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Upstream Firewall Rules for Cloud Connectivity
The Cisco Meraki Dashboard provides centralized management, optimization, and monitoring of Cisco Meraki devices. In order to manage a Cisco Meraki device through Dashboard, it must be able to communicate with the Cisco Meraki Cloud (Dashboard) over a secure tunnel. This tunnel is created between Cisco Meraki devices and Dashboard to pass management and reporting traffic in both directions.
Because the Dashboard is located on the public Internet, the tunnel is always initiated outbound from the managed device. Once a connection is established, the device maintains the connection by occasionally sending packets and receiving a response. When a firewall or gateway exists in the data path between the managed device and Dashboard, certain protocols and port numbers must be permitted outbound through the firewall for the secure tunnel to function.
Addresses & Ports to Allow
A complete list of destination IP addresses, ports, and their respective purposes can be found in Dashboard under Help > Firewall info. This list changes dynamically depending on the devices and services added on Dashboard.
CSV Version
"Source_IP","Destination_IP","Ports","Protocol","Direction","Description","Devices_using_this_rule" "Your network(s)","18.104.22.168/24, 126.96.36.199/24, 220.127.116.11/32, 188.8.131.52/20","7351","UDP","outbound","Meraki cloud communication","Access points, Cameras, MX Security Appliance, Phones, Switches" "Your network(s)","184.108.40.206/24, 184.108.40.206/32, 220.127.116.11/24, 188.8.131.52/20","9350","UDP","outbound","VPN registry","Access points, MX Security Appliance" "Your network(s)","188.8.131.52/32, 220.127.116.11/24, 18.104.22.168/24, 184.108.40.206/20","80, 443, 7734, 7752","TCP","outbound","Backup configuration downloads, Backup Meraki cloud communication, Throughput tests live tool, Backup firmware downloads, Splash pages","Access points, Cameras, MX Security Appliance, Phones, Switches" "Your network(s)","Any","123","UDP","outbound","NTP time synchronization","Access points, Cameras, MX Security Appliance, Switches" "Your network(s)","22.214.171.124/32","53","UDP","outbound","Uplink connection monitor","MX Security Appliance" "Your network(s)","220.127.116.11/32, 22.214.171.124/20","","ICMP","outbound","Uplink connection monitor","MX Security Appliance"
It's important to note that different organizations may communicate with different servers, so this list can vary between organizations.
Changes to Cisco Meraki Cloud (Dashboard) Addresses
There are some circumstances where the IP address or port used to communicate with Dashboard may change. If this type of change is required, administrators are notified in advance. Secure tunnel connectivity is also redundant and will continue to operate though a secondary connection.
Devices Using the 'backup Cloud connection'
While devices will primarily connect to Dashboard using UDP port 7351 for their tunnel, they will attempt to use HTTP/HTTPS if unable to connect over port 7351. When devices are operating like this, a message will be displayed on the device's status page indicating that the 'Connection to the Cisco Meraki Cloud is using the backup Cloud connection.' If this is observed, please ensure that port 7351 is being allowed outbound through the firewall or security appliance traffic from the Cisco Meraki devices will pass through.
If unable to configure the recommended firewall settings for the backup cloud connection due to security constraints, please note that Cisco Meraki devices will continue to operate normally, but some features of the Cisco Meraki Dashboard may be slower to respond. This includes, but is not limited to:
- Configuration updates
- Live tools
- Firmware upgrades
Unlike other features, Meraki Authentication is always sent over UDP 7351, and will not work over a backup connection
Note: While it is possible for Cisco Meraki devices to operate without the recommended firewall settings in place for the backup cloud connection, the firewall settings for Meraki cloud communication are still required for the devices to function correctly.
Devices Using the 'Uplink connection monitor'
Cisco Meraki MX Security Appliances include features to use multiple redundant WAN links for Internet connectivity.
These features rely on connectivity tests using multiple protocols to various public Internet addresses.
We ask that Network Administrators allow these common protocols (HTTP, HTTPS, DNS and ICMP) to 'any' Internet address to allow the connectivity tests to function correctly.
MX Connection Tests
The MX runs tests to determine uplink status:
DNS test
- Query the DNS servers (primary or secondary) configured on the Internet interface for the following hosts:
- meraki.com
- google.com
- yahoo.com
Internet test
- Pings to either 126.96.36.199 or 188.8.131.52. One ping per second.
- Uses a round-robin technique to send an HTTP GET to http://meraki.com or http://canireachthe.net. An HTTP response of any kind will result in a success.
ARP test
- ARP for the default gateway and its own IP (to detect a conflict).
Connection monitoring runs on the uplink once it is activated, meaning a carrier is detected and an IP address is assigned (static or dynamic).
The first test DNS query is sent, if a DNS response is received, DNS is marked as good for 300 seconds on that uplink. During this time, the MX continues running the DNS test every 150 seconds. Each successful DNS query test results in DNS being marked as good for another 300 seconds.
If a test DNS query times out at any point, the MX decreases the testing interval to 30 seconds. If the DNS test continues to fail for a time period exceeding 300 seconds which is last time the test was successful, DNS will be marked as failed on the uplink. Otherwise, a successful test will again mark the DNS as good for another 300 seconds. Once marked as good, the test is run every 150 seconds.
Note: The MX will only decrease the DNS testing interval to 30 seconds if a test DNS query times out. Any record type response to a test DNS query will result in a successful DNS test
The MX then begins performing the Internet test. If either the ICMP or the HTTP test is successful, the Internet test is marked as good for 300 seconds on that uplink. During this time, the MX continues running the Internet test every 150 seconds. Each successful Internet test (meaning either a successful ICMP test or a successful HTTP test) results in the Internet being marked as good for another 300 seconds. If any test within the Internet test group fails, the MX decreases the testing interval to 20 seconds. If the tests continue to fail for a time period exceeding 300 seconds from the last successful test, the Internet will be marked as failed on the uplink. Otherwise, any successful ICMP or HTTP test will mark the Internet test as good for another 300 seconds. Once marked as good, the test is run every 150 seconds.
When both the HTTP and ICMP tests have been unsuccessful for a period of time that exceeds 300 seconds, the uplink will be failed over. Therefore, it can take approximately 5 minutes for failover to occur in the event of a soft failure (where the physical link is still up but provides no Internet access).
Note: An MX will only failover to a backup cellular connection if all 3 tests (Internet, DNS, and ARP) are marked as failed
Upstream Firewall Rules for MX Content Filtering Categories
In instances where another firewall is positioned upstream from the MX, the following FQDN destinations need to be allowed in order for categorization information traffic to pass successfully to the MX, so it can use the proper category classifications. Keep in mind that the IP addresses these domains resolve to will be different regionally, so ensure you are allowing the correct, current IPs if using IP-based rules instead of FQDN rules on your upstream firewall.
Domain Names to Whitelist on Upstream Firewall
- meraki.brightcloud.com (resolves a CNAME to service.brightcloud.com)
- service2.brightcloud.com

subset: commoncrawl


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- Products & Services
- Solutions
- Knowledge Base
- Company
HARWINTON, CT, September 30, 2013 /24-7PressRelease/ -- CAL Business Solutions Inc, a Connecticut Microsoft Dynamics ERP software partner, is happy to announce that Rob Amoroso has joined the company as a Dynamics GP Implementation and Support Consultant. Rob will work with the implementation and support of Microsoft Dynamics GP and Microsoft SQL Server.
Since 2005 Rob has worked with all aspects of Microsoft SQL including implementation, development and support. His experience also includes computer repair, application support and ETL programming. He will assist Dynamics GP clients with technical support and implementation. Rob says regarding his new role: "I feel confident working with CAL Business Solutions because they are a stable company, with a dedicated group of clients."
Steve Brown, Project Manager at CAL Business Solutions comments: "Rob has a strong technical background that will add value to our clients and also support our internal CAL systems to help us be more productive."
About CAL Business Solutions, Inc.
CAL Business Solutions is a Microsoft certified Silver Enterprise Resource Planning Partner focused on Microsoft Dynamics GP (Great Plains) financial management systems, offering implementation, integration, data conversion, and customization plus local support and training. We work with 200 customers in more than 16 states, with a focus on companies in Connecticut (CT), Massachusetts (MA), Rhode Island (RI), and Westchester County, New York (NY). www.calszone.com
Connect with CAL Business Solutions at LinkedIn or visit their blog for additional insights into accounting software tips and trends.
# # #


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text: Cardiovascular disease The Australian Institute of Health and Welfare (AIHW) has developed core monitoring information on the incidence, prevalence, hospitalisation and deaths from cardiovascular disease (CVD) in Australia (including coronary heart disease, stroke and heart failure). This is updated on a regular basis on the AIHW website to ensure that current information and trends are readily available. 15 Jul 2020


