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Desperate for a foodie getaway? Feast on five these hand-picked food destinations just two hours or so from London worth building the ultimate country weekend break around. So go on, book that Friday off and make plans for a game-changer of a dinner-meets-weekend away. Your inner chef deserves it.
5 of the best restaurants to build a country weekend break around
1. The Sportsman, Whitstable
When this pub was crowned National Restaurant of the Year 2016, it left it's chef/patron Stephen Harris 'gobsmacked'. It won again in 2017 and was also named Gastropub of the Year for the second time in a row. The only non-London restaurant to make it into the top five, you can find the Michelin starred-pub on the windswept barren beauty of the Seasalter coast. Self-taught cook Steven swapped a career in finance in 1996 for a professional kitchen and three years later landed near his home town of Whitstable.
Previously a self-proclaimed 'grotty rundown pub by the sea' (via their Twitter bio, now minus the words grotty and rundown), Stephen used ingredients he could see from his kitchen window long before the farm-to-fork movement hit the mainstream, saying: "This bit of salt marsh on the north Kent coast was owned by the kitchens of Canterbury Cathedral, and for more than a thousand years it was the larder for this area, so it seemed right to use the land."
Now equipped with a small kitchen garden, his dishes let native ingredients do the talking with beautiful finesse. Whether going a la carte and or for the excellent value daily tasting menu, dine on Whitstable Native Oysters, slip sole grilled in seaweed butter and round it off with a rosehip ice lolly. Book far in advance and don't forget to take a trip down the coast to see the sights, shops and sounds of Whitstable seafront too.
Getting there: 1hr 40mins by car from central London.
Find it: The Sportsman, Faversham Road, Seasalter, Whitstable, Kent, CT5 4BP
2. 64 Degrees, Brighton
Tucked away in the Brighton Lanes, 64 Degrees is a tiny restaurant serving small plates using fresh, local produce from an open kitchen. Founded by chef Michael Bremner (a Great British Menu finalist), his award-winning kitchen sits bang in the middle of the seating area. Perch on a high stool — one of only 27 seats — and you'll see every slice and dice as you sit at the pass.
There are just 16 plates to choose from — four of each meat, veg, fish and sweet — and its relaxed muted interior leaves space to focus on all the drama happening before your eyes. The co-creator behind dishes such as 'tongue, pea, jowl' and 'celeriac, chestnut, yolk', head chef Sam Lambert says: 'we just stick to local, and the fact we're face to face with customers means we can tell them exactly what's in the food'. And the name? We hear it pays tribute to the optimum temperature for poaching an egg.
Getting there: 1hr train ride from Victoria + 10 mins walk
Find it: 64 Degrees, 53 Meeting House Lane, Brighton BN1 1HB
3. Hartnett Holder & Co at Lime Wood Hotel, New Forest
If you weren't aware already, Angela Hartnett's cooking is an Italian-inspired tour de force (pop to Murano and you'll know what we mean). Hartnett Holder & Co is the restaurant of the luxury country-house Lime Wood hotel set in 145 square miles of ancient heath in the heart of the New Forest and makes for an idyllic epicurean country weekend break.
Together with chef Luke Holder, Angela and the team create locally sourced Italian dishes with a respectful nod to the seasons. Pretentious fine dining and big plates are out and home cooked sharing plates are in. Expect dishes such as fresh wild garlic, served simply with gnocchi, Parmesan and pine nuts or a cashew nut hummus (as spotted on Instagram). Complete with cosy wood fires, oak interiors, and an onsite smoke house, handily there's a sumptuous bed you can roll into after dinner.
Getting there: approx 2hr drive from central London
Find it: Lime Wood Hotel, Beaulieu Road, Lyndhurst, Hampshire SO43 7FZ
Honorary mention: The Pig, Brockenhurst
Sister hotel of Lime Wood, it's another fine example of the right amount of glamour needed to make a time-precious country weekend break go with a bang. Expect locally sourced and foraged ingredients with a story without any old-fashioned stiffness. Its menu is uncomplicated seasonal British garden food influenced by the forest and coast and all to enjoy in a stunning country house.
Getting there: approx 2hr drive from central London
Find it: Beaulieu Road, Brockenhurst, Hampshire, SO42 7QL
4. Hand & Flowers, Marlow
Zoom down the M40 and you can be at chef Tom Kerridge's Hand and Flowers – the only pub in the UK to hold two Michelin stars – in just over an hour from central London. Located in the Georgian town of Marlow, there's a little whimsy to be experienced amongst it's chocolate-box pretty, winding historic streets along the Thames. A thoroughly modern British pub that you can stay over in, Tom and his wife opened in 2005 with the idea of it being a place they'd like to go on their day off. Now it's a place that folk from around the world are desperate to visit on their day off.
The menu's focus is on making the most of the best seasonal ingredients with little fuss and lots of charm. Dishes include lovage soup to start, and an Essex lamb "bun" for a main and chocolate and ale cake to finish. Book a table in advance or if you prefer to be spontaneous on a country weekend break, head to his second non-bookable pub called The Coach, also in Marlow.
Getting there: 1hr 10 mins drive from central London, or 1hr 30mins by train and bus
Find it: The Hand and Flowers, 126 West Street, Marlow SL7 2BP
5. The Ethicurean, Bristol
The Ethicurean is a must-visit destination for arguably the most beautiful setting to eat in on a country weekend break in Somerset. Focussed on sourcing ingredients from the nearby fields, forests and orchards that surround their garden, its philosophy is simple: "eat local, celebrate native foods, live well."
Its story began when friends Jack Adair Bevan, Paula Zarate and brothers Ian and Matthew Pennington met working at farmers' markets. They took a shine to an apple business at Barley Wood Walled Garden and its conservatory-style cafe was available to rent too. Together, they grabbed the opportunity and use everything from its bursting vegetable and herb patches to make their own vermouths, fermentations and of course, apple juice. Expect vibrant dishes such as cucumber with labneh at lunch to a scones adorned with jam made from their walls which 'drip with fruit' for an afternoon tea break. Check out their cookbook to try their dishes at home.
Getting there: 2hrs 40mins drive from London (okay it's not 2hours, but you need to go!)
Find it: The Ethicurean, Barley Wood Walled Garden, Long Lane, Wrington, Bristol, BS40 5SA


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Here you will find a collection of historical references on TRAVEL - around-the-world, T. Smollett, Sir Richard Burton, Captain James Cook RN, AUSTRALIAN outback, Overland journeys, YOUNGHUSBAND in TIBET, Freya Stark, H.V. MORTON, Jan Morris, Afghanistan, Chitral, INDONESIA, Wallace Line, Pacific Ocean, Papua New Guinea, Africa, ASIA, On the Road, and Truckin' down the line,,,. Use our Quick Search Box (at bottom of page) to locate books by book title, authors name or description. We are proud of our reputation for careful customer service, with efficient packing & shipping world-wide. We offer tracking with all our shipments, where possible. See the About Us Page. All prices are in Australian (AUD) $
A note on condition: We classify our books as;
NEW/FINE/VERY GOOD/GOOD/FAIR/READING COPY ONLY (+ or -)
We do not use stock photos, the picture displayed is of the actual book for sale. Click image. Every one of our books is in our Australian stockrooms ready for immediate delivery.
Author: CHRISTOPHER P. BAKER Author of Costa Rica - Cuba - Havana Handbooks
Publisher: National Geographic Society, Washington D.C., 2001, First Printing, hardcover large 8vo with d/j, black textured endpapers, 304pp., 15 Chapters & Epilogue.
Condition:Two colour Black textured boards with red cloth to spine, silver title to spine, minimal edgewear, no inscriptions, CLEAN & TIGHT in GOOD CONDITION in an unclipped GOOD DUSTJACKET with very slight edgewear.
Description: From Havana to the Cuban countryside, and after three months astride his powerful moto, Baker brings back a vivid report, packed with insight, humor, and some surprisingly candid encounters.
Author: COLIN SIMPSON - Author of Adam in Ochre - Adam with Arrows etc.
Publisher: Angus and Robertson, Sydney, 1954, FIRST Edition, hardcover 8vo with d/j, 268pp., COLOUR & B/W PHOTOGRAPHS, ILLUSTR & MAPS, illustrated endpapers, 2 Books.
Condition:Brown Ochre hardcover with silver title to spine & design to fr.cvr, rubbing to spine, corners & edges, no inscriptions, CLEAN & TIGHT in GOOD CONDITION with slight foxing to o/s page edges, in a fair DUSTJACKET w/missing piece to spine, tears & edgewear.
Description: The natives of the mountain-walled Wahgi Valley thought the white men who discovered them in 1933 were spirit-men who had walked out of the sky.
This book shows us these people 20 yrs later - violent, religious, erotic - in vivid first-hand description
Author: New South Wales Government Railways Suburban Timetable from June 21 1964 TRAINS TRANSPORT RAILWAY STATIONS TICKETS & FARES
Publisher: published by the Authority of the Commissioner of Railways, New South Wales, 1964, 112 pages in a coloured photographic cover.
Condition:Straight & Tightly bound, in GOOD CONDITION with slight general ageing, INTACT & ROBUST, A clean copy.
Description: 1. Cowan-Chatswood-City-Penrith & Cambelltown. 2. City-Strathfield-Hornsby-Cowan. 3.City- Clyde-Carlingford.3a. Sandown Line. 3b. Abottoirs Line. 4. City-Cronulla-Helensburg & RNP. 5. City-Riverwood-East Hills. 6. City-Bankstown-Lidcombe 7. Richmond Line.
Author: NATIONAL GEOGRAPHIC SOCIETY Various Authors Vol.XCV, No.1
Publisher: National Geographic Society, Washington, 1948, hardcover quarto without d/j, 552 pages, COLOUR & B/W PHOTOGRAPHS throughout, 4 different monthly issues.
Condition:Burgundy cloth-bound hardcover boards with gilt title to spine, rubbing to spine & corners, TIGHTLY BOUND in GOOD MINUS CONDITION with some insect damage to front endpaper, slight age-toning, without dustjacket (as issued?).
Description: The Yankee's Wander-world - Wildlife - Through Europe - Industry - Spices - The British Way - Biographies of Famous People.
Fascinating early photos and data.
We have more of these in stock.
Author: JIM WAFER Co-Winner of the Victor Turner Prize in Ethnographic Writing SIGNED COPY! Lecturer Dept Sociology & Anthropology University of Newcastle
Publisher: University of Pennsylvania Press, Philadelphia, 1994, 2nd paperback printing, 1st pub. 1991, softcover 8vo, 219 pages, 3 Parts, Epilogue, Glossary & INDEX.
Condition:Softcover with photo to frcvr, slight rubbing to spine & corners, first page has small hole, INSCRIBED & SIGNED to Title Page, CLEAN & TIGHT in GOOD CONDITION.
Description: This ethnography is intriguing not just because of the originality of its approach to the mor enigmatic aspects of another culture, but also because it uses insights gained from participation in that culture to reflect on the paradoxes . . .
Author: PERCY ROWE To "Putty" Read first American to fly the Atlantic
Publisher: Angus & Robertson, London, 1977, First Edition, hardcover 8vo without d/j, B/W PHOTOGRAPHS, Chapters, Bibliography, brown textured endpapers.
Condition:Red speckled cloth-bound hardcover with gilt title to spine, slight rubbing to spine & corners, no inscriptions, CLEAN & TIGHT in GOOD CONDITION, without dustjacket.
Description: In the early part of the twentieth century, men all over the world were experimenting with flying, and the race to cross the Atlantic was on.
From balloons to the early machines and during the First World War, the early pilots were treated like royalty.
Author: Written and illustrated by Lawrence Dunn
Publisher: Macmillan, New York, 1975, First US Edition, hardcover 8vo with dj, , COLOUR PLATES & ILLUSTRATIONS, 215pp. & INDEX,
Condition:Crisp aqua cloth-bound hardcover , bright gilt title to spine, STRAIGHT, CLEAN & TIGHT in VERY GOOD CONDITION, with mild rubbing and edgewear to a GOOD DUSTJACKET which has been clipped.
Description: Colour Plates
Text for Plates
Diagrammatic Comparisons
Ships by Nationality
Ships by Type & Trade.
List of Ship's names
A DETAILED ANALYSIS of the SEA TRANSPORT of the 1910-1929 period.
Author: LOWELL THOMAS, Jr. INDIA TIBET CHINA Dalai Lama Lhasa POTALA Shangri-La with the first COLOUR PHOTOS ever taken in Tibet
Publisher: Macdonald & Co., London, 1951, First Edition, hardcover 8vo with dj, 238pp., amazing B/W PHOTOGRAPHS throughout plus coloured photos, Frontispiece in colour.
Condition:Blue cloth-bound hardcover with gilt title to spine, rubbing to spine & corners, CLEAN & TIGHT in GOOD CONDITION, previous owner's name to frepr, slight foxing and age-toning to eprs and page edges, in a clipped GOOD-MINUS DUSTJACKET with chips
Description: This is the story of an arduous trek made in 1949 by the author and his father through the world's highest and most remote country, to the Holy and Forbidden capital city that only a handful of white men had ever seen.
There they met the Dalai Lama.

