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Browsing wedding venues is among the very first steps of planning your big day. But with so many wedding venues to choose from, how do you find The One? First, consider the style of venue you'd like: Garden or beach? Ballroom or barn? Then, read reviews of wedding venues in your desired city and select a few to tour in person. Happy venue hunting!
Neltner's Farm LLC is a rustic farm wedding venue based in Melbourne, Kentucky. Located just 20 minutes from downtown Cincinnati, the rural setting offers the perfect country getaway from city life. The property, which has been nurtured for six generations, features rolling hills, vintage bridges... (Barn & Farm Weddings Melbourne)
Ivy Hills Country Club is a historic wedding venue located in Cincinnati, Ohio. They feature multiple indoor and outdoor venues, including a elegantly decorated clubhouse. Your guests will experience gorgeous nature and golf course views on this pristine property. Ivy Hills Country Club prides... (Country Club Weddings Cincinnati)
Relax and let the professionals at the Holiday Inn & Suites Cincinnati Eastgate take some of the wedding stress off of your shoulders. Featuring a stunning banquet hall, world-class accommodations, and incredible service, the Holiday Inn & Suites is the perfect venue to host a dream wedding on any... (Hotel Weddings Cincinnati)
Twin Oaks Golf and Plantation Club is a wedding ceremony and reception venue located in Latonia, Kentucky. This venue is considered to have one of the best public golf courses available in the Greater Cincinnati Metropolitan Area, giving it a sense of prestige and impressiveness for your big day.... (Country Club Weddings Latonia)
A historic wedding venue in Cincinnati, The Carnegie Center of Columbia Tusculum is the perfect place to host your important day. With a mission to serve as a gathering place for learning, sharing and celebrating, you and your loved ones will have the opportunity to celebrate your happiness and... (Historic Weddings Cincinnati)
Headquarters Event Center is a cozy historic wedding venue for couples planning a wedding in the Cincinnati, Ohio or Northern Kentucky area. This location was originally constructed as a hardware store in 1870, but has since been restored by owner Mike Smith. Today it maintains all of its... (Historic Weddings Newport)
For 20 years, the Newport Syndicate has put the wow in your event. Our planner see to every event detail including the night of your wedding. Our Grand Ballroom takes you back in time with special effect lighting,a massive antique bar , incredibly large dance floor and elevated stage. The bar with... (Banquet Halls Newport)
Carnegie Hall Newport is conveniently located just one block from Newport on the Levee and minutes from downtown Cincinnati. Facilities and Capacity You'll enjoy the exclusive use of our entire 10,000 square foot venue encompassing three beautiful floors - each with it's ambience and specific use in... (Banquet Halls Newport)
A wedding ceremony and reception venue in Cincinnati, Newport Aquarium offers a one-of-a-kind experience that you and your guests will remember forever. With gorgeous views of the Cincinnati skyline and the opportunity to stroll through the aquarium for fascinating exhibits, you can expect an... (Museum Weddings Newport)
BB Riverboats is a boat wedding venue which operates out of Newport, Kentucky. The happy couple and their guests can enjoy gliding along the Ohio River as they take in the passing sights. Taking in views of the Cincinnati cityscape as well as the riverbank, everyone can relax as the soothing tones... (Boat Weddings Newport)
About River's Edge at Newport Landing Celebrate your special day with the Cincinnati skyline as your backdrop and the river as your dancefloor: BB Riverboats is proud to unveil River's Edge at Newport Landing, the city's only event center on the river. Located in our brand-new Newport Landing dock... (Banquet Halls Newport)
Hotel Covington is a luxury hotel wedding venue in Covington, Kentucky. As century-old city building, the space exudes modern elegance full of rich history. You and your guests will love the sleek decor, upscale vibe and local cultural influence.Facilities and CapacityCouples may host up to 190... (Hotel Weddings Covington)
A wedding venue in Cincinnati, Ohio, Embassy Suites Cincinnati RiverCenter is committed to helping you create the most memorable wedding day. With unique ballrooms and a wedding specialist, combined with the gorgeous city backdrop, you can guarantee the wedding of your dreams. Located on the banks... (Hotel Weddings Covington)
Radisson Hotel Cincinnati Riverfront is a waterside wedding venue located in Covington, Kentucky. This hotel is a newly renovated event space that offers an elegant setting for your special day. No matter what kind of big day that you're hoping to celebrate, Radisson Hotel Cincinnati Riverfront can... (Hotel Weddings Covington)
A newly restored luxury hotel with original Art Deco details, the Renaissance Cincinnati Downtown Hotel is an exceptional choice for couples seeking a sophisticated place to celebrate their love. Make your dream wedding a reality at this distinct wedding venue located inside the historic Bartlett... (Hotel Weddings Cincinnati)
McHale's Events & Catering is a collective of banquet hall wedding venues located in Park Hills, Kentucky. This company is pleased to offer creative menus along with dedicated staff members to their clients. They are able to provide their clients with a range of venue options that are located all... (Banquet Halls Covington)
A timeless and contemporary wedding venue in Cincinnati, Ohio, The Center offers a flexible and stunning space for you to customize the wedding of your dreams. Located in the Mercantile Building in Downtown Cincinnati, this setting is home to the Contemporary Arts Center and is filled with design,... (Historic Weddings Cincinnati)
Hilton Cincinnati Netherland Plaza is an elegant hotel wedding venue in Cincinnati, Ohio. The classic and historic building has been home to special memories since 1931. It is also a National Historic Landmark. From the remarkable personal service to the French art deco architecture, the hotel will... (Hotel Weddings Cincinnati)
The Bell Event Centre is a historic wedding venue in the Cincinnati, Ohio area. This former church brings with it all the ornate decor of a cathedral, although it has been renovated as an event venue. Couples can host their wedding in downtown Cincinnati, just five minutes from Washington... (Historic Weddings Cincinnati)
A wedding ceremony and reception venue in Cincinnati, Ohio, The Phoenix is a historic landmark perfect for your memorable and important day. With a talented team who will assist you every step of the day, this venue will ensure a day personalized to your wedding vision.Facilities and Capacity The... (Historic Weddings Cincinnati)
Located in Cincinnati, Ohio, Woodward Theater is a wedding venue, servicing occasions throughout the local area, including Northern Kentucky, Ohio, and downtown Cincinnati. The theater is a professional venue that has been part of the wedding industry since 2013, specializing in all kinds of... (Historic Weddings Cincinnati)
A family-owned and operated wedding venue in Cincinnati, The Norlyn Manor offers an elegant setting with an attentive staff and amazing services. Sitting on 19.5 wooded acres and located six miles east of I-275, just off State Route 32, the venue is in a convenient and incredible spot from all parts... (Mansion Weddings Batavia)
Summit Hills Country Club (SHCC) is an elegant, sophisticated wedding venue in upscale Crestview Hills, Kentucky. SHCC offers everything a couple needs for a truly extravagant wedding. From acres of lush greenery to an upscale ballroom and unmatched hospitality service. From the moment you make your... (Country Club Weddings Ft Mitchell)
The Cincinnati Zoo and Botanical Garden offers a unique wedding venue location in Cincinnati, Ohio. Their elegant atmosphere boasts indoor and outdoor spaces. Take advantage of their beautiful gardens and exhibits as your wedding and photo backdrops. Zookeepers will even bring out the party animals,... (Park & Outdoor Weddings Cincinnati)
With its rustic clubhouse and lakeside patio, The Golf Club at Stonelick Hills is a true hidden gem in the Cincinnati area. Forget traveling all over town on your wedding day and choose this beautiful, versatile location for your ceremony, reception, and photos. Facilities and Capacity With... (Country Club Weddings Batavia)
American Sign Museum is an innovative and engaging museum that can double as a unique indoor wedding venue located in Cincinnati, Ohio. The museum is a favorite among couples and quickly became one of Cincinnati's premier event spaces. American Sign Museum will illuminate any celebration with bright... (Museum Weddings Cincinnati)


