text: Santiago Chavez is a graphic artist, writer, painter and installation artist originally from Carlsbad, New Mexico. He was a scientist and avid outdoorsman before being found by art, and this previous life informs his practice to a great extent. Long observational walks, in which he photographs and sketches the environments he passes through, are a hallmark of this practice. These materials are then chewed up, regurgitated, redrawn, abstracted and masticated again before being painted. Santiago moved to New York City in 2010, and has since had his artwork exhibited in the Bronx, Chelsea, and Jersey City. Over the course of his time in NYC, he has run the gamut of art production, from working by night with local graffiti crews in Harlem and Washington Heights to constructing intricate site-specific installations drawing on New Mexican dreamscapes. He has also painted commissioned public murals and has begun to stage public performances. He has worked closely alongside some of the best artists, poets and musicians in the world, and he is immensely grateful for the experiences that his life thus far has offered him. Santiago graduated from the School of Visual Arts in 2016 with a BFA in Visual and Critical Studies. He is currently working as a freelance graphic designer, and is the operations manager at Name Your Game, an apparel shop in Long Beach, CA.


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X-ray tomograph with coordinate measuring machine TomoScope
Now with X-Ray Tomography
The TomoScope from Werth Messtechnik GmbH, Giessen, Germany, represents the first ever combination of an X-ray tomograph with a coordinate measuring machine. It thus allows the internal and external features of medical parts to be rapidly measured with the accuracy characteristic of coordinate measuring machines. The TomoScope is suitable for rapid initial sample inspection and for revalidating medical parts. Several hundred features can be measured in less than an hour. Thanks to the integration of grid tomography, even very small features can be measured with high resolution. The optional multisensor technology allows additional measurements to be made with high accuracy, and metrological validation to be performed on the workpiece itself.
Werth Messtechnik GmbH
Patents encourage innovation: Stay on the ball with the latest innovations in the plastics industry in our patents section.
Would you like to subscribe to our Newsletters on plastics technology and profit from the latest information?
You know the trade name but want to know the material manufacturer, type of polymer and delivery form? Search here!

subset: commoncrawl


text: Susan Cain's premise is that introverts are misunderstood, undervalued, and maligned in a world that worships extroversion. There are societal consequences to this and Cain backs up her claims with compelling research. One example is a section early in her book on the limits of brainstorming. Cain poses that brainstorming in groups is actually less effective than working alone and cites 40 years of research to prove it. The reasons?Read More


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Injuries, as well as deaths in the workplace, are often caused by accidents that happen when workers are using machinery. It is possible to avoid most of these accidents. The risk when using machinery will always be present, but you can definitely reduce the chance of an accident happening. Take the following steps at work and it will reduce the machinery-related injuries:
Supply and Wear Safety Gear
Not only should you supply all the necessary safety gear to your workers, but you have to ensure that they wear the safety gear at all times. By making it absolutely mandatory to use the safety equipment and wear the safety gear whenever the workers are near machinery or working with it, you will avoid almost all injuries.
Even staff members that are highly experienced in using the machinery should be forced to wear their safety gear. The best quality first aid kits and first aid supplies should always be readily available to all your staff. Stock up with all the first aid supplies and equipment that you think will be required in case of an accident.
Proper Training
All the machine operators in your business should be trained properly. If a worker does not understand how a machine works, it puts that person in a dangerous situation each time that he or she works with the machinery. Ensure that each worker fully understands how to operate the machinery to avoid any serious accidents. By frequently upgrading the training that each staff member receives, you will reinforce the essential safety procedures that are needed to operate each machine in a safe manner.
Supervision is Necessary
There should always be a supervisor to ensure that the workers operating the machinery are doing so in the safest manner possible. This will further guarantee that no injuries occur while people operate the machinery. New staff members should be supervised even more closely to avoid injuries and to steer clear of any reckless handling of the machinery.
Continuous Maintenance
The machinery need frequent maintenance to guarantee that they are safe to operate. If maintenance is not performed regularly, a small problem with the machinery could turn into a bigger problem, which could end up putting your workers at risk. Routine maintenance of your machinery will help to identify the machines that are getting to the end of their lifetime, or any other problems that could lead to the malfunction of the machinery.
Operating Machinery is a Serious Business
Individuals that operate machinery at your business should be focused at all times and take their work serious as well. When a worker concentrates on the work at hand and if he or she does not allow anything to distract him or her, the chances of making a mistake and being injured are remote.
It is extremely important that you make the effort to reduce the injuries caused by machinery at your business to zero. By taking absolute control of the safety issues at your workplace, you will be able to avoid serious injuries and even death, in the workplace.
Link to the following:
First Aid Kits