subset: commoncrawl


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Planned Giving: Gift Types
Note: Morality In Media, established in 1962, changed it's name to National Center on Sexual Exploitation, in early 2015 to better describe the scope and mission to expose the seamless connection between all forms of sexual exploitation. Legal documents and donations can name either Morality In Media or National Center on Sexual Exploitation.
There are only three places where you can distribute your assets or income: family, charity, and the government. That means it is very important to plan ahead. Wise planning may offer many ways for you to support your family, enjoy significant tax savings, or even a secured monthly income, while helping to preserve the right for people to freely live out their faith for generations to come.
Click on the links below to read a brief overview of the most common types of planned gifts for your consideration.
- A Gift in Your Will or Trust
- Charitable Gift Annuities
- Retirement Plans
- Appreciated Assets
- Non-Cash Assets
- Life Insurance Policies
- Charitable Remainder Trusts
- Charitable Lead Trusts
A Gift in Your Will or Trust
Charitable bequests describe anything you leave to Morality In Media in your estate plan through a Will or Trust. (Your "estate" is any property, money, or personal assets you have at the time of your death.) These are among the most important gifts you can make to support the future of our children. You can make arrangements in your estate plan to leave Morality In Media a percentage of your estate or a specific dollar amount. Making such a gift for the future allows you to maximize the use of your assets during your life and may reduce estate taxes for your family. To find out how to include a gift for Morality In Media in your Will or Trust, please click here.
Charitable Gift Annuities
A charitable gift annuity (CGA) is a contract between you and a charitable organization. In return for your gift, the charity agrees to pay you (and another annuitant if you choose one) a fixed amount – based on your age(s) – for the rest of your life. The benefits of a charitable gift annuity are that it allows you to provide an immediate gift to Morality In Media, make a one-time gift, receive a charitable tax deduction, and receive a fixed amount of income for your lifetime.
Retirement Plans
For many, retirement assets are a significant part of their estate. These assets are an excellent source of charitable gifts. When one names Morality In Media as a beneficiary of a retirement plan, Morality In Media receives the full amount of the gift, as we are exempt from income tax. Also, the estate will have no tax liability for any retirement assets that are passed on to Morality In Media.
Appreciated Assets
Giving appreciated assets – like individual stocks or mutual funds – is a great alternative to giving cash. When you give appreciated assets, you receive two tax benefits: a charitable deduction from taxable income, and you will avoid capital gains tax. Instructions on how to donate stocks or mutual funds can be found here.
Non-Cash Assets
These are sometimes referred to as "gifts-in-kind." These types of assets make great gifts and are very useful to supporting the work of Morality In Media. These assets include real estate, vehicles, jewelry, collectibles, equipment, airplanes, business inventory, etc. A gift of these types of assets generally results in a charitable tax deduction of its fair market value.
Life Insurance Policies
A gift of a life insurance policy may allow you to do more to protect against pornography than you ever thought possible. By gifting the policy to Morality In Media, or naming Morality In Media as a beneficiary, you can have a significant impact on the futures of your children and grandchildren.
Charitable Remainder Trusts
A charitable remainder trust may be a great way for you to balance your giving and income goals. It allows you to transfer assets into a trust from which you, or someone you designate, will receive an annual income for a set period of time. At the end of the trust, the remainder is given to Morality In Media. A charitable remainder trust may allow you to avoid taxes on the sale of assets as well as give you an immediate tax deduction.
Charitable Lead Trusts
You may be able to balance your giving and inheritance goals with a charitable lead trust. This tool allows you to transfer your assets to a trust fund that will make donations to Morality In Media for a fixed period of time. At the end of the trust, the remaining balance is passed back to you or another family member. A charitable lead trust is particularly helpful if you want to save taxes on the assets you pass to your heirs.
Note: This section provides general financial information, not specific financial advice. The material contained in this section does not create or imply an advisor-client relationship with Morality In Media, Inc., or any of its attorneys or allies. For specific questions, consult a qualified financial and/or legal advisor.