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Mildred K. Stark
South Roxana | Sunday, September 29 2013
Mildred K. Stark, 91, died at 7:10 a.m. Sunday, September 29, 2013 at her home. Born January 8, 1922 in Alton she was the daughter of Arthur and Laura (Buckshot) Lamparter. She married William "Bill" Page. He preceded her in death. She later married Robert E. Stark on December 15, 1973 in St. Charles, MO. He preceded her in death. Surviving are three daughters, Pamela "Sue" Duke (Dwight) of South Roxana, Debra K. White (Norman) of Brighton, and Marsha Palmer (Roy) of O'Fallon, IL, two sons, Morris "Moe" Page (Kathy) of Alton, and Steve Page of Alton, 14 grandchildren, numerous great grandchildren and great-great grandchildren. Along with her parents and husbands, she was preceded in death by a daughter, April Page, two sons, Greg and Scotty Page, seven brothers, Carl, Harold, Pete, Edward, Dick, Paul, and Stanley Lamparter, and four sisters, Katherine Miles, Leona Dugge, Loretta Kopsie, and Evelyn Roberson. Visitation will be from 10:30 a.m. until time of memorial service at 11:30 a.m. Thursday, October 3, 2013 at Gent Funeral Home in Alton. Eddie Lamparter will officiate. Burial will be private at Wanda Cemetery in South Roxana. Memorials may be made to BJC Hospice. Online guestbook and information may be found at www.gentfuneralhome.com
Gent Funeral Home


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ALBANY, N.Y. (WTEN) — The Department of Motor vehicles has made a few changes to their vehicle registration forms in the wake of the deadly Schoharie limo crash that killed 20 people last fall.
The form, known as the MV-82, now includes limos in their checklist under the vehicle information section and it includes a section titled "Vehicle modifications" which cover documentation needed for limos to operate in New York.
DMV spokeswoman Lisa Koumjian said the changes to the registration form help the DMV enforce new limo safety laws passed in last year's state budget that took effect Oct. 9.
"Another law change requires inspection stations to notify DMV whenever such a vehicle requests an inspection, and to refuse inspection if the vehicle lacks the required federal safety certification affixed to the door jamb," she said.
The DMV is no longer allowing the registration of altered vehicles that violate safety requirements.


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LONDON, UK – The City of London Corporation, Network Rail, national coffee retailers and some of the Square Mile's biggest employers have joined forces in the Square Mile Challenge initiative led by environmental charity Hubbub, in partnership with recycling company Simply Cups.
The scheme introduces coffee cup recycling facilities across the City and aims to collect and recycle half a million cups in the City of London throughout April, rising to 5 million by the end of the year.
Over 100 high street coffee retailers are offering recycling facilities and accepting coffee cups in their stores, regardless of where they were purchased.
There are unmissable Square Mile Challenge bins in the shape of bright yellow coffee cups in place on the City's streets and cups will be collected at both Liverpool Street and Cannon Street stations during rush hour every week day throughout the month.
Employers are playing their part, with over 30 organisations based in the City including Lloyd's, Deloitte, Prudential, The Barbican Centre, London Metropolitan University and major business premises such as The Leadenhall building ("The Cheesegrater") collecting paper coffee cups in their offices, helping divert them into a new waste stream.
Every day up to seven million coffee cups are thrown away across the UK, with less than 1% of these cups thought to be recycled.
The tricky issue to date has been the plastic film on the inside of the paper cups, which means that the cups can rarely be recycled with other mixed recycling.
The recycling methods used for the Square Mile Challenge will process the cups to create either a plastic or recovered fibre material which is made into new products, some of which will be donated to a new outdoor community space and cafe opening in the City next year.
Gavin Ellis, Co-founder of Hubbub said:
"We are delighted that so many organisations, including the local authority, Network Rail and businesses that are usually in competition with each other, are collaborating to tackle this issue. We hope that other parts of the UK will follow suit and eventually reach a point where recycling levels for coffee cups are on a par with those for drinks cans and bottles.
"It would be easy to suggest that everyone should use reusable cups for our hot drinks, but the reality is that disposable cups are being used in their millions and so we have to deliver a solution to this issue.
Alongside their participation in the development of recycling solutions, it's great to see that many retailers are also now providing discounts for customers using reusable cups and are investigating finding long-term solutions to ensure cups can be more widely recycled in the UK".
Deputy Mayor for Environment and Energy, Shirley Rodrigues, said:
"Until now there has been no consistent, reliable way to recycle coffee cups in the heart of London and so the Square Mile Challenge is a big step forward. We're committed to making London cleaner, reducing waste and boosting recycling. I hope this scheme is a success and will encourage local authorities and businesses to start recycling coffee cups across the capital."
Steve Presland, the City of London Corporation's Highways and Cleansing Director said:
"It's great to see the range of businesses that have signed up so far to the Challenge and we look forward to seeing more joining throughout the campaign. The City Corporation is committed to maintaining London's position as the leading financial and professional services centre in the world and strengthening our competitiveness on the global stage.
A big part of this is ensuring that we manage our waste both sustainably and responsibly. We spend £3.8million a year cleaning the City's streets and more than 400,000 people commute and into the City of London every day.
"We urge the people who live, work or visit the Square Mile to be conscious of where they throw away their coffee cups and keep an eye out for the recycling points across the City."
People working or living in the city are encouraged to view the Square Mile Challenge map to locate their nearest recycling point and look out for yellow stickers in the windows of participating organisations.
This initiative has been made possible with the support of coffee retailers: Caffè Nero, Costa, Marks & Spencer, McDonald's, Nestlé, Pret A Manger, Starbucks, Bunzl Catering Supplies and coffee cup manufacturers: Benders Paper Cups, Dart Products Europe, Huhtamaki and SEDA International Packaging Group. It follows the launch of the Paper Cup Manifesto in June 2016, which garnered over 40 signatories from companies involved in the coffee industry, committing to improve recovery and increase recycling of paper cups.


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Mason City Council has approved the distribution of $200,000 in Service Partnerships to be administered by the Mason Community Improvement Corporation that is intended to fuel recovery and future partnerships.
Purpose: This program is designed to provide up front support for small businesses with short term aid and facilitate an opportunity for a long-term service relationship with them. Qualifying businesses fit the categories that are traditionally retail and customer-facing.
Service Agreement: The City of Mason will offer a one-time payment of up to $1,000 for economic recovery purposes. At a later date, the City and small business owner will discuss opportunities for a mutually beneficial partnership in exchange for the $1,000 contribution. Options could include in-kind services, employee volunteer hours, cross-marketing, or businesses may recommend other creative options for partnership.
Application: The online application for the Mason Small Business Recovery Programs will be open June 1 through June 10 and are available through this website. Businesses are eligible to apply for all programs.
Minimum Eligibility Requirements:
- The business shall be a current Mason business with a physical location within City of Mason limits.
- The business must be open to the public, or have been open to the public the week preceding Ohio's Stay at Home Order, with regular business hours. (March 15, 2020, for food and beverage businesses and March 19, 2020, for other businesses.)
- The business should be a consumer-based, including retail or service establishments, such as those that rely on walk-in customer activity or appointments. Some examples include restaurants, salons/barbershops, retail shops, and breweries/bars.
- Corporate Franchisers not locally owned and independently operated are not eligible.
- The business shall be in compliance with all City Ordinances and in good standing with the City of Mason.
- The business shall have 50 full-time equivalent (FTE) employees or fewer.
- While not required at this time, the City reserves the right to request additional documentation to support information provided on this application and the request for assistance.
- A service agreement will be completed between the City and small business.
Thank you to all of the Mason small businesses who applied for the Service Agreement and Forgivable Loan Programs. The application period for both programs closed on Wednesday, June 10. Small Businesses in Mason still have the opportunity to sign up to be a participating location as part of the Come Together Mason E-Gift Card Program.


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New video: Empowering peer groups
This video takes us to Tampere Adult Education Centre TAKK, where we learn about the experiences of a peer group that consisted of students in vocational training and their tutors. What has been the best thing about the peer group? And how did the peer group work, when all groups and classroom teaching had to be transferred to online in spring due to the COVID-19 pandemic?
The video has subtitles in Finnish and in English.


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From there on Takumi struggles to cope with the events unfolding around him, and is soon unaware of what is real or a delusion. As his fate opens up before him, the perpetrator behind the 'New Gen' events attempts to find him, leading him into a world where nothing is as it seems.
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Bit late on the ball posting about some tasty food of late.
We made a sour cream dip with lime zest and juice with green onions for Monday Night Football.
Later with some leftover sausage from the VP debate party we added couscous, little squashes, tomatoes, and goat cheese.
Sunday night we also stir fried bokchoy and mushrooms and had some pan seared scallops.
Finally last night we made a coleslaw to go with pulled pork with cabbage, carrots, carraway seeds, mayonnaise, and apples for tonight's Monday Night Football, but we ate it too fast to get pictures 🙂
Tomorrow (the 7th) is our anniversary and if we can keep our hands off each other we will be cooking up something extra nice.