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As people prepare for 4th of July fireworks all around West Virginia, Tygart Lake was filled with both locals and out of town visitors celebrating Independence Day in their own way.
"So my wife just became a citizen a few months ago and she is from Peru. So we're celebrating this country, her citizenship and all kinds of stuff in the U.S." said park visitor Daryl Foland.
State park officials welcome all guests to celebrate until the fireworks start at 10pm around downtown Grafton.

subset: commoncrawl


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How Self-Care Can Be Achieved in a Number of Ways
You cannot demand the importance of taking care of yourself right from the state of the body to the mind. Quite a number of people and different circles have mistaken self-care for greed which is not true. One thing we need to understand is that our physical health can actually be greatly affected by our mental health. When you have reached a point where you can easily give yourself completely into something or another person, that is when you actually value yourself. The meaning of self-care is the idea of taking good care of yourself and investing in it. It is not just a matter of what we do on a daily basis such as taking food or a shower. Giving attention to your own needs of the body and mind that ensure that your health and happiness is guaranteed is what we refer to us self-care. There are a number of simple ways you can do in order to achieve self-care discover more.
A body scan is the first essential tip that can help you in order to achieve self-care. A scan is very important and will help you to accurately predict what your body and mind needs. Every single day, you should make sure you have done a scan and meditation is one tool you can use. The best position you can do this can is when you are lying down particularly on your bed and running a scan from the highest point of your head to the lowest point under your feet. This is a process that is mentally done and will help you notice any pains, stress and anything that is not right.
The second important tip that will be very instrumental in achievement of self-care is by doing positive self-talk and practicing it. You must always trust that you are the best version of you that can ever exist and you can build that confidence in yourself which you cannot get anywhere. You can try standing in front of a mirror and using a few minutes where you are just looking at yourself and giving compliments to your own self. You can practice self by simply getting yourself in front of a mirror and communicating positive things to yourself. this will be very instrumental in dealing with issues of low self-esteem and feelings of insecurity.
Furthermore, one guideline that you must follow on your path to self-care is exercise. You will not just stay fit and lose some weight through exercise but you will also benefit another great way. Through exercise, chemicals known as endorphins are released into your body. Endorphins are very instrumental in helping to brighten your mood and also get some stress out thus the name feel-good chemicals.


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Capture .NET - Windows 8 Downloads
Capture .NET 13.4.6421.3
Capture .NET is a small multifunctional desktop tool. Tons of interesting and effective utilities for your PC system. Includes many helpful tools: Capture window/Capture region/Capture color/ruler/fontViewer/reveral password/privacy eraser...
Capture .NET 13.4.6421.3 - Key details
|File Size:
|983 kB
|Aug 1, 2017
|Total: 492 | This Week: 1
|convert source code, VB.NET code, C source, Convert, Converter, .net
|Author URL:
Windows 8 Downloads - Capture .NET awards
Capture .NET - Full description
Convert .NET Converts C# source code units to equivalent VB.NET code. Convert .NET is a a useful developer's utility that allows users to Convert C# to VB.NET. You can also utilize our regular expression tester and online dictionary. A standalone tool that does not require installation.
Capture .NET for Windows 8 - Post your review
Capture .NET Windows 8 related downloads
Capture .NET is a small multifunctional desktop tool. Tons of ... for your PC system. Includes many helpful tools: Capture window/Capture region/Capture color/ruler/fontViewer/reveral password/privacy eraser... and much more. ...
... software offers a solution for users wanting to capture a specific part of the screen and save ... one corner of the area you want to capture, hold down the left mouse button and drag ...
Managing your day-to-day life is not an easy job to do. There are so many things to concern for - housekeeping, ...
... in Uganda that allows you to scan (or capture) computer information on the screen (or part thereof) without using a ...
... an individual window, a graphics from the clipboard, capture an image and much, much more to a second monitor. You ...
DragonOgg is a handy, small C# wrapper specially designed for OpenAL via OpenTK that enables the playing of Ogg Vorbis files ...
... scriptable and pluggable in IronRuby, IronPython and any .NET language that compiles down to an assembly. Requires .NET Framework 4 Client Profile, Visual C++ 2010 Redistributable ...
OneLoupe is required to view everything on the screen enlarged. Simple and easy to use, the small Magnifier is always ready ...
The TiVo service will bring you all your favorite TV shows, ready to watch whenever you want. Plus it can connect ...
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By Tess Hetzel | Corporate Responsibility Manager
This article was originally posted here in the National PTA's magazine.
October is National Cybersecurity Awareness Month (NCSAM), a collaborative effort to raise awareness and provide education on ways to be safer online at work, at home, at school, and all of the places in between.
DENVER, October 11, 2019 /3BL Media/ – Arrow Electronics presented the St. Vrain Valley School District in Longmont, Colo. with The Succeeds Prize for Excellence in Technology Enabled Learning at a recent ceremony honoring Colorado public schools and educators in Denver.
By Dina Steinke Sr. | Director and Interim Security Leader for the Consumer Business Unit, Symantec
This article was was originally posted on the National Cyber Security Alliance blog.
October is Cybersecurity Awareness Month, and Tetra Tech is proud to be a cybersecurity champion and support this important online safety and education initiative. The cybersecurity and digital privacy of our employees and customers is vital to our operations. We invite you to #BeCyberSmart today and every day by joining us throughout October as we share proactive ways to stay safe online to protect yourself, your business, and your family.
As we wrap up National Cyber Security Awareness month, join Symantec and partners The Identity Theft Resource Center and Infolock for our final webinar. Whether you are connecting to networks or collecting customer/consumer data, protection is needed. This group of speakers will help familiarize you on how to check your systems and how to keep others' data safe. Topics will include:
Symantec invites you to join us as well as TechSoup and the Michigan Small Business Development Center for a discussion on how to apply added layers of security to your devices and online accounts. The changes in technology are not slowing, with all of the changes cybercriminals are adapting to become more sophisticated. Better protect your personal info with available security features on your own devices. We will focus on small businesses and nonprofits and the topics will include:
By Avneet Hall, Symantec Cyber Career Connection Graduate
One of the first things I heard as I began my career in cybersecurity was, "Cyber is not for you because you're a mom." I was also told, "You'll never see your kids." As a first time mother of a six-week old baby, I had doubts about starting my cyber career. But, I thought about all of the women and mothers who are doctors, surgeons, and military commanders and decided, if they can do those jobs, I'm sure I can do this one.
By Tess Hetzel, Corporate Responsibility Manager
Living in Washington, D.C., "advocacy" is a word I hear every single day. Being a good corporate citizen means engaging with public policy, as local, state, and federal laws affect our employees, partners, and customers. Many of our stakeholders care not only about Symantec's commitment to and track record on issues like climate change and diversity, but also about how we're speaking out on these issues and mobilizing action.
Start October strong with Symantec and NCSAM partners, the National PTA, Connect Safely and the National Cyber Security Alliance, to learn how to protect the devices you use day to day. Understanding how to protect your most significant personal information is crucial in this world of constant connection. We will focus on elements of home and family and the topics will include:
By Calvin Hennick
Like organizations in every industry, nonprofits have valuable data they need to protect. In addition to employee payroll and donor data, nonprofits store and manage information as diverse as HIV treatment records, notes from drug counseling sessions, and the addresses and phone numbers of victims of domestic violence.