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The growth of melanocytes, the pigment-producing cells of the skin, normally is restricted to the epidermis. Transformed melanocytes, which have invaded the dermis, however, have gained the ability to grow in this new environment and to counteract apoptosis induced by the dermal connective tissue. The expression of genes contributing to the survival of melanocytes in the dermal environment, therefore, might be involved in melanoma development. Using a differential display approach, we identified osteopontin as such a gene. In melanocytes, expression of the secreted adhesion protein OPN was up-regulated by the melanoma-inducing receptor tyrosine kinase Xmrk as well as by the fibroblast growth factor receptor, which plays a decisive role in human melanoma. Activation of both receptors triggered survival of melanocytes in three-dimensional dermal collagen gels. Competition experiments revealed that the presence of OPN in the medium as a result of receptor signaling was contributing to these effects. Addition of exogenous OPN allowed melanocytes to adhere, spread, and survive in three-dimensional collagen gels, whereas in the absence of OPN, the cells underwent apoptosis. The integrin αvβ3 known to be involved in melanoma cell survival and growth was identified as an OPN receptor, which points to an OPN-mediated cross-talk between growth factor receptors and this integrin receptor in melanocytes. In summary, we could show that in melanocytes growth factor receptor-induced secretion of OPN can promote antiapoptotic signaling and mediate appropriate interactions with the extracellular matrix in an autocrine way. Our findings suggest a new role of growth factor receptors of the family of receptor tyrosine kinases in processes associated with melanoma development and progression.
Under physiological conditions, melanocytes are restricted to the stratum basale of the epidermis, where they transport pigment-containing melanosomes to adjacent keratinocytes and exhibit a low mitogenic activity. Transformed melanocytes, however, are able to leave the epidermis, to break through the basal membrane, and to invade the dermis (1) . This transition from the so-called RGPto the VGP is a biologically and clinically critical step for the establishment of malignant melanomas that exhibit a metastatic competence (1) .
A crucial difference between nontransformed and transformed pigment cells is that normal melanocytes cannot survive for longer periods in the dermal environment but melanoma cells can. The survival and continuous growth of transformed cells in the dermal tissue are important steps in melanoma progression (2) . Survival of pigment cells in the dermis seems to be dependent on the presence of cell surface molecules that regulate the contact between the cells and the dermal ECM, i.e., components of the dermal connective tissue such as collagen. A surface molecule, which can mediate the adhesion of melanoma cells to dermal collagen thereby inducing antiapoptotic signaling, is the integrin receptor αvβ3 (3 , 4) . The expression of αvβ3 has been directly linked to neoplastic progression and tumorigenicity of melanoma (5 , 6) . Also, bFGF, a growth factor most uniformly expressed by melanoma cells but not by normal melanocytes (7) , is able to counteract apoptosis induced in the presence of type I collagen. Addition of this melanoma-associated factor to melanocytes cultured in three-dimensional collagen gels, which mimic the conditions in the dermis in vitro, prevented apoptosis (8) . However, the mechanism by which bFGF exerts its positive effect on melanocyte survival is not clear yet.
The receptor for bFGF is a receptor tyrosine kinase that triggers proliferation in melanocytes as well as in melanoma cells, where it is stimulated in an autocrine way (9 , 10) . Similarly, the receptor tyrosine kinase Xmrk, the overexpression of which is the initiatory event of the formation of highly invasive melanoma in Xiphophorus (11) , induces mitogenic signaling in melanocytes and in melanoma cells (12 , 13) . Remarkably, activation of the Xmrk receptor does not only trigger proliferation, it also stimulates antiapoptotic signaling. We have established a cell system in which Xmrk-specific antiapoptotic and mitogenic signaling can be dissected (Ba/F3 cells; Ref. 14 ). Using this cell system, we identified genes that have an expression that is regulated either by mitogenic or by antiapoptotic signaling triggered by the melanoma-inducing receptor.
One of the identified Xmrk target genes, with an expression that is correlated with antiapoptotic signaling in Ba/F3 cells, is opn. Additional investigation in pigment cells revealed that OPN can promote survival of melanocytes in three-dimensional gels of the ECM component collagen. This attributes to OPN a new and relevant role in processes correlating with pigment cell transformation and tumor progression in melanoma development.
Cell Culture and Long-Term Growth.
The IL-3-dependent mouse pro-B cell line Ba/F3 (15) and Ba/F3-derived cell lines were cultured in RPMI 1640, with 5% FCS and 5% of supernatant from X63Ag8-653 BVP m-IL-3-expressing cells (16) . BaF Hm transfectants were generated by electroporation as described previously (17) . Before, stimulation cells were washed twice with PBS and starved for 2–6 h in RPMI 1640. Starved cells were treated with IL-3 (5% supernatant) or EGF (50 ng/ml) for the indicated times and collected by centrifugation. Mouse melanocytes [melan-a (18) and melan-a Hm cells (13)] were cultured in DMEM, 10% FCS in the presence of cholera toxin (12 nm), and TPA (200 nm). Human melanoma cell lines (WM35, A375, Bro, IFB, Mel26, D10) were cultured in RPMI 1640 with 10% FCS and were a kind gift of Dr. C. R. Goding and Dr. J. Becker. The MAP/ERK kinase inhibitor PD98059 (Calbiochem, Eschborn, Germany) or the solvent DMSO alone was added 30 min before stimulation. For long-term growth experiments, cells were seeded at 3 × 105 cells/well of a 6-well plate in medium containing the indicated factors. After 4 days, cells were stained with trypan blue and counted.
Differential Display Analysis.
For identification of Xmrk target genes, a modified differential display procedure according to Liang et al. (19, 20, 21) was performed. Amplifications and subsequent analyses were done in parallel from three independent cell cultures for each condition. DNase-digested total RNA (2.5 μg) from unstimulated and 2-h EGF-stimulated BaF Hm cells were used for RT using one-base-anchored oligodeoxythymidylate primers. Subsequent PCR amplifications of 1 μl of the RT reaction with the appropriate oligodeoxythymidylate primer in combination with an arbitrary 10-mer primer using [α32P]dCTP were performed. The PCR reactions were separated on a 6% polyacrylamide sequencing gel. Gels were dried and exposed to X-ray films. Differentially displayed bands were excised from the gel, and one-third of a gel slice was directly used for reamplification with the primer combinations of the original differential display PCR. PCR products were cloned, using the SureClone kit (Amersham, United Kingdom) and subsequently sequenced. GCG software was applied to compare sequences to Genbank and European Molecular Biology Laboratory databases. The differential expression of the respective genes was confirmed by Northern blot analysis using probes generated by random hexamer labeling of the gel-purified plasmid insert.
RT-PCR and Northern Blot Analysis.
After stimulation and/or inhibitor treatment, RNA was isolated with Trizol reagent (Life Technologies, Inc., Karlsruhe, Germany) following the instructions of the supplier. First-strand cDNA synthesis was performed by using Superscript RT reverse transcriptase (Life Technologies, Inc.), using 1 μg total RNA and random hexanucleotides (0.5 μm) in 20 μl following the suppliers protocol. RT reaction (0.5 μl) was then used to amplify the respective integrine genes: αv 5′-ATCCGACGAGCACTGTTTCT-3′ and 5′-TCCATCTCTGACTGCTGGTG-3′ (30 cycles); and β3 5′-GCAGTGTCTGGCTGTGAGTC-3′ and 5′-GGGACACGCTCTGTTTCTTC3′ (36 cycles). For Northern blot analysis, total RNA was blotted onto Hybond-N nylon membranes (Amersham, United Kingdom). Prehybridization and hybridization were carried out at 42°C in 50% formamide. Filters were hybridized with a 32P-labeled mouse OPN probe that was generated by random priming with [α32P]dCTP. The probes used were a 550-bp opn differential display-PCR-fragment or a mouse cDNA probe, which was kindly provided by Dr. L. W. Fisher (22) .
Western Blot Analysis.
After stimulation for the indicated times, cells were rinsed twice with PBS and lysed in 50 mm Tris (pH 7.5), 150 mm NaCl, 0.5% NP40, 1 mm phenylmethylsulfonyl, 1 mm fluoride Na3VO4, 10 μg/ml leupeptin, and 10 μg/ml aprotinin for 20 min at 4°C. Proteins were separated by SDS-PAGE and analyzed by Western blotting onto nitrocellulose. Filters were blocked for 10 min with 10 mm Tris-Cl (pH 7.9), 0.5% Tween, and 1.5% BSA and were incubated at least for 60 min with the first antibody. Horseradish peroxidase-coupled second antibodies were used for nonradioactive detection. Monoclonal anti-phospho MAPK (clone 12D4) was from Nanotools (Teningen, Germany). Anti-ERK-2 (C-14), antimouse OPN (P-18), antihuman OPN (K-20), anti-αv (Q-20), and anti-β3 (N-20) were from Santa Cruz Biotechnology (Santa Cruz, CA).
Preparation of Collagen Gels and Analysis of Cell Spreading.
Collagen gels were prepared using Cellagen solution DMEM (pH 7.4) containing type I collagen (ICN Biomedicals, Eschwege, Germany). Cells were seeded into 24-well plates (4 × 104/well) and suspended in the Cellagen solution. After gelation, either melan-a HER-mrk CM or FCS (5%) containing medium with the respective factors was added. The concentrations were as follows: 8 nm EGF; 0.3 nm bFGF; 100 nm OPN; and 200 nm TPA. Cell morphology and spreading were examined hourly the first 12 h, and cells were photographed after 48 h.
Adhesion Assay.
The adhesion assay was performed according to Smith et al. (23) . A 96-well ELISA plastic plate (Greiner, Frickenhausen, Germany) was coated with OPN (100 nm) or BSA (100 nm) overnight at 4°C. The wells were washed twice with PBS and blocked with PBS/1% BSA for 1 h at 37°C. Melan-a cells were preincubated with either anti-αv (clone H9.2B8; Pharmingen, BD Biosciences, Germany), anti-β3 (clone 2C9.G2; Pharmingen, BD Biosciences), an unspecific control antibody or without antibody in DMEM/0.1% BSA for 15 min at RT, and 5 × 104 cells/96-well were allowed to adhere to the substrate at 37°C for 2 h. Nonadhering cells were washed off with PBS, and the adhering cells were fixed in 4% paraformaldehyde/PBS for 1 h at RT and stained with 0.5% toluidine blue in 4% paraformaldehyde for 1 h at RT. After three washes with PBS, the color was solubilized using 1% SDS, and the color intensity was measured with an ELISA reader using a filter of 595 nm.
Determination of Apoptotic Cells.
Cells (2 × 105) suspended in Cellagen solution were seeded on chamber slides (Nunc,), and after gelation, the gels were overlayed with DMEM containing 5% FCS without any additives or supplemented with the indicated factors (concentrations see above). For the blocking experiments, either a neutralizing anti-OPN antibody, kindly provided by Dr. Hsin-Fang Yan-Yen (24) , was added to the medium at a concentration of 10 μl of serum/ml or anti-αv (clone H9.2B8) or anti-β3 (clone 2C9.G2) was added to the preincubated cells in a concentration of 5 μg/ml. As control, antibody anti-MAP kinase phosphatase 1 (Santa Cruz Biotechnology, Heidelberg, Germany) was used at a concentration of 10 μg/ml. After 4 days, the cells were fixed in formaldehyde for at least 30 min and after washing with PBS incubated in 0.1% Triton X-100 for 30 min. Cells were washed again in PBS, and the DNA was stained with 1 μg/ml bisbenzimide (Hoechst 33342) in PBS. After embedding the fixed cells in mounting medium, they were analyzed using an UV microscope. Condensed and fragmented nuclei were counted in a total of 1000 cells from each sample, and the amount of fragmented nuclei was calculated in percentages.
DNA Fragmentation.
Cells (4 × 106) were seeded in Cellagen on 10-cm culture dishes and cultured for 4 days under different conditions. Cell-containing gels were washed with PBS, and the cells were scraped off the dish. After centrifugation, collagen-containing cell pellets were lysed in 500 μl lysis buffer (0.2% SDS, 100 mm EDTA, and 200 mm NaCl) complemented with proteinase K (100 μg/ml) and then incubated at 80°C for 1 h. After phenol/chloroform extraction using SST tubes (BD Biosciences, Heidelberg, Germany), the DNA was recovered by ethanol precipitation. The DNA was dissolved in water, complemented with RNase A (500 μg/ml) and gel-loading buffer, and analyzed on an agarose gel.
Identification of the opn Gene as a Gene Induced by the Xmrk Kinase and Involved in Antiapoptotic Signaling.
To identify genes, which are regulated by the Xmrk receptor and involved in proliferation and/or survival, we used the well characterized IL-3-dependent cell line Ba/F3 as a sensitive system to analyze mitogenic as well as antiapopotic signaling. BaF Hm cells are a Ba/F3 derived cell line, which stably expresses a chimeric and thus regulatable Xmrk receptor (HER-mrk). EGF stimulation of HER-mrk induces activation of the Xmrk kinase domain, and treatment of BaF Hm cells with EGF leads to specific induction of intracellular Xmrk signaling (17) .
For a differential display analysis of Xmrk target genes, quiescent BaF Hm cells were treated for 2 h with EGF, and RNAs were analyzed by differential display RT-PCR for differentially expressed genes in EGF-treated and nontreated cells. One of the PCR products was found at particularly high levels after amplification of cDNA from EGF-treated cells. The respective fragment was therefore isolated from the gel, reamplified, cloned, and sequenced. The sequence matched 100% to the mouse opn gene. Differential expression of opn in BaF Hm cells was confirmed by Northern blot analysis. EGF treatment of BaF Hm cells led to a rapid up regulation of OPN, which lasted up to 14 h (Fig. 1A) ⇓ . Also mIL-3-induced opn expression in BaF Hm cells, although the expression level was significantly weaker (Fig. 1A) ⇓ .
To further examine which signaling pathways are involved in the up regulation of the opn gene induced by the HER-mrk receptor, we made use of additional Ba/F3 cell lines expressing different truncated versions of HER-mrk (BaF Hm Δ1006 and BaF Hm Δ1075, Ref. 14 ). Hm Δ1006 possesses no tyrosine that can be phosphorylated after receptor stimulation, and it is incapable of activating the MAPK pathway (Fig. 1B) ⇓ . Hm Δ1075 possesses a growth factor receptor binding protein 2 binding site and activates MAPK such as the full-length HER-mrk receptor. Activation of MAPK was detectable by its phosphorylation using anti-phospho MAPK (Fig. 1B) ⇓ . The induction of opn expression by Hm Δ1006 was clearly affected (Fig. 1C) ⇓ , and the fact that Hm Δ1075 efficiently up-regulated the opn RNA level (Fig. 1C) ⇓ points to a role of MAPK in regulation of opn expression by HER-mrk. Interestingly, Hm Δ1006 in contrast to Hm Δ1075 is inefficient in mediating antiapoptotic signaling in Ba/F3 cells (14) , confirming an involvement of OPN in cell survival as it was described in this cell system by Lin et al. (24) .
Xmrk-induced opn Expression in Melanocytes Is Dependent on MAPK Activation.
Since activation of the Xmrk receptor induces melanoma formation in fish, we asked whether the Xmrk kinase also induces opn expression in pigment cells and which role osteopontin plays in these cells. Therefore, we analyzed opn expression after stimulation of the chimeric Xmrk receptor in HER-mrk-expressing mouse melanocytes melan-a Hm. These cells proliferate, dedifferentiate, and show a transformed phenotype in response to receptor stimulation (13) . Stimulation of melan-a Hm cells with either EGF or with TPA, a general growth factor for melanocytes in vitro, led to strong activation of the MAPKs ERK1 and 2 (Fig. 2A) ⇓ . This activation was almost completely abolished in the presence of the MAP/ERK kinase inhibitor PD98059 (Fig. 2A) ⇓ .
In melan-a Hm cells, stimulation of the HER-mrk receptor resulted in a strong induction of opn expression within the first couple of hours (Fig. 2B) ⇓ . Nearly the same level of induction could be seen when melan-a Hm cells were stimulated with TPA alone confirming, the fact that opn originally has been identified as a TPA-inducible gene (25) . Because TPA activates MAPK in melan-a cells (Fig. 2A) ⇓ , MAPK might be involved in up regulation of opn expression in melanocytes. Using PD98059, we blocked MAPK activity during HER-mrk stimulation. In the presence of PD98059, no induction of opn could be detected (Fig. 2B) ⇓ , pointing to a role of MAPK in HER-mrk-induced opn expression in melanocytes.
OPN Protein Expression Is Induced by Xmrk as well as by the FGF Receptor in Melanocytes and Is Constitutively Enhanced in Melanoma Cells.
The expression of the OPN in melan-a Hm cells was analyzed after stimulation of the HER-mrk receptor using a polyclonal anti-OPN antibody. OPN was almost completely absent in cells that were factor starved (no TPA, no EGF) for 24 h, pointing to a fast turnover of the protein in these cells. After 2 h of receptor stimulation, OPN was clearly detectable as a Mr 55,000 protein, and this protein expression increased even more during the next 16 h (Fig. 3A) ⇓ .
To investigate whether the induction of OPN in melanocytes is a specific feature of the Xmrk kinase or whether it is a more general characteristic of receptor tyrosine kinases acting in pigment cells, wild-type melan-a cells were treated with bFGF and analyzed for OPN expression. Stimulation with bFGF led to a significant up regulation of OPN within 2–4 h (Fig. 3B) ⇓ , indicating that opn is also a target for the signaling induced by the FGF receptor. However, HER-mrk stimulation appeared to be more effective in inducing OPN expression. In contrast to melanocytes where OPN basal expression was almost not detectable, constitutive-enhanced expression of OPN was found in several different human melanoma cell lines (Fig. 3C) ⇓ . Interestingly, the lowest expression was seen in WM35 cells (Fig. 3C) ⇓ , which are derived from a noninvasive RGP melanoma (26) .
OPN Contributes to Adhesion of Melanocytes to Type I Collagen.
OPN is known to function both as cytokine as well as cell attachment protein with integrins αvβ3, αvβ1 and αvβ5 acting as OPN receptors (27) . In addition, OPN can bind to the ECM component collagen, including type I collagen (28) . Melanocytes, which grow in the epidermis, normally do not get into contact with type I collagen, which is an ubiquitous component of the connective tissue of the dermis. Moreover, melanocytes are not able to adhere properly and spread over a long-term period in three-dimensional type I collagen gels, which simulate the conditions in the dermis in vitro (8) . Strikingly, bFGF was found to induce spreading of melanocytes in collagen gels, although the underlying mechanism is not clear yet.
In melan-a cells, OPN expression was substantially increased in response to HER-mrk activation and also by stimulation with bFGF. Because OPN is described to act as a mediator between integrin receptors and collagens (29) , we wondered whether it might increase the capacity of melanocytes to adhere to type I collagen and to spread in three-dimensional type I collagen gels. Wild-type melan-a cells were embedded in type I collagen gels, and the cells were cultured in the presence of different factors. Cells in the presence of serum alone and no additional factors initially showed increased spreading during the first 8 h. However, between 30 and 48 h, cell rounding increased, and the cells lost the spread phenotype (Fig. 4A) ⇓ . In contrast, cells cultured in the presence of TPA, which is a general growth factor for melanocytes in vitro, spread much faster, and the spread dentritic phenotype lasted up to 48 h. Also bFGF (0.3 nm), which is described to mediate spreading of human melanocytes in type I collagen gels (8) , induced this phenotype in melan-a cells. Strikingly, the addition of 100 nm OPN to the medium also increased the fraction of spread cells in the gel (Fig. 4A) ⇓ .
Because OPN expression is up regulated after stimulation of the HER-mrk receptor in melan-a Hm cells, this secreted protein should be present in supernatants of EGF-stimulated melan-a Hm cells. The fact that melan-a Hm cells were able to spread and grow in the collagen matrix when stimulated with EGF (data not shown) supported this assumption. Therefore, wild-type melan-a cells were cultured in three-dimensional collagen gels in melan-a HER-mrk CM. Significant cell spreading could be observed under these conditions (Fig. 4A) ⇓ , pointing to factors in the HER-mrk CM that enhance interactions of the cells with the collagen matrix. That the observed cell spreading was not due to EGF present in the conditioned medium was seen in wild-type melan-a cells cultured in medium containing 8 nm EGF and FCS (Fig. 4A) ⇓ . These cells showed the same round phenotype as cells cultured in the presence of FCS alone.
Although OPN and HER-mrk CM could prevent cell rounding induced by collagen over a long-term period, they did not induce an increase in the cell number. TPA and bFGF, in contrast, very efficiently triggered cell growth in the collagen matrix. To verify that OPN, EGF, and factors in HER-mrk CM do not trigger mitogenic signaling in melan-a cells, the growth response of melan-a cells was assessed by counting the cells after 4 days in medium containing the different factors. TPA, as well as bFGF, clearly induced cell growth and led to a 3–4-fold increase. However, neither OPN, EGF, or factors in HER-mrk CM produced a significant mitogenic effect (Fig. 4B) ⇓ .
OPN Counteracts Type I Collagen-induced Apoptosis in Melanocytes.
Melan-a cells not only showed inefficient spreading in collagen gels, they also started to apoptose in the absence of any additional factors. Already after 30 h in medium containing only FCS, the first apoptotic cells could be detected, and the number increased dramatically between days 2 and 4. It should be mentioned that this is not a general response of melan-a cells to the absence of defined growth factors since cells cultured under these conditions on conventional culture plates for 6 days, although showing a starved phenotype, do not apoptose (13 , 18) .
To quantify the antiapoptotic effect of OPN on melanocytes, cells were stained with DAPI after 4 days in collagen (Fig. 5A) ⇓ , and the ratio of intact to fragmented nuclei was determined (Fig. 5B) ⇓ . The effects quantified by DAPI staining were confirmed by analysis of DNA fragmentation (Fig. 5C) ⇓ clearly showing that apoptosis is induced by type I collagen in melan-a cells.
According to the cellular changes seen by light microscopy, an increased number of intact nuclei was seen in the presence of TPA due to the mitogenic effect (Fig. 5A) ⇓ . Nuclei were also intact in cells cultured in HER-mrk CM, but the total number of nuclei was lower. Confirming the apoptotic phenotype seen in cells cultured in FCS alone, most of the nuclei were fragmented (Fig. 5A) ⇓ , and 80–90% of the cells were apoptotic (Fig. 5B) ⇓ . In contrast, TPA almost completely prevented collagen-induced apoptosis and only 5–10% of the cells showed fragmented nuclei. Also, OPN suppressed cell death in the collagen gel with only 40% of the cells undergoing apoptosis. The conditioned medium HER-mrk CM was almost as efficient as TPA in reducing the number of apoptotic cells (13%). Using a neutralizing antibody to OPN (24) , the protective effect of HER-mrk CM was significantly reduced. Approximately 60% of the cells were apoptotic (Fig. 5B) ⇓ , which clearly shows that OPN contributes to the antiapoptotic effect of the HER-mrk CM. Taken together, these data demonstrate that OPN is able to counteract apoptosis induced in melanocytes by collagen.
Integrin αvβ3 Acts as Receptor for OPN in Melanocytes and Contributes to the Survival Effect Produced by bFGF.
Because it is known that the vitronectin receptor αvβ3 is also a receptor for OPN (27) , and αvβ3 has been linked to the tumorigenicity of malignant melanoma (6) , we asked whether this integrin might also act as a receptor for OPN in melanocytes.
Using specific primers for the respective integrin subunits, the expression of αv as well as of β3 was readily detectable in melan-a cells by RT-PCR analysis (Fig. 6A) ⇓ . Specific antibodies against αv and β3 identified the respective proteins in melan-a cells (Fig. 6B) ⇓ . Strikingly, αv expression was much higher in melan-a cells than in the human melanoma cell lines IFB and A375. This was not attributable to reduced cross-reactivity of anti-αv with the human protein because the antibody used (Q-20) is directed against the human αv chain.
To further investigate the role of αvβ3 as a potential OPN receptor, we made use of neutralizing antibodies against αv and β3 in an OPN adhesion assay. The antibodies H9.2B8 (anti-αv) and 2C9.G2 (anti-β3) specifically detected expression of the integrins on the surface of melan-a cells (data not shown). Incubation of melan-a cells with OPN coated on plastic wells revealed a high tendency of the cells to specifically attach to the recombinant protein (Fig. 6C) ⇓ . Attachment of the cells to OPN was almost unaffected when a control antibody was present during the incubation. On the other hand, both neutralizing antibodies anti-αv (H9.2B8), as well as anti-β3 (2C9.G2), were highly effective in blocking the interaction of melan-a cells with OPN, indicating that αv, as well as β3, are involved in the attachment of these cells to OPN. The specificity of the adhesion assay was additionally tested by measuring adhesion of melan-a cells to vitronectin, a natural ligand of the vitronectin receptor αvβ3 (data not shown).
To examine whether αvβ3 is involved in the antiapoptotic effect in melan-a cells, the blocking antibodies against αv and β3 were used to interfere with the OPN interaction in the presence of collagen, and apoptotic cells were identified by DAPI staining as described in Fig. 5B ⇓ . The presence of the antibodies did not influence apoptosis induced in the absence of any defined factor (Fig. 6D) ⇓ . However, the survival effect brought about by OPN was significantly reduced by addition of anti-αv with ∼80% apoptotic cells compared with 40% in the absence of any antibody (Fig. 6D) ⇓ . Also, anti-β3 had an influence on OPN-mediated cell survival (55% apoptotic cells), although the effect was lower than that of blocking αv (Fig. 6D) ⇓ .
Because these data showed that OPN-mediated cell survival is correlated with binding to αvβ3, and we had found that bFGF induces OPN expression in melan-a cells (Fig. 3B) ⇓ , we wondered whether the OPN/αvβ3 interaction also contributes to the survival effect on melanocytes seen and described for bFGF (8) . Therefore, cells were cultured in the collagen matrix in bFGF containing medium either in the presence of the αv- and β3-blocking antibodies or in the presence of a control antibody. bFGF alone or in the presence of the control antibody very efficiently suppressed apoptosis with only 5–10% apoptotic cells after 4 days in the collagen gel (Fig. 6E) ⇓ . However, both blocking antibodies, anti-αv as well as anti-β3, had a significant influence on bFGF-induced cell survival in the collagen matrix, and the number of apoptotic cells increased to ∼35 and 20%, respectively (Fig. 6E) ⇓ . This clearly indicated that αvβ3 interactions are contributing to the antiapoptotic signaling brought about by bFGF.
OPN Triggers Antiapoptotic Signaling in Human Melanoma Cells.
To finally investigate if OPN is also playing a role in survival of human melanoma cells in dermal collagen, the different human melanoma cell lines were cultured in collagen gels, and the influence of constitutive OPN expression was analyzed by using the OPN-blocking antibody. The various cell lines showed a distinct behavior in the collagen matrix with Bro and Mel26 cells spreading and growing very efficiently during 4 days. Also A375 cells proliferated in the collagen gel but many cells showed a round phenotype. IFB and D10 grew very slowly, and no increase in the cell number of WM35 cells was seen during 4 days. Approximately 10% of WM35 cells were apoptotic when cultured in three-dimensional collagen. None of the other analyzed cell lines showed significant apoptosis either in the absence of any defined factor or in the presence of the control antibody. Addition of the OPN-blocking antibody, however, resulted in an increase in apoptotic cells in all cell lines except WM35 (Fig. 7) ⇓ . The highest increase was seen in Bro cells with 25% of the cells undergoing apoptosis. Mel26, A375, IFB, and D10 showed 9–20% more apoptotic cells when the neutralizing OPN antibody was added (Fig. 7) ⇓ , which points to a contribution of OPN to the survival of transformed pigment cells in dermal collagen.
OPN is a secreted, phosphorylated glycoprotein, which contains an arg-gly-asp sequence and has been described to act both as cell attachment as well as survival and growth factor (27) .
We have identified OPN as a factor that can transmit survival signals in melanocytes grown in dermal collagen, and its expression is regulated by two receptor tyrosine kinases that play an important role in pigment cell transformation and melanoma progression. opn originally was cloned as a tumor promoter-inducible gene, and it is frequently overexpressed in human tumors (27) . Its expression is regulated by various factors, including cytokines like IL-3 and granulocyte macrophage colony-stimulating factor in Ba/F3 cells, where it contributes to cellular survival and proliferation induced by these cytokines (24) . Also, growth factors (30, 31, 32) and oncogenes such as ras can induce opn expression. Increased expression of opn is associated with ras-transformation of NIH3T3 cells (33) , and its expression is enhanced in mammary tumors of v-Hras transgenic mice (34) . This points to a role of MAPK, which acts downstream of ras, in the induction of the opn promoter. It is also in line with our results showing that the HER-mrk-triggered up regulation of opn expression was dependent on intact MAPK signaling in both cell lines Ba/F3, as well as melan-a cells. This also might explain the higher level of opn expression induced by HER-mrk than by the FGF receptor in melan-a cells (Fig. 3) ⇓ because HER-mrk stimulates strong MAPK activation that lasts several hours (13) , whereas bFGF-induced MAPK activation in melanocytes is only transient (35) .
Activation of both the HER-mrk as well as the FGF receptor not only induced OPN expression but also enabled murine melanocytes to survive in three-dimensional collagen gels. This could be due to a direct activation of antiapoptotic signaling pathways by the receptors. However, using HER-mrk-conditioned medium and an OPN-neutralizing antibody, we clearly could show that OPN in an indirect way contributes to the survival effect produced by the HER-mrk receptor. For the FGF receptor, it has been described that its stimulation by bFGF induces antiapoptotic signaling in human melanocytes, but the mechanism for this effect has not been elucidated yet (8) . Because we found that bFGF stimulation of melanocytes can induce OPN expression, this might point to a contribution of OPN to the survival effect seen by Alanko et al. (8) . One function of OPN, once up regulated by either the FGF or the HER-mrk receptor, could be an interaction of the factor with other receptors present on the melanocyte surface. Our studies revealed that in melan-a cells αvβ3 can act as such a receptor for OPN and that the OPN/αvβ3 interaction is crucial for the mediation of cell survival in collagen. The fact that blocking β3 interactions with a specific antibody did not have an equally strong influence on the OPN-produced antiapoptotic effect suggests that other β-subunits such as β1 or β5 might also participate in binding OPN. Because the ability of melan-a cells to adhere to OPN was reduced to 20% in the presence of the β3 antibody, it nevertheless seems very likely that αvβ3 is the main receptor for OPN in this melanocyte cell line.
Most striking, αvβ3 is known to play an important role in melanoma cell survival (3) , and its expression correlates with melanoma progression from RGP to VGP melanoma and tumorigenicity (5 , 6 , 36 , 37) . It should be mentioned, however, that for the effects produced on melanoma cells by αvβ3, not only OPN (38) but also denatured (proteolytically-cleaved) collagen was identified as the relevant ligand (3 , 4) . Thereby, the melanoma cells were able to alter the collagen to promote a stable interaction of αvβ3 with the matrix protein. Because melan-a cells do express a functional αvβ3 but were not able to spread properly and survive in collagen gels for a long-term period in the absence of defined factors, this particular interaction seems not to occur in untreated melanocytes. Interestingly, it is described that expression of αvβ3 in the absence of an appropriate ligand, which is the case for melan-a cells in native collagen, induces apoptosis because of the presence of unligated integrins (39) . This integrin-mediated death (39) is described to be biologically and biochemically distinct from anoikis, which is characterized as apoptosis induced by the loss of adhesion, per se (40) .
The presence of OPN induced spreading and survival of melan-a cells in collagen gels, and OPN is known to bind collagen (28) . This suggests a role for OPN as attachment protein for melanocytes mediating an interaction between collagen and the OPN receptor αvβ3. A function of OPN such as an adhesive intermediate (bridging molecule) for cellular attachment to matrix components has also been discussed for vascular smooth muscle cells, where addition of exogenous OPN could restore normal cell adhesion of OPN-deficient cells to collagen (41) . On the other hand, recent studies revealed that in OPN-deficient vascular smooth muscle cells, the expression of receptors necessary for adequate adhesion was affected (29) . Hence, OPN, instead of acting directly as attachment protein for melanocytes, might also act as an activating ligand for αvβ3 thus, stimulating intracellular pathways associated with regulation of adhesion, spreading, or survival.
Just recently it has been reported that in B16 mouse melanoma cells, stimulation of αvβ3 by OPN leads to the up regulation of the matrix metalloproteinases MMP-2 and MT1-MMP (38) . OPN also enhanced cell migration and ECM invasion of the cells, demonstrating that it can induce all cellular alterations necessary for the most important step in the establishment of a VGP melanoma from RGP lesions.
The interaction of OPN with αvβ3 not only can influence cell attachment, spreading, and migration but also mediates survival signals. Such a survival signaling induced by αvβ3 has been described in endothelial cells. Stimulation of αvβ3 by OPN thereby resulted in activation of nuclear factor κB through Src- and ras- dependent pathways (42) . Activation of the nuclear factor κB with OPN as stimulating ligand for αvβ3 was also found in melanoma cells. The antiapoptotic effect of αvβ3 in melanoma cells after interaction with denatured collagen, however, was linked to an increase in the Bcl-2:Bax ratio (4) , which is known to correlate with cell survival. Whether the interaction of OPN with αvβ3 in melanocytes also leads to an induction of bcl-2 expression or triggers other signaling pathways finally leading to survival of the cells in dermal collagen remains to be investigated.
We found that OPN, once expressed after treatment of the cells with growth factors or tumor promoters, can act as a ligand for αvβ3 in melanocytes in an autocrine way. Moreover, in several human melanoma cell lines, which constitutively express OPN, blocking of OPN interactions in collagen gels enhanced the number of apoptotic cells. Therefore, constitutive expression of OPN might induce a phenotype that exhibits not only increased migratory but also enhanced antiapoptotic activities as it is found for tumor cells. Indeed, overexpression of OPN in rat mammary epithelial cells has been shown to be sufficient to produce a metastatic phenotype (43) and reduced metastasis of injected B16 melanoma cells was found in OPN-deficient mice (44) .
In summary, our data show that in melanocytes, activation of growth factor receptors such as the Xmrk and the FGF receptor, both known to be involved in melanoma development (10 , 11) , can result in the production and secretion of OPN. We have shown that OPN, then in an autocrine way, can promote cell attachment, spreading, and survival of melanocytes in three-dimensional collagen matrices. OPN has been implicated in metastasis processes of tumors (43 , 44) , and cutaneous malignant melanoma is notorious for its high metastatic potential once the pigment cells are transformed. Since recent data proved that OPN can trigger migration and invasion and enhances tumor growth of melanoma cells (38) , production of OPN by melanocytes might be a crucial step in establishing cells with the potential to give rise to tumorigenic VGP melanoma. Our data demonstrate that growth factor receptors of the family of receptor tyrosine kinases thereby contribute to this step by up regulating opn expression in melanocytes, which points to a new role of these receptors in processes associated with melanoma development and progression.
We thank Dr. H-F. Yang-Yen for providing the neutralizing OPN antibody, Dr. C. W. Fisher for the mouse opn cDNA probe, Dr. I. Hart for the melan-a cells, and Dr. C. R. Goding and Dr. J. Becker for the human melanoma cell lines.
↵1 This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 487 ("Regulatorische Membranproteine") (to C. W.). E. G. was supported by a fellowship of the Graduiertenkolleg "Regulation des Zellwachstums."
↵2 Present address: Department of Pathology, University of Würzburg 97080 Würzburg, Germany.
↵3 To whom correspondence should be addressed, at Department of Physiological Chemistry I Biocenter (Theodor-Boveri Institut), University of Würzburg, Am Hubland, 97074 Würzburg, Germany. Phone: 49-931-8884153; Fax: 49-931-8884150, E-mail: wellbrock{at}biozentrum.uni-wuerzburg.de
4 The abbreviations used are: RGP, radial growth phase; VGP, vertical growth phase; ECM, extracellular matrix; bFGF, basic fibroblast growth factor; Xmrk, Xiphophorus melanoma receptor kinase; OPN, osteopontin; IL-3, interleukin 3; Hm, HER-mrk; HER-mrk CM, Hm-conditioned medium; EGF, epidermal growth factor; TPA, 12-O-tetradecanoylphorbol-13-acetate; RT, reverse transcription; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; DAPI, 4′,6-diamidino-2-phenylindole.
- Received February 26, 2002.
- Accepted June 11, 2002.
- ©2002 American Association for Cancer Research.


