Is your company growing? Are you becoming a global company? Are you falling into the trap of developing policies before understanding local culture? Laws? Regulations? Are you forgetting the fundamental importance of cultural differences? Are you disregarding cultural differences and not leveraging in-country talent? Have you considered allowing local teams to lead the way or are you failing to consider their input in strategic decisions? Do you limit your global success or are you setting up your global expansion for failure? We would like to share our thoughts on being sensitive to differences in culture and language based on our prior experience. Let us share with you what worked for us, so you can avoid these common missteps! This discussion will provide you insights on how to leverage in-country talent to build trust and demonstrate its value, with a focus on establishing an ethical culture consistent with the parent company. Building sustainable relationships and leveraging local feedback – they are by far your most credible advisors. Lastly, we will share strategies used to develop and adopt appropriate global policies, procedures and how to cope with these differences.
I absolutely agree tha One Size Does Not Fit All. We have to recognize the big role that local culture plays in bringing the "rubber to the road" in the different affiliated companies of a globally acting corporation. The dominant anglo-armerican b/w, rules-based compliance view driven by mainly FCPA concerns cannot be translated as global policies and procedures into local practices.
For my own work in Turkey I have found it greatly beneficial to look into the research of Geert Hofstede into the 6 dimensions of national culture. Power distance, individualism vs. collectivism, uncertainty avoidance and long-term orientation are four very important dimesions influencing how compliance is framed locally. And: national culture will always trump company culture, we should not have illusions about that.
By adapting – according to my insights from the 6D model – my communication style and putting more or less emphasis on certain parts of our global Ethics & Complaince program I have been very successful to form a connection with the employees here in Turkey. But I also have more realistic expectations as to what can be achieved in a short and medium time frame.


The term federal agency is a noun phrase. Federal Agency means (1) an administrative unit of government. The Quisto editorial staff has evaluated these websites and placed them in the Federal Agency information category.
U.S. Government Printing Office. Keeping America informed.
Protecting human health, safeguarding the natural environment.
Independent Agencies and Government Corporations.


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By Janne June 4, 2014 Read More →
Sauber-Mercedes C 9 (1987-1990)
The Sauber-Mercedes C 9 racing sports car was the outcome of a longstanding innovation partnership between Mercedes-Benz and the Swiss racing team established by Peter Sauber, a relationship that dated back to 1984. That was the year in which the Stuttgart company and the Zurich-based racing car designer reached an agreement for Mercedes-Benz to supply engines for the Sauber prototype sports cars used in the Group C motor racing series. The partnership marked the first step towards Mercedes-Benz's return to international circuit motorsport since the company's withdrawal in 1955.
Sauber had already been competing in Group C racing since 1982, initially using Ford and BMW engines in its C 6 and C 7 sports car prototypes. Then in 1985, Sauber presented the C 8, powered by a Mercedes-Benz M 117 engine – a modified V8 based on series production with a displacement of 4973 cc. The C 8 promptly won the ADAC 1000 km race at Nürburgring in 1986. The following year saw Jean-Louis Schlesser win the Super-Sprint on the Nürburgring for Sauber-Mercedes in the new C 9 (still at that point powered by the M 117 engine from the C 8).
From 1988 onwards, Mercedes-Benz again competed as an official works team in Group C for racing sports cars. The C 9 with an output of more than 515 kW (700 hp) also won the 800 kilometres of Jerez, the Czechoslovakian Grand Prix at Brno, the 1000-kilometre races at Nürburgring and at Spa-Francorchamps, and the 360-kilometre race at Sandown Park. On top of this came victories in the Supercup races on the Hockenheimring, Norisring and on the airfield at Diepholz.
The ultimate prize came in 1989, when Sauber-Mercedes won the World Championship with the C 9. For the 1989 season the racing sports car was equipped with the new V8 biturbo M 119 engine with four-valve technology, which was able to develop short bursts of power up to around 680 kW (925 hp). The configuration used in the race, however, delivered an output of around 530 kW (720 hp). The cars had not only been technically improved; they were also now painted silver as a clear signal that Mercedes-Benz was back on the race circuit as a works team fighting for victories.
In 1989 Sauber-Mercedes C 9 also took the double victory in the 24 Hours of Le Mans. Jochen Mass, Manuel Reuter and Stanley Dickens won the race in the C 9 with the starting number 63, followed by Mauro Baldi, Kenny Acheson and Gianfranco Brancatelli (starting number 61). The triumph was completed by a fifth place for the third car racing for the Sauber-Mercedes team: the vehicle driven by Jean-Louis Schlesser, Jean-Pierre Jabouille and Alain Cudini, with starting number 62, achieved the best time during qualifying and started the race from pole position.
1990 saw the arrival on the racetrack of the Sauber-Mercedes C 11 as the successor to the C 9. This sports car prototype was the first Sauber car to feature a carbon-fibre chassis, which gave the vehicle outstanding strength. In 1990 Sauber-Mercedes once again took the World Championship drivers' title (Schlesser and Baldi) as well as the constructors' title. For the 1991 season, which brought the exclusion of turbocharged engines from Group C, Mercedes-Benz developed the new M291 V12 engine (478 kW/650 hp) for the C 291 racing sports car. This was the last Mercedes-Benz Group C car.
Mercedes-Sauber C 9 racing sports car (M 119 HL engine)
Raced: 1989-1990
Displacement: 4973 cubic centimetres
Output: 530 kW (720 hp)
Top speed: approx. 400 km/h
Mercedes-Benz S-Class (W116) (1972-1980)
Mercedes-Benz SL (R129) (1989-2001)
Daimler 35 hp Mercedes (1901)
Blitzen-Benz (1909)
Mercedes-Benz E-Class Coupe (124 series) (1987-1996)
Category: Classic Race Cars
Tags: 1980s Race Cars, Mercedes-Benz history, Mercedes-Benz Race Cars, Sauber

redpajama_set_name: RedPajamaCommonCrawl


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Rafael Font de Mora  (* 7. Mai 1968 in Valencia, Spanien) ist ein ehemaliger spanischer Profi-Tennisspieler und heute Leiter einer Tennisakademie in Scottsdale, Arizona (USA).

Font de Mora spielte von 1985 bis 1988 Tennis auf der ATP Tour.

1990 gründete er eine Tennisakademie mit Namen International Tennis U.S.A. (itUSA), in der junge Talente gemanagt, gefördert und trainiert werden. Die bislang berühmtesten Emporkömmlinge dieser Akademie sind Meghann Shaughnessy und Anna-Lena Grönefeld. Shaughnessy erreichte die Top 20 der Welt sowie die Top 10 im Doppel. Grönefeld schaffte es im Frühjahr 2006 bis in die Top 15 sowie in die Top 10 im Doppel.

Font de Moras Einrichtung bietet auch Tennislehrgänge für Interessierte (vom Anfänger bis zum Profi) an.

Seine Trainingsmethoden sind unter Experten allerdings sehr umstritten. Er gilt als äußerst dominant und soll Spieler stark für sich einnehmen. Deswegen galt unter anderem das Verhältnis zu Fed-Cup-Chefin Barbara Rittner, die ebenfalls für Grönefeld verantwortlich war, als ziemlich angespannt.

Weblinks
 Font de Moras Tennisakademie "itUSA"
 "Ich war sein Besitz, sein Projekt"

Tennisspieler (Spanien)
Spanier
Geboren 1968
Mann

redpajama_set_name: RedPajamaWikipedia


Sitting on Friendship Beach with views across to Chalong Bay, The Vijitt is the ideal setting to explore the aquatic life of south Phuket. Enjoy complimentary Wi-Fi throughout the resort.
7 nights in a Deluxe Villa.
Special Offer: Special room rate.
This charming and secluded hotel boasts a stunning location in an unspoilt landscape of lush green grass that rolls right up to the beach. Each villa is set amongst indigenous tropical gardens, promising a private and relaxing holiday. If you can pull yourself away from the tiered infinity pool, the V Spa offers ultimate relaxation. Like the villas, the treatment rooms and pavilions have traditional thatched roofs reminiscent of a rural Thai village. The more active will leap at the chance for a Thai boxing lesson on the beach. For a more sedate way to experience local culture, turn your hand to rubber tree tapping at a nearby farm. There is also a choice of restaurants and delicious meals allowing you to savour local ingredients including vegetables and herbs grown within the resort.
Please quote deal number 4251670 when you call.
Call 01 695036501 6950365 or email our Travel Experts to find out more about holidays to Phuket.


I have seen a few discussions on mayflies. Has this hatch begun and what does it mean for the fishing? My brother and I will be fishing the chain June 7th through the 12th. Any tips would or info would be helpful.


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Peenemünde is een plaats en gemeente op het noordwestelijke uiteinde van het eiland Usedom, dat behoort tot de Duitse deelstaat Mecklenburg-Voor-Pommeren. Het eiland ligt in de Oostzee. Het dorp telt  inwoners.

In de Tweede Wereldoorlog werd vlak naast het dorp onderzoek en ontwikkeling gedaan naar in eerste instantie geheime V-wapens, de zogenaamde Vergeltungswaffen (vergeldingswapens), die werden gebruikt door de Duitse Wehrmacht.