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. . . just links from HayYoo.com and DanKostecki.com
Thanks to satellite imagery, it's easier than ever to see how the Earth is changing over time. The Ucayali River in Peru is changing its course at an especially rapid pace, and Zoltan Sylvester, a sedimentary biologist who blogs at Hindered Settling, used Google Earth Engine and data from the U.S. Geological Survey's Landsat program to put together this neat encapsulation of how the river has changed since 1985.


text: Wild Doc Store 1 Appalachian Chai - 2 fl oz SKU FUNG_CHAI_EX $26.00 In stock Quantity: 1 Add to Bag Product Details All Forest Folk Fungi offerings are made in cooperation with *foraged or organically grown fungi and plants. We wildcraft with deep respect for our fungal friends and with love of Pachamama in our hearts. We hope you feel this integrity of spirit in each drop!Appalachian Chai Our most popular tea extracted in a potent tincture form. A vigorous blend of Southeast native plants and fungi to support deep immunity, clarity of mind, and warmth of heart. Reishi Mushroom (Ganoderma tsugae), Turkey Tail (Trametes versicolor), Crossvine (Bignonia capreolata), Spicebush (Lindera benzoin), Wood Nettle (Laportea canadensis), Lemongrass, Ambrosia apples, ginger, cardamon, raw local honey Save this product for later Favorite Track Orders Shopping Bag Sign In


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Antelope Hills Home Care - Antelope, CA
|Room Type
|Monthly Range* (USD)
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* Published prices are provided by the providers themselves, not by reviewers. Actual quotes may differ from what is presented based on timing and services required.
- Activities Onsite
- Indoor Common Areas
- Meals Provided
- Nurses on Staff
- Podiatrist Available
- Complimentary Transportation
- Activities Offsite
- Outdoor Common Areas
- Beauty & Barber Services
- Pets Allowed
- No Smoking Allowed in Private Areas Indoors
- No Smoking Allowed in Public Areas Indoors
- Wheelchair Accessible Showers
- Hospice Available
- Respite Available
- Resident Parking Available
- Male Residents Accepted
- Dentist Available
A tour with care
I toured this community for care for my mom. They do have a nurse that lives in the community full time and is always available. I was not able to have any of the meals. This community is clean and taken care of. Families should see for themselves the care and value that is offered here for a loved one.
Was very impressed with hom...
Was very impressed with home, and Tina's training and knowledge with respect to Dementia residents. She went to see Frances and assessed her needs. She will accept my Mom and cost would be $3500/mth, $4000 on Hospice. Location was very convenient as well - right off Antelope Road.


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Wow, what a day to remember! We started at the brides family home for the getting ready pictures. Capturing little moments between the bride, her mother and bridesmaids. Along with this we took pictures of the brides dress, jewelry and any other small details.Read More
We just loved Megan and Justin's wedding at the recently newly decorated Highgrove Estate in Fuquay-Varina.Read More
Samantha and Kevin tied the knot! They had a beautiful Catholic wedding at St Andrew's Catholic Church and an elegant reception at Renaissance Raleigh North Hills Hotel. We kicked off the day with some getting ready portraits at Blo in Brier Creek and the groomsmen at an apartment. Quick run to NC State's campus for some wedding party group shots. The day was a total blast and we can't wait to share these images...Read More
Ming and Brooks were married at Brook's parents home in North Raleigh on a stormy summers day.Read More
Christion and Nick were married at St. Mary's Chapel. A beautiful little white chapel nestled amongst a school brick buildingsRead More
Latrise and Lucious engagement session at Raleigh Arboretum.Read More
A brisk winters afternoon, we lucked out with a beautiful afternoon of sun to create the best natural light. I met Cony and Jason at the Raleigh Arboretum to kick off their engagement session. We started off casual and once we moved on to an industrial location I had them go to their dressed up look.Read More
Downtown Raleigh has so much to offer a couple for their photo shoot. From the gardens at one of the many parks, to an urban look and an industrial look. Looking for a good Raleigh skyline, no problem. This city has it all!Read More
Having photographed Sarah's bridal session earlier in the year I could not wait to get started on their wedding. Meredith College Chapel was a big surprise to us. After speaking with the chapel coordinator we discovered we could photograph anywhere we wished during the ceremony. This is a first and one that showed respect to our profession.Read More
After photographing Emily's bridal session earlier in the year, I knew we were in for a treat to photograph their wedding day. There's something just magical about this venue. Perhaps it is the organized, relaxed, yet on-point staff. The gorgeous natural light oozing through the large windows. Or the lawn and garden around the venue. Either way, we love it for all it's southern charm.Read More


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text: Supplement: Advances in Reconstructive MicrosurgeryRohrich, Rod J., M.D.Plastic and Reconstructive Surgery: December 2009 - Volume 124 - Issue 6 - p 1981-1982 doi: 10.1097/PRS.0b013e3181bf7f5e RECONSTRUCTIVE MICROSURGERY SUPPLEMENT: FOREWORD Buy Author InformationAuthors Article MetricsMetrics Dallas, Texas From the Department of Plastic and Reconstructive Surgery, University of Texas Southwestern Medical Center. Received for publication August 24, 2009; accepted August 24, 2009. Disclosure:Dr. Rohrich has no financial interest in any of the products, devices, or drugs mentioned in the supplement. Rod J. Rohrich, M.D.; University of Texas Southwestern Medical Center; 5909 Harry Hines Boulevard, HD01.544; Dallas, Texas 75235-8820; firstname.lastname@example.com ©2009American Society of Plastic Surgeons


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VXi 201559 Passport 10V Over-the-Head Monaural Headset with N/C Microphone
IN STOCK - FREE SHIPPING for orders over $50 to the United States
|In Stock - Limited Supply
|90 Days
Product Details
- Superior noise canceling eliminates background noise (up to 89 percent) and improves communication.
- Hearing protection suppresses sudden and unexpected sound spikes.
- Lightweight design is easy and comfortable to wear all day.
- High quality durability stands up to all-day, every-day use.
- Requires V-type QD lower cord (available separately) to connect to your phone.
Grade A: Grade A products will have overall excellent to very good cosmetic condition. Some Grade A units will be cosmetically pristine, while others may have light scratches or other minor blemishes.
This product can expose you to a chemical such as lead that is known to the State of California to cause cancer or birth defects or other reproductive harm. For more information go to Prop 65 California