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NETANYA, Israel - Jungo Connectivity Ltd. announced the availability of its MediaCore version 4.5 on the DRA74x "Jacinto 6" platform from Texas Instruments (TI).
The DRA74x "Jacinto 6" is the most recent generation of TI's OMAP, a system-on chip designed for multimedia applications running in automobiles. The porting of MediaCore 4.5 to "Jacinto 6" allows the companies to benefit from future opportunities in the In-Vehicle Infotainment (IVI) market.
MediaCore 4.5, from Jungo Connectivity, is the most advanced MediaCore release from Jungo to date. It supports playback and distribution of media in the car and provides connectivity to all the different smartphones and protocols needed for an enhanced IVI multimedia experience.
MediaCore 4.5 includes support for complete audio/video/photo playback and distribution in the vehicle, on both the infotainment center stack as well as on RSE (Rear Seat Entertainment) units and brought-in devices like smartphones and tablets.
Jungo has optimized MediaCore 4.5 to support hardware accelerated capabilities offered by the "Jacinto 6" SoC, such as HD video playback. In addition, MediaCore 4.5 brings with it dedicated support for the latest technologies introduced in devices from Apple and Google, along with proprietary smartphone SDKs for advanced, non-standard, capabilities.
A number of automotive customers have already selected the Jungo MediaCore solution on TI platforms. "Porting MediaCore 4.5 to TI 'Jacinto 6' reaffirms our commitment to having our best of class multimedia and connectivity middleware support Texas Instrument's latest Automotive platforms, for the benefit of our mutual customers" said Jungo Connectivity CEO Ophir Herbst.
"We're pleased to have Jungo's MediaCore version 4.5 running on TI's DRA74x 'Jacinto 6' automotive processor," said Matt Watson, product line manager automotive infotainment processor, Texas Instruments. "Jungo's MediaCore 4.5 is a natural match with TI's Jacinto 6 processor as together this solution empowers Tier1s and OEMs to unleash innovative automotive multimedia and connectivity applications on this powerful In-Vehicle Infotainment (IVI) platform".
For more details, visit http://jungo.com