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Group of Latin America and the Caribbean 2020
Background Guide Coming in Jan. 2020
Welcome to UCBMUN XXIV! I am an Electrical Engineering and Computer Science major, an intern at Apple, a former intern at HP Inc., and a former Editor and Webmaster of the Berkeley Student Journal of Asian Studies. I also do research on non-linear dynamics and the use of analog computation on approximating NP-Hard problems. I was raised in Poway, CA where I co-founded our local high school's MUN team. In the little time I have not writing code, doing math, at MUN, or sleeping I get deeply confused about how I have free time and proceed to read fantasy books and play Dungeons and Dragons.
I am elated to have the opportunity to return as a Chair to UCBMUN, and even more elated to be facilitating debate on how Latin America will continue to grow into a better region of the world. Can this committee lay out a framework for an ever growing regional economy? For ensuring regional stability? For preventing refugee crises before they occur? I am optimistic that we'll hear new ideas and create a new vision for the region.
Parth Nobel
Chair, Group of Latin America and the Caribbean 2020
I am currently a senior in UC Berkeley, studying Peace and Conflict Studies and Political Economy. After having been in this club since my freshman year, I have to say that UCBMUN has become like a family to me with individuals who are truly inspiring and caring. I was born in Los Angeles, California, and grew up there till I was nine years old. Afterwards, my family and I moved to China and lived there in several different provinces for the next eight years. My hobbies include exploring new areas with friends, playing video games, watching oddly specific documentaries, and hanging out with my girlfriend. I am honored to serve as your co-chair for this committee, and I promise to do my best to facilitate constructive and engaging debate. Latin America's future has so much potential as a new decade comes around the corner, but in order to move forward, its countries must come together to solve key issues. I look forward to seeing how this committee comes together to form innovative solutions and promote negotiations.
Kenny Kang
Chair, Group of Latin America and the Caribbean 2020