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There were plenty of ponytails and curls rocked on the runways at this fall's New York Fashion Week shows! The curls were gorgeous, and definitely showstopping! Some of the best products on the market were used for textured hair, to really achieve sleek and bouncy, beautiful curls. Ponytails and buns …Read More »
Home / Tag Archives: Naturally Curly
Review, Best Hairstyle Trends, 2017, 2018, Looks: NYFW Fall/Winter 2017, Ponytails, Braids, New York Fashion Week, Naturally Curly, Cantu, Shea Moisture, Redken
Ponytails and braids are some of the easiest and most chic hairstyles. We spotted some of the best on the NYFW Fall 2017 runways. At NaturallyCurly's signature event, Texture On The Runway, we saw a variety of different styles – from luscious fros and cascading waves to wild ringlets and …Read More »


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Craig Sim
Head of Client Technology
My job at JCRA is to continue and expand the JCRA digitisation strategy, and help bring the benefits of leading edge computing methods and disruptive technology to the development of the JCRA Client Technology offerings, which will remain a fundamental strategic focus for the business going forward.
T: +44 (0)207 493 3310 LinkedInEmail Craig
- PGDip Software Engineering, Napier University of Edinburgh
- BEng (Hons) Mechanical and Electrical Engineering with Avionics, University of Lincoln
About Craig
I am a fintech, risk, quantitative and data science professional with extensive experience delivering trading and risk management platforms in investment banking and clearing house environments. I spent the first two years of my career as a software developer for the derivatives trading platform Summit and the following seven years working for Barclays Capital as a development and project manager across a range of asset class risk management and quantitative solutions. My experience allows me to deliver Agile projects utilising the most up-to-date development techniques and, in addition, Big Data solutions utilising Machine Learning and Deep Learning.
Prior to joining JCRA I spent 14 years as an independent consultant working on implementations of investment banking risk management systems and regulatory driven market infrastructure solutions. I have a Bachelor's degree in Engineering and a Postgraduate Diploma in Software Engineering.


text: Richard Valdez earned bachelor degrees in History, English and Education from Western State University in Gunnison, Colorado, and a master's degree in Educational Leadership from the University of Colorado, Colorado Springs. Teaching writing at the elementary and secondary level provided him many opportunities to develop his love of storytelling. He lives with his wife in rural Colorado.


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It's no secret that we are living in a noisy online world.
Now more than ever, with an overload of information, it is becoming increasingly difficult to filter what we find in search of our own true voice.
With a proven past of finding his feet off the well worn path, Tyger provides a balanced approach to presenting that marries entertainment with engagement and insight with inspiration.
By shedding light through the lens with which he has lived his life thus far, he provides an alternative perspective and authentic approach to the day to day which cultivates positive change across his world wide audience both online and more recently at events.
After traveling to over 35 countries working on creative campaigns with brands such as Sony, Omega, Nautica and Calvin Klein, Tyger retired from life as a world renown travel influencer after three years. He coined the phrase "Live your dream, not the dream" and continued on a mission to reach the limits of his physical capabilities through his qualification into the 2019 Ironman 70.3 World Championships in Nice, France.
He is also a health and wellness figurehead to many as a committed vegan for over three year as well as a popular podcast host, playing anchor on the recently rebranded "The Den FM" conducting interviews with the action oriented leaders from the millennial generation across the health, fitness, photography, business and social media sector.
With multiple keynote, MC, presenting and public appearance roles under his belt - his authentic approach, ability to engage and profound hold of rooms with large audiences; coupled with his ability to connect, communicate and leave an everlasting change to audiences of all demographics has him in the early phases of a career as a highly sought after appearance professional.
For any details pertaining to hiring Tyger for your event or occasion, fill out the form below.


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For the last week or two, my Xnet connection seems to be very slow compared to what it has been.
While my speed seems to stay steady around the 2Mbit/s mark (day AND evening - which is strange, because before this I could get 3-4Mbit/s easy during the day), often at night general web browsing seems to be a very slow (eg: pages take forever to load etc.) Also streaming media seems to be a bit problematic (needing to pause to buffer etc).
Also, looking at the ADSL stats from my router gives some rather worrying numbers.'
The router has be on for: 3 days 7 hours 28 minutes 24 seconds
There are 303 errored seconds
CRC errors: 1137
Data rate: 8128kbps
The SNR margin and line attenuation looks fine at 13-16db and 23.3db respectively.
It seems to be a very large number of errored seconds and CRC errors for the length of time that the router has been on for.
I do have interleaving OFF, however these seem to be the sorts of figures I'd expect after more than a week - not just over 3 days.
Even if these figures are acceptable, I have certainly noticed a significant decrease in my connection quality over the last couple of weeks.
My routers configurations have not changed (as my ADSL router is connected to a wireless router [im connected to that via ethernet cable])
The ADSL router is the DSE XH1173. Wireless router is netgear WGR614 v7
Both routers are rock solid stable and haven't give me any problems.
Am running Windows XP SP2 (fully updated) and using Firefox 220.127.116.11
XP has been reinstalled a couple of times over the last couple of weeks, so whether this has any relavence or not I don't know. I am also using a different firewall (zonealarm as opposed to kerio and comodo that I had used before)
Anyone any ideas as to what the problem could be?


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Homes for Mythical Creatures
The myth of our separation from animals is compounded by stables and leashes, cages and zoos. Our view of animal life is centered on human needs. How could it not be? Our job is too rethink a positive interaction with animal life. We control animals by making them mythical creatures, objectified- the horse and cow, the griffin and centaur, the baby gorilla. The dodo is still with us, we shoot him everyday. As the species that has the power to drive mass extinction, we must realize our responsibility to live with and foster life. We must embrace our stewardship of animals and understand how they are used, vilified, celebrated and mythologized. We can make space for animals in the city, edges of our urban environments and infrastructure. Architecture has the means to empower, through relatively simple measures to reconnect with animal species.


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912 Bluerock Dr, ANTIOCH
Open House Saturday 10/19 from 1 to 2 PM Remodeled 3 Bedroom, 2 Bathroom and 1075 Sq Ft. New Carpet, Lights and Outlets. Laminate Wood Floors in Kitchen with Granite Counter tops, New Appliances and Plenty of Cabinet Space. New Lawn in Front & Backyards with Shed and RV Parking. 2 Car Attached Garage and Close to Parks, Shopping and Restaurants. Rent Includes Gardener
Attached Garage, Int Access From Garage, Side Yard Access, RV/Boat
Ceiling Fan(s), Central 1 Zone A/C
Brick, Family Room, Woodburning
Composition Shingle, Dual Pane Windows, Stucco
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Environmental Stewardship
A grassroots initiative involving real grass and real roots, the Environmental Stewardship Committee is parishioner-established, parishioner-led, and pre-dates the 2009 general convention mandate to establish a liturgical Creation Cycle.
Early programs included ways to reduce the congregation's carbon footprint and environmental tips to promote sustainability. Today, the committee's influence has grown to encompass the stewardship of all life—self and planet.
The committee was instrumental in making the Chapel of the Cross the first church in the diocese of North Carolina to adopt the House of Bishops' Pastoral Teaching on the Environment, encouraging parishioners to speak and act on behalf of God's good creation.


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A SHAKESPEAREAN tragedy of hatred, murder and cruelty, Titus Andronicus will be at the city's Unity Theatre for two days only - today and tomorrow.
What does TA stand for?
TA stands for Titus Andronicus
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And when Stickles backs away from the narrative somewhat, there are moments in which Titus Andronicus sounds more in line with, say, the Gaslight Anthem, another New Jersey somewhat-punk band, although one with a more focused sense of songcraft and storytelling, and one less apt to ramble than Titus Andronicus has been.
If you don't know the play Titus Andronicus you'll laugh for an hour.
Richard Fahey, trainer of Titus Andronicus and Sloop Johnb "Titus Andronicus has had two injuries.
Martyred Bodies and Sacred Space Readings of Shakespeare's grim drama of mutilation Titus Andronicus have time and again focused on the play's marred bodies.
Byline: Andrew Pain NEW Jersey rock'n'rollers TITUS ANDRONICUS arrive on Teesside on Wednesday as part of their British tour.


