text:
"Are you ready?" Isn't this what we ask each other when we have some place to go and a particular time to get there? I really don't want to get into the "husband versus wife" discussion on this subject but I feel safe in saying that one of those two is generally ready before the other one.
Most of us go to the big box stores these days and picking up what we need off the shelf and paying whatever price is printed below the item. More and more retail outfits are trying to do business this way and so we do our research about what we will pay for something ahead of time, usually online. But it hasn't always been this way. For all the years I was in the furniture business we knew that we could not put our lowest price on the tag because we knew folks wanted to dicker.
We all know that Mississippi is right next to Alabama. It would make sense to understand that we share similar topography, people and many attitudes. But in the minds of most of the residents, Alabama and Mississippi are definitely two different things. One thing we do have in common is that both states find themselves looked down upon by many of our supposed betters in the rest of the country. But folks do still keep moving here, don't they?
Baptism is important. If it was insignificant or a mere adjunct to salvation we would not find it mentioned as it is by Paul, Peter and the Lord Himself. Most folks reading this article know the passages in the New Testament that reference baptism, among which are Mark 16:16, Acts 2:38, Acts 22:16, and 1 Peter 3:21. From the very beginning of my exposure to the New Testament, the passage that has helped me most has been Romans 6. I think this is the case because this passage helped me understand how baptism works.
"Curse God, and die." This is one of the saddest and most pitiful expressions to be found in the Bible. Bible students know that these words came from the mouth of Mrs. Job. We also know why she was moved to say such a thing.
Job had been a very rich man. He had at least eleven thousand animals and "very great household." He had a large and fine family of seven sons and three daughters. The Bible says that Job was "perfect (blameless) and upright, one that feared God and eschewed evil" (1:1).
The scribes and Pharisees of the first century believed mightily in adhering to what they called "the tradition of the elders" (Matthew 15:2). Jesus rebuked them because of their hypocrisy which they utilized to contradict God's will: "Thus you have made the commandment of God of no effect by your tradition" (Matthew 15:6). The Lord continued His rebuke with a quotation from Isaiah 29:13: "These people draw near to Me with their mouth, and honor Me with their lips, but their heart is far from Me.
Our group, consisting of Suzanne, Andrew and Ashley Sims, Pam and Katie Pepper, Perry, Gina, Laura and Jacob Martin, Brent Peek, John Colgan, Steve Carr and me, met at the Huntsville Airport at 5:00 AM Friday morning, July 15. We went down to Atlanta (one always goes to Atlanta first) and then on to Miami. Going through security in Miami was easy as could be because the crowds were simply not there. Next was a stop in Trinidad where we stayed on the plane for perhaps two hours and then zipped down into the Cheddi Jagan International Airport in Guyana.
The Christian religion can be seen as a historical entity. As such its existence can be traced from its beginning to the present. The story of the first century of Christianity is most reliably told by the twenty-seven books of the New Testament. After that the account moves out from under inspiration (2 Timothy 3:16-17). There is a wealth of information about the things that happen to the church from the end of the first century forward; obviously, the historical accounts are more numerous as time moves toward the present.
For some time now (since 1999) we have been involved in the work for Christ in Guyana. We have sent teams down once or twice a year and this year is no exception. Fourteen of our folks will leave on Friday, July 15 to help the church there at Bartica with a Vacation Bible School and a Gospel Meeting. We always look forward to seeing the people of that good church, particularly Michael Osborne and his good wife Jennifer.
Paul wrote to the churches of Galatia because he was extremely concerned about their future. Indeed he said "I marvel that you are turning away so soon from him who called you in the grace of Christ, to a different gospel" (Galatians 1:6). When we read the letter it becomes clear that the specific challenge before these people was the temptation to leave the Christian faith and return to the Law of Moses. This would be spiritually disastrous, so much so that Paul said that whoever promulgates such a thing should be accursed (Galatians 1:6-9).


text:
Honda in the U.S. has recalled 641,302 Odyssey minivans and has issued a stop-sale for two separate issues.
The first recall affects 2011-2016 Honda Odysseys built between Aug. 17, 2010, and Oct. 1, 2015, according to a report from Automotive News. The recall will address a mechanism that "allows the outboard second-row seats to tilt and slide forward for access to the third-row seating area may not properly lock the seat into place when the seat is returned to its normal position," Honda said in a statement.
The defect increases the risk of injury of people in the second row, although no injuries or crashes related to this issue have been reported. The defect was discovered through warranty claims. Honda will fix the issue by installing new brackets and springs to the second-row seats, but parts won't be available until spring 2017. Honda will begin notifying owners in mid-February.
The second recall affects 7,549 2016 Honda Odysseys built from Sept. 23, 2016, and Oct. 24, 2016. The recall will address a latch in the second-row seats that might not lock into place properly, increasing the risk of injury to second-row passengers. No injuries related to this recall have been reported, and the issue was discovered during internal quality checks.

subset: commoncrawl


text:
In order to best serve our patients, we have two convenient locations in Kansas City and St. Joseph. Both facilities feature state-of-the-art equipment and a friendly knowledgeable staff to assist in your eye care needs. To learn more about how Wiles Eye Center helps our patients in Kansas City and St. Joseph, explore your cataract surgery options or discuss various general ophthalmology treatments, contact Wiles Eye Center today.
Kansas City Clinic
211 NE 54th St. #202
Kansas City, MO 64118
(816) 455-2020
(888) 525-2745
St. Joseph Clinic
3201 Ashland Ave.
St. Joseph, MO 64506
(816) 279-7015
(800) 776-6864


text:
What is acupuncture?
While Acupuncture is still relatively new to the United States it represents one component of a complete healthcare system developed in China over the last 2,000 years. It has been one of the primary sources of healthcare for over one billion people or roughly 20% of the world population. What the practice can offer to a patient today is an invaluable complement to modern medical care. Prevention and long-term health maintenance are the foundations and goals of treatment with acupuncture. Acupuncture is effective for a wide range of conditions. The system is very effective side by side with physician primary care and/or diagnosis.
What is acupuncture known to be helpful for?
Acupuncture and Chinese Medicine can help with a wide range of health conditions. The World Health Organization, in its 2003 report, Acupuncture: Review and Analysis of Reports on Controlled Clinical Trials, confirmed that acupuncture has been shown to be effective for over 100 common health conditions, including:
- Disorders of the Bones, Muscles, and Joints such as arthritis, fibromyalgia, pain in the low back, neck and shoulder, sciatica, carpal tunnel syndrome, wrist pain, and tennis elbow
- Gynecological Disorders, such as infertility in women and men, morning sickness, premenstrual syndrome (PMS), irregular, heavy, or painful menstruation, and menopause
- Nervous System Disorders such as migraine headaches, headaches, neuralgia, insomnia, dizziness, chronic fatigue, facial palsy/tics, and trigeminal neuralgia
- Gastrointestinal Disorders, such as food allergies, irritable bowel syndrome (IBS), peptic ulcers, chronic diarrhea, constipation, indigestion, gastrointestinal weakness, colitis, and gastritis
- Stress Related Symptoms such as headaches, insomnia, fatigue, and poor digestion
- Emotional and Psychological Disorders, including depression, anxiety, anorexia, and seasonal affective disorder
- Respiratory Disorders, such as emphysema, sinusitis, asthma, allergies and bronchitis
- Uro-genital Disorders, including stress incontinence, urinary tract infections, and sexual dysfunction
- Circulatory Disorders, such as hypertension, angina pectoris, arteriosclerosis and anemia
- Addictions to alcohol, nicotine and drugs, food, and work
- Eye, Ear, Nose and Throat Disorders
- Nausea and vomiting, associated with chemotherapy drugs used in cancer treatment.
Finally, it is important to note that acupuncture is often an effective therapy for other chronic and painful debilitating disorders that have no clear explanation or origin.
What are further benefits of acupuncture?
Acupuncture is helpful for many concerns from headaches to joint pain. It has also been found effective for chronic conditions where pinpointing the cause has been difficult to determine. Those who receive ongoing treatment for maintenance and the promotion of good health have said that they:
- Tend to get sick less often and recover more quickly
- Have improved stamina and vitality
- Are better managers of their own health
- See reductions in long-term health care costs
- Tend to visit physicians less often
- Enjoy deepened, more harmonious relationships with others
Are there side effects to acupuncture?
According to the National Institutes of Health (NIH) Consensus Statement on Acupuncture, when treating the same condition, Acupuncture and Chinese Medicine offer reduced side effects compared to conventional biomedical treatment:
"One of the advantages of acupuncture is that the incidence of adverse effects is substantially lower than that of many drugs or other accepted medical procedures used for the same conditions."
The NIH Consensus Statement further noted that the evidence supporting the effectiveness of conventional western procedures and the effectiveness of acupuncture are often equally strong:
"While it is often thought that there is substantial research evidence to support conventional medical practices, this is frequently not the case. . .The data in support of acupuncture are as strong as those for many accepted Western medical therapies."
What can acupuncture do for me?
Acupuncture is at least two thousands of years old but likely much older. In this time it has been used to support good health and to help heal various aliments. It is perhaps best know for addressing all manner of pain issues ranging from back pain to migraines to arthritic pains to systemic pains such as fibromyalgia pains and also for localized pains in specific areas. Acupuncture can also be useful for a number of internal diseases (such as those listed above) and can be used very successfully with Chinese herbs and medical qi gong for even deeper healing. It is very useful for a wide range of conditions including acute pain, chronic pain, anxiety, depression, stress related problems, insomnia, headaches, menstrual pain and menstrual issues, infertility, digestive issues, relaxation, general well being, and more.
What can I expect from acupuncture treatments?
Acupuncture is a simple and safe technique involving the insertion of sterile, very thin, single use needles in acupuncture points known to benefit health and well being. Acupuncture sessions are relaxing, and many find the sessions meditative, some feel the flow of qi in their channels, and some even fall asleep. These sessions take place on comfortable massage tables with relaxing music chosen to enhance the healing experience.


text:
The Historic Brook Forest Inn
Easter Brunch Menu
Adults $34.99 / Seniors $28.99 / Kids $17.99
Ages 6 and Under - Free!
Sunday April 5th, 10AM - 3PM
Full Buffet Offering:
Roast Beef and Ham Carving Stations,
Made Before Your Eyes Omelet Station, Eggs Benedict,
Scrambled Eggs, French Toast, Pancakes
Biscuits and Gravy,
Bacon, Sausage,
Home-style Potatoes,
Fresh Baked Breads, Pastries, Desserts
Salads, Fruit Trays and More!
Make Your Reservations Now!