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- File Name: morphyre_1v57.exe
- File Size: 5.21 KiB
You're downloading Morphyre. File morphyre_1v57.exe is compatible with:
Morphyre is a 3D plug-in music Visualizer that works on music players such as Windows Media Player and iTunes. There are programs that can "transform" sounds into moving images. This type of program was popular thanks to the now discontinued... View More
Thank you for downloading Morphyre. Your download will start immediately. If the download did not start please click here: Download Morphyre for Windows 7 and Windows XP
Clean File 0/56 Virus Total Report
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Jake Hoot performs The Eagles' "Desperado" during The Voice Live Top 8 Performances 2019.
Episode: 23
Week: 5
Coach: Kelly Clarkson
Song: "Desperado" by The Eagles
Jake was born in Texas, but his parents are missionaries and relocated the family to the Dominican Republic when he was nine. While living there, he began singing and playing guitar while also becoming fluent in Spanish. At 20, he moved to Tennessee where he began gigging and attended Tennessee Tech University as a walk-on football player. Jake later got married and now has a four-year-old daughter. After getting divorced, Jake is a newly single dad and hopes to start anew by making his daughter proud on "The Voice."
The Eagles are an American rock band formed in Los Angeles in 1971. The founding members were Glenn Frey (guitars, vocals), Don Henley (drums, vocals), Bernie Leadon (guitars, vocals) and Randy Meisner (bass guitar, vocals). With five number-one singles, six number-one albums, six Grammy Awards, and five American Music Awards, the Eagles were one of the most successful musical acts of the 1970s. Their albums Their Greatest Hits (1971–1975) and Hotel California rank first and third, respectively, among the best-selling albums in the United States, with 38 million and 26 million album units in sales. The Eagles are one of the world's best-selling bands, having sold more than 200 million records, including 100 million albums sold in U.S alone. They were ranked number 75 on Rolling Stone's 2004 list of the 100 Greatest Artists of All Time.
The seventeenth season of the American reality television show The Voice premiered on September 23, 2019, on NBC. John Legend, Kelly Clarkson and Blake Shelton returned as coaches for their second, fourth, and seventeenth season, respectively. Gwen Stefani, who last coached in the twelfth season, will return, replacing Adam Levine. With Levine's departure, Shelton serves as the last remaining coach from the show's inaugural season. Meanwhile, Carson Daly returned for his seventeenth season as host.
The Voice is an American singing competition television series broadcast on NBC. It premiered during the spring television cycle on April 26, 2011, and expanded into the fall cycle with the premiere of the third season on September 10, 2012. Based on the original The Voice of Holland, and part of The Voice franchise it has aired sixteen seasons and aims to find currently unsigned singing talent (solo or duets, professional and amateur) contested by aspiring singers, age 13 or over, drawn from public auditions.
The winner is determined by television viewers voting by telephone, internet, SMS text, and iTunes Store purchases of the audio-recorded artists' vocal performances. They receive US$100,000 and a record deal with Universal Music Group for winning the competition. The winners of the sixteen seasons have been: Javier Colon, Jermaine Paul, Cassadee Pope, Danielle Bradbery, Tessanne Chin, Josh Kaufman, Craig Wayne Boyd, Sawyer Fredericks, Jordan Smith, Alisan Porter, Sundance Head, Chris Blue, Chloe Kohanski, Brynn Cartelli, Chevel Shepherd, and Maelyn Jarmon.
The series employs a panel of four coaches who critique the artists' performances and guide their teams of selected artists through the remainder of the season. They also compete to ensure that their act wins the competition, thus making them the winning coach. The original panel featured Christina Aguilera, CeeLo Green, Adam Levine, and Blake Shelton; the panel for the current seventeenth season features Shelton, Gwen Stefani, Kelly Clarkson and John Legend. Other coaches from previous seasons include Shakira, Usher, Pharrell Williams, Miley Cyrus, Alicia Keys, and Jennifer Hudson. In the fifteenth season, Kelsea Ballerini was featured as an off-screen fifth coach for "Comeback Stage" contestants. Bebe Rexha took over as the "Comeback Stage" coach for the sixteenth season. In October 2019, it was announced that the series would continue into its eighteenth season.
Also, check these topics out: The Voice Rose Short I Want To Know What Love Is, The Voice Ricky Duran Let It Be, The Voice Hello Sunday Don't You Worry 'Bout a Thing, The Voice Marybeth Byrd Before He Cheats, The Voice Katie Kadan Rose Short Express Yourself, X-Men movies in order of release date, The Voice Ricky Duran Will Breman Your Love, Shameless Season 10 Episode 6, AGT judges, Mr. Robot Season 4 Episode 11, X Factor UK 2019, The Voice Katie Kadan Lady Marmalade, The Voice Katie Kadan Rolling in the Deep, The Voice Kat Hammock Somewhere Only We Know. The Voice 2019: Jake Hoot sings "Desperado" (Semifinals). The Voice 2019: Jake Hoot sings "Desperado" (Semifinals) | Kelly Clarkson | Top 8 | Music.


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Experience & Car Maintenance in WA You Can Trust
Transmission trouble, check engine light, or broken A/C, we can handle it. Head to the nearest Firestone Complete Auto Care for car troubles both big and small. You can trust our knowledgeable technicians to deliver professional auto services near Roy on top of brake services, maintenance, oil changes, car batteries, engine tune-ups, alignment, and much more. We know cars and trucks from bumper to bumper, but we also know drivers. That means we'll only recommend services and repairs we believe are a good match for your needs. After all, we're drivers too! Plus, our Triple Promise Guarantee means that your car will be Fixed Right, Priced Right, and Done Right On Time. Given that there are 1,700 Firestone Complete Auto Care shops around the U.S., you should always be close to vehicle maintenance and car repair you can trust.
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We help take care of all your car's parts and pieces, but also your tires and wheels. Investing in the best car or truck tires can be one of the easiest ways to help keep your vehicle on the road for the long haul. Whether you're shopping for rugged all-terrain tires or smooth touring tires, we have some of the best tires for your vehicle type, driving style, climate, and budget. And if you need a pressure check or tire patch? Just point your dash in our direction. Browse tires in-store or online and come to Firestone Complete Auto Care near Roy to keep your tires inflated, aligned, and driving smoothly. We're one of Washington's top tire provider, and have been for years.
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Now when it comes to making sure your engine runs strong and long, there are two things you shouldn't forget: car batteries and oil changes. Car batteries may look small, but they provide big power. When your battery is weak or the terminals are loose, your car probably won't start. That's where we come in! Visit Firestone Complete Auto Care for a free car battery test near Roy. A quick test will determine if your car battery is providing sufficient power and at what temperature it may die. You can also request a car battery test when you stop by for your regular oil change, another service that helps keep your engine healthy. Whether you prefer synthetic blend, synthetic, conventional, or high mileage oil, your car needs new oil at the factory recommended interval, which is typically every 3,000 miles. Fresh, new oil helps keep your engine lubricated, clean, and at the right temperature. When you need an oil change or new car battery, head our direction. We install more than 800,000 car batteries a year, and perform more than 19,000 oil changes every day. Book an appointment online and save money with our budget-friendly service offers, oil change coupons, or tire deals. Whether you're the proud owner of a hatchback or a heavy-duty truck, visit your local Firestone Complete Auto Care near Roy today!