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|Microsoft was founded by Bill Gates and Paul Allen on April 4, 1975, to develop and sell BASIC interpreters for Altair 8800. It rose to dominate the personal computer operating system market with MS-DOS in the mid-1980s, followed by Microsoft Windows. The company's 1986 initial public offering, and subsequent rise in its share price, created three billionaires and an estimated 12,000 millionaires from Microsoft employees. Since the 1990s, it has increasingly diversified from the operating system market and has made a number of corporate acquisitions. In May 2011, Microsoft acquired Skype Technologies for $8.5 billion in its largest acquisition to date.
|Zimbra Collaboration Suite is a collaborative software suite, that includes an email server and web client, currently owned and developed by Zimbra, Inc. Zimbra was initially developed by Zimbra, Inc., and first released in 2005. The company was subsequently purchased by Yahoo in September 2007, According to former Zimbra President and CTO Scott Dietzen, the name for Zimbra is derived from the song "I Zimbra" by Talking Heads.
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Yammer: Verizon, Rakuten,Nationwide, DHL, Westfield, Telefonica, 7-Eleven, Red Robin, Intuit, eBay,Darden, Suncorp, Tyco, Xerox, and ModCloth.
Microsoft Office SharePoint Server: Del Monte Foods, Unicredit Leasing, Dudley Metropolitan Borough Council, Nokia Czech Republic, Perkins Eastman, JLL, ICA, óxito Software, Dorset Software, PKP Cargo, Arcapita Bank B.S.C., AVE CZ, Chesapeake Energy
Microsoft 365 Business: Urban Agriculture Co., The Detroit Wallpaper Co., TransBlue Facility Management, Garner Food Company
Microsoft Teams: Honeywll, AIRFRANCE, AccuWeather, Lilly
Microsoft Exchange: Paderborn-Lippstadt Airport, Scitec Nutrition, British Airways, InnoGames, Osteology Foundation, Franz Haniel & Cie. GmbH, NTC Contracting
Microsoft Exchange Online: Bank Alfalah Ltd., Paderborn-Lippstadt Airport, Blue Star Infotech, Scitec Nutrition, Resolution Films, British Airways, Empire Cinemas, InnoGames
Zimbra Social: Escorts, Wasgau & VNC, UniMAP, HOLA, Ring Line, TIGC, Xmission, Lafayette College, Future Group, Sheela Foam
Zimbra Collaboration: NEC Biglobe, City of Ventura, Monterey Bay Aquarium Research Institute, Hola Publishing, BIG, Sleepwell, LaFayette College, Xmission, DNA, Ring Line, Future Group, TIGC
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A winter morning… freezing cold… the mist is still floating over the marshland… you can already smell the coast and wadden sea. I have to move faster to reach the coastline before the fog is gone.
This is image #2 of 4 of my series: Minimalism
A winter morning… freezing cold… the mist is still floating over the marshland… you can already smell the coast and wadden sea. I have to move faster to reach the coastline before the fog is gone.
This is image #2 of 4 of my series: Minimalism
A reworked version of the "Rolling Hills" of Devon. Spectacular view and stunning landscape. Can't beat that!
If you like it, please follow me on Instagram.
There will be a few changes. Starting with the image above, all images posted, will show the visible watermark – Reinhold Staden Photography – in the center. I am sorry, but I found several places in the internet where my images have been misused – without permission -. You can even download them "for free". This is definitely over now. In addition my images are also tagged with "Copyright" information on the file basis in any possible form. In my blog and other internet platforms I will post a 1:1 – 1080 x 1080px (72dpi) format (Instagram). I am sorry for the disturbing watermark but obviously there is no way around. I hope you will still like my images. Reinhold
© RSP – Reinhold Staden Photography
October 2016
It is sunny, but still quite cold over here. I headed off for a neighborhood walk this morning. All photos are taken in a range of 3-5 miles from where we live. I used my old Fuji X100. It is light, small and I can put it into my jacket. I used the film simulation B&W Red, ISO L100 and the JPG format. So most of the development work is done in camera. I wanted to do something different today. I used LR for post and worked mainly with the "Clarity" slider. I normally push the slider a fraction to the right. So it will sharpen the images a bit. This time I pushed it to the left. To the ultimate left. I am still discussing this with myself. My brain doesn't like it, but my stomach and heart does. The landscape of the Ammerland is special and I think this technique boosts this special character a bit more. Enjoy the virtual walk in my neighborhood. Hope you like it! Smiles. Reinhold
Design, Grafiken und Fine Art
Stories and photos from Scotland
"It's never too late to become what you might have been."......................George Elliot
Photography - Oman & UK.
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Health, Lifestyle, Photography, Travel
Digital & Film Photography - Platinum/Palladium Printing
Die Poesie des Augenblicks - Photography
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Candida spp. are opportunistic fungal pathogens that are among the most common causes of nosocomial bloodstream infections. The mortality attributable to disseminated candidiasis is 40 to 50% despite antifungal therapy. Clearly, new strategies are needed to prevent this life-threatening infection. Because risk factors for disseminated candidiasis are well defined and frequently of limited duration, vaccination is an appealing prophylactic strategy. We have identified a cell surface protein, Als1p, that mediates adherence of Candida albicans to a variety of human substrates and plastic. Here we report that immunizing BALB/c mice with the recombinant N-terminal domain of Als1p (rAls1p-N) improved survival during a subsequent challenge with a lethal inoculum of C. albicans. The protective 20-μg dose of rAls1p-N significantly increased Candida stimulation of Th1 splenocytes and increased in vivo delayed-type hypersensitivity. In contrast, antibody titers did not correlate with protection. Finally, the vaccine was not protective in T-cell-deficient mice but was protective in B-cell-deficient mice. These data indicate that the mechanism of action of the rAls1p-N vaccine is stimulation of cell-mediated, rather than humoral, immunity against C. albicans. The majority of efforts to date have focused on the development of passive immunization strategies to prevent or treat disseminated candidiasis. In contrast, our results provide proof of principle for vaccination with an adhesin of C. albicans and emphasize the potential for cell-mediated immune modulation as a prophylactic or therapeutic strategy against disseminated candidiasis.
Candida spp. are the fourth most common nosocomial bloodstream isolates (53). The mortality attributable to disseminated candidiasis is 40 to 50%, even with modern antifungal therapy (16, 34, 40, 65). Furthermore, development of resistance to conventional antifungal therapies has created concern regarding the future ability to treat infections caused by Candida spp. (9, 23, 38, 63). Clearly, new strategies to prevent Candida infections are needed.
The major clinical risk factors for developing disseminated candidiasis have been well described (58). These key risk factors include colonization with the organism, gastrointestinal or cardiac surgery, a prolonged stay in an intensive care unit, burns, and use of central venous catheters, broad-spectrum antibiotics, and parenteral nutrition. Patients with these risk factors are extremely common. For example, they constitute the large population of patients recovering from surgery or those hospitalized in medical intensive care units for treatment of cardiac and respiratory failure. These patients are not profoundly immunosuppressed by cancer chemotherapies or drugs to prevent organ transplantation; they are likely to respond favorably to a Candida albicans vaccine. A smaller population of patients at risk for disseminated candidiasis includes those who are immunocompromised by cancer, neutropenia, corticosteroid use, or human immunodeficiency virus. While these patients may be less likely to respond to vaccination, there is extensive precedence for the efficacy of a variety of vaccines in these patient populations (1, 8, 10-12, 17, 24-27, 29, 30, 33, 39, 46, 52, 55, 56, 61, 62). Hence, these patients may also be considered candidates for vaccination.