text:
"The Bachelor" 2016 Ben Higgins and winner Lauren Bushnell are set to tie the knot this summer on TV.
There have been rumours that the two are planning to get married in June and that it will be on TV. Us Weekly quoted a source saying that the couple will get married "very soon, probably this summer" and that "it would be an ABC special." Although the couple has not confirmed if they will have a wedding on TV, Higgins has hinted that will be a good idea.
"We're open to it. I think it'd be fun," "The Bachelor" star has told Extra. When asked by ABC News if they will get married on TV or have a private wedding, he replied, "That is a good question, one that we haven't discussed fully yet. We want a wedding fairly quickly. But we also want to try and take things as normal as possible for now. We are open to anything I think."
Another insider told Entertainment Tonight that "They are both so in love with each other and will definitely be one of the few couples to make it from the show."
Hollywood Take noted that if the couple do get tie the knot on TV, they will definitely get an elaborate wedding plan and ABC would be paying for all of the details of the wedding.
Ben Higgins earlier told People magazine that he wants to have a big reception. "I want a huge reception. How often in life do all your friends and family gather in one room to celebrate something? Why get married tomorrow if we can plan a big ass party?" said Higgins.
Higgins and Bushnell got engaged on the finale of "The Bachelor." She has since moved to Denver from Portland to be with her fiancé.
Amidst wedding speculations, there were also rumours that the couple is heading to splitville. It was earlier reported that Bushnell is allegedly not happy with Higgins anymore and the reason for the falling apart is "The Bachelorette" 2016 star JoJo Fletcher. Bushnell is reportedly jealous of Fletcher because Higgins is showing signs that he is still in love with "The Bachelor" 2016 runner-up.


text:
Interpersonal coordination is an important feature of all social systems. From everyday activities to playing sport and participating in the performing arts, human behaviour is constrained by the need to continually interact with others. This book examines how interpersonal coordination tendencies…
Paperback – 2017-11-13
One of the greatest paradoxes of human behavior is our tendency to say one thing and do something completely different. We think of ourselves as positive and fair-minded, caring about other people and our environment, yet our behavior lets us down time and time again. Part of the reason for this is…
Paperback – 2017-10-30
Originally published in 1990. Each of the 12 chapters in this book build upon an approach to the analysis of spoken and written texts that is centred upon the recipient rather than the producer, for the abilities of listeners and readers deserve much attention. This book should be of interest to…
Paperback – 2017-08-29
Routledge Library Editions: Communication Studies
Originally published in 1945, this title was a follow-up to the author's previous book The Human Hand. This time she looks at the psychology of gesture and its relation to personality. The special place that a psychology of gesture merits is obvious. It permits a direct knowledge of personality…
Paperback – 2017-08-08
Collected Works of Charlotte Wolff
This is a classic edition of Geoffrey Beattie's and Andrew Ellis' influential introduction to the psychology of human language and communication, now including a new reflective introduction from the authors. Drawing on elements from many sub-disciplines, including cognitive and social psychology,…
Paperback – 2017-05-15
Psychology Press & Routledge Classic Editions
There is a fundamental, powerful, and universal desire amongst humans to interact with others. People have a deep-seated need to communicate, and the greater their ability in this regard the more satisfying and rewarding their lives will be. The contribution of skilled interpersonal communication…
Paperback – 2016-09-29
Challenging all of our old assumptions about the subject, Rethinking Body Language builds on the most recent cutting-edge research to offer a new theoretical perspective on this subject that will transform the way we look at other people. In contrast to the traditional view that body language is…
Paperback – 2016-05-26
In the World Library of Psychologists series, international experts themselves present career-long collections of what they judge to be their finest pieces - extracts from books, key articles, salient research findings, and their major theoretical and practical contributions. This volume of…
Hardback – 2016-04-21
Psychology Press
World Library of Psychologists
Reissuing works originally published between 1971 and 1993, this set offers a fantastic variety of texts on communications, connecting with psychology, media, sociology, development studies, gender studies and history. Specific volumes look at topics from listening, third-world mass-communication,…
Hardback – 2015-11-04
Routledge Library Editions: Communication Studies
Charlotte Wolff (1897-1986) was born in Riesenburg, West Prussia (now Prabuty, Poland) into a middle-class Jewish family. She studied philosophy and then medicine at several German universities, completing her doctorate in Berlin in 1926. Working in various institutions over the next few years…
Hardback – 2015-08-25
Collected Works of Charlotte Wolff
Few people today would admit to being a racist, or to making assumptions about individuals based on their skin colour, or on their gender or social class. In this book, leading psychologist Geoffrey Beattie asks if prejudice, more subtle than before, is still a major part of our everyday lives.…
Paperback – 2012-11-28
The group of papers presented in this volume represents ten years of involvement of a group of eight core therapists, working originally with approximately forty families who suffered the loss of husbands and fathers on September 11, 2001. The project focuses on the families of women who were…
Paperback – 2012-02-15


text:
80 20 Inc Catalog 21 Page 191 Profiles
80/20 Inc. For the most up to date information on 80/20 products visit 8020.net 191 Quick Frame Proles PROFILES Quick Frame Standard Machining Services * The above proles are sold per inch or stock length. Part No. Series Stock Length Material Grade Finish Moment of Inertia Surface Area Yield Strength Modulus of Elasticity Weight 9010 * 145 Aluminum 6105-T5 Clear Anodize #204-R1 .2828 in. 2 35,000 psi 10,200,000 lb / in. 2 0.0291 lb / in. 9010-Black-FB per inch Black Anodize 9010 Prole 9010 is a 1.00 x 1.00 Quick Frame prole with two single 0.5 anges on adjacent sides, and a grooved interior used to hold nylon connectors into place. The prole has a smooth surface for a sleek appearance, allows for easy cleaning and holds paneling in place, lending itself to applications such as framing, displays, or retail kiosks. 1.000 TYP .690 TYP R .083 TYP .060 TYP .500 TYP .250 TYP 1.00 X 1.00 Tube Prole - Single 0.5 Flanges on Adjacent Sides Service No. Series Service Description Reference Page 7310 Cut to Length 847 7301 45 Flange Milling 869Previous Page


text: 2-3 ROBERT STREET LIMITED has been working since 7/14/2015. The current status of the business is Active - Proposal to Strike off 2-3 ROBERT STREET LIMITED located on KINGS LODGE LONDON ROAD, WEST KINGSDOWN, SEVENOAKS, KENT, UNITED KINGDOM, TN15 6ARCompany Director Chapman Jamie Richard is known as a Director of the company. "Buying and selling of own real estate" is a known activity of the company.


text:
You must be dreaming of food 24 hours a day, I said. Twenty eight, was the reply, almost before I had finished speaking.
Davide Cananzi, executive chef at The Park, was right. Twenty eight was probably a more accurate estimate. Spend a few minutes with him and you know that his brain is always brimming with ideas. The possibilities are endless. The sky is the limit. No ingredient is too commonplace. Anything can be conjured up into something exotic. Innovation and creativity are cornerstones of his art.
We were sitting at Aqua, a new dining destination in the city, sampling the menu, which is entirely his baby, gestation and all. They have created an al fresco dining area on a suspended timber deck by the hotels poolside, as well as an air-conditioned indoor space with a glass front so that if its warm in the daytime, guests can wine and dine inside and still have the feeling of being by the poolside.
It is a menu that defies categorisation. Tradition sits easily next to modern. Ideas find expression. The Sandwich and Panini Corner with burgers, baguettes, grilled sandwiches and the traditional club sandwich has shades of a coffee shop menu, while the Aqua Specialities, a small selection of seven items, has nuggets like Stir Fried Tofu with Garlic and Peas Pulao, Thai Green Curry with Steamed Rice and Dahi and Grilled Jumbo Prawns with heads on, with soft vegetable and polenta mash and asparagus. If there is a leaning, it is towards Cananzis Italian and European roots, but there is an open-mindedness, and a sourcing from his direct environment, which makes it refreshing.
Cananzi also happens to be a jamai of ours; he is increasingly enjoying Bengali and Indian cuisine and follows cricket. The future is full of possibilities.
Soup of the Day was a Chicken Sweet Corn Soup with the surprise inclusion of asparagus which is sauteed with the chicken and corn kernels before the chicken stock is added and clarified with egg white.
Another surprise ingredient is star anise which gives it a unique character. Finished with chopped spring onions, it made a delicate beginning.
We were then served a platter of six different hors doeuvres, taken from the section of the menu headed Old World Savouries. There were Arancini Rice Balls, made by cooking arborio risotto rice with onions, parmesan cheese and green peas in white wine and water, and finishing with butter.
When the rice cools, it is shaped into spheres (its sticky nature makes this easy), the spheres are stuffed at the centre with mozzarella cheese and a coriander-pesto sauce and then egg-and-crumbed and fried.
Seafood Croquettes, Cheese and Jalapeno Peppers and Stuffed Button Mushrooms were three other items crumb-fried after being dipped in egg batter. The Seafood Croquettes are cylindrical shapes of roughly chopped salmon, crabmeat, shrimps, bekti and pepper and later Dijon mustard and egg yolk, before being shaped and fried.
The Cheese and Jalapeno Peppers are triangular in shape, made with chopped jalapenos, grated cheddar cheese, egg yolk and seasoning and the stuffed mushrooms involve only the caps, not the stems. These are partially scooped out and stuffed with blanched, chopped spinach and mozzarella cheese before being fried.
There were bite-sized Mini Chicken Tikka Pizzas topped with Italian tomatoes, peeled, chopped and raw (no sauce is made) along with mozzarella cheese and chicken before being baked, and the finale was slices of parma ham skewered with a cube of honeydew melon.
Four excellent dips were served with this platter. There was the classic alioli garlic mayonnaise sauce, the classic Italian arrabbiata and two innovative ones a pesto (basil, pine nuts, garlic, parmesan cheese and olive oil pureed together) with the unusual addition of coriander leaves and the papaya relish, made like a compote, stewing raw papaya flakes in water with sugar, cumin and turmeric and finishing with ghee.
For the main course, there were two items. Grilled Fresh Tuna with Fried Rice and Tomato Coriander Vinaigrette, and Risotto with mixed seafood and Lobster Bisque. For the first, 100 gram tuna steaks are marinated in olive oil, garlic, oregano, thyme, salt and crushed black pepper and grilled rare, medium or well-done as tuna is red meat. The vinaigrette accompaniment is tomatoes, coriander, garlic and lemon juice simmered in white wine. The fried rice is straight ahead, but no soya sauce is used.
The seafood risotto involves the same seafood as the croquet and the rice-seafood combination, which is sauteed (first with garlic and onion, is cooked by very slowly adding lobster bisque, a thin soup, or stock, made with lobster head. The risotto is finished with butter and chopped basil. For dessert, homemade Italian gelato (ice-cream) with fruits. What a meal. Like music, food is only great if it is memorable, and this will remain in memory for a long time.
Apart from Cananzis creations, Aquas attractions include the most extensive wine, spirits, cocktails, aperitifs and liqueurs list I have ever seen (at least 160 selections!), a fine cigar collection and surroundings that make it a unique destination for tasteful hedonism.
Secluded, wings with mattresses and bolsters for couples to enjoy champagne and caviar by the pool, double beds housed in enormous circular wicker-baskets and a jacuzzi to wallow in just behind the main pool with attention to detail such as heavy glasses placed on suction-padded coasters. Enjoy.