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Hoping I get a response here because I really don't see much activity in this forum.
I would like a Jagex's Ace of Spades Deuce skin for BUILD AND SHOOT. Not OpenSpades, but Build and Shoot. If you don't know what I'm talking about, look at this.
http://aceofspadeswiki.info/w/images/a/ ... yGreen.png
A uniform with bags all over it. There is also a backpack.
Request for Deuce Reskin
Ask others for their services or be of service to others.
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Guys really, really like to hear that. How about I do a free in-depth video profile critique for you as long as I can show it on my site. Analytical, kinesthetic thinker The spotlight is not my friend. Women are very attracted to intelligence. Relocating for the right person is definitely an option.
This statement has no purpose whatsoever. Howdy I know the post was a bit long because of the examples so I think you may have skipped several awesome profiles. For even more short dating profile examples, click here. You are beautiful, kind, compassionate, intelligent, witty, wonderful, giving, generous, self-assured, modest, humble, outgoing, shy, etc. Thousands of guys have already made lasting connections with beautiful women, and we're ready to make you our next success story.
He has a great sense of humor and comes off as goofy but real. His confidence comes out through his sense of humor. We keep ourselves a mystery partly because women like that and partly because we are afraid we might say something about ourselves that will make a woman judge us and never even wish to meet us.
Anyway it was really a triple whammy on boldness, because of my fear of flying, traveling to a new country solo and first date jitters all rolled into one. One caveat to this though Dustin is that too many guys are complete pushover pleasers and are scared to mention even the main things they find most important for fear of running off a girl. Dustin and Mike are spot on.
Dear Radio, You are hilarious! Second, a cookie-cutter profile is, by definition, speed dating tyne and wear going to be a bit generic. This rule holds true for any type of profile. He starts off his profile by being humorous and even a bit on the mysterious side.
Start With The Basics
How to meet women online
Knows how to treat a lady, ready for a long term relationship this would sound a bit too eager or even desperate to most guys. And the more attractive the woman, the fiercer the competition. Need more motivation to care about grammar? For even more OkCupid profile tips that will help you crush the competition, check out this article. Take the quiz for instant enlightenment!
Dating profiles three awesome examples you can learn from - eharmony
Like a good recipe, an awesome dating profile is all about a combination of ingredients working in your favour. There is no big secret to success when it comes to online dating profiles. Online Dating Profile Examples for Men. If you recognize yourself in some of them, I think it might be worth taking the time to keep on reading my profile. All profiles repeat the same.
Another issue with playing it safe and trying to cast a wide net is that you force the girl to switch her screening process over to depend more heavily on superficial things like looks, height etc. You want to look like an attractive prospect in more than just your photos. Did I make them feel stupid with my lack of tactfulness? You also want to be aware of certain words that will attract men. Someone to remember the days with, and to grow with.
The comedian
Many of them are looking for a special connection with a special woman. What city would you like to find dates in? Again thank you for your advice. Just fill in the missing info and boom!
Taking care of others, helping people, and making people smile. While each of the sample profiles below is specific to a gender, the core elements remain the same. Best to keep things brief. What's your current relationship status?
Good Dating Profile Examples
Old fashioned to a certain degree. As the editor-in-chief of DatingAdvice. Including your specific sense of humor is important. Lots of people say shorter is better, but as a girl looking at one, I want more than just a picture, personally. Your dating profile headline is the short phrase that usually appears next to your photo.
But in no way is he a pushover or worse yet, boring. Also, marriage not dating thai sub I would love to be blessed with the lady of my life. We handle the messages and set up the dates too!
Editorial opinions expressed on the site are strictly our own and are not provided, endorsed, or approved by advertisers. Remember, trust builds attraction, messaging instant which increases the odds of her agreeing to meet you in person. You need to give her a reason to believe it. How old are the oldest women you'd like to meet and date?
Make her want to keep reading. It goes back to evolution and the way women are wired. This would make the reader believe that she is not looking for anyone special, but just someone to kill time with and subdue her loneliness. What happened to the Top Secret profiles? It is more about him being secure with his masculinity and having fun with it at the same time.
The worst thing you could do is use old photos of yourself. Tofino is magic, I first learned to surf there. He is searching for love and putting himself out there. Compatibility criteria apply. Most women like the notion of being grabbed hard and kissed soft, and this fellow looks like he can get the job done.
4 Online Dating Profile Examples (To Attract Men)
Having high expectations exudes confidence, and confidence is an attractive trait. If selected, how soon can you be ready to start meeting the matches we hand-pick for you? Have you ever seen it in a movie when a hot actor has to reveal his naked ass? Smartphones have some awesome camera capabilities now, so get your best friend to take updated photos of you and help you determine what pose and background looks good.
- Fa M ily and friends A re impo R tanT to me as well.
- This guy shares an enduring story of his first attempt at on-line love.
- When I stopped trying to please everyone and learned to communicate my main needs without worrying about who I was going to push away, I started attracting the type of women that I really fit with.
- So your saying a male model got more emails than you did with the same profile.
- Not really any responses but much more interest.
- So your profile needs to stand out from all those other guys if you want her to send a message your way.
- Not only are selfies way overplayed, but they really only make sense in the context of a social media site like Instagram.
- Guys know women are extremely judgemental creatures and will judge everything and anything about a guys profile.
Struggling to come up with the perfect profile to attract women
The studio version sounds neutered. But having the perfect dating profile is just the first step in the process. This guy has a zest for life and is all about positive energy, so much so, that when you read his profile, it puts you in a good mood. See how it looks like she just rolled out of bed late for Sunday brunch with the girls? First, meet a guy, then decide what you want out of him.
You also have the opportunity to add even more topics to your OkCupid profile if you wish. He represents the kind of guy that will keep me in stitches and feeling good. This guy is a walking dichotomy. Along with key review factors, this compensation may impact how and where products appear across the site including, for example, the order in which they appear.