Because the risk factors for disseminated candidiasis are often identifiable in patients prior to the development of infection, vaccination of these selectable, high-risk patients to prevent the onset of disseminated candidiasis is an appealing strategy. Furthermore, many of these risk factors are of relatively short duration, generally 4 to 6 weeks. Therefore, an immunization approach would need to protect patients for the short period of time during their increased susceptibility, in contrast to periods of years for vaccines such as those against tetanus, Streptococcus pneumoniae, and Haemophilus influenzae.
While searching for a dominant adhesin in Candida, by using surrogate genetics, we found that the protein product of the agglutination-like sequence 1 (ALS1) gene is an adhesin that mediates C. albicans binding to human cells (13, 14). ALS1 is a member of a gene family composed of eight identified members (67). We and others have determined that Als proteins function as adhesins to biologically relevant substrates (13, 15, 32, 54). Consistent with their structural homology to the immunoglobulin superfamily, we have found that the substrate specificity of distinct Als proteins is determined by their N-terminal regions (32, 54). The recombinant N-terminal domain of Als1p (rAls1p-N) is an appealing candidate for use as a C. albicans vaccine because it is expressed at the cell surface (32), because antibody directed against it eliminates C. albicans adherence to endothelial cells (32), and because of its potential immunological cross-reactivity with other members of the Als family of proteins (54).
In these studies, we verified the potential for rAls1p-N to serve as an anti-Candida vaccine. The efficacy of the rAls1p-N immunogen was evaluated in a murine model of hematogenously disseminated candidiasis. Also, the mechanism of vaccine-mediated protection was identified.
C. albicans and mice strains.C. albicans SC5314, a well-characterized clinical isolate that is highly virulent in animal models (59), was supplied by W. Fonzi (Georgetown University). The organism was serially passaged three times in yeast peptone dextrose broth (Difco) prior to infection.
Female BALB/c mice were obtained from the National Cancer Institute (Bethesda, Md.). To explore the impact of age on vaccine efficacy, both juvenile mice (8 to 10 weeks old) and retired breeders (≥6 months old) were used. Female B-cell-deficient mice bearing a homozygous deletion of the igh loci (C.129B6-IgH-Jhdtm1Dhu), T-cell-deficient nude mice (C.Cg/AnBomTac-Foxn1nuN20), and congenic wild-type BALB/c littermates were obtained from Taconic Farms (Germantown, N.Y.). Mice were housed in filtered cages with irradiated food and autoclaved water supplied ad libitum. For survival experiments, mice were immunized with various doses of antigen (see below) and subsequently infected via the tail vein with the appropriate inoculum of C. albicans SC5314 blastospores or a phosphate-buffered saline (PBS; Irvine Scientific, Irvine, Calif.) control. Results of replicate survival studies were combined if the individual data sets demonstrated no statistical heterogeneity (see below). All procedures involving mice were approved by the institutional animal use and care committee, in accordance with the National Institutes of Health guidelines for animal housing and care.
rAls1p-N immunization protocol.rAls1p-N (amino acids 17 to 432 of Als1p) was produced in Saccharomyces cerevisiae and purified by gel filtration and Ni-nitrilotriacetic acid matrix affinity purification (13). The amount of protein was quantified by modified Lowry assay. A high degree of purity (∼95%) was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, as well as circular dichroism and Fourier transform infrared spectroscopy, as previously described (54). Mice were immunized by intraperitoneal injection of rAls1p-N mixed with complete Freund's adjuvant (CFA; Sigma-Aldrich) at day 0, boosted with another dose of the antigen with incomplete Freund's adjuvant (IFA; Sigma-Aldrich) at day 21, and infected 2 weeks following the boost.
rAls1p-N ELISA.Antibody titers were determined by enzyme-linked immunosorbent assay (ELISA) in 96-well plates. Wells were coated at 100 μl per well with rAls1p-N at 5 μg/ml in PBS. Mouse sera were incubated for 1 h at room temperature following a blocking step with Tris-buffered saline (TBS; 0.01 M Tris HCl [pH 7.4], 0.15 M NaCl) containing 3% bovine serum albumin. The wells were washed three times with TBS containing 0.05% Tween 20, followed by another three washes with TBS. Goat anti-mouse secondary antibody conjugated with horseradish peroxidase (Sigma) was added at a final dilution of 1:5,000, and the plate was further incubated for 1 h at room temperature. Wells were washed with TBS and incubated with substrate containing 0.1 M citrate buffer (pH 5.0), 50 mg of o-phenylenediamine (Sigma), and 10 μl of 30% H2O2. The color was allowed to develop for 30 min, after which the reaction was terminated by addition of 10% H2SO4 and the optical density (OD) at 490 nm was determined in a microtiter plate reader. Negative control wells received only diluent, and background absorbance was subtracted from the test wells to obtain final OD readings. The ELISA titer was taken as the reciprocal of the last serum dilution that gave a positive OD reading (i.e., more than the mean OD of negative control samples plus 2 standard deviations).
C. albicans-induced cytokine profiles.To determine the effect of the rAls1p-N vaccine on cell-mediated immunity and in vivo cytokine profiles, mice were immunized as described above. Two weeks after the final boost, splenocytes were harvested and cultured in complete medium at a density of 4 × 106 cells/ml as previously described (59). To stimulate cytokine production, splenocytes were cocultured with heat-killed C. albicans SC5314 germ tubes. We used heat-killed C. albicans in lieu of rAls1p-N to stimulate the splenocytes to mimic the in vivo situation during infection. The C. albicans cells were pregerminated in RPMI 1640 medium with glutamine (Gibco BRL) for 90 min to induce expression of Als1p (13). The resulting C. albicans germ tubes were heat killed by incubation for 90 min at 60°C (22). The heat-killed fungal cells were added to the splenocyte cultures at a density of 2 × 107 pseudohyphae/ml (a ratio of five fungal cells to one leukocyte). After 48 h, splenocytes were profiled for Th1 (CD4+ IFN-γ+ [gamma interferon positive] IL-4− [interleukin-4 negative]), Th2 (CD4+ IFN-γ− IL-4+), or CD4+ IL-10+ frequencies by intracellular cytokine detection and flow cytometry as previously described (59). Three-color flow cytometry was performed on a Becton Dickinson FACScan instrument calibrated with CaliBRITE beads (Becton Dickinson, San Jose, Calif.) with FACSComp software in accordance with the manufacturer's recommendations. During data acquisition, CD4+ lymphocytes were gated by concatenation of forward and side scatter and fluorescein isothiocyanate-conjugated anti-CD4 antibody fluorescence properties. Data for each sample were acquired until 10,000 CD4+ lymphocytes were analyzed. Results are presented as the median ± the 25th and 75th quartiles of the percentage of all gated lymphocytes that were Th1 or Th2 cells.