text:
Homeschool.com loved my article on turning educational placemats into magnetic learning tools, and they asked if they could use it on their site. See the article here, then go to Homeschool.com's Facebook page and LIKE my post there to increase the chances of them using me for more guest posts. Then maybe you'd like to try making your own magnetic learning aids by following my article's simple instructions! Your friends will be ooo-ing and ahh-ing over your cool, new magnets, so be sure to share the article with them, too.
My Guest Post Is Up at Homeschool.com
November 12, 2012 by Leave a Comment


text:
Download Lovely Mahjong apk 1.0.9 free for Android smartphone
Posted by GrupoAlamar in Strategy | Aug. 2, 2016 | 6 Comments
Apk file size: 17.0 MB
Lovely Mahjong is a tile matching puzzle game. You must touch on any free tiles (those that haven't other at left or right) to select them and match them with other free tiles with the same face to eliminate them from the board. This mahjong is inspirated in Valentine's day and is dedicated to people in love. Mahjong is a strategy game, so it's best to think about your moves before you do them but also hurry up because there is a limited time in each level. With great graphics and a good music we would like that you liked this mahjong game.
GrupoAlamar part of our Strategy and have average installs from 10000 to 50000. Last Update Aug. 2, 2016. Google play rating is 79.5376. Current verison is 1.0.9. Actual size 17.0 MB.
Similar applications
Mahjong Fauna: Animal Tiles LE155 Comments
Rebuild 3: Gangs of Deadsville3576 Comments
6 Comments
Heather Laraby
mahjong I love this game it's very addicting
Laura Mitchell
lovely mahjong awesome game
Sharonjune Heard
Sharonjuneheard Give it go soon
Sharonjune Head
sharonjuneheard I will on soon
Kathy Simth
Lovely Mahjong Really neat
Adilene Barrios
Wow??? Loved it! Was very addicting, and I can't believe it didn't take me long to bet the whole thing!...


text: i ordered difficult child's chart from the hospital, it showed up today. wow i was so shocked. why i was shocked i do not know. all lies. they totally fudged it except for labs, and vitals. difficult child's vitals her heartrate was only normal on 3 days while there. it went as high as 170 one day. she was sick while there i did not know, her temp was high for two days straight, must of had a viral infection. they claimed she was peeing on herself thru choice, and defiance. like day i picked her up and she was peeing on herself totally sedated and didnt' click in i was even there. they bad mouthed me a whole lot in it you can imagine. they lied said she completed meals within a short time frame which she never did. lied and said upon discharge was stable, meanwhile kid lost 9 lbs while there! and was dehydrated according to labs yet no one ever gave her an iv. i went thru all the blood work online tonight. her red blood cell count is up, huge iron deficiency, phosphate levels indicated huge dehydration. a few other levels off. weird thing red blood celll count off symptoms are fatigue, exhaustion, dizziness, etc. to read this report was like reading a fiction book. i knew they'd do this, my mom even said it that day their going to fudge it. i said how could they do that, that's sick?! shocking is all i can say, a reputable hospital. you just never truly know and always gotta be ever so careful. going to hospital tmrw for difficult child's check up where i'm going to ask them to re run all these specific blood tests. i can't believe the things they wrote about her that never happened, i spoke to nurses first hand and i knew what had gone on, what truly happened not their version of it. this doctor was a sick sick man with a godlike complex i'd never seen before.