Hoofdzakelijk bestaan er twee soorten onbemande vliegende wapens met een explosieve lading: de V1 (een vliegtuig) en de V2 (een raket). Deze laatste werd op Peenemünde getest en was het eerst gebruikte ballistisch wapen, dat naar zijn doelwit geleid kon worden. In 1936 was het ontwerp voor de raket klaar en begon men onderzoek en experimenten te verrichten in Peenemünde. In 1942 vond de eerste lancering plaats van de V-2 en gaf Hitler de toestemming voor de massaproductie ervan. Na bombardementen in 1943 door de RAF werd de productie verplaatst naar de Harz, waar in grotten de productie plaatsvond in het kamp Mittelbau-Dora.

Tegenwoordig is het dorp grotendeels verlaten. Hele woonblokken (Oostblok-blokkendozen) staan leeg of er wonen slechts één à twee families in zo'n blok.

De toegang tot de bosrijke omgeving is grotendeels verboden omdat het een natuurreservaat is en om archeologische redenen. Hierdoor en door de ligging op een uitloper van het eiland is Peenemünde een erg geïsoleerd dorp.

De energiecentrale (bunker) van het onderzoekcentrum en de directe omgeving daarvan is een museum met als thema de techniek van de V-wapens. Daarnaast staan een speelgoedmuseum en een centrum voor wetenschapsbeleving (E=mc²).

Gemeente in Mecklenburg-Voor-Pommeren
Lanceerbasis


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Home >> Trending Topics >> Sports >> Dodgers Have No Plans to Kneel for Anthem During World Series
Dodgers Have No Plans to Kneel for Anthem During World Series
Posted by: Donn Marten in Sports October 24, 2017	Comments Off on Dodgers Have No Plans to Kneel for Anthem During World Series
Major League Baseball is poised for a big jump in popularity thanks to the NFL's ongoing descent into the morass of black-identity grievance mongering and left-wing politics.
While the NFL's ratings have been tanking and more people are showing up to stadiums on Sunday afternoons dressed as empty seats, baseball has capitalized on a thrilling postseason to set itself up for future success and a return to being America's game.
Throughout the protests against social injustice, the police, President Trump or whatever the NFL-NBA's multimillionaire players may be pissed off at on any given week, baseball has been steadfast in the refusal to disrespect the flag outside of a misguided rookie catcher for the Oakland A's who took a knee last month.
With the 2017 World Series opening on Tuesday night, the hometown Los Angeles Dodgers were asked whether they would use the national attention to take a knee during the playing of the Star-Spangled Banner.
Fat chance.
Dodgers Reportedly Won't Kneel During Anthem Before Game 1 of 2017 World S… #Dodgers https://t.co/uwwJJNunBD pic.twitter.com/T0P39s2bTW
— Dodgers Report (@dodgers_fanly) October 24, 2017
Via the Bleacher Report "Dodgers Reportedly Won't Kneel During Anthem Before Game 1 of 2017 World Series":
The Los Angeles Dodgers will stand in unison for the United States national anthem before Game 1 of the World Series against the Houston Astros on Tuesday night at Dodger Stadium.
TMZ Sports reported none of the Dodgers plan to take a knee during the anthem as a form of protest and team management hasn't even discussed the issue with the players.
No member of the Los Angeles organization has protested during the anthem throughout the 2017 season. Oakland Athletics catcher Bruce Maxwell was the only MLB player to follow the lead of numerous NFL players and other athletes by kneeling to make a statement about racial injustice.
Dodgers manager Dave Roberts explained his view of the potential protests last month.
"Personally, yeah, I'd have a problem because my father served this country for 30 years and I understand—I can appreciate any player's individual, however they act, and that's personal," he told reporters. "But I would just ask every person to really be educated. When you make a point, something like that—and it's been in baseball. It's been in sports. But the thing is, really think long and hard, and really be educated on why you're doing what you're doing.
The National League Champions aren't biting and are clearly more focused on winning a championship than crying for Colin Kaepernick.
No word has yet been given by the American League Champion Houston Astros on whether they intend to hit their knees but since they have not chosen to engage in this malarkey through the duration of the playoffs it's highly unlikely.
There will, of course, be more grumbling from the racial-animosity peddlers that there aren't enough blacks in MLB and that it is the equivalent of crackerball but the NFL has provided a warning to other sports leagues of the ratings catastrophe that awaits if the focus is shifted from the ballgame to politics.
Los Angeles Dodgers National Anthem Protests The NFL The World Series	2017-10-24
Donn Marten
Tagged with: Los Angeles Dodgers National Anthem Protests The NFL The World Series
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Donn Marten is a fearless truth teller who calls it like he sees it despite the prevailing establishment narrative. The opinions expressed belong solely to this author and not do not necessarily reflect those of CDN itself.