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One of the best experiences associated with Apple is in its retail stores. But due to legal restrictions, Apple hasn't been able to provide that experience directly to its retailers. But that could soon end as the iPhone-maker is finally launching its first online store in India to serve its customers director instead of having to rely on e-commerce and other offline partners.
"We're proud to be expanding in India and want to do all we can to support our customers and their communities," said Deirdre O'Brien, Apple's senior vice president of Retail + People. "We know our users are relying on technology to stay connected, engage in learning, and tap into their creativity, and by bringing the Apple Store online to India, we are offering our customers the very best of Apple at this important time."
Apple Online Store | Benefits
Naturally, Apple India's online store will showcase the entire range of Apple products and provide support and service to Indian consumers through a local contact centre in both Hindi and English languages. Through its online store, Apple is providing a host of other services, including special deals for students.
Here are the benefits of Apple online store in India:
- Easy financing options
- Trade-in program
- Students discount
- Free online sessions with Apple experts on various creativity programs
- Personalised engraving on select Apple products, such as Pencil, AirPods
- Apple Specialists will help custom-configuring any Mac, set up new devices
- Customers can get advice, guidance and learn about new products
- Contactless delivery
The launch finally comes after Apple got the nod from the Indian government, which relaxed its local sourcing norms. Tim Cook had confirmed the launch of its online store during an earnings call earlier this year, but the delay was due to COVID-19 pandemic. But at least the launch of the Apple online store comes in time for the festive sale period in the country.