text:
Deficiency and Inhibition of Cathepsin K Reduce Body Weight Gain and Increase Glucose Metabolism in Mice
Jump to
Objectives— Previous studies demonstrated increased levels of cysteine proteases cathepsins in serum and adipose tissues from obese patients. We now provide evidence from a mouse model of obesity to suggest a direct participation of cathepsin K (CatK) in mouse body weight gain and glucose metabolism.
Methods and Results— Using real-time polymerase chain reaction, we detected 12-fold increase in CatK transcripts after adipogenesis of human preadipocytes. Using an immunohistology analysis, we consistently observed high levels of CatK expression in adipose tissues from obese humans and mice. Selective inhibition of CatK activity blocked the lipid accumulation in human and mouse preadipocytes. In mice, CatK deficiency reduced significantly diet-induced body weight gain and serum glucose and insulin levels. Similar results were obtained in diet-induced and genetically created (ob/ob) obese mice after animals were treated with a CatK-selective inhibitor. Mechanistic study demonstrated a role for CatK in degrading fibronectin, a matrix protein that controls adipogenesis. Deficiency or inhibition of CatK leads to fibronectin accumulation in muscle and adipose tissues.
Conclusion— This study demonstrates an essential role of CatK in adipogenesis and mouse body weight gain, possibly via degradation of fibronectin, thus suggesting a novel therapeutic strategy for the control of obesity by regulating CatK activity.
Cysteine protease cathepsins play important roles in cancer, autoimmune diseases, infectious diseases, and cardiovascular diseases. Recent observations indicate that expression of cathepsin S (CatS) is associated with adipogenesis and obesity in humans. Increased expression of CatS, both at RNA and protein levels, has been reported in subcutaneous adipose tissues of obese patients,1 where CatS mRNA levels are significantly associated with body mass index. In humans, surgery-induced weight loss is associated with significant reduction of CatS levels in serum and white adipose tissues.2 In cultured human preadipocytes, inhibition of CatS reduced cell adipogenesis.3 It has been suggested that CatS participates in adipogenesis by degrading fibronectin, an important extracellular matrix protein that regulates preadipocyte differentiation4 via downregulation of lipogenic gene expression and interference with cytoskeletal and morphological changes necessary for new gene expression.5 Similar to CatS, increased CatK expression was also detected in differentiated preadipocyte 3T3-L1 and in adipose tissues from db/db obese mice, especially in lysosome-enriched fractions.6,7 However, it remains unknown whether increased levels of cathepsins in human/murine adipose tissue or serum merely serve as a hallmark of inflammation, and more importantly, whether cathepsins offer a potential drug target to control human obesity.1,2,6,7
In this study, we demonstrate that CatK is highly expressed in adipose tissues from obese humans and mice. Deficiency or selective inhibition of CatK activity reduces preadipocyte differentiation and impairs mouse body weight gain in diet-induced and genetically created obese mice.
Preadipocyte Culture and Differentiation
Human subcutaneous preadipocytes (Cambrex Corporation) and murine 3T3-L1 were differentiated with or without a nonselective cathepsin inhibitor E64d (20 μmol/L, Sigma), a CatK-selective inhibitor-II (0.5∼1 μmol/L, Calbiochem), or a CatS-selective inhibitor N-morpholinurea-leucine-homophenylalanine-vinylsulfone-phenyl (LHVS)8 as we described previously.9 Differentiated human and mouse adipocytes were fixed and stained with oil-red O. To quantify adipogenesis, we extracted intracellular oil-red O with 100% isopropanol and quantified OD510 nm. Data were presented as percentage of OD510 nm reading relative to cells without protease inhibitors.
Real-Time PCR
Real-time PCR and data analysis were performed as described elsewhere.10 Five human housekeeping genes, peptidylprolyl isomerase A (PPIA), Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), eukaryotic elongation factor 1A (EEF1A), ribosomal protein L13a (RPL13A), and ubiquitin, were used as experimental controls.
CatK knockout mice (CatK−/−) (C57BL/6/129S background)11 and their littermates (CatK+/+, CatK+/−) began a high-fat diet (HFD, Research Diet) at 6 weeks of age for 16 weeks. Body weight was monitored biweekly. To examine the effect of CatK inhibitor in mouse body weight gain, we started feeding female wild-type mice (C57BL/6, 6 weeks old) a HFD while also giving mice a CatK-selective inhibitor K4b (1 mg/kg/d) or DMSO for 14 weeks. Mouse body weight was monitored biweekly. To examine the ability of K4b to control body weight gain in ob/ob mice, we treated 4-week-old female ob/ob mice (C57BL/6, Jackson Laboratory, Bar Harbor, Maine) with K4b (1 mg/kg/d) for 8 weeks. Because of fast body weight gain of ob/ob mice, we monitored their body weight weekly. Energy expenditure, serum insulin level, and glucose tolerance were determined as we previously reported.9
Paraffin sections of human white adipose tissue and normal muscle (n=9 per group with unknown gender and age) were obtained from the Department of Pathology, Brigham and Women's Hospital under a preapproved human subject research protocol. Mouse visceral fat and muscle tissues were fixed in 3% paraformaldehyde and paraffin sections were prepared for immunostaining with antibodies against human fibronectin (1:10,000, Dako), mouse fibronectin (1:10,000, NeoMarkers), mouse CatK (1:75, Calbiochem), and mouse Mac-2 (1:1200, Cedarlane Laboratories, Ontario, Canada).
Western Blot
Equal amount of proteins (40 μg/lane) from fat, muscle, or 3T3-L1 cells were separated on 8% SDS-PAGE for immunoblot analysis with antimouse fibronectin (1:200, NeoMarkers), Glut4 (1:100, R&D Systems), insulin receptor (IR) β-subunit (1:200, Calbiochem), CatK (1:1000, Santa Cruz), and tubulin (1:1000, Santa Cruz) monoclonal antibodies, and anti-GAPDH (1:1000, Abcam) and CatK (1:1000) polyclonal antibodies.
In Vitro Fibronectin Digestion With CatK
Human plasma fibronectin (10 μg/reaction, Chemicon) was incubated with different amounts of recombinant human CatK (Calbiochem) in a pH5.5 buffer.12 After 45 minutes of incubation at 37°C, samples were separated on a 8% SDS-PAGE.
Cysteine Protease Active Site Labeling and Immunoprecipitation
Active cathepsins in mouse splenocytes, peritoneal macrophages, fat and muscle tissues were detected by incubating protein lysate (50 μg/sample) with [125I]-JPM as we previously described.12 To examine the inhibitory specificities of cathepsin inhibitors in mouse adipocytes, differentiated 3T3-L1 cells were incubated with E64 days (20 μmol/L) or CatK-selective inhibitor-II (0.5 to 1 μmol/L) for 6 hours followed by labeling the cell lysate (200 μg/sample) with [125I]-JPM at 37°C for 1 hour. Labeled cell lysate was neutralized with 1 mol/L Tris.HCl, pH10.0, boiled for 5 to 10 minutes, and then incubated with mouse CatK monoclonal antibody (Santa Cruz)-coated protein A agarose beads at 4°C overnight. Affinity bound CatK proteins were boiled and separated on a 12% SDS-PAGE.
Because of the relative small sample sizes and data distribution abnormality, we selected the nonparametric Mann–Whitney test to examine the statistical significances throughout this study. P<0.05 were considered significant.
Expression of Cathepsins and Cathepsin Inhibitors in Human Adipocytes
Increased expression of CatS and CatK have been detected in human adipocytes,3,6 but a broad view of cathepsin expression profile is still unavailable. Following the process of human primary adipocyte differentiation, we measured the mRNA levels of a list of selected cathepsins and their endogenous inhibitors cystatins with real-time PCR. As shown in supplemental Table I (available online at http://atvb.ahajournals.org), among all tested cathepsins, CatS and CatK demonstrated the highest induction after preadipocyte differentiation (∼12-fold). In human adipocytes, CatB, CatK, and CatL transcripts were 42- to 100-fold greater than those of CatS. In contrast, among all tested cystatins, cystatin C is the most abundant cathepsin inhibitor, >30- to 2000-fold more transcripts than other cystatins. Importantly, although all tested cathepsins are increased after preadipocyte differentiation, cystatin C expression remains unchanged.
CatK Inhibition Reduces Human Preadipocyte Adipogenesis
Increased expression of CatK in human adipocytes suggests its high expression in human adipose tissues. Using human CatK antibody-mediated immunohistology analysis, we detected CatK expression in human adipose tissues (supplemental Figure IB), but negligibly in human skeletal muscles (supplemental Figure IA). Although prior experiments from Xiao et al6 demonstrated that the nonselective cathepsin inhibitor E64 reduces human preadipocyte differentiation, it is unknown whether their observations were attributable to the inhibition of CatK or other cathepsins. To test this possibility, we differentiated human preadipocytes in the presence of Boc-Phe-Leu-NHNH-CO-NHNH-Leu-Z (Calbiochem), a CatK inhibitor that is 50-fold more sensitive to CatK than CatL and 2 to 4 orders of magnitude more selective to CatK than to CatB or papain.13 Oil-red O staining showed adipogenesis or lipid accumulation after the cells were induced for differentiation. When human preadipocytes were incubated with E64d (20 μmol/L), we observed strong inhibition of adipogenesis. When we used 0.5 to 1 μmol/L of CatK-selective inhibitor, concentrations that inhibited CatK (supplemental Figure IIB) but not other major cathepsins such as cathepsins B and L (supplemental Figure IIA),13 we also detected significant reduction of adipogenesis (supplemental Figure IC-G). A quantitative analysis of adipogenesis in response to different cathepsin inhibitors is presented in supplemental Figure IH by determining the relative content of intracellular oil-red O staining.
CatK Expression in Mouse Adipose Tissues
Visceral fat from HFD-induced obese mice contains CatK. By coimmunostaining mouse adipose tissue section with CatK polyclonal antibody (red) and Mac-2 (macrophages, green) monoclonal antibody, we detected clusters of CatK-positive macrophages (orange) in the adipose tissues (Figure 1A), indicating an infiltration of CatK-positive macrophages to the adipose tissues. When we labeled the fat and muscle tissue extracts with a cysteine protease active site probe [125I]-JPM, which detects only active cathepsins, we revealed much stronger total cathepsin activities in the fat than the muscle. Importantly, fat from obese mice contained even more cathepsin activities than fat from lean mice (Figure 1B). These cathepsins may come in part from infiltrated macrophages. Immunoblot analysis using an antimouse CatK monoclonal antibody we demonstrated higher amount of the 28-kDa active form of CatK proteins in fat tissues from obese mice than those of lean mice. In contrast, we detected negligible CatK signals in muscles from either obese or lean mice under this experimental condition (Figure 1C).
CatK Inhibition Reduces 3T3-L1 Cell Adipogenesis
Increased CatK expression in mouse adipose tissues (Figure 1A and 1C) suggests its participation in mouse preadipocyte differentiation. To examine this hypothesis, we induced 3T3-L1 cells in the presence of nonselective cathepsin inhibitor E64d and CatK-selective inhibitor. Insulin-induced 3T3-L1 cell differentiation is clearly blocked by E64d (20 μmol/L) and CatK-selective inhibitor (0.5 to 1 μmol/L). Inhibition of CatS with 10 nmol/L LHVS, which demonstrated limited inhibitory effect on CatL or CatB in live macrophages (supplemental Figure IIC), showed minimal inhibition on 3T3-L1 cell differentiation (supplemental Figure IIIA to IIIF). A role for CatK in 3T3-L1 cell differentiation was further proven by enhanced adipogenesis in cells overexpressing CatK. Using a Fugene-mediated gene transfection, we overexpressed the full-length human CatK in 3T3-L1 cells followed by stimulation of adipogenesis with insulin. As shown in supplemental Figure IIIH, a 28-kDa active human CatK and its precursor were detected by CatK immunoblot analysis in CatK-transfected cells, but not in nontransfected or vector-transfected 3T3-L1 cells. Importantly, CatK-transfected 3T3-L1 cells demonstrate significantly more advanced adipogenesis, as reflected by increased accumulation of intracellular oil-red O-positive lipid deposition (supplemental Figure IIIG/I), supporting a role of CatK in preadipocyte differentiation.
CatK Deficiency Reduces Body Weight Gain in Mice
Increased CatK expression in human and mouse adipose tissue could be one of the hallmarks of obesity. To examine the direct participation of CatK in obesity, we fed CatK-deficient (CatK−/−) and heterozygous (CatK+/−) mice a HFD for 16 weeks to induce obesity. Compared with wild-type littermate control (CatK+/+) mice, overall body weight was reduced in male CatK−/− and CatK+/− mice (Figure 2A), but most data points did not reach statistical significance. However, body weight gain in female CatK−/− mice was significantly reduced compared with that of female CatK+/+ mice at later time points (Figure 2B). To test whether reduced body weight gain in female CatK−/− mice was attributable to possible alterations of food/water consumption or metabolic rate, we performed energy expenditure analysis in mice that consumed a HFD by monitoring mouse food consumption (gram/24 hours), water uptake (ml/24 hours), O2 consumption (ml/min), CO2 production (ml/min), and metabolic rate (cal/min), and found no significant differences in these parameters between CatK+/+ and CatK−/− mice (supplemental Table II). Importantly, CatK contributes to body weight gain in a gene dose-dependent manner. CatK+/− mice gained more weight than CatK−/− mice but less than the CatK+/+ mice (Figure 2B). Consistent with reduced body weight gain, both male and female CatK−/− mice demonstrated significant reduction of total visceral and subcutaneous fat weight compared with those of the CatK+/+ mice, and such reductions were more prominent in females (Figure 2C). Interestingly, adipocytes in CatK−/− mice visceral fat are bigger than those from CatK+/+ mice (Figure 2D), suggesting reduced adipocyte contents in CatK−/− mouse adipose tissues. Therefore, lean fat does not necessarily contain small adipocytes. The same is true in collagen VI-null mice, which also gained less body weight but had larger adipocytes than the wild-type controls, although mechanisms behind these phenotypes remain unknown.14
Prior in vitro studies suggest that CatS promotes adipogenesis by degrading fibronectin,3 an extracellular matrix protein that regulates preadipocyte differentiation.5 When 3T3-L1 cells were cultured on fibronectin-precoated plates, adipogenesis was impaired.4 Therefore, we examined whether reduced body weight gain in CatK−/− mice correlated with higher tissue fibronectin levels. Using immunoblot analysis, we did detect fibronectin accumulation in fat (Figure 2E) and muscle (Figure 2F) from CatK−/− mice. Female mice had lower body weight (Figure 2A and 2B) and less adipose tissues (Figure 2C) and higher fibronectin proteins in the fat (Figure 2E) and muscle (Figure 2F) compared with those in male mice (Figure 2A, 2B, 2C, 2E, and 2F). Increased tissue fibronectin levels in CatK−/− mice or female mice were not attributable to altered gene transcription. RT-PCR analysis did not reveal significant differences of fibronectin transcripts among different genotypes or genders (Figure 2G). Similar results were obtained from immunohistology analysis. Strong immunogenic fibronectin signals were detected in fat and muscle from CatK−/− mice, but were almost negligible in tissues from the CatK+/+ mice (Figure 2H). These observations suggest a role of CatK in adipogenesis in part by reducing tissue fibronectin protein levels. To examine this hypothesis in vitro, we digested human plasma fibronectin with recombinant human CatK. Fibronectin digestion with 1 to 250 nmol/L of CatK yielded 90 to 110 kDa degradation fragments (Figure 2I).
CatK Deficiency Reduces Mouse Serum Insulin and Glucose Levels
Visceral obesity is often associated with increased serum glucose and insulin levels.15 Therefore, it is possible that reduced body weight gain in female CatK−/− mice associates with a reduction of serum insulin levels. To examine this possibility, we detected a significant reduction of serum insulin in CatK−/− mice (both males and females) with an insulin ELISA kit. Although lower serum insulin levels were also observed in CatK+/− mice, this reduction did not reach statistical significance (Figure 3A). It is possible that reduced serum insulin in CatK−/− mice could result from enhanced insulin metabolism, mediated by IR. To test this hypothesis, we performed immunoblot analysis in visceral fat and skeletal muscle from female mice. Although we did not detect differences in IR protein levels in fat from different mice (Figure 3B), increased levels of IR (95-kDa β-subunit) were detected in muscles from CatK−/− and CatK+/− mice (Figure 3C), suggesting that IR turnover in the endosomal compartment requires CatK.16
By measuring fasted mouse serum glucose levels, we detected significant reduction in female CatK−/− (P<0.02) and CatK+/− (P<0.04) mice but not in males (Figure 3D), indicating improved insulin sensitivity in CatK−/− mice. Muscle has long been considered the major site of insulin-induced glucose uptake in vivo,17 mediated by a family of glucose transporter proteins, which are expressed in specific tissues. Among these proteins, Glut4 is the major glucose transporter isoform in tissues that exhibit insulin-stimulated glucose uptake, such as adipose tissue and skeletal muscle.18 Consistently, both fat and muscle tissues from CatK−/− and CatK+/− mice also contain higher amounts of Glut4 than tissues from CatK+/+ mice (Figure 3E and 3F).
CatK Inhibition Reduces Body Weight Gain in Mice
We tested whether we could reduce mouse body weight gain by selectively inhibiting CatK activity. A recently discovered CatK-selective inhibitor Nα-phenoxybenzyloxycarbonyl-l-leucine(2-phenylaminoethyl)amide (K4b) was prepared according to an established method.19 K4b inhibits preferentially CatK with IC50 <0.006 μmol/L, whereas it inhibits cathepsins S and L with IC50 >10 μmol/L.19 Because significantly reduced body weight gain was observed mainly in female CatK−/− mice (Figure 2B), we injected female wild-type C57BL/6 mice intraperitoneally with K4b (1 mg/kg/d) and detected reduction of HFD-induced body weight gain, although some time points did not reach statistical significance (Figure 4A). To examine whether K4b inhibited other major tissue cathepsins under this concentration, we performed cathepsin active site labeling using splenocyte, one of the best tissue cell types expressing spectrum of cathepsins, harvested 6, 12, and 24 hours after K4b injection, which did not reveal obvious inhibition of CatB, CatS, or CatL (not shown). CatK inhibition with K4b also increased the fibronectin levels in skeletal muscle and visceral fat (Figure 4B). In contrast, fat or muscle from obese wild-type C57BL/6 mice that were injected with vehicle (DMSO) contained negligible fibronectin (not shown).
Genetically altered ob/ob mice on a chow diet gain body weight consistently. Mice received K4b (1 mg/kg/d) at 4 weeks of age, when wild-type mice and ob/ob mice did not show significant body weight differences. Female ob/ob mice that received K4b demonstrated significant reduction of body weight gain at all time points tested compared with those that received only vehicle (Figure 4C). In ob/ob mice, inhibition of CatK with K4b also led to accumulations of both muscle and fat fibronectin (Figure 4D). However, all tested energy expenditure parameters, including food/water intake, O2 consumption, CO2 production, and metabolic rate were not affected in C57BL/6 or ob/ob mice by this compound (not shown).
Both CatS and CatK are expressed in adipose tissues from humans and mice.1,2,7 However, increased expression of these proteases can be the result of inflammatory infiltrates, including macrophages and lymphocytes. It is now well accepted that macrophages, rich in cathepsin expression, are recruited to the adipose tissues20 where they further polarize to adipose tissue-specific macrophages.21 In diet-induced obese mice, consumption of a HFD also stimulates adipose tissue chemokine expression for the recruitment of macrophages, lymphocytes, and other inflammatory cells. Recent studies suggest that CatS promotes human preadipocyte differentiation.3 Inhibition of CatS activity delayed adipogenesis. These data are consistent with our finding that CatS and CatK had the greatest induction among all tested cathepsins after human preadipocyte differentiation (supplemental Table I). Although we cannot exclude the possibility that CatS controls human adipogenesis, we did not see reduced body weight gain from a HFD-fed CatS/low-density lipoprotein receptor (LDLr)12 or CatS/apolipoprotein E (ApoE) (Shi, unpublished data) double mutant mice compared with their wild-type controls. We do not know whether these phenotypes were attributable to the deficiency of LDLr or ApoE or because CatS expression levels were too low relative to other cathepsins (42- to 100-fold less than CatB, CatK, and CatL; supplemental Table I), or perhaps human CatS acts differently from mouse CatS. These theories remain to be examined.
In this study, we used an in vitro human and murine preadipocyte culture system, genetically altered mice, and pharmacologically treated obese mice to test a hypothesis that CatK participates directly in obesity. Although the exact mechanisms by which CatK participates in adipogenesis or obesity require further investigation, our data suggest that CatK affects at least two molecules that are essential to adipogenesis: fibronectin and IR β-subunit. Participation of fibronectin in adipogenesis has been proposed since the early 1980s.5 Although mice lacking fibronectin are lethal,22 which makes it difficult to test a direct role of fibronectin in obesity, human and murine preadipocytes fail to differentiate on fibronectin precoated culture dishes.4 Significant inhibition of adipogenesis was also observed when mouse 3T3-L1 cells were cultured in 5 to 15 μg/mL of fibronectin (data not shown). In this study, we demonstrated in vitro that CatK degraded 220-kDa fibronectin into 90- to 110-kDa fragments. Similar size fragments were also detected from fat and muscle tissues from CatK+/+ mice (Figure 2E and 2F), suggesting an in situ CatK activity in fibronectin degradation. However, this hypothesis is challenged by the observations of 90- to 110-kDa fibronectin fragment production in tissues from CatK−/− mice (Figure 2E and 2F). Therefore, proteases other than CatK are also involved in native fibronectin proteolysis. Nevertheless, we detected accumulation of fibronectin in fat and muscle from both CatK−/− mice and CatK inhibitor-treated mice (Figures 2E, 2F, 2H, 4B, and 4⇑D), which may account at least in part for the reduced body weight gain in these mice.
Internalization of insulin-IR complex contributes to insulin clearance23 However, the exact intracellular enzyme(s) responsible for this processing pathway remains unidentified. Prior studies suggested a role of thio-proteases in IR catabolism.24 Despite the observation that the rate of insulin-IR internalization and degradation is reduced in cells from obese patients, the pathological implication of altered IR processing remains unknown. It is anticipated that alteration of IR processing influences insulin action and glucose metabolism. Indeed, obese Zucker fatty rats treated with E64 demonstrated reduced proteolysis of cell membrane IR β-subunits25 and improved the insulin resistance.24 Our observations demonstrated that CatK was one of these thio-proteases responsible for IR β-chain processing, and absence of CatK resulted in accumulation of IR β-chain (Figure 3C). We also showed that CatK-deficiency reduced insulin and glucose circulating levels (Figure 3A and 3D). These changes could be secondary to reduced weight gain in CatK−/− mice. Alternatively, CatK-deficiency could improve insulin action per se, by undefined cellular and molecular mechanisms. Among the potential candidates, increased Glut4 expression in muscles and fat of CatK−/− mice (Figure 3E and F) could contribute in part to improve insulin effect on glucose utilization.18
Although body weight gain showed no significant differences between male CatK−/− and CatK+/+ mice (Figure 2A and 2B), serum insulin levels did (Figure 3A). In contrast, both body weight gain and serum insulin levels are reduced in female CatK−/− mice, compared with female CatK+/+ mice. Therefore, at least two questions remain. First, why are female mice more sensitive to CatK than male mice in body weight gain? Cathepsins play a role in hormone activation or degradation. For examples, cathepsins produce active forms of thyroid hormones,26 which regulate body weight gain.27 It is possible that obesity-associated hormone activation by CatK is differentially regulated in different genders. Second, why did male CatK−/− and CatK+/+ mice show differences in serum insulin levels (P=0.02; Figure 3A) but less so in body weight gain (Figure 2A)? These observations suggest different mechanisms of body weight gain and insulin secretion or clearance, although how CatK involves in these regulations remains unknown.
In conclusion, our data suggest an important participation of cysteine protease CatK in obesity by degrading matrix protein fibronectin. Deficiency and pharmacological inhibition of CatK reduces mouse body weight gain, indicating a potential means of controlling human obesity by targeting CatK activity.
Sources of Funding
This study is partially supported by the grants from the NIH (HL67283, HL60942, HL81090, and HL88547 G.P.S.). INSERM U872 received a grant from the French National Agency of Research (Obcat No. ANR-05-PCOD-026-01) and from the Fondation pour la Recherche Médicale and Danone Institute.
G.-P. Shi declares a competing interest in NMPI, LLC. All authors declare no competing financial interests.
Original received June 16, 2008; final version accepted September 15, 2008.
- ↵
Taleb S, Lacasa D, Bastard JP, Poitou C, Cancello R, Pelloux V, Viguerie N, Benis A, Zucker JD, Bouillot JL, Coussieu C, Basdevant A, Langin D, Clement K. Cathepsin S, a novel biomarker of adiposity: relevance to atherogenesis. FASEB J. 2005; 19: 1540–1542.
- ↵
Taleb S, Cancello R, Poitou C, Rouault C, Sellam P, Levy P, Bouillot JL, Coussieu C, Basdevant A, Guerre-Millo M, Lacasa D, Clement K. Weight loss reduces adipose tissue cathepsin S and its circulating levels in morbidly obese women. J Clin Endocrinol Metab. 2006; 91: 1042–1047.
- ↵
- ↵
- ↵
- ↵
- ↵
- ↵
Villadangos JA, Riese RJ, Peters C, Chapman HA, Ploegh HL. Degradation of mouse invariant chain: roles of cathepsins S and D and the influence of major histocompatibility complex polymorphism. J Exp Med. 1997; 186: 549–560.
- ↵
Shi GP, Dolganov GM. Comprehensive transcriptome of proteases and protease inhibitors in vascular cells. Stroke. 2006; 37: 537–541.
- ↵
- ↵
- ↵
- ↵
Wang D, Pechar M, Li W, Kopeckova P, Bromme D, Kopecek J. Inhibition of cathepsin K with lysosomotropic macromolecular inhibitors. Biochemistry. 2002; 41: 8849–8859.
- ↵
Scherer PE. Adipose tissue and acute phase response. Molecular control of adipogenesis and obesity. Keystone Symposia, Banff, Alberta, Canada, Feb. 19–24, 2008.
- ↵
- ↵
Authier F, Metioui M, Fabrega S, Kouach M, Briand G. Endosomal proteolysis of internalized insulin at the C-terminal region of the B chain by cathepsin D. J Biol Chem. 2002; 277: 9437–9446.
- ↵
- ↵
- ↵
- ↵
- ↵
- ↵
- ↵
- ↵
Knutson VP, Donnelly PV, Balba Y, Lopez-Reyes M. Insulin resistance is mediated by a proteolytic fragment of the insulin receptor. J Biol Chem. 1995; 270: 24972–24981.
- ↵
Trischitta V, Brunetti A, Chiavetta A, Benzi L, Papa V, Vigneri R. Defects in insulin-receptor internalization and processing in monocytes of obese subjects and obese NIDDM patients. Diabetes. 1989; 38: 1579–1584.
- ↵
Tepel C, Brömme D, Herzog V, Brix K. Cathepsin K in thyroid epithelial cells: sequence, localization and possible function in extracellular proteolysis of thyroglobulin. J Cell Sci. 2000; 113: 4487–4498.
- ↵
This Issue
Jump to
Article Tools
- Deficiency and Inhibition of Cathepsin K Reduce Body Weight Gain and Increase Glucose Metabolism in MiceMin Yang, Jiusong Sun, Tinghu Zhang, Jian Liu, Jie Zhang, Michael A. Shi, Froogh Darakhshan, Michèle Guerre-Millo, Karine Clement, Bruce D. Gelb, Gregory Dolgnov and Guo-Ping ShiArteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2202-2208, originally published November 19, 2008https://doi.org/10.1161/ATVBAHA.108.172320
Citation Manager Formats
Share this Article
- Deficiency and Inhibition of Cathepsin K Reduce Body Weight Gain and Increase Glucose Metabolism in MiceMin Yang, Jiusong Sun, Tinghu Zhang, Jian Liu, Jie Zhang, Michael A. Shi, Froogh Darakhshan, Michèle Guerre-Millo, Karine Clement, Bruce D. Gelb, Gregory Dolgnov and Guo-Ping ShiArteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2202-2208, originally published November 19, 2008https://doi.org/10.1161/ATVBAHA.108.172320Permalink:


text:
The Science Behind Power Napping
This type of sleep is rumored to have been around for 100's of years. Its origins date back to mainly being used by artists and travelers from spain.
The benefits of this type of sleep are minimizing the feelings of being groggy or more tired than before you took a nap.
Normal power naps are meant to last no longer than 10-30 mins tops. This allows you to get rest but not enter a deeper sleep than stages I or II.
The results of a proper nap using this method include waking to find ones self more alert, and more thoroughly rested than if you had slept for a prolonged period of time.
Other benefits include enhanced performance and learning. Your ability to memorize new information is said to also increase. Many scientific studies have developed to support evidence that this type of sleep is beneficial.
NASA has also done studies on this type of sleep, finding eveidence that these types of naps can improve certain memory functions.
During days of prolonged learning, training, or working in an environment that requires taking in a large amount of new information, sleep of this kind has shown to help decrease memory overload.
Positive ways of utilizing this technique include limiting your caffeine intake, securing a healthy daily diet, and developing a positive mental routine to follow each nap.
Oversleeping at night can damper the effectiveness of short term sleep. Make sure to have a way of alerting yourself when the alotted time of the nap is completed.
Some of us may need to come up with a method of taking a nap without being caught. Wearing tented glasses and napping in a comfortable upright chair is recommended.
The most successful way of getting away with a nap or two would be to take a short nap after reading this, followed by reading it again. Informing your boss that these naps are boosting your performance rate at work, are backed by scientific research, and are recommended by your doctor, should help minimize tension between the two of you.
If all else fails, take a short nap during an alleged bathroom break! Just be sure to set an alarm of some sort, and bring a padded toilet seat cover. Hopefully you will enjoy many such naps, share this positive information with others, and ultimately feel more rested each work day!