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Climate Change Poses Alarming Threat to Food Security in Pacific Islands
By Razeena Raheem	Reprint | | Print |
Pacific leaders gather at FAO before participating in the UN Climate Conference COP23. in Bonn. Credit: FAO
ROME, Nov 12 2017 (IPS) - A high-level meeting of political leaders -– hosted by the Food and Agriculture Organisation (FAO) -– sounded an ominous warning: that climate change poses an "alarming threat to food systems and food security in the Pacific islands."
And for many island nations, the impact of climate change also represents the "gravest of threats to their survival and viability", including, for some, through the loss of territory due to sea-level rise—and the potential danger of being wiped off the face of the earth.
Chaired by FAO Director-General José Graziano da Silva, the meeting of leaders from nine small island developing states (SIDS) and representatives of regional development bodies, plus New Zealand and Australia, focused on "Improving food security and nutrition, building resilient livelihoods and promoting partnerships for sustainable development in the Pacific Islands."
The nine participating countries included Kiribati, Vanuatu, Nauru, Marshall Islands, Micronesia, Samoa, Cook Islands, Papua New Guinea and French Polynesia, whose inhabitants face a potentially severe food crisis triggered mostly by climate change.
José Graziano da Silva. Credit: FAO
In his opening remarks on Saturday, Graziano da Silva shared the Pacific leaders' concerns about the negative impact of climate change on food security and nutrition and its role in exacerbating the burden of malnutrition as well as the alarming overweight and obesity levels.
"You are suffering from things that you didn't cause, from things you are not responsible for – the impact of climate change," the FAO Director-General said.
"This is what FAO offers – support so that you can face climate change; scale up growing local products as we see you import more and more food. Obesity is a big problem. It is an epidemic that we need to address."
"Together with partners such as WHO, we promote the uptake of healthy, fresh food – fruits, vegetable and fish instead of processed food. We promote local products – bread fruit, for which we have a pilot programme in the Marshall Islands, Samoa, Nauru, and which we want to scale up and multiply," he added
In a joint statement, following the meeting Saturday, the Pacific leaders called upon all countries to "exceed previous commitments and pursue efforts to limit the temperature increase to 1.5 °C as above pre-industrial levels, to reduce the adverse impacts on food security and nutrition, coastal habitats and the livelihoods of those depending on oceans."
The 1.5 degrees limit will allow "for a greater change at maintaining resilient livelihoods and promote partnerships for sustainable development in the Pacific Islands," the statement read.
Also participating in the meeting were officials from the Secretariat of the Pacific Community, Secretary-General of the Pacific Islands Forum, Director-General of the Pacific Islands Forum Fisheries Agency and Chief executive officer of the Pan Pacific Power Association.
The joint statement was also a "call to action" to the UN climate change Conference of Parties (COP 23), currently underway, in Bonn, where the Pacific leaders will present their case.
The meeting, which concludes November 17, will be presided over by the government of Fiji, a small island developing state in the Pacific.
The leaders also raised concerns about the negative impacts of malnutrition evidenced by the growing incidence of Non-Communicable Diseases (NCDs), which accounts for 75 percent of adult deaths in the Pacific, and called for "more proactive and integrated actions to promote policies to tackle food insecurity challenges, especially on issues related to obesity, stunting, wasting and NCDs."
They acknowledged the importance of the FAO and partners' Global Action Programme on Food Security and Nutrition in SIDS, which recommends action at global, regional, national and local level to accelerate food security and nutrition, calling for its endorsement and immediate implementation.
With Pacific island states highly dependent on their oceans for their livelihoods and food security, leaders reiterated their anxiety about ecosystem degradation, and called upon the international community to assist in maximizing the sustainable utilization of the fisheries and aquaculture sectors for the benefit of small island developing states.
According to FAO, the Pacific islands are among the most environmentally vulnerable nations in the world. Drought, extreme high tides, violent winds, and storm surges pose major risks to small island nations, and their efforts to achieve sustainable development.
With "Oceans Day" events taking place at COP23 on Saturday, Graziano da Silva highlighted the importance of the FAO Port State Measures Agreement (PSMA), described as "today's main tool in the hands of the international community to tackle illegal, unreported and unregulated fishing".
Urging all Pacific Island states to adhere to the agreement, he said: "You are countries with more water and natural resources to preserve than any other countries. This is why the Port State Measures Agreement is important."
He said FAO is "committed to support you to implement and monitor your PSMA process. We can provide assistance for your national legislations, training and funding to put the agreement in place. We will not be able to safeguard our ocean environment if we don't combat illegal fishing," he declared.
In the joint statement, the leaders also reiterated their anxiety about ecosystem degradation and other challenges encapsulated in the Sustainable Development Goal 14 and called upon the international community to assist in maximizing the sustainable utilization of the fisheries and aquaculture sectors for the benefit of the small island developing states.
They further recalled the endorsement of the Global Action Programme on Food Security and Nutrition in SIDS and called for immediate implementation.
Additionally the leaders also called upon the international community to ensure partnerships are genuine and enduring South-South and triangular cooperation are encouraged and facilitated, and synergies to maximize the use of financial resources for the Pacific Islands are pursued and built
The political leaders at the high level meeting included: Taneti Maamau, President, Republic of Kiribati, Baron Waqa, President, Republic of Nauru, Hilda Heine, President, Republic of Marshall Islands, Yosiwo P. George, Vice President, Federated States of Micronesia, Henry Puna, Prime Minister, Cook Islands, Charlot Salwai Tabimasmas, Prime Minister, Republic of Vanuatu, Fiame Naomi Mataafa, Deputy Prime Minister, Samoa, Joshua Kalinoe, Special Envoy of the Prime Minister, Papua New Guinea, James Shaw, Minister for Climate Change, New Zealand, Aupito William Sio, Minister for Pacific Peoples, New Zealand and Édouard Fritch, President, French Polynesia.
Other participants included: Colin Tukuitonga, Director-General, Secretariat of the Pacific Community, Dame Meg Taylor, Secretary-General, Pacific Islands Forum, James Movick, Director-General, Pacific Islands Forum Fisheries Agency and Andrew Daka, Chief executive officer, Pan Pacific Power Association.
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Address correspondence to: Lawrence Brass, University of Pennsylvania, Room 915 Biomedical Research Building II, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA. Phone: (215) 573-3540; Fax: (215) 573-2189; E-mail: Brass@mail.med.upenn.edu.
J Clin Invest. 2005;115(12):3385–3392. https://doi.org/10.1172/JCI26869.
The mechanisms of platelet activation have grown increasingly familiar. Vascular injury exposes tissue factor within the vessel wall (or allows the local accumulation of circulating tissue factor–containing microparticles), which leads to local generation of thrombin and fibrin. Simultaneously, newly exposed collagen fibrils within the vessel wall become decorated with plasma-derived vWF, circulating platelets adhere long enough to be activated by collagen and thrombin, and a growing mound of platelets is formed as additional circulating platelets are recruited by soluble agonists, including thrombin, ADP, and thromboxane A2 (TxA2). Activated platelets stick to each other via bridges formed by the αIIbβ3 integrin and multivalent adhesive proteins such as fibrinogen, fibrin, and vWF. They also accelerate thrombin formation. The net result is a hemostatic plug or thrombus composed of activated platelets embedded within a fibrin mesh — a structure that can withstand the shear forces generated by flowing blood in the arterial circulation.
In general terms, this description has withstood the test of time, evolving as new molecules are shown to be participants in or regulators of hemostatic plug formation. Equally important, a number of successful drugs have been developed that target key events in platelet activation with the goal of preventing pathological thrombus formation. These include drugs that block ADP receptors, impair TxA2 synthesis, or prevent the binding of adhesive proteins to activated αIIbβ3. However, even as it accounts for the initiating events of platelet activation, this model leaves some intriguing questions unanswered. For example, what happens after activated platelets stick to each other? Are interactions between platelets required beyond those mediated by αIIbβ3? What prevents destabilization of the hemostatic plug during the time needed for wound healing to occur? What keeps the integrin engaged with its ligands? What is happening in the gap between activated platelets? How do events on the surface of opposing platelets compare with events on the unopposed surfaces of activated platelets? This Review will address some of these issues, focusing on events within and across the gap between activated platelets and the role that those events play in thrombus growth and stability.
In contrast to most cells, platelets are not normally in stable contact with each other but develop such contacts once aggregation has begun. Electron micrographs show the close proximity of the plasma membranes of adjacent platelets but do not show adherens or tight junctions such as those formed by epithelial and endothelial cells (1–3). Estimates for the width of the gap between adjacent platelets range from as little as 0 to as much as 50 nm (4). This short distance between platelets should make it possible for molecules on the surface of one platelet to bind to molecules on an adjacent platelet. This could be a direct interaction, as when one cell adhesion molecule binds to another in trans, or an indirect interaction, such as occurs when multivalent adhesive proteins link activated αIIbβ3 on adjacent platelets. In either case, these interactions can theoretically provide both an adhesive force and a secondary source of intracellular signaling. Junctional molecules have been detected in platelets, as have some of the molecules associated with junction formation in other types of cells (5). Close contacts between platelets not only allow platelet/platelet interactions to occur but can also limit the diffusion of plasma molecules into the gap between platelets and prevent the escape of platelet activators from within the gap. This might, for example, limit the access of plasmin to embedded fibrin, thereby helping to prevent premature dissolution of the hemostatic plug. It might also foster the accumulation of platelet activators within a protected environment in which higher concentrations can be reached and maintained. Seen in this context, clot retraction, which is dependent on the interaction between actin/myosin complexes and the cytoplasmic domain of αIIbβ3 as well as the binding of fibrinogen or vWF to the extracellular domain of the integrin, can be viewed as a mechanism for narrowing the gaps between platelets and increasing the local concentration of soluble ligands for platelet receptors (6).
Any list of molecules that participate in contact-dependent and contact-facilitated interactions between platelets is likely to be incomplete, but a number of participants and potential participants have been identified. Those that will be discussed here include integrins and other cell adhesion molecules, direct interactions between receptors and surface-attached ligands, and bioactive molecules that are either secreted or proteolytically shed from the surface of activated platelets (Figure 1 and Table 1). Some of these molecules also play a role in the interaction of platelets with other types of cells, but the focus here will be on platelet/platelet interactions.
Events in the gap. The gap between activated platelets in a growing thrombus is small enough for integrins and other cell adhesion molecules (CAMs) to interact and for interactions to occur between receptors such as Eph kinases and their cell surface ligands, known as ephrins. The space between platelets also provides a protected environment in which soluble agonists (ADP and TxA2) and the proteolytically shed exodomains of platelet surface proteins can accumulate. Signaling by ephrins and Eph kinases promotes integrin engagement and outside-in signaling. The mechanical forces generated by the contraction of actin/myosin filaments may compress the space between platelets, improving contacts and increasing the concentration of soluble agonists. The binding of cell adhesion molecules to their partners may limit diffusion into and out of the space between platelets in addition to stabilizing platelet/platelet interactions.