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P-750 3M25 Grom Meteorit (Thunder)
The P-750 Grom supersonic winged cruise missile with a range of 3000-4000 km was developed to replace the Kh-55 [AS-15 KENT]. The AS-X-19 Koala was an air-launched land-attack version derived from the SS-NX-24 Scorpion submarine-launched missile. A pair of AS-19 missiles was expected to arm the Tu-142 Bear-H bomber. The history of the X-90 began in 1971. Then developers appealed to the government of the USSR with the construction project of a small strategic cruise missiles that could operate at low altitudes, applying to the terrain. This offer did not find a response from the leadership. However, after the United States in 1975 began the development of strategic cruise missiles (Cruise Missile), the leaders remembered it.
Work on the X-90 hypersonic missile was launched in 1976, under a December 9, 1976 Resolution of the USSR Council of Ministers. Developers missiles were ordered to start development to be completed in the middle of 1982. By December 31, 1983 a rocket was supposed to adopted. One of the main requirements was that, to ensure that the missile supersonic speed. By the end of the 1970s the new missile was able to reach speeds of Mach 2.5-3.0, and by the end of the 1980s, this value reached Mach 3 to 4.
The Meteorit program was begun in the late 1970s, and ended in the early 1990s. Deployment of the Ground Launched variant was curtailed by the 1988 Intermediate-Range Nuclear Forces Treaty between the U.S. and then-Soviet Union. Air-, ship- and submarine-launched variants of the turbojet-powered missile were designed to include a number of novel technologies. The weapon featured a high supersonic cruise speed and range of several thousand kilometers. Around 20 launches were conducted off a Tu-95MA flying testbed bomber.
The Meteorit used a turbojet sustainer, though NPVO Plamya had designed a 780 mm ramjet engine for it. The air-launched variant of the Meteorit, probably designated Kh-80, was dropped from an inboard pylon of a Tupolev Tu-95 Bear bomber.
The GELA was definitely not linked to the 3M25 Meteorit program. They were designed by different design bureaus - Meteorit by NPO Mashinnostrenya and GELA by Raduga - and at different timeframes - the 3M25 project was begun in 1976 and cancelled in 1989, the GELA was a late 1980s - early 1990s project. The GELA was probably linked to the Kh-90 air-launched cruise missile program.
The Marabu plasma-field generating system to reduce the radar-cross section of the high-flying missile is believed to be one of the novel technologies. Scientific and Engineering Production Association (NPO Mash) declassified a unique plasma gun, made invisible to enemy radar and air defense systems strategic supersonic cruise missile 3M25 "meteorite". At the time of irradiation by enemy radar "Meteor" created around it impenetrable for the radar radiation cloud of ionized gas. Unique gun will be within the next year transferred to the Russian universities as a textbook for future engineers and designers in the design of hypersonic vehicles. As told to "News" in Dec 21, 2016, the NPO Mash was negotiating the transfer of unique products come with the leadership of the Moscow Aviation Institute, National Technical University. NE Bauman, the Baltic State Technical University "Voenmech" them. DF Ustinova and Ural State University. BN Yeltsin.
It is best when irradiated plane or cruise missile radar can see the blades of the turbine engine and the inlet edge. These design elements like corner reflectors, - says the "News" editor in chief of Internet project Militaryrussia Dmitry Kornev. - Hiding from the radar of these structural elements, the problem with the radar signature of the aircraft is decided by 70-80%. Therefore, stealth planes make the air intake in the form of the Latin letter S. His bending blocks the passage of radio waves, but at the same time does not allow a rocket or an aircraft to fly at supersonic speeds. Designers NPO Mash equipped product normal air intake, allowing to develop a supersonic speed, and protect it from enemy radar.
By one account, in early 1997 engineers from the Raduga Design Bureau in Dubna (located just outside Moscow) displayed a new class of airborne vehicle -- the Kh-90 experimental cruise missile -- at the International Aviation Aerospace Salon (MAKS) in Zhukovsky. In the West, it was called the AS-19 Koala. This rocket was made to replace the Kh-55 strategic cruise missile that is carried by the Tu-160 bomber. Its flight range was 3,000 km. The missile could carry two warheads with individual guidance, each capable of hitting targets at a distance of 100 km from the point of separation. The carrier was to be a modernised version of the Tu-160M strategic bomber. However, according to official data, work on the missile was suspended in 1992.
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The #DecarbIndustry webinar took place on 29 November 2018. It was attended by 60 people who raised interesting questions and brought fruitful discussions. The webinar aimed at promoting the best examples and European projects in which is involved. The goal is to share knowledge of the best innovative application of heat humps in the industrial sector and promoting their replicability across Europe, stepping towards the decarbonisation path.
´´Heat pump technology shows potential to reach energy-savings, impossible to be reached by other technologies. It is considered to open doors for heat pump technology in AGRANA's production plants in the future.´´
Emmerich Haimer, responsible Technician at AGRANA Starch GmbH
"DryFiciency is offering a competitive advantage through demonstrating best available heat pump technology to recover latent energy from moist air flows. It´s what the industry needs."
Dirk Saldsieder, Head of R&D and Process Technology at Wienerberger AG
"With DryFiciency project, we aim for 60-80% energy reduction in our drying operations. This a very 'hot topic' and an important step in our journey towards becoming 100% fossil fuel-free operation by 2040. Indeed, DryFiciency is an exciting project with a lot of potentials!"
Ingeborg Peters , Global Petcare Technology Development Manager at Mars GmbH


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Watkinsville, GA
Watkinsville, GA is home to our offices and workroom.
Although we are in our workroom most days, we are technically not open to the public at this location. This is where we receive shipments, make all our feather pillows and other soft goods, and ship items to our clients. To see where you can shop for our collections, see locations and shows.
Or email us anytime at firstname.lastname@example.com
Also see our "About Us" section to find more about what we do.


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Follow below mentioned steps to get your Google Client ID and Secret Key:
Step 1 : Go to Google Developer portal
Step 6 : Click on Enable APIs and Services
Step 7 : Search for Google Play Android Developer API here. You can even scroll down to Mobile section.
Step 8 :Click on Google Play Android Developer API
Step 9 : Click on Enable to activate the key
Step 10: Click on Credentials
Step 11: Go to OAuth Consent Screen
Step 12: Enter Application Name, Authorized Domains.In the Authorized Domains field, enter the URL - snappy.appypie.com. If you want, you can add privacy policy link here.Once you are finished, click on Save to continue
Step 13: Open Create Credentials dropdown menu
Step 14: Click on OAuth Client ID
Step 15: Select Web Application here
Step 16: Provide Authorized JavaScript Origins and Authorized Redirect URLs.In the Authorized JavaScript origins field, enter the URL - https://snappy.appypie.com and in Authorized redirect URLs field ,enter the URL - https://snappy.appypie.com/app/iap-token . Once done, click on Create to continue
Step 17: Here is your Client ID and Secret Key.Copy them
Step 18: Paste the copied keys in the respective fields on the creator software and click on connect.
Step 19 :Go to Google Play Console
Step 20:If you have a Google Developer account, login, else Signup
Step 21: Go to Settings
Step 22: Click on API Access under Developer Account
Step 23: Here you will see all your projects. To access the API, you need to link your account to one of your Google Developer project. Select your desired project and click on Link. You can even create a new project by clicking on Create New Project
Step 24: Here you will see the project linked.