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Welcome to Saber Simulator! HOW TO PLAY: ⚡ Train your character by swinging your sword and gathering strength. 💪🏻 Use strength to fight other players. 💰 Sell your strength for coins and upgrade your character in the shop. 📈 Try to get to the top of the leaderboards! Latest Update: [Update 56🎉]: v2.018 - The Cyber Sale begins! (50% OFF game-passes, crowns, coins, and charms!) - Cyber Sale ends Nov. 30 - New Class (Shadow Gladiator) - New Black Friday themed Egg (9 new pets to hatch!) - New Island (Island 70) - New saber added (Lich) - Thanksgiving event has been removed, turkey have been converted into crowns! - 400M event coming soon! - 10x CROWNS Event continues! - 5x Strength Event continues Updates every Friday at 10 PM PST! Join the group HD Games. for an in-game reward: 💰 20% Extra Coins ⚡ Chat Tag 👑 Name Tag Made by HD Games
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DHS Softball celebrates Senior Day with dramatic victory
Katie Smith races home with the winning run in the eighth inning. (Doug Daniels Photo)
By Doug Daniels
1351sports.com / duquoinsports.com
May 11, 2018
(Du Quoin & Red Bud, Ill.) - The Lady Indians celebrated Senior Day in style last week, defeating Murphysboro in walk-off fashion in eight innings, 4-3, with Katie Smith and Chloe Hill coming up with huge hits in the final at-bat for Du Quoin.
The Lady Devils got a run on two hits in the top of the first, but the Lady Indians got it right back in the bottom of the inning after Smith double and scored on a ground ball RBI by Grace Haney, one of three seniors honored after the game.
The bats went quiet on both sides until the sixth, when Du Quoin took a 2-1 lead when Smith singled and later came in when Haney reached on an error.
One out away from defeat, Murphysboro found a way to send the game to extra innings in the top of the seventh with a double and a single, and with the international tie-breaker in effect in the eighth, the Devils grabbed the lead 3-2 thanks to a Du Quoin error.
"(Hill) could have gotten discouraged, we had some errors behind her," said DHS head coach Jason James, "but she didn't shut down, didn't show any emotion, she just kept chucking and throwing. The kids came up with some key plays towards the end, she did a good job of holding her composure to get us to that point."
It wouldn't matter in the end, though, as Smith tripled to start the bottom of the eighth to tie it. Murphysboro then elected to walk both Morgan Bullar and Haney to set up a force out at any base, but Hill made them pay with a game-winning single.
"(Even with a runner on second) there was no way we were bunting Smith, she's our hottest hitter," James said. "She came through clutch. I wasn't quite sure what they'd do with Bullar and Haney, but they put them on and Hill came through. We told her to look for the first pitch. Bases loaded, (Murphysboro's pitcher is) going to try to get ahead, and (Hill) jumped on it."
Smith (3-4, 3 R, RBI, 2B, 3B), Hill (1-4, RBI) and Olivia Whitley (1-3) had Du Quoin's five hits against the Red Devils. Hill surrendered two earned runs on six hits and two walks while striking out six to get the win in the pitching circle.
Haney, Avery Shively and Kaylee Aleshire represented the senior class for the Lady Indians, and each agreed after the game there wasn't a much better way for a Senior Day game to end.
"This was a big win, Chloe really came through in the clutch," Haney said.
Shively added "It was definitely memorable to win like that on Senior Day."
Shively and Aleshire saw limited playing time at the varsity level through the junior season, but have become key parts to this year's team's success.
"I just kept working harder every year," Aleshire said, "trying to be an example for everybody else to stick with it and make your senior year the best one."
For Haney, it was her first senior night of the year that she got to share with some teammates after being the only senior on both the volleyball and basketball teams at DHS.
Du Quoin 13, Red Bud 2 (May 2, 2018):
Bullar and Aleshire (grand slam) both homered and the Lady Indians routed Red Bud 13-2, racking up 16 hits. Hill got the victory, allowing one earned run on three hits and two walks with eight strikeouts.
Hitting for Du Quoin: Smith (3-4, 3 R, RBI, 2 2B, BB), Bullar (3-5, 3 R, 3 RBI, 2B, HR), Haney (1-3, R, BB), Hill (2-4, RBI), Shively (1-3), Aleshire (1-4, R, 4 RBI, GS), Chloe Hess (1-2, R, 2 BB), Avery Waller (1-4, R) and Maci Mckinnies (3-4, 3 R).
Mater Dei 7, Du Quoin 6 (May 4, 2018):
A five-run fourth inning for Mater Dei gave them a 5-2 lead before the Lady Indians rallied back to cut it to 6-5, but the Knights would tack on an important insurance run in the seventh and hang on for the road win at Du Quoin.
Hitting for Du Quoin: Smith (2-5, R, RBI), Haney (1-1, R, 2 BB, HBP), Hill (1-4, R), Hess (1-4, R, RBI), Waller (1-3, R, BB), Aleshire (1-2, R, 2 BB) and Mckinnies (1-3, 2 RBI, 2B, BB).
Photos and Video by Doug Daniels / DuQuoinSports.com


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You wouldn't like me when I'm angry.
Ok, I'm not angry. Not at all, actually. I just hadn't done a black and light highkey image in a while and I love them. I decided I just wanted to have some energy about this one, so I tried to go for kinda some anguish. You know, at shows, these sold better than any of my other artwok ever. I really should try to get some of my prints online and for sale sometime.
Would anyone be interested?


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Info: This event has been cancelled.
|LDWA Member
|Non Member
A challenge event for walkers and runners in the Durham Moors and Dales. As usual there will be a choice of routes, 30 miles and 14 miles.
Start Times: both routes 09.00
Time limits: 12 hours for the 30 mile route, and 9 hours for the 14 mile route.
Refreshments: will be available at all checkpoints.
Route description: A full route description and a gpx file of the route will be available on the website prior to the event.
Venue: Masonic Hall, Wolsingham DL13 3AN
Parking: To be advised ahead of the event.
Entry Fee: Includes a commemorative T-Shirt.
General Notes:
A significant donation is made to Teesdale & Weardale Search & Rescue Team.
Entry limited to 300.


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Can I use this on OSX / Windows?
I am big fan of Ubuntu Linux. However, now and then I need to dive into OSX to prepare presentations in Keynote - OpenOffice is just too inefficient for me.
Can I download and install Ubuntu font family on other platforms? Are TTF files available somewhere?
Question information
- Language:
- English Edit question
- Status:
- Solved
- Assignee:
- No assignee Edit question
- Solved by:
- actionparsnip
- Solved:
- 2010-10-24
- Last query:
- 2010-10-24
- Last reply:
- 2010-10-24
Thanks actionparsnip, that solved my question.
I simply websearched......
|Matt Sturgeon (mattsturgeon) said :
In-case the external link becomes broken, the page instructs one to head over to http://
|Paul Sladen (sladen) said :
Just to follow-on from Matt's answer. The .zip contains the actual fonts you'll want to use. The .tar.gz tarball is source code; it contains many files ending '.ttf' which are combined to produce the final font. Individually they are pretty useless as which only contains part of the final font, and will cause problems if installed.


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As Colombiaãs ãMusical City,ã Ibaguûˋ places a strong emphasis on the arts. This can be observed in the bars and restaurants downtown as well as at the events at Teatro Tolima. In addition to the cityãs art and culture, the valley surrounding Ibaguûˋ provides outdoor pursuits, especially in the Combeima Canyon. Experienced hikers may also attempt to conquer the Nevado del Tolima peak.
Enter your username and password here in order to log into the website:


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Property Details
The combination of the minimalist touch and the classic elements of the Eixample de Barcelona, are united in a perfect harmony in this wonderful renovated apartment of 265sqm, in the Quadrat d'Or of our city. An ocean of light on a real fifth floor with wonderful views of one of the most emblematic buildings of Barcelona. 4 double bedrooms (3 of them en suite) with east and west orientation, a modern semi-open kitchen and a spectacular 50sqm living room with Catalan volta form the set of this super luxury apartment next to Rambla Catalunya. High-end finishes, air conditioning ducts, concierge service, wide-wall parquet, high quality enclosures.
The Ciutat Vella district of Barcelona is the oldest nucleus of the city and its historic centre, with most buildings having a historical significance. Ciutat Vella, is a booming area, with a charm and an atmosphere ideal for dreaming that transports us to remote times. In recent years it has become a modern, multicultural and delicious district to enjoy on a daily basis with its medieval streets, narrow, twisted and intertwined. In addition, the southern area of the neighborhood is increasingly open to the Mediterranean.
Amat Luxury, which forms part of the Amat Group, is a high standing real estate dedicated to the sale of exceptional houses and flats. Our proximity to the client, transparency and rigour in the work is what makes us different. Contact us without commitment to see this property or any other of our wide portfolio; www.amatluxury.com
Additional Resources
Premis Cambra 2014 - YouTube
Spectacular apartment in the Quadrat d'Or