Outside-in signaling refers to the intracellular signaling events that occur downstream of activated integrins once ligand binding has occurred. Since this topic has been reviewed by others (7) and is covered in another Review in this series (8), only a few points will be made here. Integrin signaling depends in large part on the formation of protein complexes that link to the integrin cytoplasmic domain. Some of the protein/protein interactions that involve the cytoplasmic domains of αIIbβ3 help regulate integrin activation; others participate in outside-in signaling and clot retraction. Proteins capable of binding directly to the cytoplasmic domains of αIIbβ3 include β3-endonexin (9), CIB (10), talin (11), myosin (12), Shc (13), and the tyrosine kinases Src (14) and Syk (15, 16). While some of these interactions require the phosphorylation of tyrosine residues Y747 and Y759 in the β3 cytoplasmic domain, others do not. Shc, for example, requires Y759 phosphorylation (13). Myosin binding requires phosphorylation of both Y747 and Y759 (12). Fibrinogen binding to the extracellular domain of activated αIIbβ3 stimulates a rapid increase in the activity of Src family members and Syk. Studies of platelets from mice lacking these kinases suggest that these events are required for the initiation of outside-in signaling and for full platelet spreading, irreversible aggregation, and clot retraction (17–20).
The phosphorylation of the β3 cytoplasmic domain is an event of particular relevance to this Review. Phosphorylation is mediated by 1 or more Src family members and can require both activation of the integrin and its engagement with an adhesive protein (18, 19). Mutation of Y747 and Y759 in β3 to phenylalanine produces mice whose platelets disaggregate and which show reduced clot retraction and a tendency to rebleed from sites on the tail where bleeding times were previously measured (21). Loss of clot retraction is also a hallmark of αIIbβ3-deficient platelets from patients with Glanzmann thrombasthenia — reflecting the dependence of clot retraction on the interaction of αIIbβ3 with extracellular fibrin and with intracellular actin/myosin filaments.
JAM-A and JAM-C. Junctional adhesion molecules (JAMs) are Ig domain–containing, Ca++-independent cell adhesion molecules. Three have been identified thus far: JAM-A (also known as JAM-1 and F11R), JAM-B (JAM-2, VE-JAM), and JAM-C (JAM-3) (22, 23). Platelets express JAM-A and JAM-C. JAMs have an extracellular domain with 2 Ig domains, a single transmembrane region, and a short cytoplasmic tail that terminates in a binding site for cytosolic proteins with an appropriate PDZ domain. JAM-A localizes to tight junctions of endothelial and epithelial cells and is also found on monocytes, neutrophils, and lymphocytes. JAM-C has been found on endothelial cells, lymphatic vessels, DCs, and NK cells. JAM-A contributes to cell-cell adhesion by forming trans interactions involving the N-terminal Ig domain. However, JAMs also support heterotypic interactions, in particular integrin binding via their membrane-proximal Ig domain. For example, JAM-A binds αLβ2 integrin on leukocytes and contributes to leukocyte extravasation across the endothelium (24). JAM-C forms adhesive interactions with JAM-B and binds to leukocyte αMβ2 (25).
Platelet JAM-A was originally described as the antigen for a platelet-activating antibody (26). Subsequent studies showed that the activating effects of the antibody are dependent on activation of platelet FcγRII receptors, a property shared with mAbs directed against other platelet surface proteins as well (27). However, JAM-A has also been shown to induce platelet adhesion and spreading via interactions with immobilized JAM-A in vitro, suggesting that it might play a role in homotypic platelet/platelet and platelet/endothelial interactions as well as mediating heterophilic interactions between platelets and leukocytes by binding to αLβ2 (24, 28). Similarly, JAM-C was found to bind αMβ2 integrin on leukocytes, suggesting a role for JAM-C in platelet/leukocyte interactions (25). The contribution of JAMs to platelet-platelet adhesion has yet to be determined. Interestingly, the cytoplasmic tail of JAM-A becomes phosphorylated via a PKC-dependent mechanism following platelet aggregation (29), suggesting that JAM-A may have a role in contact-dependent signaling.
ESAM. Endothelial cell–specific adhesion molecule (ESAM) is structurally similar to the JAMs (30) with an extracellular domain consisting of 2 Ig domains and a single transmembrane domain. The cytoplasmic tail of ESAM is longer than any of the JAMs and contains several proline-rich regions, as well as a C-terminal PDZ target domain (30). ESAM was identified as a cell adhesion molecule in endothelial cells (30), but it is also expressed by platelets. In endothelial cells ESAM binds via homotypic interactions (30, 31), colocalizes with tight junction proteins (31), and binds to the PDZ domain–containing adaptor protein MAGI-1 (32). ESAM is readily detected on the surface of activated platelets, but not on resting platelets, suggesting that it may be located on an intracellular structure, such as the membranes of α-granules (31). Its function on platelets is unknown.
CD226. CD226, or DNAM-1, is a fourth Ig superfamily adhesion molecule on the surface of platelets (33). CD226 consists of an extracellular domain with 2 Ig domains, a single transmembrane domain, and a cytoplasmic tail (34). CD226-mediated adhesion of NK cells is dependent on phosphorylation of Ser329 within the CD226 cytoplasmic tail by PKC (35). Cross-linking of CD226 on NK cells results in tyrosine phosphorylation of the cytoplasmic domain and increased cytolytic activity, indicating a possible role in signal transduction. In addition to an association with the integrin αLβ2, a recent study identified the polio virus receptor (PVR; CD155) and the adherens junction protein nectin-2 (36) as potential ligands for CD226. CD226 has been shown to participate in the binding of activated platelets to endothelial cells in vitro (34). Endothelial cells express nectin-2, so it is possible that it serves as a ligand for platelet CD226 as well. It is unknown whether platelets express nectins, or whether CD226 also mediates platelet-platelet adhesion. However, CD226-mediated adhesion and CD226 tyrosine phosphorylation are dependent on platelet activation (34), again suggesting the possibility that CD226 participates in platelet signal transduction pathways in the late stages of platelet activation and thrombus formation.
PECAM-1. Platelet–endothelial cell adhesion molecule (PECAM-1; CD31) is known for its high level of expression on endothelial cells, where it accumulates at junctions between cells. However, as its name suggests, PECAM-1 is also expressed on the surface of resting and activated platelets. PECAM-1 is a type 1 transmembrane protein with 6 extracellular Ig domains and an extended cytoplasmic domain of approximately 118 residues (reviewed in ref. 37). The most membrane-distal Ig domain can support homotypic interactions in trans. The C-terminus contains phosphorylatable tyrosine residues that represent tandem ITIM domains capable of binding the tyrosine phosphatases SHP-2 and, possibly, SHP-1 (38). Loss of PECAM-1 expression in mice increases responsiveness to collagen via the GPVI collagen receptor, consistent with a model in which platelet activation leads to tyrosine phosphorylation of PECAM-1, allowing SHP-1/2 to bind and bringing the phosphatase near its substrates, including the Fcγ chain partner of GPVI (39, 40). This may normally provide a braking effect on collagen-induced signaling and prevent unwarranted platelet activation, but how this fits within the context of contact-induced signaling once platelets begin to aggregate remains to be clarified.
SLAM and CD84. Signaling lymphocytic activation molecule (SLAM; CD150) and CD84 are members of the CD2 family of homophilic adhesion molecules that have been studied extensively in lymphocytes, but have now been shown to be expressed in platelets as well (41–43). The members of the family are type 1 membrane glycoproteins in the Ig superfamily. Notable differences among them are in the cytoplasmic domain, which supports binding interactions with a variety of adaptor/partner proteins. SLAM and CD84 are expressed on the surface of resting as well as activated platelets and become tyrosine phosphorylated during platelet activation, but only if aggregation is allowed to occur (41). Immobilized CD84 causes platelet activation in vitro. Mice that lack SLAM have a defect in platelet aggregation in response to collagen or a PAR4-activating peptide, but a normal response to ADP and a normal bleeding time. In a mesenteric vascular injury model, female SLAM–/– mice showed a marked decrease in platelet accumulation. Male mice were normal (41). The presence of SLAM, CD84, and 2 of their known adaptor proteins (SAP and EAT-2) in platelets provides a novel mechanism by which close contacts between platelets can support thrombus stability.
Eph kinases and ephrins. Direct contacts between platelets promote signaling by more than 1 mechanism. In addition to signaling events that occur downstream from cell adhesion molecules, there are receptors that interact in trans with cell surface ligands. This type of interaction is illustrated by Eph kinases and their membrane-bound ligands, known as ephrins. Eph kinases are a large family of receptor tyrosine kinases with an extracellular ligand-binding domain and an intracellular kinase domain and PDZ target domain. Like signaling by other receptor tyrosine kinases, signaling by the Eph kinases is promoted by the clustering and transphosphorylation induced by ligand binding. The ligands for Eph kinases are cell surface proteins known as ephrins that fall into 2 groups depending on whether they have a glycophosphatidylinositol anchor (the ephrin A family) or a transmembrane domain (the ephrin B family). In turn, Eph kinases are divided into 2 groups by ligand preference. For the most part, A ligands bind to A kinases and B ligands bind to B kinases, although exceptions do exist (44, 45). The cytoplasmic domains of the ephrin B family members are highly related. Each is composed of 90–100 residues with 5 conserved tyrosines, at least 3 of which can become phosphorylated (46), and a C-terminus that can serve as a binding site for cytoplasmic proteins with appropriate PDZ domains (47–50).
Eph kinases and ephrins are best known for their role in neuronal organization and brain development (51–53), and as markers distinguishing arteries from veins during vasculogenesis (54). Ephrins can also serve as viral entry receptors (55). Eph/ephrin interactions are particularly relevant to contact-dependent signaling because the binding of an ephrin to an Eph kinase triggers signaling in both the receptor-expressing cell and the ligand-expressing cell (47, 48, 56–60). These events can be dependent on the tyrosine phosphorylation of Eph and ephrin, but phosphorylation-independent interactions have also been described, including those mediated by the PDZ target domains (47–49, 57, 61–65) and the sterile α motif domains (66–69). Taken together, these binding domains make possible the regulated formation of large signaling complexes around clustered Eph kinases and ephrins (45, 51, 70, 71).
Human platelets express 2 Eph kinases, EphA4 and EphB1, and at least 1 ligand, ephrinB1, that can bind to both (72). Forced clustering of either EphA4 or ephrinB1 causes platelets to adhere to immobilized fibrinogen. Clustering of ephrinB1 also causes the activation of Rap1B, a known intermediate in integrin activation in platelets (73, 74), and promotes platelet aggregation initiated by suboptimal concentrations of agonists (72, 75). During platelet activation the signaling complexes that form with EphA4 include the Src family members Lyn and Fyn (72). Blockade of Eph/ephrin interactions leads to reversible platelet aggregation at low agonist concentrations and limits the growth of platelet thrombi on collagen-coated surfaces under arterial flow conditions (72, 76). It also impairs phosphorylation of the β3 cytoplasmic domain, inhibiting the association of myosin with αIIbβ3 and, as a result, impairing clot retraction (76). EphA4 is constitutively associated with αIIbβ3 in both resting and activated platelets and colocalizes with the integrin at sites of contact between aggregated platelets (76). Collectively, these observations suggest a model in which the onset of aggregation brings platelets into close proximity and allows ephrinB1 to bind to EphA4 and EphB1. Signals downstream of both the receptors and the kinases then promote further integrin activation (in part by activating Rap1b) and integrin signaling (in part by promoting β3 phosphorylation). In turn, these events promote thrombus growth and stability (Figure 2).
Eph/ephrin interactions between platelets. Agonists such as thrombin, ADP, and TxA2 are ligands for G protein–coupled receptors, causing a rapid increase in the cytosolic Ca2+ concentration and producing the inside-out signaling events that lead to integrin αIIbβ3 activation (i). The increasingly stable contacts between platelets permit ephrinB1 to bind to EphA4 and EphB1. As discussed in the text, Eph/ephrin interactions support inside-out signaling by activating Rap1b (ii) and also promote outside-in signaling by promoting the tyrosine phosphorylation of the β subunit of αIIbβ3 (iii).
PEAR1. Platelet endothelial aggregation receptor 1 (PEAR1) is a newly described molecule expressed on platelets and endothelial cells (77). It is a 140- to 150-kDa type 1 transmembrane protein with 15 EGF repeats that is equally expressed on the surface of resting and activated platelets and has, as yet, no known ligand. Platelet activation leads to the phosphorylation of tyrosine and serine residues within the PEAR1 cytoplasmic domain and supports association with Shc. Phosphorylation in activated platelets can be inhibited by prevention of aggregation, suggesting that PEAR1-dependent events are dependent on contact and not just activation.
More than just an empty space, the gap between platelets provides a safe harbor in which platelet-derived molecules can accumulate. In addition to the numerous plasma- and megakaryocyte-derived proteins that are secreted from platelet α-granules (78), activated platelets release agonists such as ADP and TxA2 and presumably continue to do so even after thrombus formation has begun. Platelets also shed surface molecules, including GPIbα (79), GPV (80), GPVI (81, 82), and P-selectin (83). Cleavage of each of these proteins can be prevented with inhibitors of metalloproteases, and, in at least 2 cases (GPIbα and GPV), a role for a particular metalloprotease, ADAM17, has been established through studies on platelets from mice that lack it (79, 80). The advantage that the platelet derives from shedding surface proteins can be surmised but is not entirely clear. Downregulation of responsiveness to collagen has been proposed as the benefit derived from shedding GPVI (82). Loss of the exodomain of GPIbα, which serves as the primary vWF receptor on platelets, would also impair platelet interactions with collagen, but since cleavage occurs after platelet activation, the impact on thrombus prevention is not readily apparent. It is possible that the reduction in net surface charge that would accompany loss of the negatively charged GPIbα exodomain allows platelets to pack more closely together in a thrombus. It may also expose interaction sites on the remaining extracellular portion of GPIbα that are occluded in the intact molecule, but this remains speculative. In contrast to GPIb and GPVI, where cleavage of the exodomain may predominantly impair function, cleavage of 2 other molecules on the surface of activated platelets, CD40 ligand and sema4D, gives rise to bioactive fragments that can stimulate platelets as well as other nearby cells.