Footpad swelling.Footpad swelling was determined by the method of Oomura et al. (41). Briefly, mice were immunized with the appropriate dose of rAls1p-N or CFA alone as described above. Two weeks following the boost, baseline footpad sizes of immunized mice were measured with an electronic digital caliper. Fifty micrograms of rAls1p-N in 25 μl of PBS was injected into the right footpads and PBS alone was injected into the left footpads of the immunized mice. Twenty-four hours later, the footpads were again measured. Antigen-specific footpad swelling was calculated as follows: (right footpad thickness at 24 h − right footpad thickness at baseline) − (left footpad thickness at 24 h − left footpad thickness at baseline).
Statistical analysis.The nonparametric log rank test was used to determine differences in the survival times of the mice. Titers of antibody, frequency of Th1 or Th2 lymphocytes, and footpad swelling were compared by the Steel test for nonparametric multiple comparisons (47) or the Mann-Whitney U test for unpaired comparisons, as appropriate. Correlations were calculated with the Spearman rank sum test. To determine if heterogeneity existed in replicate survival studies, the Kolmogorov-Smirnov test was used. P values of <0.05 were considered significant.
An intermediate dose of the rAls1p-N vaccine induces protection against murine disseminated candidiasis.To determine the most effective dose of the rAls1p-N immunogen, a 107-fold dose range was evaluated (20 pg to 200 μg per mouse). Female retired breeder BALB/c mice were immunized with rAls1p-N plus adjuvant (CFA or incomplete Freund's adjuvant) or with adjuvant alone. Immunized mice were bled 2 weeks after boosting to determine anti-rAls1p-N antibody titers (see below). The mice were subsequently infected with a lethal inoculum of C. albicans (2 × 105 blastospores). The survival data from repeat experiments were combined since the individual experiments demonstrated no statistical heterogeneity (P > 0.05 by the Kolmogorov-Smirnov test). The 20-μg dose of rAls1p-N resulted in long-term survival of 25% of the infected mice and a significant increase in overall survival compared to that obtained with adjuvant alone (P = 0.044 by log rank test, Fig. 1). Neither 10-fold higher (Fig. 1) nor lower (data not shown) doses significantly increased survival compared to that obtained with adjuvant alone.
The above findings established a protective dose for the rAls1p-N vaccine. Next we evaluated the efficacy of the vaccine in a more rapidly lethal model of mice infected with 106 blastospores (median survival, 3 versus 11 days for 106- versus 2 × 105-blastospore inocula in unvaccinated mice, respectively). Again the data from repeat studies were combined as the results of the individual experiments demonstrated no statistical heterogeneity (P > 0.05 by the Kolmogorov-Smirnov test). When administered as a 20-μg dose plus CFA to BALB/c mice infected with 106 C. albicans blastospores, the rAls1p-N vaccine more than doubled the median survival and resulted in a significant increase in overall survival versus that of unvaccinated controls (P = 0.001 by log rank test, Fig. 2A). To determine if the age of the mice influenced their response to the rAls1p-N vaccine, we tested it in juvenile mice. A similar survival benefit was found when juvenile mice were vaccinated and infected with the same high inoculum (P = 0.02 by log rank test, Fig. 2B).
Protection induced by the rAls1p-N vaccine did not correlate with antibody titers.Although the 200-μg dose of rAls1p-N resulted in inferior protection compared to the 20-μg dose, only the 200-μg dose of antigen induced a significant increase in serum anti-Als1p antibody titers (P ≤ 0.005 for the 200-μg dose versus all other groups, Fig. 3). No significant increases in anti-Als1p antibody titers were detected at the intermediate, protective antigen dose (P = 0.1 for the 20-μg dose versus adjuvant). When the serum anti-Als1p antibody titers of individual mice were plotted against the survival time of each mouse, no correlation between antibody titer and survival was found (R2 = 0.03, P > 0.05 by the Spearman rank sum test). Indeed, mice immunized with the highest dose of antigen (200 μg) had anti-rAls1p-N antibody titers in excess of 1:100,000 but had survival durations no different from those of mice immunized with lower doses of antigen, whose titers were at the lower limit of detection (∼1:100).
Only the protective dose of the rAls1p-N antigen induced significant Th1 polarization and a delayed-type hypersensitivity reaction.Since humoral immunity did not correlate with rAls1p-N-induced protection, we examined the cell-mediated immune response induced by protective and nonprotective doses of rAls1p-N. Mice were immunized with 0.2, 20, or 200 μg of rAls1p-N or with adjuvant alone as described above. Two weeks after the boost, splenocytes were harvested and cultured in the presence of heat-killed, pregerminated C. albicans, which is known to express Als1p (13). Following 48 h of culture, splenocytes were harvested for intracellular cytokine detection by flow cytometry. Only the lymphocytes from mice immunized with the protective 20-μg dose of antigen developed a significantly increased frequency of Th1 cells compared to mice given adjuvant alone (P = 0.03, Fig. 4). No significant differences in Th2 frequency (Fig. 4) or in the frequency of IL-10+ T lymphocytes (data not shown) were detected between mice immunized with adjuvant and those that received any of the doses of antigen.
To confirm that type 1 immunity was stimulated by r-Als1p-N in vivo, delayed-type hypersensitivity was tested by measuring footpad swelling. Only mice vaccinated with the protective 20-μg dose of rAls1p-N developed a significantly increased delayed-type hypersensitivity reaction compared to the control, and this response was also significantly greater than that induced by the nonprotective 0.2- and 200-μg doses (Fig. 5, P < 0.05 for all comparisons versus the 20-μg dose by the nonparametric Steel test).
The Als1p vaccine is effective in B-cell-deficient mice but not in T-cell deficient nude mice.To define the role of antibody and T cells in vaccine-mediated protection, B-cell-deficient, T-cell-deficient nude, or congenic BALB/c wild-type control mice were immunized with 20 μg of rAls1p-N plus adjuvant or given adjuvant alone and infected with a lethal inoculum (8 × 105 blastospores) of C. albicans. B-cell-deficient mice tended to be more resistant to infection, whereas T-cell-deficient mice were more susceptible, than were wild-type control mice given adjuvant alone (P = 0.065 and 0.01 for B-cell-deficient and T-cell-deficient mice versus adjuvant-treated wild-type mice, respectively, Fig. 6). Finally, the rAls1p-N vaccine maintained its efficacy in B-cell-deficient mice (P = 0.04 for rAls1p-N vaccination versus adjuvant alone, Fig. 6) but was ineffective in T-cell-deficient mice (P = 0.4 for rAls1p-N vaccination versus adjuvant alone, Fig. 6).
By using surrogate genetics, we identified a cell surface adhesin, Als1p, that mediates binding of C. albicans to host constituents including human endothelial and oral epithelial cells (13, 14, 32, 54). Herein we report proof of principle that immunization with the N terminus of this protein improved the survival of both juvenile and mature BALB/c mice during subsequent hematogenously disseminated candidiasis. Interestingly, an intermediate dose of rAls1p-N (20 μg) provided superior protection compared to both lower doses and a higher dose (200 μg). Nevertheless, the nonprotective 200-μg dose of rAls1p-N was immunogenic, as it induced 100-fold higher titers of antibody than did the protective 20-μg dose.
The inverted-U-shaped dose-response efficacy curve, with lower protection at the highest dose of rAls1p-N, is reminiscent of the classical studies of Parish and of Parish and Liew, who first described the inverse relationship between the induction of humoral and cell-mediated immunity by a given dose of antigen (42-44). In the context of Parish's seminal data, an inverted-U-shaped dose-response efficacy curve could be explained if (i) vaccine efficacy depended on cell-mediated immunity and (ii) intermediate doses of rAls1p-N stimulated superior cell-mediated immunity compared to the high, antibody-stimulating dose. We therefore hypothesized that the inverted-U-shaped dose-response efficacy curve seen with the rAls1p-N vaccine was due to superior induction of cell-mediated immunity by the protective, intermediate doses of antigen.
