatory phosphorylation sites are still difficult to handle. Here combination with the domain-oriented lumping technique
Additional file 6
Layer based reduced model of insulin signaling (214 ODEs)
Click here for file
Additional file 7
Application of the domain oriented approach to the insulin model with 214 ODEs
Click here for file
Additional file 8
Reduced model resulting from combination of both approaches (56 ODEs)
Click here for file
So, combination of layer based reduced modeling with the domain-oriented approach
We present a reduced modeling approach which allows to tackle the problem of combinatorial complexity in signal transduction and regulation networks. For physiologic systems combinatorial complexity is dramatically decreased, as demonstrated on insulin signaling. Similarly to Pawson and Nash
A modularization principle is introduced. There, one has to distinguish between graded interactions and all-or-none interactions. Modules, which correspond to layers of signal transduction, are chosen such that they only interact via all-or-none interactions. All processes inside layers are connected directly or indirectly via graded interactions. For each layer we formulate a detailed reaction scheme comprising all processes of the current layer but neglecting all other processes. In the subsequent modeling step one has to formulate gross reaction rates for all of these reactions. A step by step procedure for building reduced modular models is given.
A potential drawback of the method is that even small changes to the assumptions of the model may lead to merging of layers which results in lower decrease of combinatorial complexity. This is the case if additional graded interactions between processes of different layers are introduced.
Mathematical analysis as well as simulation and optimization studies using insulin signaling models show that the approximation quality is excellent for relevant parameter settings. In the considered examples it is even possible to reconstruct the eliminated micro-states with high accuracy. As we also showed the method allows an enormous reduction of the number of necessary ODEs compared with detailed combinatorial models.
The method can be combined with the domain-oriented lumping technique
Initial conditions
The total concentration of insulin receptor in hepatocytes was reported to be 105 receptors per cell
Parameter values
Insulin receptor autophosphorylation
nM, nano molar (10-9
Competing interests
The author(s) declares that there are no competing interests.
Authors' contributions
MK developed the method, provided the example systems and performed the optimization study. HC performed the mathematical analysis and participated in development of the method. ME took part in mathematical analysis and development of the method. SE took part in development of the method. EDG initiated and supervised the study. All authors approved the final manuscript.
The authors acknowledge support from the german federal ministry of education and research (Bundesministerium für Bildung und Forschung, BMBF). This work was funded by the Network Systems Biology HepatoSys.
Application of Petri net based analysis techniques to signal transduction pathways
A methodology for the structural and functional analysis of signaling and regulatory networks
A rigorous derivation of the chemical master equation
A computational study of feedback effects on signal dynamics in a mitogen-activated protein kinase (MAPK) pathway model
A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling
Effect of epidermal growth factor receptor internalization on regulation of the phosphoslipase C-gamma1 signaling pathway
Mathematical modeling of epidermal growth factor receptor signaling through the phospholipase C pathway: mechanistic insights and predictions for molecular interventions
Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor
Temperature dependence of the epidermal growth factor receptor signaling network can be accounted for by a kinetic model
Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors
A mathematical model of metabolic insulin signaling pathways
Investigation of early events in Fc(epsilon) RI-mediated signaling using a detailed mathematical model
A network model of early events in epidermal growth factor receptor signaling that accounts for combinatorial complexity
The complexity of complexes in signal transduction
Predicting temporal fluctuations in an intracellular signalling pathway
Molecular model of a lattice of signalling proteins involved in bacterial chemotaxis
Combinatorial complexity and dynamical restriction of network flows in signal transduction
A domain-oriented approach to the reduction of combinatorial complexity in signal transduction networks
BioNetGen: software for rule-based modeling of signal transduction based on the interactions of molecular domains
Graphical rule-based representation of signal transduction networks
Graph theory for rule-based modeling of biochemical networks
Signaling through receptors and scaffolds: independent interactions reduce combinatorial complexity
Assembly of cell regulatory systems through protein interaction domains
Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways
Insulin signaling pathways in time and space
Insulin signalling and the regulation of glucose and lipid metabolism
Critical nodes in signalling pathways: insights into insulin action
Insulin signaling and the regulation of glucose transport
Central insulin action in energy and glucose homeostasis
Transcriptional regulation by insulin: from the receptor to the gene
Insulin signaling defects in type 2 diabetes
Biochemical and molecular basis of insulin resistance
Why diabetes incidence increases – a unifying theory
Insulin resistance and improvements in signal transduction
A review of types 1 and 2 diabetes mellitus and their treatment with insulin
Type 2 diabetes: principles of pathogenesis and therapy
Insulin analogues
Quaternary structure of the insulin-insulin receptor complex
The IRS-signalling system: a network of docking proteins that mediate insulin action
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation
Modulation of insulin action
From molecular to modular cell biology
Modular Analysis of Signal Transduction Networks
Dissecting the puzzle of life: Modularization of signal transduction networks
An Approach for Dividing Models of Biological Reaction Networks into Functional Units
Trading the micro-world of combinatorial complexity for the macro-world of protein interaction domains
The Regulation of Cellular Systems
Evidence that IRS-2 phosphorylation is required for insulin action in hepatocytes
The dephosphorylation of insulin and epidermal growth factor receptors. Role of endosome-associated phosphotyrosine phosphatase(s)
A role for tyrosine phosphorylation in both activation and inhibition of the insulin receptor tyrosine kinase in vivo
Insulin receptor binding kinetics: modeling and simulation studies
SH2 domains exhibit high-affinity binding to tyrosine-phosphorylated peptides yet also exhibit rapid dissociation and exchange