CD40L. CD40 ligand (CD40L; CD154) is a 33-kDa transmembrane protein that is present on the surface of activated platelets, but not resting platelets (84–86). Its appearance on the platelet surface is followed by the gradual release of an 18-kDa exodomain fragment of CD40L (85). Both the surface-bound form and the soluble form of CD40L (sCD40L) are trimers (87). Platelets also express CD40, the 48-kDa transmembrane protein that acts as a receptor for CD40L (85, 88, 89). Unlike CD40L, CD40 is detectable on the surface of resting as well as activated platelets (85, 88). CD40L is a member of the TNF family, and platelet-derived sCD40L or activated, CD40L-expressing platelets can elicit responses from endothelial cells and monocytes that appear to be proatherogenic (84, 85, 90–92). The extracellular portion of CD40L includes a binding domain for CD40 and a KGD (RGD in mice) integrin-recognition sequence. The binding of sCD40L to activated platelets is blocked by mutations in the KGD sequence and by antibodies to αIIbβ3. Binding occurs to platelets that lack CD40, but not to platelets that lack β3, all of which suggests that sCD40L can bind to activated αIIbβ3 on platelets and that the KGD sequence is involved (88). Consistent with a role in thrombus formation, CD40L–/– mice show delayed occlusion following vascular injury and decreased thrombus stability (88). Loss of the gene encoding CD40 has no apparent effect (88). Infusion of sCD40L into CD40L–/– mice reverses the phenotype observed after FeCl3-induced vascular injury, but sCD40L with an altered KGD sequence does not. Notably, platelet aggregation is normal in CD40L–/– platelets, although growth of platelet plugs on collagen-coated surfaces under shear is affected (88, 93). All of this suggests that the effects of CD40L on platelets are mediated by αIIbβ3, not CD40, and that platelet behavior in the relatively low-shear conditions present in an aggregometer cuvette may not fully reflect the events that are relevant to thrombus stability.
Sema4D and its receptors. Semaphorins are a large family of structurally related proteins (94, 95). Like Eph kinases and ephrins, semaphorins are best known for their role in the CNS, but individual family members have been found elsewhere, including hematopoietic cells. Semaphorins have in common a 500–amino acid residue extracellular "sema" domain that forms a 7-bladed propeller structure (96). Sema4D, or CD100, is a 150-kDa type 1 glycoprotein that forms a disulfide-linked homodimer. Each subunit has an N-terminal sema domain, an Ig domain, a lysine-rich stretch, a transmembrane domain, and a cytoplasmic tail with consensus tyrosine and serine phosphorylation sites whose role is unclear. Sema4D is best known for its role in lymphocyte biology. Soluble sema4D released from activated lymphocytes inhibits immune cell migration, acts as a costimulator for CD40-induced B cell proliferation and Ig production, and induces release of proinflammatory cytokines by monocytes (97–100). Sema4D–/– mice are viable but show defective B cell development, impaired T cell activation, and blunted immune responses (101). Two receptors have been identified for sema4D: plexin-B1, a high-affinity receptor expressed on endothelial cells (102, 103), and CD72, which is expressed on lymphocytes (104–106). Plexin-B1 was recently shown to elicit proangiogenic responses and signaling in endothelial cells (102, 107, 108).
We have recently identified sema4D on the surface of human and mouse platelets (109). Platelet activation causes progressive loss of intact sema4D and the shedding of its disulfide-linked exodomain. Shedding is sensitive to metalloprotease inhibitors (110). These results suggest that at least some of the sema4D expressed in platelets is initially located on the cell surface and that platelet activation leads to cleavage of the protein by a platelet-associated metalloprotease, releasing a larger fragment and leaving a smaller fragment behind in the membrane. Western blots show that platelets also express CD72 and, therefore, may be capable of responding to as well as releasing sema4D (110). The rate at which sema4D is shed from activated platelets, like the rate of CD40L shedding, lags behind the rate of platelet aggregation. This suggests that at least some of the shed sema4D exodomain should be protected in the gaps between platelets, while the rest is washed downstream where it can bind to endothelial cells.
Gas6 and its receptors. Growth arrest–specific gene 6 (Gas6) is a 75-kDa secreted protein related to protein S. Like protein S and other proteins whose synthesis requires vitamin K as a cofactor, Gas6 contains γ-carboxylated glutamic acid residues that allow it to bind to negatively charged phospholipids in a Ca++-dependent manner (111). Gas6 is expressed in a number of tissues, including vascular smooth muscle, and levels of expression are upregulated following vascular injury. In mouse platelets, Gas6 is found in the α-granules (112, 113). Upon activation by thrombin, ADP, or collagen, Gas6 is secreted from rat platelets (112). Gas6 is a ligand for the related receptor tyrosine kinases Axl, Sky, and Mer (114, 115), all of which are expressed on platelets (113). Like other growth factor receptors, Axl family members have been shown to stimulate PI3K and phospholipase Cγ (111). A reasonable hypothesis is that secreted Gas6 could bind to receptors on the platelet surface and cause signaling that would promote platelet plug formation and stability, perhaps while binding to negatively charged phospholipids on adjacent platelets. Consistent with this hypothesis, platelets from Gas6–/– mice were found to have an aberrant response to agonists in which aggregation begins but ends prematurely (113). Furthermore, although the tail bleeding time of the Gas6–/– mice was normal, the mice were resistant to thrombosis (113), as are mice lacking any 1 of the 3 Gas6 receptors. Platelets from the receptor-deleted mice also failed to aggregate normally in response to agonists (116–118). Biochemical studies showed that Gas6 signaling promotes β3 phosphorylation and, therefore, clot retraction (117).
Collectively, these results are consistent with a role for secreted Gas6 in promoting integrin outside-in signaling and helping to perpetuate and stabilize platelet plug formation. Most granule secretion occurs after the onset of aggregation, and Gas6 secreted into the confined spaces between platelets might achieve high local concentrations and cause receptor activation. However, a number of issues remain to be settled before this hypothesis can be fully accepted. In particular, the biology of the Gas6 system needs to be explored further in humans, as most current evidence is from experiments with mice. At least 1 recent study suggests that human platelets do not store and secrete Gas6 (119).
There is now ample evidence that the signaling events that support platelet activation continue after integrin activation, granule secretion, and platelet aggregation have begun. Some of these events can reasonably be expected to promote the growth and stability of the hemostatic plug, support clot retraction, and help to maintain the plug in place until wound healing is complete or at least well under way. In contrast to the initiating events of platelet activation, these "late" events can take advantage of the close proximity between platelets once aggregation begins and may even extend to the contacts that develop between platelets, endothelial cells, and leukocytes as the hemostatic plug evolves. The models of contact-dependent signaling discussed in this Review are just examples of what will probably turn out to be a more complex process involving additional cell surface molecules whose function remains to be identified. The picture that emerges is that the gaps and contact points between activated platelets in a thrombus are sites of highly relevant activity.
This work was supported by grants from the National Heart, Lung, and Blood Institute (to L.F. Brass) and the American Heart Association (to T.J. Stalker).
Nonstandard abbreviations used: CD40L, CD40 ligand; ESAM, endothelial cell–specific adhesion molecule; Gas6, growth arrest–specific gene 6; JAM, junctional adhesion molecule; PEAR1, platelet endothelial aggregation receptor 1; sCD40L, soluble CD40L; SLAM, signaling lymphocytic activation molecule; TxA2, thromboxane A2.
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Bergmeier, W, et al. Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates GPIbalpha shedding from platelets in vitro and in vivo. Circ. Res. 2004. 95:677-683.
Rabie, T, Strehl, A, Ludwig, A, Nieswandt, B. Evidence for a role of ADAM17 (TACE) in the regulation of platelet glycoprotein V. J. Biol. Chem. 2005. 280:14462-14468.
Bergmeier, W, et al. GPVI down-regulation in murine platelets through metalloproteinase-dependent shedding. Thromb. Haemost. 2004. 91:951-958.
Stephens, G, et al. Platelet activation induces metalloproteinase-dependent GP VI cleavage to down-regulate platelet reactivity to collagen. Blood. 2005. 105:186-191.
Berger, G, Hartwell, DW, Wagner, DD. P-selectin and platelet clearance. Blood. 1998. 92:4446-4452.
Locksley, RM, Killeen, N, Lenardo, MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001. 104:487-501.
Inwald, DP, McDowall, A, Peters, MJ, Callard, RE, Klein, NJ. CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Circ. Res. 2003. 92:1041-1048.
Mach, F, Schonbeck, U, Sukhova, GK, Akinson, E, Libby, P. Reduction of atherosclerosis in mice by inhibition of CD40 signaling. Nature. 1998. 394:200-203.
May, AE, et al. Engagement of glycoprotein IIb/IIIa on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells. Circulation. 2002. 106:2111-2117.
Danese, S, Fiocchi, C. Platelet activation and the CD40/CD40 ligand pathway: mechanisms and implications for human disease. Crit. Rev. Immunol. 2005. 25:103-122.
Crow, AR, Leytin, V, Starkey, AF, Rand, ML, Lazarus, AH. CD154 (CD40 ligand)-deficient mice exhibit prolonged bleeding time and decreased shear-induced platelet aggregates. J. Thromb. Haemost. 2003. 1:850-852.
Tamagnone, L, Comoglio, PM. Signalling by semaphorin receptors: cell guidance and beyond. Trends Cell Biol. 2000. 10:377-383.
Yu, HH, Kolodkin, AL. Semaphorin signaling: a little less per-plexin. Neuron. 1999. 22:11-14.
Love, CA, et al. The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D. Nat. Struct. Biol. 2003. 10:843-848.
Kumanogoh, A, et al. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity. 2000. 13:621-631.
Ishida, I, et al. Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses. Int. Immunol. 2003. 15:1027-1034.
Delaire, S, et al. Biological activity of soluble CD100. II. Soluble CD100, similarly to H-SemaIII, inhibits immune cell migration. J. Immunol. 2001. 166:4348-4354.
Wang, X, et al. Functional soluble CD100/Sema4D released from activated lymphocytes: possible role in normal and pathologic immune responses. Blood. 2001. 97:3498-3504.
Shi, W, et al. The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity. 2000. 13:633-642.
Basile, JR, Barac, A, Zhu, T, Guan, KL, Gutkind, JS. Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res. 2004. 64:5212-5224.
Conrotto, P, et al. Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood. 2005. 105:4321-4329.
Kumanogoh, A, Kikutani, H. The CD100-CD72 interaction: a novel mechanism of immune regulation. Trends Immunol. 2001. 22:670-676.
Adachi, T, Flaswinkel, H, Yakura, H, Reth, M, Tsubata, T. The B cell surface protein CD72 recruits the tyrosine phosphatase SHP-1 upon tyrosine phosphorylation. J. Immunol. 1998. 160:4662-4665.
Baba, T, et al. Dual regulation of BCR-mediated growth inhibition signaling by CD72. Eur. J. Immunol. 2005. 35:1634-1642.
Tamagnone, L, et al. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell. 1999. 99:71-80.
Conrotto, P, Corso, S, Gamberini, S, Comoglio, PM, Giordano, S. Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene. 2004. 23:5131-5137.
Zhu, L, et al. Semaphorin 4D (CD100) is expressed on the surface of human platelets and proteolytically shed during platelet activation [abstract]. Blood. 2003. 102:292a.
Zhu, L., et al. 2005. Regulated shedding of sema4D from the platelet surface produces a bioactive second messenger in thrombotic disorders [abstract]. Blood. In press.
Melaragno, MG, Fridell, Y-W, Berk, BC. The Gas6/Axl system: a novel regulator of vascular cell function. Trends Cardiovasc. Med. 1999. 9:250-253.
Ishimoto, Y, Nakano, T. Release of a product of growth arrest-specific gene 6 from rat platelets. FEBS Lett. 2000. 466:197-199.
Angelillo-Scherrer, A, et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat. Med. 2001. 7:215-221.
Stitt, TN, et al. The anticoagulation factor protein and its relative, Gas6, are ligands for the Tyro3/Axl family of receptor tyrosine kinases. Cell. 1995. 80:661-670.
Varnum, BC, et al. Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by the growth-arrest-specific gene 6. Nature. 1995. 373:623-626.
Chen, C, et al. Mer receptor tyrosine kinase signaling participates in platelet function. Arterioscler. Thromb. Vasc. Biol. 2004. 24:1118-1123.
Angelillo-Scherrer, A, et al. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J. Clin. Invest. 2005. 115:237-246. doi:10.1172/JCI200522079.
Gould, WR, et al. Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses. J. Thromb. Haemost. 2005. 3:733-741.
Balogh, I, Hafizi, S, Stenhoff, J, Hansson, K, Dahlback, B. Analysis of Gas6 in human platelets and plasma. Arterioscler. Thromb. Vasc. Biol. 2005. 25:1280-1286.