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Leverage simply means the use of borrowed money to execute your stock market strategy. In a margin account, banks and brokerage firms can loan you money to buy stocks, usually 50% of the purchase value. In other words, if you wanted to buy 100 shares of a stock trading at $100 for a total cost of $10,000, your brokerage firm could loan you $5,000 to complete the purchase.
While most online brokers do not offer international trading, some do. Nearly every broker supports trading American depositary receipts (ADRs), which offers US investors an easy, simple way to invest in foreign companies. However, if you want to buy physical shares of an international company, then you need to do your research. Interactive Brokers is the leader in this space but is built for professionals. For casual investing, both Fidelity and Charles Schwab offer international stock trading.
Should the company management and majority owners choose, they can pay one or more dividends per year to stockholders. The money for these dividends will typically come from profits earned within the business. In most countries, these dividends are subject to income tax payable by the receiver. Often there is a withholding tax taken at source to ensure that non-resident shareholders pay as well.
Pump and dump: this characterises a movement where a group of people with influence will either spread rumours, share hypothetical information or shill (shameless promotion) about a given cryptocurrency project. Their followers will start to buy massively the related cryptocurrency, initiating a « pump » movement, i.e. price starts going up very high and fast. At the same time, the people who spread those rumours will leverage the high increase to do a « dump » movement, i.e. sell the same cryptocurrency (that they had bought at very low prices) at the newly reached high price. The result: the group that initiated the pump will make a large profit, while the people who jumped on the pump train (those who bought in because of FOMO, fear of missing out) will have bought at a high price and are now with an asset that is worth only a fraction of the purchase price
When selecting a new online broker, the first step is to read reviews and see what features matter most to you. Are low-cost trade commissions most important? What about customer service, the trading platform, mobile app, investment research, ease of use, or education? With many brokers specializing in different areas, it is crucial to evaluate all categories by reading full-length broker reviews.
ECN/Level 2 quotes: ECNs, or electronic communication networks, are computer-based systems that display the best available bid and ask quotes from multiple market participants and then automatically match and execute orders. Level 2 is a subscription-based service that provides real-time access to the Nasdaq order book composed of price quotes from market makers registering every Nasdaq-listed and OTC Bulletin Board security. Together, they can give you a sense of orders being executed in real time.
Investopedia requires writers to use primary sources to support their work. These include white papers, government data, original reporting, and interviews with industry experts. We also reference original research from other reputable publishers where appropriate. You can learn more about the standards we follow in producing accurate, unbiased content in our editorial policy.
Before making your first investment, take the time to learn the basics about the stock market and the individual securities composing the market. There is an old adage: It is not a stock market, but a market of stocks. Unless you are purchasing an exchange traded fund (ETF), your focus will be upon individual securities, rather than the market as a whole. There are few times when every stock moves in the same direction; even when the averages fall by 100 points or more, the securities of some companies will go higher in price.
Then what? You might be new to investment but already wealthy, what do the super rich do to diversify? They use real estate in New York, London and the Cote d'Azure as a reserve currency. They change their country of residence to a tax haven, pursue naturalization through one of the EU citizenship by investment countries and then buy a sports franchise. Sorry, the sports franchise isn't actually an investment...
For example, there may be three buyers who have placed orders for buying Microsoft shares at $100, $105 and $110, and there may be four sellers who are willing to sell Microsoft shares at $110, $112, $115 and $120. The exchange (through their computer operated automated trading systems) needs to ensure that the best buy and best sell are matched, which in this case is at $110 for the given quantity of trade.
Many online brokerages do not limit their customers to just online stock trading. Full-service brokerages offer banking services including checking accounts, savings accounts, credit cards, mortgages, and more with deposits of up to $250,000 backed by the FDIC. Bank of America (Merrill Edge) and Chase (Chase You Invest Trade) are two examples of banks that also offer online trading.
The stock exchanges also maintain all company news, announcements, and financial reporting, which can be usually accessed on their official websites. A stock exchange also supports various other corporate-level, transaction-related activities. For instance, profitable companies may reward investors by paying dividends which usually comes from a part of the company's earnings. The exchange maintains all such information and may support its processing to a certain extent. (For related reading, see "How Does the Stock Market Work?")
Disclaimer: NerdWallet strives to keep its information accurate and up to date. This information may be different than what you see when you visit a financial institution, service provider or specific product's site. All financial products, shopping products and services are presented without warranty. When evaluating offers, please review the financial institution's Terms and Conditions. Pre-qualified offers are not binding. If you find discrepancies with your credit score or information from your credit report, please contact TransUnion® directly.


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Shitty Ideas Trending (SIT) the YouTube channel which brings about interesting sketches about the day to day situations in a person's life, will soon be coming up with another new channel by name Witty Ideas Trending (WIT).
The idea behind this new setup will be to target new audiences. WIT will come up with web-series on various genres. This will be a different kind of programming, which will have only web-series while the sketches will continue on SIT.
As per a reliable source, "The current audience for SIT is already there and enjoy the sketch content. Now the idea is to target a new audience and cater to many other genres through our web-series."
When contacted, Chhavi Mittal of SIT confirmed the news of WIT being in the pipeline. "We are in the pre-production stage right now."
So for all those waiting to watch the fresh programming of web-series, wait on for Witty Ideas Trending!!
Way to go, Chhavi and Mohit!!


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Global Chamber Mumbai was pleased to feature a special presentation: "Building Sustainable Global Business and India's New Role in the Partnership". Special thanks to Vinod Bhimrajka and his team at BIG for their sponsorship. Thank you everyone for participating!
We live in an age where the professional world has become boundary-less, and technology has made it possible for businesses to thrive and prosper, across continents, catering to a global audience. In such a world, collaboration, partnerships, alliances and co-existence is the new name of the game. Having said that, building sustainable businesses is the key to that growth. This was the main focus of our panel discussion at the launch, where senior professionals from the Private Equity, Advertising, Media & Entertainment, CSR & Sustainablility, Technology including Artificial Intelligence and Investors, spoke about building sustainable global businesses with a focus on how India can contribute to it, in its renewed avatar. I am excited about this discussion because it touches on all relevant factors required for local and global business growth.
Global Chamber® Mumbai, will be focusing on exactly that, and taking initiatives to enable and facilitate business relationships and collaborations, in that exact seamless manner. We hope to be able to grow this chapter by adding meaningful contributions to our members, and the industry at large. The positive changes in the Indian social, economic and political environment, makes it even more encouraging to establish businesses in India, and being the vibrant and financial hub, moreso in Mumbai. It is an opportune time to ride the wave and make the best of the times that are changing!


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SITES in Trowbridge, Westbury, Warminster and Bradford on Avon could be used for fracking in the near future, according to the Government.
Up to 27 locations throughout the country were granted a licence for fracking by the Oil and Gas Authority in an announcement made by David Cameron earlier this week, with further locations chosen for assessment.
The controversial process, which involves drilling into the earth to release shale gas, would be the first placed within Wiltshire if potential sites are put forward and granted the appropriate licences.
Dr Becky Martin, from Keep Wiltshire Frack Free, said: "Where fracking has happened in the USA it has caused great damage to the countryside and people's health.
"Google 'the list of the harmed' and you can see the devastating effects of the air and water contamination this industry causes.
"A quick look on Google earth at Dimmock, Pennsylvania, will show you the scars it leaves on the landscape.
"It's not just one or two wells, this industry requires hundreds and thousands of wells to make a profit, all requiring hundreds of lorries each carrying chemicals and ridiculous amounts of waste water contaminated with carcinogens and radioactive substance."
A Wiltshire Council spokesman said: "Wiltshire Council is studying the consultation with interest in order to understand what this means for the county. We have not been made aware of any licencing applications made in Wiltshire."


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Coronavirus: the latest update from A-SAFE - find out more
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Cold Storage Bollards are available in black with blue trim.
They come in three height variations: 32 ⅞, 47 ¼ and 78 ¾inches and are suitable for vehicles with an impact height of 47 ¼inches.
To give you the best website user experience we use anonymized Google Analytics and Google Adwords tracking to report on website traffic. By continuing to browse this website you accept that cookies may be stored on your device. Learn more about our Cookies Policy and Privacy Policy.


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The 2020-2021 Sports season is currently on hold due to COVID19.
From mid August to late October, students in upper grades can participate in a number of athletic teams on behalf of their school. To participate in these co-curricular programs students must show proof of an athletic physical by a medical professional and proof of insurance coverage. Information about how families can be assisted with both the sports physicals and insurance is available.
2020-2021 Schedule


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The Salmon Run mini-galas will be COVID safe- held outdoors, each with a maximum of 35 guests, with social distancing and face coverings when not eating or drinking.
Three traditional salmon runs on our local rivers were in the spring (n̓ty̓tyix- chinook), early summer (kísuʔ- coho), and late summer/fall (tʕan̓yaʔ- late sockeye). From these salmon, we have named our three Salmon Run events:
N̓ty̓tyix Salmon Run, September 19, 2020. Sold Out.
Kísuʔ Salmon Run, September 26, 2020. Sold Out.
Tʕan̓yaʔ Salmon Run, October 3, 2020. Tickets are $100 per person. Only 35 seats available.
At each Salmon Run, guests will have dinner and drinks in a beautiful outdoor setting along the Little Spokane River, will be entertained by Salish School of Spokane students and staff, will hear testimonials from our families, and will have the opportunity to make a donation or pledge of support for Salish School of Spokane.
Tax Status
Salish School of Spokane is a non-profit public charity with 501(c)3 status under Internal Revenue Service code. Our tax identification number is: 27-1126478. 75% of the the cost of Salmon Runs tickets are tax-deductible to the extent allowed by the IRS code.
Website powered by Network Solutions®


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At French Classes you will find one of the largest collections of transcribed French language learning materials available on the internet today.
- 108 French lessons and exercises
- More than 200 transcribed audio reports
- 120 dictation exercises
Listen on your smartphone, on your tablet, on your PC, at home, in the train, in the car. French Classes is compatible with all modern devices.
Sign-up today and gain access to all our online materials for 29.50€ per year – a 30% saving on our regular price of 45€.