text:
First Sight
It was a warm dawn in the summer of my sixteenth year when I finally snapped. I rose early, and dressed in a tight silken gown, of a delicate creamy color that matched the gorgeous shade of my wings. It reached my mid thigh, and had thin straps. It was almost like a human design, but in another way looked almost like the toga-gowns of the Greek Gods. It's material was almost see-through, but was criss-crossed with ribbons of the same color, giving it an ethereal look. It was the look all young Angels were wearing. Of course, a human could never wear it, for it had long slits cut up the back. I fit my wings through these slits and shuffled them, getting comfortable. Then, silently, I opened the window and floated softly to the soft street below, which was paved with cloud.
Once in the streets, I padded, barefoot, through the sleeping streets. It took me only a short time to reach the outer wall of heaven, made entirely of flawless white marble. If it had been built with bricks, it was not possible to tell where one brick started and another ended. There were no lines or cracks. The pearly gates were shut, and I was far too cowardly to try and open them. Instead, I merely flapped my wings and jumped, landing atop the wall.
Then, ignoring all my mothers warnings never to fly before I was given proper training, I spread my wings and leaped, soaring downwards toward the blue planet. The Planet of my childhood. As I soared down, my excitement grew and grew. I gained speed, plummeting down. The driving wind forced me to shut my eyes for a time, and when I reopened them, there was a green glade just meters below me. I righted myself, snapping out my wings and fluttering gently to the ground. I landed atop a beautiful hillock, grass and mud under my toes. I smiled, reveling in the feeling.
Below was a large town, its buildings tall and made of orange and yellow bricks. My vision, as keen as a bird of prey's, could single out people travelling through the streets. One figure, on the edge of town, caught my eye. I focused my gaze, zooming in on him. Soon it was like he was right before me. He was... beautiful. His skin was a pale golden and atop his head sat a crown of coal-black curls. They were cropped short against his skull, a few curling over his forehead. He was tall and lean, and was wearing strange trousers made out of a dark blue material, along with a jacket which must have been made from some kind of animal hide. But the thing that caught my eye most was his features. He had a wide mouth, the corners tilted up in an almost constant smile, his nose was proud and straight, and black stubble coated his chiseled jaw. But the most entrancing feature were his eyes. They were a dark chocolate brown and glowed with a spark I had not seen in Angel guys.
When I thought of it later, I realized it must have been.. the sparkle of a trouble-maker, a mischievous rebel... It made my heart flutter with the thought. But just then, as I gazed upon him, I happened to glance at the sky behind him. With a jolt, I realized it was lightening rapidly. I had to go. My parents would be worrying.
Without a thought of who might see me, I spread my wings once more and soared easily back toward the sky.
*Damien's p.o.v*
I wove through the streets easily, on my way to the hilltop. I was always an early riser, apart from if I'd been drinking, and I liked to see the sunrise from up high. But as I reached the edge of the town, I saw something, a flash of white, in the corner of my eye. I looked up, and there, atop the hill, was a gorgeous woman, dressed in a short, silky dress. Her white-gold waves hung to her elbows, and I could see from the low neck-line of her attire that she had curves. I looked up, meaning to gaze upon this beauty's face, but as I did, she did something that made me breath out in a shocked blast.
She... she wouldn't.. didn't.. couldn't have.. have had wings, could she? I only caught a brief glimpse of blue eyes, a straight nose and full pink lips before she spread her wings and soared into the sky, disappearing.
Surely... Surely I couldn't have just glimpsed an Angel, could I?