To test this hypothesis, the abilities of high, intermediate, and low doses of antigen to stimulate Th1 cells and delayed-type hypersensitivity were determined. To stimulate cytokine production from splenocytes, we specifically activated the cells by exposure to heat-killed C. albicans, instead of rAls1p-N, to mimic the in vivo situation during infection. Only the protective 20-μg dose significantly increased the frequency of C. albicans-stimulated splenic Th1 lymphocytes. The frequency of Th1 cells seen in ex vivo C. albicans-stimulated splenocytes was similar to that detected in vivo during disseminated candidiasis in mice (59), underscoring the relevance of this approach.
To determine if the detected ex vivo Th1 cells were of functional significance in vivo, we compared the delayed-type hypersensitivity responses induced by different doses of rAls1p-N immunization. Concordant with the frequency of Th1 cells, only the protective 20-μg dose of rAls1p-N stimulated a significant in vivo delayed-type hypersensitivity reaction. These results are consistent with the hypothesis that vaccine-induced protection was due to induction of type 1 cell-mediated immunity. Surprisingly, despite induction of markedly elevated antibody titers by the 200-μg dose of rAls1p-N, we did not find an increase in splenic Th2 lymphocytes in mice vaccinated with this dose. One possible explanation is that Th2 cells were activated in peripheral lymph nodes rather than the spleen. Alternatively, other T-cell populations (e.g., NKT cells) may have been responsible for inducing the high antibody titers seen in response to the 200-μg dose of rAls1p-N.
The lack of correlation between antibody titer and protection did not completely exclude a role for antibodies in mediating vaccine-induced protection. For example, ELISA titers are the result of enumeration of antibodies with a variety of specificities and affinities. Therefore, the possibility that small subsets of antibodies were generated that did participate in vaccine-mediated protection could not be excluded by measuring antibody titers. To confirm the role of cell-mediated and not humoral immunity in rAls1p-N vaccine-mediated protection, we tested the efficacy of the vaccine in B-cell- and T-cell-deficient mice. B-cell-deficient mice tended to be more resistant to disseminated candidiasis than did wild-type controls, and the efficacy of the vaccine was not eliminated in B-cell-deficient mice. In contrast, T-cell-deficient mice were more susceptible to disseminated candidiasis than were wild-type controls, and the efficacy of the vaccine was lost in T-cell-deficient mice. Our findings therefore confirm that the efficacy of the rAls1p-N vaccine is dependent on induction of T-cell-mediated, and not humoral, immunity. Also, because B-cell-deficient mice were not more susceptible to disseminated candidiasis than their congenic wild type littermates were, antibody is not a dominant effector against disseminated candidiasis in this model. These results are consistent with previous reports, including the seminal studies by Romani et al. and Cenci et al., indicating that cell-mediated (type 1), rather than humoral (type 2), immunity is the key to host protection against murine disseminated candidiasis (6, 49, 57, 59).
Although we and others (28, 64) have found that B-cell-deficient mice are not more susceptible to candidemia than wild-type controls are, numerous studies have reported that passive immunization against C. albicans improves survival during murine disseminated candidiasis (18, 20, 45, 60). Indeed, a monoclonal antibody directed against a C. albicans heat shock protein (35) is currently in clinical trials. The paradox that exogenous antibody can mediate protection against infection even when normal host protection is due to type 1 cell-mediated immunity has been noted previously (57). One likely explanation of this paradox is that administration of exogenous antibody is not equivalent to induction of an endogenous type 2 immune response. Rather, passive immunization with exogenous antibody garners the benefits of a humoral response without the added deficit of IL-4-, IL-10-, and IL-13-mediated suppression of phagocytic activity (57). Such benefits mediated by the exogenous antibody could include serving as opsonins to assist activated phagocytes, as well as interfering with the ability of a pathogen to adhere to host tissues. Another potential explanation of the paradox that passive immunization is effective despite the lack of protection afforded by endogenous antibodies is the passive transfer of "protective" antibodies versus endogenous production of "nonprotective" antibodies, as described by Casadevall's group in murine models of Cryptococcus infection (5, 66). Similarly, Bromuro et al. have shown that mice vaccinated with heat-killed C. albicans produced antibodies that prevented protective immunity and that when these antibodies were adsorbed out of serum, the remaining antibodies were protective during passive immunization (2). Indeed, the lack of protection afforded by the high antibody titers induced by the 200-μg dose of rAls1p-N in our model may be due both to a lack of induction of protective cell-mediated immunity and to induction of antibodies that bind to nonprotective epitopes on C. albicans.
In sum, we report that the novel rAls1p-N vaccine mediates protection against experimental disseminated candidiasis by inducing cell-mediated rather than humoral immunity. Enhancement of the modest protective effect of the rAls1p-N vaccine may therefore be accomplished with additional priming of cell-mediated immunity with optimized adjuvants and/or cytokines or an alternate route of immunization. Indeed, in our ongoing studies we have already found a marked increase in efficacy by administering rAls1p-N subcutaneously rather than intraperitoneally.
Despite the extensive basic immunology literature indicating that cell-mediated immunity is the key to host defense against C. albicans infection (6, 7, 37, 48-51, 58, 59), to date applied immunotherapies against Candida infection have largely focused on the humoral immune system (3, 18-21, 31, 35). The few recent studies of active vaccination against disseminated candidiasis have reported dramatic protection (2, 4, 36). However, these studies focused on the use of whole-cell vaccines, which are less likely to be used clinically than protein vaccines. A mannan-conjugated active vaccine strategy was also described by Han et al. (21). In contrast, to our knowledge, this is the first demonstration of in vivo protection by immunization with an adhesin from C. albicans. Our data support the potential for protein-based vaccination to modulate cell-mediated immunity as a prophylactic or therapeutic strategy against disseminated candidiasis and provide a basis for the pursuit of additional strategies to selectively enhance the cell-mediated immune response.
This work was supported by Public Health Service grants PO1AI-37194 and RO1AI-19990 to J.E.E. J.E.E is also supported by an unrestricted Freedom to Discover Grant for Infectious Disease from Bristol Myers-Squibb. A.S.I. is supported by Public Health Service grant RO3 AI054531 and a Burroughs Wellcome New Investigator Award in Molecular Pathogenic Mycology. B.J.S. and S.G.F. are supported by Public Health Service grants KO8 AI060641-01 and R01 A1054928, respectively.
- Received 26 August 2004.
- Returned for modification 27 September 2004.
- Accepted 12 October 2004.
Editor: T. R. Kozel
- American Society for Microbiology


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