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Thank you for supporting us through these tricky times, we really appreciate every little order---Orders over £100 (weighing less than 2 kg) get free shipping ( sale items are excluded) within the UK---Please note that as the current crisis unfolds we are unable to guarantee delivery times and orders received will be processed twice a week. We now offer free PICK UP as an option on the website as well. If you would like to speak to us please: DM us on INSTAGRAM @wickle.co.uk OR EMAIL us with your number on email@example.com and we will get back to you . Shop is now open Mon-Fri 10 am - 4 pm and Saturday 10 am - 5 pm
Regular price
Made form recycled card board and printed using vegetable inks, this smaller insects are perfect as a quick activity, but even better to decorate with.
We had a go making them, and really enjoyed it. We would suggest they are great for 8 years and up.
approx. 18 cm long


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Don't Believe the Media Hype -- After the Oscar Grant Verdict, Oakland Stayed Home
EMERYVILLE, Calif. -- From the balcony, I can see the only supermarket serving a wide swath of West Oakland and neighboring Emeryville. In addition to the Pac 'N' Save, the same shopping district is home to a variety of other chain businesses: Best Buy, Sports Authority, GameStop, Baskin-Robbins and a massive Home Depot.
If there had been any real riots in Oakland last night -- on par with what happened after the Rodney King verdict in 1992 or when the Raiders won the AFC Championship game in 2002 -- I would have had a catbird seat to witness the carnage. No matter what the front page of the San Francisco Chronicle might lead you to believe, those riots didn't happen.
Before night fell, I was in downtown Oakland listening to very articulate and passionate young people -- many from the organization Youth Uprising -- decrying violence, pushing a line that helped keep things relatively calm immediately after the Johannes Mehserle verdict came down. There were maybe 500 people -- a very diverse crowd in terms of age, ethnicity, gender and race -- and hundreds of police.
The people were obviously upset and the police were obviously ready for anything -- they'd been practicing for weeks. The streets knew that, and they kept their cool. Oakland is too smart to get caught up fighting the National Guard and hi-tech crowd suppression tactics.
The relatively minor damage and looting that took place later in the evening has overshadowed the real story.
For, perhaps, the first time in California history, a cop was found guilty of something (however vague, not murder) after shooting an unarmed black man in the back. Whether or not Mehserle gets any real jail time for his crime will be decided in early August. What is clear now, though, is that Oakland fooled everyone. The expectation was that the city would burn. What happened was that the city stayed home.
On the streets last night, there were almost as many journalists, news cameras and regular people with cell phone cameras as protestors/anarchists.
The biggest indication that the so-called riot was a media creation is the fact that Oakland's Chinatown, just blocks away from the ruckus downtown, was left untouched.
During the Rodney King rebellion, there was palpable tension between the black and Asian communities. Months before the L.A. riots in 1992, a young black woman had been shot in the back of the head by a Korean woman for allegedly stealing -- an incident caught on videotape. After the King verdict, looters targeted Korean stores.
In Oakland, there was supposedly the same kind of tension between the black and Chinese communities in the wake of some recent high-profile attacks against Asians that resulted in injury and death.
If that tension was all it was hyped up to be, Chinatown would have been targeted last night. It wasn't. Oakland stayed home.


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- Heat stock and lentils in a pot at highest level up to vegetable window. Cook at low level approx. 3 minutes. Stir in instant couscous and let it soak approx. 5 minutes.
- Clean spring onions and cut obliquely in fine rings. Mix with lentils and couscous.
- Whisk yoghurt with vinegar and olive oil and season with salt, pepper and cumin. Mix with remaining ingredients in a Lasagnera and season well once more.
- Wash lemon with hot water and remove peel thinly and cut in fine strips, extract juice. Add over the salad to serve.
Couscous salad with yoghurt dressing
Nutritional values per portion: 335 kcal
Products used
Pot 20 cm, 3.0 l


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Office 365 Admin
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Increase 30 messages per minute limit
The 30 message per minute limit causes problems for software that needs to send out to many users. Now that we've migrated to Exchange Online our payroll system can no longer send out payslips because of this feature. Very limiting and a very low limit. It should at least be able to be configured to allow accounts to be exempted or have different limits.744 votes
Our service is designed to protect the resources and ensure that certain users will not overwhelm it and cause latency for others. This limit is in place to protect against spike sending that we wish to discourage. As such, we have no plans to change the limit for regular mailboxes.
Where possible, we encourage customers who have these requirements to seek solutions that do not send emails all at once, can make use of DLs, or use services like Dynamics or third-party services to send large volumes of emails to customers or student and parents.
However, we are thinking about alternatives we can provide to solve this issue of higher sending for automated email scenarios to address this customer need.
- Don't see your idea?


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Some of the things that made me happy about interviewing there and working there include:
- One of the leads (who shares an office with the Director of Software Development) has this displayed prominently in his window. The link is work-safe unless you work for Clear Channel or similar company.
- When it came up that I use XEmacs as my editor, the systems architect said, "And we hired you?" The other fellow that was hired at the same time said that he used vi so the architect said that it was okay then as long as parity is kept.
I like a place where people care about what editors they use and those editors are Emacs and vi.
- …There are others but I forget right now.
One of the lack of socialization areas that I've never been able to really repair is that I just don't understand where boundaries are for most people. I'm "Master of TMI" not because I want to shock people but because my boundaries are in different places than most. The way that I generally handle this is to stay clear on _this_ side of the boundary. Unfortunately, this means that sometimes I get viewed as a bit stiff and possibly distant at times. I'm going to have to be very careful in making humorous comments that I don't go past the boundaries that most humorous comments don't go past. Not sure how well this will work but what's life without a bit of challenge?


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Eight St. Lucie Public Schools have been recently recognized by the University of South Florida and Florida Department of Education as outstanding Positive Behavior Support (PBS) Response to Intervention B model schools by meeting specific criteria and utilizing innovative, creative, and functional ways of supporting PBS behavior approaches in their respective school. The PBS process results in the creation of effective intervention plans that will impede problem behaviors, teach new skills, and create support systems for the student. The PBS process is a team-based approach that relies on a strong collaboration between families and professionals from a variety of disciplines regardless of the level implemented. Pictured, from left, are Bayshore Elementary principal Lori Reid, St. Lucie Elementary principal Bernadette Floyd, district PBS coach Dawna Guiel, Superintendent Michael Lannon, Allapattah Flats K8 principal Jonetha Maness, Weatherbee Elementary principal Mike Hitsman, school board chairman Carol Hilson, Lawnwood Elementary principal D'Jion Jackson, Garden City PBS coach Lisa DeCosa, Student Services director Barbara Casteen, Forest Grove Middle dean Beth McGee, Dale Cassens principal Ellen Harden, Assistant Superintendent Bill Tomlinson, and Garden City principal Teri Barenborg.
St. Lucie County schools that are recognized at the Gold level are Forest Grove Middle School, Garden City Early Learning Academy, and Lawnwood and Weatherbee elementary schools. Silver level model schools include Allapattah Flats K8 and St. Lucie Elementary schools, while Bayshore Elementary and Delaware School have attained bronze status. As one of the annual leading PBS school districts in Florida, the transition from PBS to the more comprehensive RTI:B initiative has been more easily developed because the PBS models are so firmly entrenched in school operations.
The Florida Department of Education initiated the PBS Response to Intervention initiative during the 2009-2010 school year with two specific components: RtIA for academic improvement, and RtIB for behavior interventions. Specific characteristics of PBS:RtIB Model Schools are their consistent methods of utilizing data to better serve the students and staff, teaching PBS:RtIB to new students throughout the school year, creative and engaging reward systems, extending PBS:RtIB throughout the campus and partnering with the community and parents, and including PBS:RtIB into daily activities across all available teaching opportunities.
Bronze level model schools report a comprehensive system of support at Tier 1. Critical elements of Tier 1 PBS:RtIB are implemented with fidelity, and data are utilized within a problem-solving framework in order to improve the outcomes of students. Bronze level schools have developed innovative, creative, and functional ways of implementing Tier 1 PBS:RtIB that set them apart from other schools.
Silver level schools report all of the characteristics of bronze level schools and implement with higher levels of fidelity. Visibility, political support, parent involvement, and funding strategies are in place to ensure continued success with their implementation efforts. Silver level schools "drill down" into their data to ensure that their Tier 1 system is effective for all groups of students, and have taken steps to build systems of support for behavior at Tier 2.
Gold level schools report all of the characteristics of bronze and silver level schools, implement with the highest levels of fidelity, and have developed systems of support at Tiers 2 and 3. Gold level schools exceed their peers in both the quality and depth of implementation across all three tiers of support. Practices that are consistent with positive behavior support are evident in decision making, and steps are taken to ensure PBS:RtIB systems are supported. Positive outcomes for students are evident at the Tier 1, Tier 2, and Tier 3 levels of behavior support.