Violation of any rule or blatant disregard for the safety of others may subject a participant to disqualification from the current year's race and possible disqualification from future races.
Racers are required to start in the wave they are assigned to ensure accurate race timing, safety, and balanced wave sizes. There is a mechanism to request a wave (bib) change. Any blatant disregard of this rule may subject the participant to disqualification from the current year's race and possible disqualification from future races.
All racers must reach the Cut-Off time Checkpoint on the mountain before the cut-off times listed below AND complete the race before the cut-off times listed below, or they will be disqualified from the race.
Any racer who continues on the race course after the cut-off times on the mountain will be disqualified from entering future Mount Marathon races.
Adult racers must cross past the Junior Race Point (1/2 way up the mountain) within one hour (60 minutes) of their start time. Adults that do not complete the race within 2.5 hours will not receive an official time.
Junior racers must cross by Squirrels' Inn within 30-minutes of their start time, and complete the race in 1.5 hours or less to remain eligible for Priority Status.
Before first-time racers will be allowed to pick up their bib, racers (or their parent or guardian if under 18) must sign a statement stating they have completed the entire race course prior to race day.
Routes on the race course can be closed by emergency responders and by race officials. Racers who continue along a close section of the race course after being informed of the closure may be disqualified from the current race and banned from participating in future races. The most commonly closed section of trail is the waterfall due to the location of an injured runner and responding emergency personnel. Race officials will station volunteers at intersections to inform racers of closures.
Racers who picked up a bib that do not start or finish the race must notify a race official at the finishline as soon as possible.
No shoes with metal cleats.
No identifying markers on the trail to guide runners.
No assistance on the trail except for first aid and dispensing of water.
No unfair or unsafe acts.
No headphones or listening devices.
Every runner must give way to a runner shouting "trail" in the act of passing.
Any runner still on the trail from an earlier race shall give way to runners in the current race.
Applicants may not falsify any information on the application form.
Participants in the adult races must show a valid photo I.D. when picking up their bib or face disqualification.
Participants may not trade bibs or provide their bibs and race identification to other individuals.
Runners must have their race bib with embedded timing chip when crossing the finish line.
Adults that finish the Mt. Marathon Race in 2.5 hours or less will receive an official time and their finish will be counted towards 10-year status (a racer who has completed 10 or more non-consecutive adult races) for priority registration status.
Bandits are individuals who join the field of Mount Marathon Race® competitors under fraudulent circumstances – obtaining a legal bib using false identification, using another runner's bib, or breaking into the field of runners at any point without a bib or using a falsified bib.
A bandit creates safety and liability issues for both other participants and race officials. Bandits also create errors in race timing if they cross the finish line. Bandits steal resources meant for registered runners who pay for them such as emergency personnel, permit fees, insurance costs, etc. If a bandit sustains an injury or other medical emergency, the race officials may not know who that person is or may think it's someone else. This could result in serious consequences.
Bandits violate the spirit of sportsmanship endorsed by the Mount Marathon Race® and more importantly, impair the safety of all participants.
As a result, identified bandits may face a lifetime ban from participating in the Mount Marathon Race®, ban from other Alaska running events, and possible legal action.
Each participant must sign a Waiver of Liability absolving the City of Seward, the Seward Chamber of Commerce, and any or all individuals connected with the race of any responsibility for injuries incurred while training for the race or during the race.
A parent or legal guardian must sign the waiver on behalf of any participants in the Junior race.
Acknowledgement of this Waiver of Liability during the online MMR Racer Registration and Lottery Application processes constitutes your signature on the Waiver.
1. I understand and acknowledge that the mountain race I am about to engage in as a participant bears certain known risks and unanticipated risks which could result in physical or emotional injury, death, paralysis, or damage to myself or spectators or other third parties. I understand that such risks simply cannot be eliminated without jeopardizing the essential qualities of the race.
The risks inherent to mountain trail running.
Risks incurred due to inclement weather conditions, including but not limited to high winds, rain, snow as well as excessive heat.
Risks incurred due to hazardous contact with plants or wild animals.
My own physical condition, or my own acts or omissions.
Risks incurred due to conditions of the race trail or terrain.
Risks incurred from receiving First Aid, emergency treatment or other wilderness medical services rendered.
Risks incurred due to the distance of this activity's location from emergency medical facilities.
2. Being aware that this activity entails known and unknown risks of injury to myself and a risk of injury to spectators or other third parties as a result of my actions, I expressly agree, covenant, and promise to accept and assume all responsibility and risk for injury, death, illness or disease, or damage to myself to others arising from my participation in this race. My participation in this activity is purely voluntary, no one is forcing me to participate, and I elect to participate in spite of the risks.
3. I hereby voluntarily release, forever discharge, and agree to hold harmless and indemnify the Mt. Marathon Race organizers and their employees, volunteers and all other persons or entities from any liability, claims, demands, actions or rights of actions, which are related to, arise out of, or are in any way connected with my participation in this race, including specifically but not limited to, the acts or omissions of the Mt. Marathon Race organizers, their volunteers or employees, and all other persons or entities for any and all injury, death, illness or disease, and damage to myself.
4. Should it become necessary for the Mt. Marathon Race organizers or someone on the Mt. Marathon Race organizers behalf, incur attorney's fees and costs to enforce this agreement, or any part thereof, I agree to pay the Mt. Marathon Race organizers reasonable costs and attorney's fees thereby expended, or for which liability is incurred.
5. I certify that I have sufficient health, accident and liability insurance to cover any bodily injury I may incur while participating in this event and to cover bodily injury caused to a third party as a result of my participation in this event. If I have no such insurance, I certify that I am willing to and capable of personally paying for any and all such expenses or liability.
6. In the event that I file a lawsuit against the Mt. Marathon Race organizers, I agree to do so solely in the state of Alaska, and I further agree that the substantive law of that state shall apply in that action without regard to the conflict of law rules of that state.
7. I authorize the use of my photogenic image for inclusion in any Mt. Marathon Race brochure or for any other advertising purposes.
8. The Mount Marathon Race committee recognizes that the use of performance enhancing drugs give users an unfair performance advantage over non-users. Performance enhancing drugs include anabolic steroids and any other natural or synthetic substance used to increase muscle mass, strength, endurance, speed or other athletic ability, excluding dietary and nutritional supplements such as vitamins, minerals, and proteins which can be lawfully purchased over-the-counter. Those individuals who use performance enhancing drugs are prohibited from participation in the Mount Marathon Race. I attest that I am, and will remain, performance enhancing drug free.
BY SUBMITTING MY RACER REGISTRATION OR LOTTERY APPLICATION ONLINE, I FULLY RECOGNIZE THAT IF ANYONE IS HURT WHILE I AM ENGAGED IN THIS EVENT, I WILL HAVE FREELY GIVEN UP MY RIGHT TO MAKE A CLAIM OR FILE A LAWSUIT AGAINST THE MT. MARATHON RACE ORGANIZERS, AS WELL AS THEIR OFFICERS, AGENTS, VOLUNTEERS AND EMPLOYEES, EVEN IF THEY OR ANY OF THEM CAUSED THE BODILY INJURY. I RECOGNIZE THAT MOUNTAIN TRAIL RUNNING IS INHERENTLY RISKY AND DANGEROUS AND AM PARTICIPATING IN THIS EVENT IN SPITE OF THE RISKS. CHECKING THE BOX BELOW INDICATES THAT I HAVE READ THIS ENTIRE DOCUMENT, UNDERSTAND IT COMPLETELY, UNDERSTAND THAT IT AFFECTS MY LEGAL RIGHTS, AND AGREE TO BE BOUND BY ITS TERMS.