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Atlas Junior
Updated for 2019, the Atlas Bag is amazing quality and value for money. Perfect for festival goers and those taking their first step into the world of camping, this mummy-shaped bag boasts a cosy 9.5 TOG rating for a comfortable night's sleep. Now with stylish reflective prints and reverse zippers; stylish yet functional.
More info
- Grade A Quality Fill – Superior fibre fill which is designed to be durable, warm and lightweight while retaining its loft and soft touch
- Independently Tested - Gives you reassurance that the temperature ratings are accurate ISO 23537-1:2016
- Hanging Loops - Allows you to easily hang your bag for quick and easy drying
- Woven Zip Puller - Allows you to quickly and easily move the zip
- Mummy-shaped sleeping bag - Tapers from the shoulders to the foot. Reduces packsize and increases thermal efficiency
- Single-layer stitch through construction - Maintains even fill distribution and keeps weight down
- 2-Way Zip - Can be opened from the top or bottom for versatile ventilation
- Polair® Shell - Smooth to touch, hardwearing and washable Polair polyester fabric (190T )
- Polair® Lining - Super soft lining which is also hardwearing and easily washable, Polair polyester.
- ThermoLock Insulation - Provides warmth and retains loft in damp conditions
- S-Stitching - Holds the insulating fibre in place for an even distribution across the body, providing warmth and comfort
- Stuffsack with Drawcord – Allows for easy packing while minimising pack size for easy transportation
- Junior Size - Slightly smaller than our standard size, to keep kids warmer while saving on space and weight
- Shaped hood with elasticated opening - Reduces heat loss from the head. No drawcord closure on Junior models for safety
- Scout Recommend - Used by The Scout Association
Data sheet
|Fill Type
|30% Single Hole siliconised hollow fibre/70% polyester fill
|Pack size
|37.0 x ø21.0cm
|Suggested Usage Min
|Suggested Usage Max
|Int Foot Width
|Int Length
|2 Season
|Ext Chest Width
|Zip Side
|Int Chest Width
|Max User Height


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Iraqi Prime Minister Mustafa al-Kadhimi is set to receive the Iranian foreign minister Mohammad Javad Zarif on Sunday.
Accompanied by a "high-level diplomatic delegation", the Iranian foreign minister will also meet his Iraqi counterpart Fuad Hussein.
This will be Zarif's fourth trip to Baghdad since he is in the office as the foreign minister of Iran.
The visit comes only days after French Foreign Minister Jean-Yves Le Drian traveled to Baghdad and Erbil amid the concerns over the new coronavirus outbreak.
The Iraqi prime minister travel to Saudi Arabia and Iran back-to-back next week, carefully balancing ties to regional rivals in his first foreign trip as premier, officials said Saturday.
Baghdad has often found itself caught in the tug-of-war between Riyadh, Tehran and even Washington, which the premier is also set to visit within the next few weeks.


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Welcome to the Christ's Mission Church Website
Here you will find information concerning our church and its ministries. We hope you find your time spent here helpful. Our church is a warm and loving family, and we want you to feel comfortable and at liberty to call on us for anything you need. Feel free to browse through the various areas of our website and learn about our church family.
Members will find our site helpful as they can download lessons, Bible studies and other important information. There is also an online directory under the Info Center (password protected) where you can find other member's email addresses, phone numbers, etc. You may also submit prayer requests, view pictures of recent activities, contact ministry leaders and much more.
If you are NOT a member of Christ's Mission Church you will love this site too. Here you will be able to see what we believe and email us with any questions you may have. You might even like to sign our guestbook - we'd love to hear from you!
If you are looking for a church home or are considering relocating to our area, we would be honored to have you be our guest for Sunday School and worship. If you're curious as to what to expect when you come, just click HERE.
When you visit our church, you will find:
For His Kingdom,
Jeff Brown, Evangelist
We are now live-streaming each Sunday at 9:00 a.m. to our YouTube channel which can be found by clicking this link: https://m.youtube.com/watch?v=kmAhhJayDGM
Meeting every Wednesday, 6:30 - 8:00 PM at CMC!
No Youth groups on the following dates:
Let's read through the Bible together! Find the Handbook, reading schedules and current outlines under the Info Center.
Worship Assembly - 9:00 a.m.
Fellowship Time - Immediately after worship assembly
Sunday School - Immediately after fellowship time
Ministry Leader: Jerry Strong
The number and address below are for member's use only
Number: 5735286011