text:
Botanical Name: Phlox adsurgens
Other Names: There are many varieties and hybrids, both annuals and perennials.
Phlox and Creeping Phlox are highly adaptable plants that serve nicely as ground cover, border plants and edging fill. They fill out garden beds easily and add dramatic splashes of color wherever planted. Some varieties, such as Wild Sweet William, grow wild throughout the woodlands of North America.
Phlox come in a wide range of types, sizes and colors, both annuals and perennials.
» Height: 8 to 12 in.
» Spread: 15 to 18 in. on average
» Exposure: Full to Partial Sun
» Zones: 3 through 11


text:
Students connect with seasonal changes and cycles by observing a tree and a garden plant throughout the school year with this learning resource from Captain Planet's Learning Gardens Program.
For more information, see Project Learning Garden and the Captain Planet Foundatin's Learning Garden Lessons.
© 2018 PBS & WGBH Educational Foundation. All rights reserved.
You must be logged in to use this featureLog In Enter Code Need an account?


text:
The Battle between Sailing Clubs
There now appears to be 2 Sailing Clubs for children in San Pedro. One operates outside the Holiday Hotel without a professional trainer and is run by Tammy Peterson. The Ambergris Daily considers it very dangerous that young children sail in the busy waterways of downtown San Pedro. It also appears that some of the sponsors of the sailing boats used there are upset that their boats have been taken away from Caribbean Villas. Sunrise Realty and others are considering legal action to get their sponsored boats back, as they bought them with the idea of their children, and all other children being able to use them. Also, the children from this club have been told that they are not allowed to even talk to the children of the other sailing club, with threats of not being able to compete at various Regattas, and even having their school funding being stopped.
The Ambergris Daily thinks this is insanity to use children and charitable causes as weapons against others.
On the other hand, the San Pedro Sailing Club, operating out of Caribbean Villas Hotel, is open to all children on Saturdays and Sundays if they wish to sail or not. Over the next few weeks various other beach games and activities will be made available under the supervision of Andy Milner, Forrest Jones, Cindy Vigna, Amanda Syme and many others. These children are allowed to talk to any children and this club exists for positive reinforcement and enjoyment of sailing. Andy Milner is the only person who is qualified to teach sailing in San Pedro, and if you spend 5 minutes with him you will quickly learn about his passion to teach every child in San Pedro how to sail… otherwise his conversations are a trifle boring!
He is ably assisted by Forrest Jones, who is retired from the US Navy and a very experienced sailor. Anyone how knows him realizes that he is one of the most respected residents of San Pedro.


text:
General Motors new CPO Program
We don't certify a lot of vehicles in order to keep our costs down, but I am curious as to how GM's new CPO program is going. Has anyone been certifying cars? How has it been working for you. The biggest added benefit to the consumer is the 2 year maintenance plan in my opinion.
Steve, We Certify all valid vehicles. Yes, the cost factor does come into play but it opens the door to F & I. We have been doing very well in our used car numbers since this release. You have to have the sales floor drink the kool-aid to get the best out of it. Our back-end product penatration for pre-owned has incresed by approx. 10% using this as a lead in to ESC's and continued maintenace programs. It is a tool that you need to use. Tim
I'm scared that the .09% financing promotion (or whatever the promotional rate actually is) would hurt our back end profits.
I have not experienced the Finance options being discussed by our clients often. In the last 10 months I believe that we have had 4-5 deals at that promotional rate. The advertised programs are showing the short term rates and that ends up being easy to overcome. I personally feel that taking the flat for selling at the buy rate will open the clients budget for better product penetration. Our plan is to balance rate income with product income to protect against chargeback situations. Our F & I department realistically does 60% of our retail finance deals at the buyrate because of aggressive dflats being paid from most lenders (2,3 and 4% flats). Selecting to go that route can build client trust and sway their attention when reviewing other products.
Suggested Discussions
Michael Pokora • 13 hours ago
Last reply by Michael Pokora
• 13 hours ago
• 13 hours ago
Jim Chamberlain • Aug 2, 2009
Last reply by Dave Molyneux
• 10 hours ago
• 10 hours ago
Last reply by Michael Pokora
• 10 hours ago
• 10 hours ago
Featured Masters
No members found
Rate a Vendor Give feedback in three quick steps
Select a Vendor & Product
Can't find what you're looking for?
Add a Vendor or Add a Product
Add a Vendor or Add a Product


text:
Bound for the game parks of southern Africa, our sights are set on Johannesburg. Check in at The Four Seasons Hotel The Westcliff, where we are sheltered well away from common commotion.
Our welcome into Africa could not be more insightful. Enjoy a tour of Johannesburg, embracing the vast plains and endless skyline that mark our temporary home.
This afternoon, take a moment of private reflection or enjoy the very first Your World experience.
At Livingstone, gateway to Victoria Falls, we fall into the embrace of the colonial-style Royal Livingstone Hotel, where we'll spend two nights.
Doctor Livingstone, the first European to see Victoria Falls, named his discovery in honour of his monarch, Queen Victoria. However, it is also known by its indigenous name, Mosi-oa-Tunya – 'the smoke that thunders'.
The remainder of the afternoon is spent on your own terms or with a Your World experience.
In the dry season, elephants flock to the Chobe River in unimaginable numbers, making it one of the best places to view these gentle giants. Propped perfectly beside the riverside, we arrive at the Chobe Chilwero.
We cannot yet dream of rest – the waterways are too enticing. It's time to head out on our first river safari. Cruising in the warm glow of sunset, we secure front-row seats to the pageantry of Africa at sundown. Families of hippos wallow in the river as elephants slosh towards the water's edge to drink, bathe and play.
We take to open-air 4WDs and travel away from the banks of the river, listening for branches snapping – it usually means elephants are nearby.
Back at our lodge, the afternoon unfolds as we please. Kick back and enjoy the view of the Chobe River from your terrace or join our Your World experience.
Fed by flood water from the Angolan Highlands, the Okavango Delta fans out across the country like slender veins, forming an intricate web of palm-fringed channels, lagoons and lush islands. Take a private charter directly into the heart of the Okavango Delta.
Upon arrival we are transferred to the Khwai River Lodge overlooking Moremi Reserve, the first wildlife area to be set aside by tribal people rather than colonial powers. Tonight's dinner is served in a delightful outdoor setting embraced by bushland. Under the setting sun, the delta's hushed water is blanketed in crimson radiance.
Travellers regard the Okavango Delta as one of the most beautiful natural areas of the continent. If safari dreaming has brought you here, the game viewing will exceed your wildest imaginings. We search for wildlife each morning and in the late afternoon, open-air 4WDs taking us along the island's floodplains. Leopards stalk through thick thorn scrub. Hippos bellow from faraway lagoons.
A journey by air lands us along the wind-swept Skeleton Coast. Countless ship wrecks shrouded in dense ocean fogs give this haunting place its name. We have this afternoon to spend at Swakopmund, a typical Hans town built by the Germans, where banks of sand rush to meet the thundering waves of the Atlantic Ocean. We overnight at the Swakopmund Hotel.
In South Africa and Namibia, raw treasures are known to hide off the beaten track; unpolished and often otherworldly in their beauty. From the elegance of our Deluxe Suite on board Rovos Rail, Africa unfolds before our eyes. We stake our claim on a wing-backed chair and contemplate what life must have been like during the heyday of steam locomotion.
From the peaceful solitude of Rovos Rail we arrive in Tsumeb to explore Etosha National Park. Nestled between camel thorn and mopani trees, Mokuti Etosha Lodge welcomes us. After lunch, we head out on our first game drive. Etosha is one of the few places that the endangered black rhino resides, almost unaffected by poaching. It will be a privilege to spy the wrinkly creatures.
Amongst the changing colours of the early morning, we set off in 4WDs. Parched and cracked, the shimmering surface of the saline desert creates an eerie effect, the animals seemingly floating in pools. Game viewing in Etosha is certainly a unique experience. We return to our train and continue the journey south.
Classic steel wheels deliver us to Windhoek where our light aircraft is awaiting to carry us to Sossusvlei. Transfer to Namib-Naukluft National Park, and retreat to the luxury of Sossusvlei Lodge. On an afternoon drive, we sail up and down the ancient dunes, among the highest in the world. Back at the lodge, a bush dinner is served al fresco within the atmospheric confines of our lodge's private reserve.
The orange dunes of Sossusvlei burn so deep they appear lit from within. We embark on a 4WD desert excursion to experience this illuminating display. After a return flight from the coast to Windhoek, it's back to our noble train in time for lunch and an afternoon spent relaxing to the rhythm of the rail.
This morning we discover the settlement of Keetmanshoop and learn of its German heritage. Later, a detour takes us out to the Quiver Tree Forest and we consider the formations at Giant's Playground before continuing on to Fish River Canyon. Almost 1.5 billion years of geological history stretches out before us. Peer over the expanse in search of baboons, rock dassies, ground squirrel and tiny klipspringers.
Upington is wild at its very core. Shrouded in stories of diamond smugglers and horse rustlers, highway robberies and ruthless fortune-seekers, we come to grips with this frontier town during a stroll along Date Palm Avenue.
A cloud of fuchsia materialises on the edge of a shallow lake, as if conjured by the wave of a magic wand. Our train edges ever closer and we clamber towards the windows hoping to see flamingos dancing a fantastical ballet.
We roll into Kimberley, a mining town cloaked in tales of diamonds. The De Beer name is synonymous with the city, home to one of the world's most successful diamond mines. We tour the city, the Big Hole and the Mine Museum before retiring to our train.
Our journey draws to an end in Pretoria today and we take a coach to Johannesburg where our flight is waiting, ready to whisk us home.
Ever so reluctantly, we land on home soil this morning, brimming with memories and tales – unsure of which we should recount first.
Sometimes travelling can be a chore, distracting you from the fascinating places you are in. That's why everything mundane has been moved behind the scenes. You will never have to carry a map, luggage, small change for tips or bargain for a taxi fare.
There are no hidden costs. Everything is included – flights and other travel arrangements, luxurious accommodation, travel insurance, all dining and drinks, and even sightseeing trips. Even the Your World experiences within your itinerary and internet access when available.
Welcome to your homes away from home. Each one has a certain something that sets it apart from every other residence at its location. Whether for its history, cultural significance or natural setting, we've selected only the very best.
Almost a village, tightly bound by courtyards and terraces, Four Seasons Hotel The Westcliff presents a remarkable reception into Africa. Prepare for our daily discoveries with a steaming mug of coffee on your private balcony or ground-floor garden, welcoming the sounds and smells of South Africa's bustling capital.
Not all game drives have to be on four wheels. As the Pride of Africa tumbles and turns, we are granted the rare opportunity to traverse the natural wonderland that of Namibia and Southern Africa. Crank open the Lounge Car windows and peek outside – you never know, there just might be a playful creature peeping back.
An oasis within the Okavango Delta, Moremi Wildlife Reserve was the first wildlife area to be protected by tribal people rather than colonial powers. From our private suites at the Khwai River Lodge, we are offered the perfect vantage point for viewing migratory animals.
Fares are based on a Deluxe Suite aboard Rovos Rail. Per Person, Twin Share.
Fares are in Australian dollars and include Qantas flights from Sydney, Melbourne or Brisbane. Prices from other cities available on request.
Land Only Guests join the tour in Johannesburg for dinner on Day 1 and depart Johannesburg at the airport on Day 19.
Solo availability at the above price is limited.
Trip notes: This journey is reserved for a group of just 20 guests.