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When I said that PMMM was an example of four genres, and maybe five, this one - centred around Kyoko - was the maybe. Perhaps it's a story type rather than a genre – I don't know. It still needs to be mentioned, though. Kyoko deserves no less.
Kyoko's is a human-scale redemption story. In that capacity it bears an obvious analogy to the cosmic redemption of Madoka herself (which I have yet to discuss), but a more useful parallel may be with something like Silas Marner or A Christmas Carol. These are stories of people who started out open to life's possibilities, but who for one reason or another – either some traumatic shock or betrayal, or gradual disillusionment – drew down the shutters against the world, till loneliness or depression or even cruelty became, it seemed to them and others, a settled part of their characters:
a style
Our lives bring with them: habit for a while,
Suddenly they harden into all we've got
And how we got it
Then, something happens – something that wakens the part of them that had seemed dead. Perhaps, like Scrooge, they are shown their own former self and forced to compare it their present façade of cynicism, especially as seen through the eyes of others. And, in seeing that, they are reborn.
Does this kind of story have a general name? I don't know, and I don't mind, really. In making the comparison I don't mean that Madoka is retelling Dickens or that Scrooge is really much like Kyoko, but I do find his situation a useful analogue for hers. When Kyoko's wish for her father ends in his madness and the murder of her family, she survives only by giving up on the part of herself that had made the wish – the Kyoko who believed witches were worth fighting and her father's ideas worth fighting for. In the new, harder, smaller world she inhabits when we meet her she views everything in purely selfish and utilitarian terms: ideals are an illusion, all that matters is survival and maintaining one's place in the "food chain" (compare Scrooge's jibe about decreasing the "surplus population"). Naturally, anyone who reminds Kyoko of her own former perspective is going to be treated with hostility. But it's only such a person who can – like Scrooge's visions or Silas's Eppie – offer hope of salvation.
Sayaka fulfils that role. As someone who espouses the "naïve" version of MG-hood that had led Kyoko to disaster she naturally arouses her antipathy – but in her doomed and tenacious heroism she also rekindles that part of Kyoko, and for Kyoko saving Sayaka becomes a way of saving herself. Kyoko's and Sayaka's arcs (but here we are straying into structure) follow opposite trajectories, as is typical of the show's interest in balance: as Sayaka falls further into despair and nihilism, Kyoko holds ever more tightly to her rediscovered generosity and idealism. As she tells Madoka, she became an MG because as a child she loved stories in which love and justice triumph over all, and it was Sayaka who recalled that destiny to her, and her to it. The two begin and end in fighting, as Kyoko notes, and Kyoko ensures that in death they are not divided. While Kyoko's is not a happy ending like that of Scrooge or Silas (this is Madoka after all) she leaves on her own terms: "Hey, God. If you're there, my life sucked. So for once, please, let me have a happy dream."
That wish, too, is granted.


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The line of work I've chosen is very difficult because it's so close to my heart. As a person in long-term recovery, I become emotionally invested in my media messaging and business-to-business communications for Infinite Recovery. When I speak about recovery, I have a visible physical reaction. My voice gets louder. I begin speaking with my hands. My leg gets restless, and my feet tap incessantly. My eyes get wider and more alert.
The harsh reality is that the sheer volume of people suffering from substance use disorder, the potency of the substances legally and illegally available, the misconceptions around recovery, the nondisclosure traditions of 12-step anonymous programs and the staggering number of unethical facilities in operation have created a climate for low reporting and subsequently low statistical success of long-term recovery.
Don't be discouraged: There are a vast number of people recovering from substance use disorder. It's just more newsworthy to focus on the issues and fatalities. Tragedy equals clicks.
There is mistrust surrounding recovery positioning strategies.
We live in a time where we've learned more about mental health than ever before. It's a truly optimistic era for the industry as we've begun to innovate the ways in which people are treated.
There is, however, a certain feeling of mistrust in the industry around positioning strategies. There are responsible ways to market treatment strategies that clearly state the person of concern's willingness to actively pursue recovery will add to success. Then there are strategies that imply, "This solution is the silver bullet." Whether it's a new modality that's being exploited as a gimmick, an old-school approach or a new scientific innovation, there is a treatment center applying these methods in hundreds of different ways.
How can health care marketers responsibly market and position recovery solutions?
The reality of long-term recovery from substance use disorder and mental illness is that it ebbs and flows. There is no guarantee that any treatment stint or modality will be the one that sticks. In fact, the National Institute of Substance Abuse states that the chronic nature of the disease means that relapsing to drug abuse at some point is not only possible, but likely. The biggest statement from the site that stuck out to me was, "Lapsing back to drug use indicates that treatment needs to be reinstated or adjusted or that another treatment should be tried."
Treatment providers, private practice clinicians, advocacy groups and mental health professionals have to be transparent about recidivism rates. It's our ethical responsibility to inform families and loved ones that treatment is as effective as the client's motivation to change, the support structure that awaits them once leaving a facility and the treatment of co-occurring disorders.
Health care providers are increasingly paying attention to outcomes reporting in their authorization of health care claims, and we as marketing and communications professionals must take note of this. Health care giant Humana has even built its own clinical infrastructure CareHub to turn raw data into actionable health intelligence at the most critical moments for patients and subscribers. What this means for health care providers is what marketing professionals have known all along – client testimonials and raw data can be crafted into beautiful stories of your service's success and reinforce any communications strategy.
Turning these numbers and statistics into stories takes time and creativity. Simply stating a percentage doesn't convey the amount of work it takes to get there. What's been effective for us is compiling data on lengths of sobriety, activities each client participates in, a "cumulative healing" quantitation of family and personal relationships, and assimilation into normal daily life. You can distribute these stories through social media, in video testimonials and blogs to connect with the person and convey their transformation.
Data will drive the future.
Over the past year, the organization I work for has begun diving deep into outcomes, statistics and measurable data points including but not limited to average length of stay, levels of care completed, support system engagement, recidivism rates, etc. We also partner with a third-party organization that supports our outcome-tracking initiatives to support relapse prevention and ensure patients are provided the community and clinical resources necessary to support long-term sobriety.
What we've found is when we're able to compile data and report it in the clearest and most concise manner, we're not only able to get the families and loved ones to participate; we're also able to engage the clients in the best circumstances for success. Compiling this data has also helped us identify our key partners for treatment collaboration and form relationships with ethical, high-quality treatment providers.
Best practices that we have identified are:
• Gather as much data as possible. Ask each client as much as they are willing to share to tell a story.
• Make it measurable. So often in behavioral health care, information is subjective. It's necessary to begin compiling quantitative data so as to make it tangible.
• Consistency is key. Creating a workflow that can be followed and repeated helps remove barriers from the follow-up process and ensure each individual receives attention.
Going forward, our entire attitude will have to shift as an industry to not only reach more people affected with substance use disorder, but to shed stigma and create awareness. There are a large number of ethical and responsible treatment providers with honest communications about their programs, but my hope is that their data will help them leverage even stronger continuing care models and let this speak to the families and health care providers.
Data is the future. We've always known this for industries like chemical engineering and technology, but now is the time to apply it to behavioral health care. By simply compiling data and using it to illustrate successful treatment strategies and outcomes, we can more confidently recommend continuums of care to each specific client and create more accurate, measurable depictions of an individual's trajectory.


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Corn Husk Spoons
Brilliant Idea: Serve Corn in Its Own Husk
There are a countless number of corn preparation ideas at the peak of the vegetable's season, but one of my preferred ways to eat the warm-weather vegetable standout is by giving its kernels a quick sauté with herbs and spices. Recently, I learned a new way of serving my favorite dish.
At this year's SF Chefs, chefs Laurence Jossel and Gonzalo Guzman of Nopalito offered charred corn with cotija in a minispoon of actual corn husk, tying the edges with another thin strip of husk. The result? An attractive, eco-friendly, fun way to eat corn that's not on the cob. Have you ever tried something similar?


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Google's new VR headset and controller are built on the Daydream platform. It has already gained a lot of moment and Google predicts that more than 50 Daydream apps will be available at the end of the year on a VR-focused app store similar to Google Play. The Daydream View VR headset is affordable and retails at only US$79.
How can Google Daydream View be so affordable when other VR headsets like HTC Vive retails at about $1,900? The reason is that Daydream View is an "empty" headset shell. It requires pairing with a compatible smartphone that supports Daydream and that slots into the front of the headset. In addition, the graphics of the paired smartphone needs to be powerful enough to support a VR experience and VR apps. Hence, Daydream View is conceptually similar to Samsung Gear VR since another device drives the VR experience.
Compatible phones
Which phones are compatible with Daydream View? Only two initially: the newly announced Google Pixel and Pixel XL of course. Google writes on its website that more compatible phones are on the horizon, but doesn't state any specific details.
Headset material and colours
The material used for the VR headset is a plastic frame with cloth surrounding it similar to Oculus Rift. The predecessor VR headset Google Cardboard used cardboard, so cloth is step-up for Google. The cloth blocks out the light and ensures a low weight. In addition, cloth is relatively cheap compared to many other materials and also stylish. The fabric comes in red, white and slate colours with only the latter one being available at launch.
Pricing and availability
The Daydream View VR headset will be available in November. The local price in NZ inclusive of GST is about NZ$126.


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Grain: World Markets and Trade
October 9, 2020
This monthly report includes data on U.S. and global trade, production, consumption and stocks, as well as analysis of developments affecting world trade in grains.
World Agricultural Production
October 9, 2020
Monthly report on crop acreage, yield and production in major countries worldwide. Sources include reporting from FAS's worldwide offices, official statistics of foreign governments....


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AIMETIS - Software Add-Ons
Aimetis Symphony Mobile
Aimetis Symphony Mobile
Symphony Mobile works seamlessly with Aimetis Symphony and E3200/E7000 Series appliances. It is available as a download on Google Play and the App Store. Symphony Mobile consists of two items, an application for your smartphone or tablet and a server component called the Mobile Bridge. The Symphony Mobile Bridge server component can be installed on the same Symphony server or a dedicated server.


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Pelion™ Device Management and Connectivity Management Services
The Renesas RA MCU Family supports the Pelion IoT Platform which is a flexible, secure, and efficient foundation for connectivity, device, and data management. It accelerates time to value of IoT deployments helping to easily connect trusted IoT devices on global networks, seamlessly manage them, and extract real-time data to drive competitive advantage.
Key Features
- Support for Device Mgmt. services across entire Renesas RA family of devices
- Works out-of-the-box with FSP (Flexible Software Package)
- Leverages RA enhanced security through secure crypto engine and PSATM certification – "chip-to-cloud security"
- Comprehensive and Turnkey service for faster IoT deployments
- Faster Time-To-Market for device development and deployments
- Easily scalable to support any use case across any verticals
- Unified view of devices, networks, and data
- Choice of deployment options, device types, communication protocols
Block Diagram
Target Markets and Applications
- Transportation & Logistics
- Consumer Electronics
- Industrial Automation
- Energy & Utilities
- Oil & Natural Gas
- Manufacturing
- Smart Cities
- Automotive
|Last Updated Date
|PelionTM Device Management and Connectivity Management Services
PelionTM Device Management and Connectivity Management Services for the Renesas RA Partner Ecosystem
|27 Mar 2020
|Arm Pelion IoT Platform Overview
|03 Jul 2020
Disclaimer: THIS MATERIAL IS PROVIDED "AS-IS" FOR EVALUATION PURPOSES ONLY. RENESAS ELECTRONICS CORPORATION AND ITS SUBSIDIARIES (collectively, "Renesas") DISCLAIM ALL WARRANTIES, INCLUDING WITHOUT LIMITATION, FITNESS FOR A PARTICULAR PURPOSE AND MERCHANTABILITY. Renesas provides evaluation platforms and design proposals to help our customers to develop products. However, factors beyond Renesas' control, including without limitation, component variations, temperature changes and PCB layout, could significantly affect the product performance. It is the user's responsibility to verify the actual circuit performance.