Lowertown grew up at the Lower Landing on the Mississippi River, beginning in the 1840s. As Saint Paul grew, Lowertown evolved into a major warehouse and distribution center serving the entire Upper Midwest.
Lowertown's railroad, manufacturing, and wholesaling companies expressed their pride and permanence in the structures they erected, beginning in the 1880s. A significant concentration of these buildings survive, unified by similar architectural styles and construction materials. Many were designed by the city's most prestigious architects, including Cass Gilbert and Clarence Johnston. Each of the buildings listed below has a page devoted to them. Please click on their respective links to learn more.


text:
using System;
using System.Linq;

namespace Ragnar.Integration.InterestV3.Calculator
{
    public class InterestCalculator : Contract.IInterestCalculator
    {
        private readonly Repository.IBankRepository bankRepository;
        private readonly Helpers.IPolicyHelper policyHelper;
        private readonly Helpers.ITaxHelper taxHelper;
        private readonly Helpers.IInterestHelper interestHelper;
        private readonly Helpers.IInterestRateHelper interestRateHelper;

        public InterestCalculator(
            Repository.IBankRepository bankRepository,
            Helpers.IPolicyHelper policyHelper,
            Helpers.ITaxHelper taxHelper,
            Helpers.IInterestHelper interestHelper,
            Helpers.IInterestRateHelper interestRateHelper)
        {
            this.bankRepository = bankRepository;
            this.policyHelper = policyHelper;
            this.taxHelper = taxHelper;
            this.interestHelper = interestHelper;
            this.interestRateHelper = interestRateHelper;
        }

        public Contract.DepositProjectionSummary ProjectDepositSummary(Guid userId, Guid bankId, Guid depositId)
        {
            Model.Bank bank = bankRepository.Detail(bankId, userId);

            Model.Deposit deposit = bank.BankAccount.Deposits.First(x => x.ID == depositId);

            Model.BankInterestRate interestRate = bank.Rates.First(x => x.StartDate >= deposit.StartDate && x.StartDate <= deposit.EndDate);

            Model.TaxSystem taxSystem = bank.TaxSystem.First(x => x.Key >= deposit.StartDate && x.Key <= deposit.EndDate).Value;

            decimal depositInterest = deposit.Amount * interestRateHelper.ForPeriod(interestRate, deposit.StartDate, deposit.EndDate);

            decimal taxPercentage = policyHelper.ApplyPolicy(CreatePolicyCalcContext(taxSystem, deposit));

            Contract.Tax tax = taxHelper.Tax(depositInterest, taxPercentage);
            Contract.Interest interest = interestHelper.Interest(depositInterest, taxPercentage);

            return new Contract.DepositProjectionSummary()
            {
                DepositID = depositId,
                StartDate = deposit.StartDate,
                EndDate = deposit.EndDate,
                InitialAmount = deposit.Amount,
                Interest = interest,
                Tax = tax
            };
        }

        private Helpers.PolicyCalculationContext CreatePolicyCalcContext(Model.TaxSystem taxSystem, Model.Deposit deposit)
        {
            return new Helpers.PolicyCalculationContext() { TaxPolicies = taxSystem.TaxPolicies, Deposit = deposit };
        }
    }
}