text: Greetings fellow Accord owners. I've just taken delivery of an ex-demo (2012) 2.2 I-DTEC EX in Crystal Black with 18" Deltas. Currently working my way through the owner's manual to see what's different (my previous car was a 2006 I-CTDI EX in Graphite). First impressions are good. Missing the touchscreen. Not missing the rear tyre noise!


text:
Manila, 11.11.2013 - A TURBOSOUND TCX series loudspeaker system has been installed at the Iris Club in Ghantoot, Dubai by audio designer Joe Chidiac of Pulse Middle East, delivering a high quality sound reinforcement system.
Riding on the success of the celebrated Diablo nightclub and recent Café del Mar projects and the company's excellent reputation in the UAE market, Pulse Middle East was asked to propose a sound system for the venue. Chidiac based his system design around TURBOSOUND's TCX contracting loudspeakers, which are designed with integral rigging points, rotatable high frequency waveguides, barrier strip connectors and optional colour finishes to provide great performance on a budget.
The passive 15" TCX-15 two-way full range loudspeaker and TCX-15B 15" bandpass subwoofer were chosen as the optimum solution for the venue, striking the right balance between quality and price. Additionally four Milan M15 powered portable loudspeakers can be moved around and deployed wherever needed.
In total the venue was populated with 28 TCX-15s and 16 TCX-15B subwoofers, covering around 600 square metres of floor space to complete an up-front sounding surround system.
The audio system was powered by 10 RACKDP-50 four-channel digital amplifiers with built-in DSP, and the configuration for the venue was loaded initially from the factory presets which were then optimised slightly with some frequency band adjustment. Delay was dialed in to deliver a cohesive and balanced sound throughout the venue.
"The RACKDP-50 was the best choice for us with its ease of configuration, allowing us to tune and complete the project in record time," says Chidiac. "The owner, Mr. Maher Arabi was really pleased with the result, and this marks another successful project for Pulse Middle East and TURBOSOUND."
Für den Inhalt der Pressemitteilung ist der Einsteller, PresseBox.de, verantwortlich.
Es wurde noch kein Kommentar zu diesem Thema abgegeben.


text:
Report: Jonathan Martin went AWOL at OTAs, Dolphins ignored issues
The Jonathan Martin hazing saga is like a giant onion. Layers are being peeled off quickly and the closer we get to the center of it, the worse it stinks. The latest rumors about the Dolphins brass asking Richie Incognito to "toughen up" Martin are the smelliest. And the odor isn't helped by a report that Martin went AWOL during offseason training activities before this season.
And according to Jason Cole of the National Football Post, the Dolphins "ignored early warning signs of problems" with Martin and Incognito during that time by not speaking with Martin when he didn't show up for OTAs.
"They would have found out that he was already feeling threatened by the situation," a source told Cole. "There was already a problem, but they didn't ask him what was bother him."
This is when, as reported earlier by the South Florida Sun Sentinel, the coaches (allegedly) told Incognito to toughen up Martin.
All of this is allegation at this point. The public back-and-forth subsided once the actual investigation began. Even Incognito is simply trying to "weather the storm." But the more we start to hear what is filtering out about this case, the worse it looks for Dolphins management. The idea that they could have prevented this fiasco months ago is particularly damning.


text:
Product Description
The Android Homme Propulsion Mid returns for the new SS16 season with a fantastic makeover. This black sneaker is guaranteed to make a statement. This mid shoe features unique wrinkle patterned side panel with a black glossed sole stamped with signature Android Homme details. Metal eyelets and tongue hold the brand's signature.
Make these Android Homme Sneakers the central part of your luxe casual outfit this season with a pair of Tramarossa Jeans and a plain black tee from Sunspel. Complete the look for the Spring/Summer with a McQ Sweatshirt. Protect your sneakers with a can of our Sneaky Spray footwear protector.
- Fits true to size. Take your usual size.
- Black tonal waxed laces.
- Comes with an Android Homme Dust bag.
- Glossed sole unit.
- Handmade in Portugal. Designed in Los Angeles.
- Product code; AHP1601037


text:
Ringworm in Horses:
There are lots of things I like to share with my horse. Ringworm isn't one of them. I've seen ringworm on all kinds of creatures--dogs, cats, horses and myself when I was about seven years old. Back then it was a good excuse to be off school, besides the 'ewwww' factor the name of the skin condition inspired. Thankfully, although it looks unsightly, and your horse may be uncomfortable for a bit, ringworm is pretty easy to treat and if treated promptly is ewww, but not very harmful.
Ringworm, Tinea or Dermatophytosis in horses.
The name ringworm suggests that this form of dermatitis on horse's is caused by a worm. In fact, ringworm is caused by fungus. It has nothing to do with worms, internally or externally. Ringworm fungi like to live on the warm, moist surface of your horses skin and hair. The really bad news is, ringworm is not choosy about who or what it lives on. Ringworm is a zoonotic disease, and it can be transferred to any of your human or animal family members. Without proper hygiene procedures ringworm can be transmitted quite easily. The medical name for ringworm is Dermatophytosis or Tinea. Youngsters, senior horses and horses in poor condition are more likely to be affected. Do not confuse ringworm, with roundworms, which are an internal parasite, best controlled with a parasite control schedule.
Ringworm on horses may appear at first as staring patches of hair.
The hair in the center of the patch will fall away, leaving the typical circular lesions that give the skin condition its name. The lesions may appear first in the saddle and girth area, where the skin stays damp longer and the contact makes it spread more easily. The hairless patches may appear inflamed and encrusted with flaky skin.
Ringworm may start out as only one or two patches but quickly spread. This is one time grooming is not recommended as brushing may spread the fungus to other parts of the body.
While a horse with ringworm may be uncomfortable, ringworm is really more of an unsightly nuisance. Ringworm may disappear on its own weeks or months after the initial outbreak. But in the meantime, ringworm can spread to other horses, cattle, humans and pets as the fungus can persist on stall walls, brushes, tack and other items the horse may come in contact with. A horse with ringworm will not be welcome at shows or other events. That is why most people opt to treat the condition, to help it heal faster. Once a horse has had ringworm, it is unlikely it will get it again.
The lesions caused by ringworm are typical enough that the skin condition can be diagnosed by eye. But if there is any question, your veterinarian can take a skin scraping and examine it. Then the horse will be treated with anti-fungal wash. Some vets may suggest shaving the area. Because the fungus will persist on the horse's brushes, tack and stable, all must be washed down with an anti-fungal solution to prevent further spread.
It's important to wear gloves during the treatment time and take care not to pass the fungus on to other people or animals. Some people have had good results with natural remedies that contain ingredients like tea tree oil or solutions that contain iodine.
Keeping your horse in good health is they key to avoiding many problems. It is a good idea for each horse to have its own tack and brushes. If ringworm is suspected, the horse should be kept away from others until the lesions disappear. Any new horses brought into a stable should be carefully examined and kept seperate if there is any health concern. I have seen a situation where a horse with ringworm was turned out with others without spreading the fungus, but I would not recommend the practice.


text:
Tourist guides in Varanasi
A tourist guide is a person who guides the tourists in their respective language, interprets, shows and explains the culture, heritages and other customs of any specific destination. He is considered an expert of that specific destination/city/region. To work as a tour guide he has to be recognized or authorized by local of central Govt/Authority.
Why a Varanasi tour guide is needed when you visit to Varanasi ?
If we will see a guide in context of Varanasi tourism, a would recommend highly to hire a Varanasi local tourist guide for your visits and tours. This becomes even more compulsory for tourists coming from abroad to this holy Varanasi city.
A town as recent as time. A town that has seen the globe flip, tides amendment and generations of humans born and die. Varanasi, Benaras or Kashi, that has been standing the tests of your time for over four thousands and even more years is claimed to be one in every of the oldest peopled cities within the world. This city has many secrets folded inside it.
There are many reasons why you should hire a tour guide in Varanasi for your visits or exploring its point of interests –
1- The main charm of Varanasi lies in the thousands years old streets which are countless in numbers. Persons visiting first time into these streets may lost into it and it will take hours for him to come to main road. A Varanasi tour guide will easily navigate all these streets and help you explore these sights to its best form.
2- To visit the biggest cremation ground on this planet which is located in Varanasi, you will be needing a guide. No books will teach you why and how a body is cremated but a tour guide of Varanasi will explain deep details and show you in practical for a better understanding.
3 – To save you from Varanasi touts. If you are alone and without a tour guide chances are that you will be approached by these touts who may play any possible to tricks to fetch money from you.
4- To explain deeply about any Varanasi sights. Just by reading a few books, you will never understand what Varanasi is. A Varanasi tour guide who is more like a city expert has gone through various real experiences, books and gained knowledge from locals will be able to explain much more in details.
5- To take to you hidden jems of Varanasi. Like countless temples, Varanasi countless hidden jems to explore. Every path you choose around the Ghat will take you to a very new and unusual sights. A place wherein on every step you gonna en-counter a new thing, you will be needing a guide to explain what that is.
6 – Learn about Varanasi's local art, artists, culture and custom. Varanasi has been a home of many musicians, poets and authors. If you are interested in knowing arts and about these famous personalities , it is not possible without a guide.
7- Gain a fresh perspective about Varanasi with a local tour guide. What we read in books and listen and carry some difference perspectives all together. These Varanasi guides will surly have a different and interested perspective about this city.
There are many more such reasons which will prove why you need a tourist guide while touring in Varanasi. We have list of Govt approved tour guides in Varanasi with expert in different foreign and Indian languages.
Spanish speaking guide in Varanasi :
Varanasi is very popular among Latin American Countries such as Brazil, Mexico, Colombia, Argentina etc. Spanish language are spoken widely in these countries. Tourists coming from these countries to Varanasi, seek for guides who speak good Spanish to guide them in Varanasi. Apart from English, we have lots of Varanasi Spanish speaking guides in our panel who hold an excellent command on Spanish Language and who are guiding since last 10-20 years in Varanasi.
Click here to – reserve un paquete turístico en Varanasi con guía local de habla hispana.
Italian Speaking guide in Varanasi :
Italy has a major share in international arrivals in India. Varanasi is quire popular in tourists coming from Italy so these has resulted a good demand of Italian speaking guides in Varanasi. To meet these demand many Italian speaking tour guides has come into Varanasi and made guiding their profession. We have some very fine guides who speaks Italian fluently and are tour expert recognized by Ministry of Tourism, Govt of India. All these are in these guiding profession since last many years.
Clicca qui per prenotare – pacchetto tour Varanasi con guida turistica italiana di Varanasi.
German Speaking guide in Varanasi :
With each day passing, number of visitors from Germany are increasing day by day for Varanasi. They love Indian culture and Varanasi being the cultural capital of India attracts them. A few years ago there were no German Speaking guides in Varanasi but now a few guides has come who speak very fluent German Language and they have been trained and authorized by Ministry of Tourism Govt of India.
Buchen Sie Varanasi Tour-Paket mit Varanasi lokalen deutschsprachigen Führer.
Japanese Speaking guide in Varanasi :
With each day passing, the number of visitors from Japan is multiplying. Varanasi culture, customs and daily life is what Japanese love must. As the number of Japanese Tourists are in creasing, it is becoming hard to meet the number of that much Japanese Language speaking guide or Interpreter. We, have a huge number of these guides who devotedly working for our clients.