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design and analysis of a horizontal shaft
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There are two well-known subpopulations of activated platelets: pro-aggregatory and procoagulant. Procoagulant platelets represent a subpopulation of activated platelets, which are morphologically and functionally distinct from pro-aggregatory ones. Although various names have been used to describe these platelets in the literature (CoaT, CoaTed, highly activated, ballooned, capped, etc.), there is a consensus on their phenotypic features including exposure of high levels of phosphatidylserine (PSer) on the surface; decreased aggregatory and adhesive properties; support of active tenase and prothrombinase complexes; maximal generation by co-stimulation of glycoprotein VI (GPVI) and protease-activated receptors (PAR). In this chapter, morphologic and functional features of procoagulant platelets, as well as the mechanisms of their formation, will be discussed.
- procoagulant
- platelet
- mitochondria
- necrosis
- apoptosis
- coagulation
1. Introduction
Blood has different components, like plasma, red blood cells (RBC), white blood cells (WBC), and platelets. Platelets, although being only "tiny fragments of megakaryocytes (mother cell)," are essential for life. We need them, together with about two dozen of coagulation factors, to keep all that nutrient-rich liquid plasma, infection-fighting WBCs, and oxygen-carrying RBCs in our bodies in the case of trauma and bleeding. Platelets and coagulation get activated immediately upon being exposed to things they normally do not have contact with (e.g., during blood vessel wall rupture, collagen gets exposed and activates platelets). Upon activation, platelets form a mesh-like structure using another plasma protein called fibrinogen as bridges between them. This process forms a so-called "unstable clot." At later stages of blood clotting, generated thrombin converts soluble fibrinogen to insoluble fibrin, stabilizing the initial platelet plug. These processes are collectively called hemostasis. Every aspect of hemostasis has its history. Although exploring history can sometimes be tedious, studying the bridge between past and present is essential in basic understanding of the subject, the subject of procoagulant platelets in this case.
Unlike WBCs, which exist as functionally and morphologically distinct subpopulations, it has been thought for years that platelets are rather simple in their function, being just "cell particles." It was later revealed that platelets, although lacking nuclear material, are indeed very complex not only in their nature but also in function. Nowadays, the existence of two different subpopulations of activated platelets, pro-aggregatory and procoagulant, is a widely accepted fact. Pro-aggregatory platelets, historically known as activated, have been a major focus since the initiation of platelet research. The history of procoagulant platelets, on the other hand, can be subdivided into two periods. The first one is the discovery of platelet procoagulant functionality, whereas in the second period, procoagulant platelets were discovered and characterized as a distinct subpopulation of activated platelets.
In 1912, long before we learned that prothrombinase supporting platelets are distinct from pro-aggregatory ones, Howell discovered that unsaturated cephalin is a phospholipid factor that triggers clotting [1]. This discovery was followed by decades of controversial results of what phospholipid or what mixture of phospholipids is responsible for this effect until, in 1960, Karl Slotta demonstrated the presence of phosphatidylserine (PSer) is an absolute requirement [2]. This discovery established the central role of PSer in prothrombinase activity, which in a way, paused research activities in the procoagulant platelet field.
The history was resumed when two decades later, Bevers and colleagues spectrophotometrically showed that thrombin and collagen co-stimulated platelets possessing about 5-fold higher prothrombinase activity than those stimulated with thrombin or collagen alone. This effect was even more pronounced in the presence of exogenous factor Va [3]. Later that year, the same group confirmed their spectrophotometric observations in one-stage prothrombinase assay [4]. In 1985, Rosing et al. more thoroughly described the role of platelet PSer exposure in prothrombin (FII) and factor X (FX) activation [5]. They revealed that collagen and thrombin co-stimulation significantly increases prothrombinase and tenase activity, while this increase was abolished in the presence of phospholipase A2 (PLA2) from N. naja. Also observing no cellular lysis in these conditions, they concluded that PSer exposure, which is followed by thrombin and collagen co-stimulation, is responsible for this phenomenon. In 1993, with the discoveries of annexin V and advancement in flow cytometry, Dachary-Prigent et al. established a protocol to detect PSer exposing platelets, the methodology that has overtime become fundamental in procoagulant platelet field and has been widely used since then [6]. In 1997 Heemskerk and colleagues discovered that a percentage of platelets adhering to collagen, but not fibrinogen, balloon and expose PSer [7]. In parallel to these findings, there was a series of publications determining the extent and ultrastructure of PSer exposure, as well as the essential role of calcium in this process [8, 9, 10].
Although numerous studies described platelet procoagulant function in response to dual stimulation [3, 5, 11, 12], a breakthrough discovery that identified procoagulant platelets as a distinct subpopulation of activated platelets is the work by Alberio et al., where they demonstrated that only a certain percentage of activated platelets retain factor Va (FVa) on their surface [13]. This subpopulation was generated by co-stimulation with convulxin/collagen (GPVI agonists) and thrombin; hence they were named CoaT platelets. A few years down the road, Kulkarni and Jackson introduced a new term—'sustained calcium-induced platelet morphology (SCIP)' by discovering the fact that procoagulant platelets require prolonged elevation in cytosolic calcium to form [14]. Diversifying terminology of procoagulant platelets did not stop there, in 2005 revealing that procoagulant platelets retain multiple α-granule proteins on their surface in transglutaminase-dependent manner led to the introduction of a new term—'coated' (by α-granule proteins) platelets [15, 16]. Further studies by Panteleev et al. revealed that this subpopulation of activated platelets binds high levels of factors IXa and Xa [17]. In 2008, Jobe et al., characterizing molecular mechanisms of procoagulant platelet formation, introduced another term—highly activated platelets [18]. There are few more terms used in the literature like ballooned [7], ballooned and procoagulant-spread [19], and super-activated platelets [20].
Just like in a famous Indian parable, where blind men try to describe an elephant they have never encountered before by touching different parts of it, researchers have been describing different (morphological and functional) features of procoagulant platelets and introducing different terms based on their discoveries. Whereas indeed, everyone has been describing "different parts of the same elephant."
2. Mechanisms of procoagulant platelet formation
The discovery of procoagulant platelets as a distinct subpopulation of activated platelets at the beginning of the twenty-first century triggered research activities into cellular and molecular mechanisms of their formation. As shown by Alberio et al. and confirmed in later studies, procoagulant platelets are maximally generated upon co-stimulation of glycoprotein VI and PAR1/4. In 2005, Jobe and colleagues discovered that the absence of FcRγ, a key component responsible for glycoprotein VI signaling, ablates procoagulant platelet formation almost to baseline levels, evidencing GPVI stimulation is the major component of their generation [21]. The same year, Remenyi et al. demonstrated the role of mitochondrial permeability transition (MPT) in procoagulant platelet formation [16]. MPT is a Ca2+-dependent molecular process that leads to mitochondrial swelling and cell death [22, 23]. During the onset of MPT, large pores are formed on the mitochondrial inner membrane making it non-specifically permeable to all solutes and molecules of molecular weight up to 1500 Da [24, 25]. It is a very well-known fact that mitochondrial Ca2+ overload can induce MPT, although the structure of MPT pore remains unknown.
Ca2+, being a key signaling molecule in most cells, is important for many processes including platelet shape change and integrin α2bβ3 activation [26, 27]. In resting platelets, free Ca2+ is tightly regulated and maintained at about 100 nM in both the cytosol and mitochondria through the action of Ca2+-ATPases in the plasma and cell membranes. Thus, platelet cytosolic-free Ca2+ is substantially lower than the blood Ca2+ levels, which are around 2 mM. With stimulation, however, cytosolic Ca2+ increases instantaneously. As outlined in Figure 1, this increase is mediated by activated phospholipase C (PLC). There are two major isoforms of PLC in human platelets, PLCβ and PLCγ. PLCβ is only activated downstream of Gq protein-coupled receptors (GPCRs). Whereas, PLCγ is activated downstream of numerous receptors like GPVI, glycoprotein Ib-IX complex (GPIb-IX), Fcγ receptor IIa (FcγRIIa), and C-type lectin-like receptor 2 (CLEC-2). As illustrated in Figure 1, both isoforms of PLC induce the release of Ca2+ from the dense tubular system (DTS) as well as activating transient receptor potential channel 3 (TRPC3). DTS release of Ca2+, in turn, triggers its extracellular entry through store-operated calcium entry (SOCE). For some time, it remained mysterious on how the release of DTS calcium stores into the cytosol induces more Ca2+ to flow into the cell, further increasing its cytosolic concentrations. However, with the discovery of core components of SOCE, everything falls into place. STIM1 and ORAI1 are parts of the same complex. When STIM1 senses drop in Ca2+ levels within the DTS, it signals to ORAI1 located on a cell membrane to allow Ca2+ passage from extracellular space into the cell. As evidenced by the study in the early 2000s, increased cytosolic Ca2+ levels are one of the requirements of procoagulant formation [14]. Mitochondria, being the major and perhaps the only Ca2+ buffering system within platelets, equilibrate increased cytosolic Ca2+ following PAR and GPVI co-stimulation. The ensuing fate of mitochondrial Ca2+ overload is the opening of the mitochondrial permeability transition pore (MPTP), followed by PSer exposure and integrin deactivation (Figure 1), ultimately leading to a cell death. However, in this case cell death shall be considered physiologic considering the essential role of procoagulant platelets in hemostasis.
It brings us to another aspect of procoagulant platelet research, debated since their discovery, which is whether procoagulant platelets are necrotic or apoptotic. Cell death, both necrosis and apoptosis, is an essential event in the normal life of many cells in the human body, including platelets. Apoptosis, or programmed cell death, occurs in many organs throughout human lifetime. Necrosis, although considered to be mostly a catastrophic uncontrolled cell death, can also occur physiologically, as in the shedding of decidual endometrium during human menses. Necrosis and apoptosis differ in many aspects. The ultimate event during necrotic cell death is the osmotic swelling of the cell followed by the rupture of a cell membrane, whereas in apoptosis, cell shrinkage with preserved cell membrane is evident in later stages of this process.