redpajama_set_name: RedPajamaGithub


text:
A Very Spring Break Tour of Netflix
By Bwog Staff on Mar 07, 2009 1 Comments
Image courtesy of Florida State University
Bwog's Official Cinephile Mark Hay uses the silver screen for some Spring Break pointers.
This week's movie list could be about anything–intrigue, crisis, existential inertia, curb stomping. But, just like you, the only thing Bwog can concentrate on right now is the imminent salvation of spring break, and these films reflect our monomania. O Valhalla of rest, O promise of change, save us! O save us from the ruts into which we have fallen and from these God-damned midterms from which escape seems inconceivable!
Proudly (and slightly prematurely) we present the answer to your prayers (if what you prayed for was a list of three movies relating to your spring break): there's one about what you wish you could do, one about what you should do, and one what you inevitably will do if (when!) you return home.
What You Wish You Could Do
The Graduate (1967)
As evidenced by its continued popularity and the inability of modern-day imitators to supplant it, director Mike Nichols's opus is absolutely anthemic for our culture. Benjamin (Dustan Hoffman), upon returning home from college, is confronted with the incessant buzz and urgent pressure from family (and, even worse, family friends) to make something of himself–to continue his life as the all-American boy. Benjamin, however, just like you or me, wants nothing more than to sit for a while and adjust to the shock of being pitched from the educational bubble into the real, and really scary, world.
His escapades encompass our deepest desires: to indulge in ourselves, to satisfy our ego and escape our destinies (in this case by gettin' some in an affair with the emblematic Mrs. Robinson), to escape and defy the pressures of our families and our obligations, to eschew sense for self and still somehow find everything in its right place in the end. Sure, over spring break you may not have an affair with a MILF, nor devote yourself to your libido, ego or any other Freudian force, nor find true love in the process of wild self-gratification, but you know you want to. And watching the innocent and relatable Benjamin wander through this meandering and searching farcical epic is possibly the most realistic and harmless way of realizing such a desire.
What You Should Do
American History X (1998)
On the topic of director Tony Kaye's one flirtation with everlasting glory, many are too quick to attack the film for its shortcomings. Some have gone so far as to say the film feels too much like a loosely tied series of powerful scenes, focusing too much on the always somewhat undeveloped Derek (Edward Norton), an ex-neo-Nazi on the path to redemption. But that's exactly it: Derek doesn't fully click until his journey begins and never feels fully transformed until the very last scene of the film. Only the entire process of the movie, the fragmentation, the isolated moments of poignancy (often shown through a rich black and white filter, accenting contrasts and highlighting poignant features of the shot) can fully convey the power of the sudden thrusts of revelation that drive the slow process of change.
Kaye's film revolves around this change, the catalyst for its clear and meaningful discussion of racism and violence. Peace and reconciliation, the realization of our ideals and all our idle talk: wouldn't life be so much better if we could just push ourselves to become that which we know we should be? The character of Derek is a promise that no matter how far we fall, no matter what we believe, we can always return to grace, though the price may be terrible. And at the very least, it is compelling to watch the journey in someone else; go ahead, watch the change.
What You Most Likely Will Do
Director George Lucas has taken us to many a strange and wonderful world, flown us around a galaxy (far far away) and back, but he has only once shown us something so strange and so fascinating as the innocence of home.
Something about the simplicity of the world of Lucas's American Graffiti makes it understandable that the aimless drives along the main drag–the long night of wandering–is somehow more fascinating than the occasional breaks from the journey. Always, the characters are in search of something, of the elusive blonde in the T-bird, of Wolfman Jack, of the thrill of the race, but always they reach out for some beauty in their lives, some divinity, and fall back to the meandering drive. The big race, the monumental climax, ends as quickly as it begins, with a tire blow-out a few feet down the road, and even the extremity of the explosion of the car is muted by the focus on the people climbing out and falling right back into the normalcy of their lives. Though long and slow, the film has a gripping and profoundly reminiscent innocence, and the journey–its path and its conclusion–is ultimately cathartic. Just as, undoubtably, your trips home will also be.
Images courtesy of IMDB.com
watching stuff on your tiny laptop screen
mark hay's says:
11 years ago at 1:55 pm
@mark hay's da bomb


text:
Q: Pushing a collection to a subdocument by Index? I'm running the below code, in an attempt to create a subdocument under an existing subdocument. The basic structure is:
User -> (Many Comments) -> (Many Ratings).
The rating object is a basic javascript object, with the structure;
rating: {
    userId: "userId",
    rating: 4
}

So, for the comment at index [0], I'm attempting to push a new rating with the following;
db.getCollection('Users').update(
                {id: "user123", },
                {
                    $push: {
                        comments[0].ratings: rating
                    }
                })

The return from the mongo console (with rating just set to a test string of "test"), is;
Error: Line 5: Unexpected token [

I attempted to get around this by wrapping comma's around the comments[0];
db.getCollection('Insights').update(
                    {id: "b5e5bf69-071b-4af2-99b2-5165b47499cb", },
                    {
                        $push: {
                            "comments[0].ratings": "test"
                        }
                    })

This is actually returning with success;
Updated 1 existing record(s) in 2ms

However, the subdocument does not appear at all.
Could someone point me in the right direction on this?

A: Found an answer to this; the array[index] format does not work with Mongo. Instead, use object notation. So, instead of;
$push: {"comments[0].ratings": "test"}

use;
$push: {"comments.0.ratings": "test"}

redpajama_set_name: RedPajamaStackExchange


I've always been a Christmas guy. Meaning, I've always been part of a family that put much stock in Christmas. I've also always been part of a family lucky enough to fill our table with a full Christmas dinner, a Christmas tree with overflowing presents underneath it and plenty of love to spread around. Since having kids, we've had the opportunity to continue those traditions.
In Ottawa there are many people celebrating whatever holiday it is they celebrate and many of those families have plenty of the love to go around but maybe not enough of the rest. Perhaps not surprisingly, it was our kids who pointed out to us that not only is that not right, but that it isn't right for us to do nothing about it.
So this holiday season, I encourage everyone to do something to make another family's holiday season a bit more comfortable. It doesn't have to be anything monetary, it could be as simple as holding open a door for someone carrying gifts through a door. Trust me, being someone who goes through periods of up and down emotional stages, something as simple as a smile can change a person's day.
If you would like to make a financial contribution, there are plenty of organizations out there to help local families celebrate with their loved ones. Many of these organizations are smaller ones that rely on the generous donations of families who can and would be thrilled to have your help.
My personal suggestion is to make this part of your own family tradition–start teaching your children from young age that it's everyone's responsibility to take care of everyone else. Let them help you hold the door, let them put some change in a collection jar or let them put a non-perishable food item in a collection bin. I promise you'll all feel better and a family you might even know will be able to put something on their table this holiday season.
I love the idea that for the holidays you can make someone else's holiday amazing! While also having an amazing and heartfelt holiday because you know that you have done something good.


text:
Our People Are Farmers, We Can't Lockdown North – Northern Govs
The Northern States Governors' Forum, following a meeting they held Monday, April 13, came to the conclusion that total lockdown would not work in their regions as most of the indigenes are farmers.
The meeting, which was conducted via teleconference by the governors to discuss the impact of coronavirus in the region suggests another measure to curb the spread of the global pandemic in the regions rather than declaring a total lockdown of its states.
The Chairman of the forum, Governor Simon Lalong of Plateau State, who spoke in a statement via his Director of Press and Public Affairs, Dr Macham Makut, revealed that the governors have agreed in one voice to strengthen preventive measures again so the Coronavirus (COVID-19) pandemic through enhanced boundary controls and surveillance.
The forum resolved on Monday after receiving reports from various states, not to shut down the states like governrs from other regions did, but rather provide means to have control over the spread, considering the survival strength of the region, adding that it will also ensure that there was a synergy among them in restriction of movement.
The statement read thus: "They (northern governors) agreed that at the moment, each state would adopt the measure suitable to its setting because total lockdown of the region will come at a very high cost since most of its citizens are farmers who need to go to farms since the rains have started."
"Another issue discussed by the northern governors was the issue of palliatives from the Federal Government where they regretted that so far, no state in the region had received a dime as special allocation despite the fact that some of them have recorded cases while others are making frantic efforts to prevent any outbreak, as well as prepare against any eventuality."
READ Nobody must maltreat Osinbajo – Northern youths
"This they observed has eaten deep into the pockets of the states as they have spent a lot of money already and may not be able to sustain this for a long time. Since prevention is better than cure, they canvassed that the Federal Government grant them some special funds just as it has done to other states.
"The northern governors lamented that the region has no testing centre, which is very disturbing. They resolved to again liaise with the Federal Government to ensure that each state at least gets one testing centre while highly populated ones get two.
"The governors also discussed the economic impact of COVID-19 on the region and decided that they needed to take a holistic look at the economic prospects of the region with a view to repositioning it for less reliance on federal allocation and to prepare for the future by diversifying to areas of comparative advantage such as agriculture, manufacturing, tourism and human capital development."
"They consequently set up a seven-man committee chaired by the Governor of Kebbi State, Atiku Bagudu, to fashion out the way forward.
"Other members are the governors of Kaduna, Sokoto, Kwara, Nasarawa, Jigawa, Gombe and Nasarawa states."
#EndSARS: Northern Governors Say Thugs Trying To Use Protests To Overthrow Government
Judiciary Conflict As Appeal Court Says Adeleke Qualifies To Be Osun Governor
New minimum wage: Outcome of Osinbajo, Governors' meeting revealed
Gov Lalong Thanks Plateau Citizens for Warm Reception Accorded Buhari
Northern Elders Reveals 'Plot' To Weaken North Before 2023
BREAKING: North Launches Its Own Security Outfit Code-named 'Shege-Ka-Fasa'
READ Vladimir Putin Reacts To Trump's Impeachment Charges, Says It Is A Political Infighting
I Won't Return To Abuja Until Boko Haram Is Substantially Defeated – Buratai
Former Presidential Aide, Reno, Lost His Grandfather


text:
Q: Cloudflare pages proxy with basic auth Is there a way to write a cloudflare rewrite/proxy similar to netlify as per https://docs.netlify.com/routing/redirects/rewrites-proxies/#proxy-to-another-service and adjust the header with basic auth credentials?
For example I would need /api/* to redirect to a WordPress at domain.com/wp-json/* with basic auth headers (ideally not visible to client itself - not sure if this is also possible)


Crime Cymru author Katherine Stansfield and Clare Mackintosh will be holding a crime and thriller writing course at Ty Newydd Writing Centre in Gwynedd in November (18th-22nd). Full details here.
Okay, so November is a long way off, but… book now, until midnight on Sunday (27th January) and there's 15% off the fee, to celebrate St Dwynwyn's Day.