text:
March 7: A son of Osama bin Ladens deputy has given crucial information on the whereabouts of al Qaida leaders after being captured by Pakistani forces in a lawless frontier area close to Afghanistan, intelligence officials in Islamabad have revealed.
Ayman al-Zawahiris son, Khalid, was seized along with 20 other suspected foreign militants in a raid by Pakistans security forces in the remote South Waziristan area 10 days ago, officials told The Daily Telegraph.
Information gleaned from him by interrogators has helped direct Pakistani and American forces in their drive to capture bin Laden and other senior al Qaida figures, being conducted in the mountainous areas on both sides of the border.
The authorities in Islamabad are unwilling formally to announce the capture of the younger al-Zawahiri, but officials have privately confirmed that he is being questioned by a joint team of intelligence officers from Pakistans Inter-Services Intelligence agency and the CIA at a secret location in Pakistan.
They say that recent sweeps by British and American special forces in the Tora Bora mountains of Afghanistan have been linked to disclosures made by Khalid al-Zawahiri and others including his wife captured with him in raids on houses in Azam Warak, nine miles from Wana, the main town of South Waziristan.
Pakistani security forces also recovered ammunition, passports, video cassettes and other literature belonging to the al Qaida terrorist network in the raids in the lawless frontier area. Al-Zawahiri is said to have been in touch with his father recently.
Hundreds of troops from Pakistans paramilitary Frontier Corps, backed by helicopter gun ships, have been deployed in the area to tackle the foreign militants and either capture bin Laden, or drive him across the Afghan border into American hands.
More than 1,600 American troops, including special forces units, are in place at Salerno base near Khost in eastern Afghanistan ready for an all-out spring offensive to capture bin Laden.
By next month, that figure will have more than doubled, bolstered by a heavy contingent of SAS soldiers who have been assigned a key role in the operation. American engineers are currently enlarging and upgrading a landing strip at Salerno so that large military planes can land there to support the mission.
Pakistan is reported to have secretly agreed to permit American and British forces to cross into its volatile border tribal areas from Afghanistan in large enough numbers to pursue al Qaida and Taliban fighters.
The extremely sensitive agreement is said to be part of an unofficial deal, in return for Washington supporting President Pervez Musharrafs controversial decision to pardon Dr Abdul Qadeer Khan, the man behind Pakistans nuclear bomb, for selling nuclear weapons materials on the international black market.
According to The New Yorker magazine, an intelligence official said: Musharraf told us, Weve got guys inside. The people who provide fresh fruits and vegetables and herd the goats (for bin Laden and his followers). Its a quid pro quo: were going to get our troops inside Pakistan in return for not forcing Musharraf to deal with Khan.
There has been heavy speculation that American and Pakistani forces are finally closing in on bin Laden, who slipped through the fingers of the coalition hunting him in the Tora Bora mountain region at the end of 2001.
The terrorist leader and his assistants are suspected to have been hiding in the semi-autonomous regions along the 1,500-mile border with Afghanistan, where inhabitants remain sympathetic to the Taliban movement as well as the Arab fighters who came to support it.
Tribals join the hunt
Tribal leaders today assured Islamabad that armed bands of their community would help Pakistani authorities search for al Qaida and Taliban militants in remote western regions of the country, according to a Reuters report. A grand jirga, or council, of tribesmen decided that up to 2,000 armed tribal fighters would help the government search for foreign terror suspects believed to be hiding there.


text:
I think some of the best things to acquire are skills and tools. And cheerful friends with skills and tools.
I started this blog some months after I learned to spin yarn. I think my posts might be helpful to someone going through the same discovery process. Along the way I've improved my knitting skills, learned to weave, learned to do språng, tried out lots of equipment, read many books, hung out with passels of handspinners, gotten a fair whack of people started on spindles, and gone to wool festivals near and far. I've been fortunate enough to meet and talk with a number of makers and producers of fiber arts supplies.
Some of the themes of this blog are re-skilling, the environment, fair labour practices, and history. And Shakespeare, just because I like Shakespeare and sometimes his plays mention textiles.
As it says on the home page of the blog, my name is Kristen M. Hughes. I am a handspinner, twisting fibre into yarn with a hand-powered drop spindle. This blog records what I learn and do. You may be here looking for a story, a solution, or information.
I spin yarn, finish objects, listen to experienced makers, and research methods. I want handspun clothes out of local fibre in natural colours. I want more linen cloth in my life and more språng (an ancient braiding technique).
I spin yarn in public as often as I can, talk about handmade textiles to anyone who will listen, and help new spindle spinners. I am active in my local handspinners guild. I see handspinning as a worthwhile and relevant skill.
I am a homesick Canadian, and I live in Virginia.
You can find my how to videos and interviews on YouTube as thesojourningspinner and my pins of fiber arts objects in museums on Pinterest as brighthughes. On Etsy, you can buy from me (Rosetwist LLC) stitch markers handmade from rose petals, drop spindle kits, and witty fiber arts-themed buttons, as well as jewellery made from rose petals. I started the company recently. I am developing new products, you can see the process behind the scenes on my page on Facebook. My Twitter feed is kind of sparse and boring.
Visit Kristen's profile on Pinterest.
Follow @RosetwistLLC


text:
Plumassier, what is that?
It doesn't translate well but literally it means "featherworker".
A plucker?
No, a plumassier is a master of the art of the plume, highly skilled in making beautiful haute couture creations out of feathers and silk.
Darling! Remind me again about haute couture?
High-fashion clothes made by hand to the specification of private clients, at prices normally associated with luxury cars. It's big in Paris.
And is that where you found him?
Naturellement. His name is André Lemarié, a graceful, grand man of the French fashion world who operates a traditional atelier packed with plumes from all around the world. The studio is on rue du Faubourg St Denis, in a rather less well-dressed part of the 10th arrondissement amid fruit stalls and street girls plying for trade.
The bohemian artist working alone in his studio?
Hardly . . . he and his 25 full-time assistants work around the clock producing pieces for Paris couture and deluxe prêt-à-porter shows; some pieces take as many as 200 hours to create.
Does he design the clothes, then?
No, he has to translate a sketch and make real the flights of fancy of the designers of the big fashion houses: his client list reads like a who's who of high fashion: Yves Saint Laurent, Christian Lacroix, Jean-Paul Gaultier, Alexander McQueen, John Galliano. Monsieur Lemarié has been a loyal courtier to every Parisian couturier since Coco Chanel. But today, at 74, he is worried about what will happen when he is gone.
Why is that?
Well, in the aviary of Parisian couture, he's a rare bird, the last of a breed of couture artisans. The house of Lemarié was founded by his grandmother in 1880, who passed on her knowledge to his father, who in turn taught Lemarié everything there is to know about decorative plumage. But the family line stops with him, so the savoir-faire he inherited is in danger of disappearing.
A little like the exotic birds he uses?
He doesn't lose a lot of sleep over the plight of the plucked but he is concerned from an artistic viewpoint. While his flowers and ruffles can be made from silk, lace or synthetics, there is no alternative to bird feathers. "We can't compete with what nature provides," says M. Lemarié. "Exotic birds are fewer and more protected, so today we use more farmyard birds. The problem is that the feathers are no longer collected by hand but by machine, which damages them."
A man of high standards . . . where can I buy?
Mainly through the designers' collections, although he does have a few select private clients.
How select?
To quote the maestro, "The Queen, the Duchess of Kent, Madame Kashoggi . . . we're very expensive, so that's about it."
How expensive?
Well, a haute couture dress created in the Lemarié ateliers can cost £100,000 or more. Still interested?
OK. How about a simple feather boa?
Monsieur Lemarié doesn't do simple feather boas; you can go to John Lewis for that sort of thing.
Well, can I at least see his work?
The best place to view a Lemarié creation is on the catwalks of the twice-yearly haute couture shows. Seats are reserved for A-list celebrities and the mega-rich. If you don't qualify, try a tour of the designer shops in Paris's fashionable 8th arrondissement. Here you can play fashion detective while savouring the rarefied atmosphere of exclusivity. Stroll past the impeccably dressed sales staff and see if you can spot the handiwork of the Lemarié atelier.
Feather tip
- Don't be taken in by any old plume; look for an ensemble perfection. As Lemarié says: "We don't sell feathers, we sell creativity."
Shops to check out
Chanel, 42 avenue Montaigne (00 331 47 23 74 12)
Christian Lacroix, 73 rue du Faubourg St Honoré (00 331 42 68 79 00)
Dior, 10 rue François 1er (00 331 40 73 54 44)
Givenchy, 28 rue du Faubourg St Honoré (00 331 42 65 54 54)
Thierry Mugler, 49 avenue Montaigne (00 331 47 23 37 62)
Yves Saint-Laurent, 38 rue du Faubourg St Honoré (00 331 42 65 74 59)
For more grail trail articles click on