text:
Chicago, Nov 28: United Airlines says a flight bound for Hong Kong from Chicago was diverted near Tokyo after 12 hours because of an "unruly passenger."
Chicago-based United Airlines spokesman Charles Hobart said Sunday that Flight 895 left O'Hare International Airport for China yesterday.
The plane instead landed at Narita, which is one of Tokyo's main airports. No injuries were reported. He says 241 passengers and 15 crew members were aboard.
Read More: Air India Express plane lands under emergency conditions
Hobart says law enforcement met the aircraft in Japan, but he declined to offer further details. Hobart says the flight has departed from Japan and is expected in Hong Kong.


text:
Buy in advance and save 43% on average*
Buying in advance can help you save up to 43% vs. a walk-up fare on the day of travel. Buy tickets below with Trainline – the UK's largest independent ticket retailer.
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text:
Super Crazy! World's Smallest V8 engine, Can Hand HeldSuper Crazy! World's Smallest V8 engine, Can Hand Held
Jakarta - In the automotive world the V8 engine is one of the most fearsome machine. Voiced fierce with great strength is its characters. Normally, the machine has a large capacity V8, but look at this one machine. It is the world's smallest V8 engine with a capacity of only 100 cc.
Reported motoauthority, Friday (05/10/2012) V8 engine is a machine made Conley Precision Engines which they named Stinger 609. Although small, four-stroke engine is equipped with a supercharger.
But because it was considered too small for a car, the engine is capable of spinning up to 10,000 rpm with peak power in the 9 hp is not going to be placed beneath the hood of a car, but likely only be a machine for model cars are small or remote controls.
In dimension, this machine is only 35 cm in length with a width of 15.24 cm and height 25.4 cm. So we were like fingers can play on this machine.
Even so, the appearance, voice and ability can be fairly capable for its size and is not inferior to the normal V8 engine.
And although this is just a small machine, pocket which must be removed to get fairly large, reaching U.S. $ 7,000 or approximately USD 67.2 million.


text:
Vanpool Fares
How to Calculate Your Fare
Fares are based upon two factors: 1) the operating cost of the van, and 2) the assigned portion of fixed administrative costs.
C-TRAN includes the cost of fuel in your monthly lease based upon miles traveled and the anticipated annual average cost for a gallon of regular unleaded gasoline. This means that some months the price of fuel charged by C-TRAN will be higher than market price, but some months it will also be lower. Our goal is the money collected for fuel roughly equals what is spent on fuel each year. C-TRAN will issue these vanpools a credit card to use to purchase fuel. This allows vanpool groups to have the convenience of a steady fare with pre-paid fuel.
Note: To calculate each individual rider's rate, divide the total rate by the number of passengers in your vanpool:
Download 2017 Vanpool Rates for 7 and 12 Passenger Vans


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- 4 Buttons Tilt Wheel
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MS Mobile 4000 06/21/2013
This review is from: Microsoft Wireless Mobile Mouse 4000 - Graphite
-Functionally, no complaints.
-4th button for a back button is wonderful
-tilt wheel is handy on occasion.
-Tracking is good and so is the feel.
-Size is good for mobility
Power Switch is defective
I go through decent AAs in about 3-4 weeks if I take them out at night, quicker if I do not remove them.
My work switched to low quality Ray**** AAs and now I am only getting about a 2 weeks if I'm lucky. I probably should have RMA'd it, but it was not bad at first and I didn't want to deal with the hassle.
Other Thoughts:
I have had this for almost a full year now. Primarily used on my laptop at desk and to carry to meetings. Sometimes I switch it to my XFR for field use in and around construction equipment. It goes into a rather full backpack often, so size was a concern.
I was a huge MS mouse fan for the longest time, but their selection has declined and my last couple experiences were not up to par so I have switched to Logitech. I bought a MX910 to replace it with. This one will probably be relegated to purely XFR field use on a limited basis. The touchpad on that laptop does not always like dirty hands or cold weather.
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