Although the proposal that PSer is not homogeneously distributed on the surface of activated platelets was made back in 1985 [5], it took three decades to visualize that experimentally due to the complex nature of procoagulant platelets. In 2016, Podoplelova et al. presented a detailed structure of procoagulant platelets and cellular changes that give them the characteristic morphology. They elegantly demonstrated how the balloon is blown out from the platelet, leaving it as a "cap" [29]. The existence of bulges in a phospholipid bilayer, known as the open canalicular system (OCS), is essential, as it provides platelet a fair amount of surface reserve for ballooning. Morphologic appearance, in this case, resembles the classical osmotic swelling of necrotic cell death, as schematically presented on the left side of Figure 2. Another feature of necrosis, which is a collapse of energy production, is present in procoagulant platelets, as they lack energy-requiring contractile function [18]. Moreover, depletion of oxidative phosphorylation due to MPT, deactivates flippases that normally maintain the asymmetry of phospholipids. After the onset of MPT, contents of mitochondrial matrix get released to the cytosol leading to the second wave of cytosolic Ca2+ increase. This in turn leads to scramblase activation. Synergistically with deactivated flippases, scramblase performs its raison d'etre, which is flipping negatively charged PSer out in order to equilibrate its concentration. And finally, recent work demonstrated that platelets undergoing cell death through necrotic pattern and not apoptotic are functionally procoagulant as measured by prothrombinase support [30].
Platelet apoptosis (Figure 2, right side), on the other hand, has been widely implicated in platelet lifespan via the action of the intrinsic mitochondrial apoptosis pathway [31, 32]. Normally, antiapoptotic members of the BCL-2 family (e.g., BCL-xL) restrain the activity of proapoptotic Bax and Bak proteins, which are present within the cytosolic fraction of a platelet. When BCL-xL wears off, oligomerized Bax and Bak translocate to the mitochondrial outer membrane and permeabilize it, which leads to cytochrome C leakage into the cytosol, triggering apoptosome formation and eventually cell death. This is supported by the fact that the genetic ablation of murine BCL-xL reduces platelet life span from about 5 days to 5 hours [33, 34].
Thus, procoagulant platelets are indeed necrotic, while apoptosis is essential in platelet clearance. It should, however, be mentioned that the presence of PSer on the surface of a platelet is a signal for the reticuloendothelial system in the spleen and liver for clearance. Therefore, any procoagulant platelet that happened to escape the site of the active hemostatic process will be cleared out of the system by liver or spleen, just like aged apoptotic platelets do.
3. Functions of procoagulant platelets
The physiological relevance of procoagulant platelets had been questioned for a long time. In recent years, however, after the demonstration of a procoagulant platelet being predictive of bleeding or ischemic complications in patients with coronary artery disease, brain hemorrhage, traumatic brain injury, stroke, etc. [35, 36, 37, 38, 39, 40, 41, 42] it is gaining more and more recognition. The importance of this subpopulation is further highlighted on a novel ex vivo model (which integrates all the core components of hemostasis [43]), where pharmacologic inhibition of platelet transition to a procoagulant state without affecting pro-aggregatory phenotype results in a decreased thrombus stability [44].
It was initially thought that the only function of procoagulant platelets is to support coagulation. However, with recent advances in the field, we learn that depending on their localizations, procoagulant platelets can play different functions within the thrombus. For general consideration, these two functionalities will be discussed separately here.
3.1 Coagulation support
Coagulation, a cascade of serine protease enzymatic reactions, is achieved by cleaving fibrinogen to fibrin, which transforms blood from a liquid to a gel-like state. Although platelet contribution to coagulation has been known for decades, the exact role of platelet phospholipids has been a matter of major debate. Dependence of hemostasis on biological membranes is very extensive, ranging from subendothelial membranes triggering coagulation and platelet activation to procoagulant platelet surface assembling tenase and prothrombinase complexes. It is very well known that at least two coagulation reactions are highly dependent on phospholipid surface, namely the activation of factor X and prothrombin by intrinsic tenase and prothrombinase, respectively. Both intrinsic tenase and prothrombinase are composed of the serine protease (FIXa for tenase and FXa for prothrombinase) and its protein cofactor (FVIIIa for tenase and FVa for prothrombinase). It is important to know that although both proteases alone are capable of activating their substrates, the presence of cofactors profoundly amplifies the catalytic process for up to 10,000 fold.
The current understanding of this process, based on numerous studies including mathematical modeling, is that phospholipid surface increases the rate of reactions by increasing the local concentration of coagulation factors, and thus increasing the probability of their interaction [29, 45, 46, 47, 48, 49, 50, 51]. This increase in a local concentration of factors, essential for tenase and prothrombinase complexes, is accomplished by the interaction of negatively charged gamma-carboxyglutamic acid (GLA) residues of the coagulation factors with negatively charged phosphatidylserine on the surface of procoagulant platelets. It is supported by the fact that GLA domain-containing (also known as vitamin K-dependent) factors predominantly bind to a procoagulant subpopulation of activated platelets [17, 29, 30]. Both enzymatic factors for intrinsic tenase (FIX) and prothrombinase (FX) are GLA domain-containing proteins and bind to PSer in a calcium-dependent manner. Whereas cofactors (FVIII and FV) structurally are not GLA proteins and bind to a procoagulant surface by different mechanisms.
In the case of FVIII, it has been shown by Gilbert et al. that it is not specific to a procoagulant surface [52]. It was further confirmed by Podoplelova et al. in their efforts exploring procoagulant platelet characteristics, they demonstrated that both (pro-aggregatory and procoagulant) subpopulations of activated platelets bind FVIIIa [29]. The fact that PS increases the catalytic activity of the intrinsic tenase complex by about 1500-fold [53] can be explained by FIXa's specificity to PSer. As outlined in Figure 3A, initially FIXa and FX bind PSer. This binding reaction is calcium-dependent for all GLA domain-containing proteins. FIXa possesses enzymatic activity to convert X to Xa, whereas in the presence of its cofactor (FVIIIa), the catalytic activity raises 100,000-fold.
As for the FV—there are two different probabilities of binding to the procoagulant surface, as demonstrated in Figure 3B. In the first one, prothrombinase forms by the surface Xa reacting with factor Va in solution. Whereas, in the second case, both FVa and FXa form binary complexes with PSer first, and then lipid-protein rearrangement leads to prothrombinase formation [50]. The addition of exogenous FVa to procoagulant platelets increases the velocity of prothrombinase reaction [4], whereas in the absence of exogenous FVa, procoagulant platelets are still prothrombinase active [54]. These findings indicate that both pathways are physiologically important.
3.2 Limiting thrombus growth
During hemostasis, there is a time point when a thrombus needs to stop growing in order not to occlude the lumen of the vessel, which may compromise the blood supply to an end organ. Stoppage of the thrombus growth is probably the most intriguing part of thrombogenesis, although being the most understudied at the same time. When coagulation is initiated by subendothelial tissue factor, it leads to the formation of small amounts of thrombin. Thrombin then, via a positive feedback mechanism, by activating FXI and FVIII triggers the contact activation pathway and amplifies its production. This self-accelerating process is essential within the hemostatic plaque as it is the only way to overcome the anticoagulant nature of plasma, which is due to the presence of antithrombin III (ATIII). Besides the presence of ATIII in the active form, other mechanisms limit coagulation beyond its border zone. Another one of high importance is the presence of thrombomodulin, an integral membrane protein that is expressed ubiquitously on the surface of endothelial cells. Thrombomodulin converts procoagulant thrombin to an anticoagulant enzyme. Not only these mechanisms limit coagulation to the injured site but also degrade activated factors that happened to escape the hemostatic plaque. These processes outline the general principles of limiting coagulation to its border zone. However, not only coagulation but also processes of platelet adhesion, aggregation, and activation have to stop in order at a certain timepoint. How and when thrombus stops growing concerning cellular component had been a mystery for a long time.
In 2007, Maroney et al. demonstrated that procoagulant platelets express active tissue factor pathway inhibitor (TFPI) on their surface [55]. But why platelets expressing procoagulant PSer would also need a strong anticoagulant (TFPI) on their surface remained a question for about a decade until in 2019 a breakthrough work by Nechipurenko et al. characterized a phenomenon, together with its mechanisms, of procoagulant platelets translocating to the thrombus periphery [57]. They demonstrated that during clot retraction procoagulant platelets are squeezed out to the periphery of the thrombus, as shown in Figure 4. Another important study in this context is the 2008 work by Jobe et al., which demonstrated that procoagulant platelets do not possess contractile function [18]. This explains why pro-aggregatory and procoagulant platelets have different translocation vectors within the hemostatic plaque (Figure 4). Being bound to the thrombus by its "cap," procoagulant platelets do not get detached but rather are squeezed out during pro-aggregatory platelets contraction. At the luminal surface of the hemostatic plaque, procoagulant platelets limit its further growth not only by expressing low adhesive and aggregatory surfaces [58, 59, 60], but also with TFPI terminating any extrinsic tenase and prothrombinase activity.
The fact of procoagulant platelet being non-adhesive, however, gives rise to a legitimate question. If procoagulant platelets are not capable of adhesion and aggregation, how do they get attracted to a thrombus? It turns out to be, as described in recent studies, that procoagulant platelets do not form de novo from a resting state, but rather temporally transitioning from pro-aggregatory phenotype by the onset of the MPT and regulated necrosis within a hemostatic plaque [61, 62].
Many are aware of an ancient Roman god of duality — Janus, who had two faces as he was able to look to the future and the past. Procoagulant platelets can also demonstrate a functional duality by supporting coagulation on one side and limiting thrombus growth on the other, making them be "Janus" of hemostasis.
Conflict of interest
The author has no conflict of interest to disclose.
|activated protein C
|antithrombin III
|Cyt C
|cytochrome c
|dense tubular system
|FC receptor gamma
|factor V
|activated factor V
|factor VIII
|activated factor VIII
|factor IX
|activated factor IX
|factor X
|activated factor X
|glycoprotein Ib and IX complex
|glycoprotein VI
|mitochondrial calcium uniporter
|mitochondrial permeability transition
|mitochondrial permeability transition pore
|open canalicular system
|protease-activated receptor
|protein C
|phospholipase A2
|protein S
|red blood cell
|store-operated calcium entry
|tissue factor
|tissue factor pathway inhibitor
|transient receptor potential channel 3
|white blood cell


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2nd Annual HDJ VIP Night @ the Triple AAA T Wolves vs Heat
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Season 2 Episode 3: Sherri
In August of 1962, Sherri Chessen boarded a flight to Sweden in order to get an abortion after she was unable to obtain one in the United States. Sherri had accidentally taken medicine containing thalidomide, a drug that caused children to be born with internal injuries and shortened limbs. Thalidomide also caused women to miscarry, deliver stillborn babies, or have children who died during their infancy. Her decision to terminate this risky pregnancy and her journey abroad attracted international attention from journalists, politicians, and religious leaders. Sherri's ordeal made public what countless American women experienced when they sought to terminate their pregnancies. Her widely shared story changed the way many Americans thought about abortion laws and even about abortion itself.