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Subject: Re: OpenC2 Language Specification draft for approval
To progress a working draft to CSD a simple motion suffices and triggers the public review for people outside of the TC like so (in the suggested It is for CS where a ballot is required. Sample motion in the current case could be: "I move that the TC approve the OpenC2 Language Specification V1.0 Working Draft 03 and all associated artifacts packaged together in https://www.oasis-open.org/committees/download.php/61772/oc2ls-v1.0.0-wd03.zip as a Committee Specification Draft 01 and designate the PDF version of the specification as authoritative. I further move that the TC approve submitting the aforementioned Committee Specification Draft 01 for 30 days of public review and direct the Chair perform and tasks as required by TC Admin to facilitate that issuance." /Stefan On 12/10/17 18:51, Jason Keirstead wrote: > Just my opinion - I think one of the things not being considered here is > how long it takes for a ballot. > > While there is no official oasis rule on the time-frame, a ballot for a > CSD has to be open for a *reasonable* period of time to allow TC members > to vote. Given the importance of a CSD, that time-frame should be at > least in the two week range to account for people's schedules and > vacations etc. > > If you are pre-planning to do 4 CSDs, you're basically pre-writing-off 2 > months of time waiting for ballots, as you can't make any material > changes to the document while people are voting. > > - > Jason Keirstead > STSM, Product Architect, Security Intelligence, IBM Security Systems > www.ibm.com/security > > Without data, all you are is just another person with an opinion - Unknown > > > > > From: Duncan <email@example.com> > To: <firstname.lastname@example.com> > Date: 10/11/2017 05:45 PM > Subject: Re: [openc2] OpenC2 Language Specification draft for > approval > Sent by: <firstname.lastname@example.com> > ------------------------------------------------------------------------ > > > > > Allan, > Yes I am proposing a different approach from CTI. I would not word it as > more immature but I do agree it will take more ballots. Im just > trying to incrementally get full agreement on I think we have already > reached agreement on. If nothing else, this should draw out issues if > there are any in what we thought wed already agreed to. My > understanding of the CSD process is that it was designed to allow this > incremental approach. The current work plan calls for us reaching CSD04 > before going for CS. Ie we have broken the work down into 4 increments. > Quickie OASIS searches show 212 standards have made it to CSD04 before > approval. 167 made it to CSD05. 2 have even made it to CDS10. Hopefully > we dont make it to 10 for no other reason than that would take 10 month > and we are hopefully to finish sooner than that :-) > > iPhone, iTypo, iApologize > > Duncan Sparrell > sFractal Consulting, LLC > The closer you look, the more you see > _____________________________ > From: Allan Thomson <email@example.com_ > <mailto:email@example.com>> > Sent: Wednesday, October 11, 2017 4:08 PM > Subject: Re: [openc2] OpenC2 Language Specification draft for approval > To: <firstname.lastname@example.com_ <mailto:email@example.com>>, > <firstname.lastname@example.com_ <mailto:firstname.lastname@example.com>> > > > Duncan Im only comparing the process in which STIX/TAXII followed for > CSD process vs google doc review. > > The STIx/TAXII community spent significant time on the google doc (as it > was easier to revise/edit) and getting that close enough to the 95% of > what a final CSD would look like. > > It sounds like the OpenC2 TC want to follow a route where the CSD is > much more immature and therefore will require many more ballots/edits. > > Im only one voice and observing the difference between the processes. > Whether one is better than the other, time will tell. > > Allan > > *From: *<<email@example.com_ > <mailto:email@example.com>> on behalf of > "email@example.com_ <mailto:firstname.lastname@example.com>" > <firstname.lastname@example.com_ <mailto:firstname.lastname@example.com>>* > Date: *Wednesday, October 11, 2017 at 12:37 PM* > To: *"firstname.lastname@example.com_ > <mailto:email@example.com>" <email@example.com_ > <mailto:firstname.lastname@example.com>>* > Subject: *[openc2] OpenC2 Language Specification draft for approval > > Alan, > We did review the document at the last LSC, which I realize you could > not attend. I thought we did actually take alot of your comments into > account and made changes. For example you'll note that in the approval > copy the entire Goals section consists of "TBS". We took out the > existing text since you had issues with it so we kicked that text into > future versions. We did similar with your comments on serialization (ie > we took out the text and replaced with TBS) and did the same with the > text on actuator type. > > The substantive thing being agreed to is the list of actions. Do you > have issues with the action list? > > And let me point out again - the text being proposed for the CSD is only > 13 pages. The google doc is 150 pages. We are only including the parts > we think we've have reached agreement on. We are eating the whale in > smaller bites. > > Duncan Sparrell > sFractal Consulting LLC > iPhone, iTypo, iApologize > > -------- Original Message -------- > Subject: Re: [openc2] Groups - OpenC2 Language Specification uploaded > From: Allan Thomson <firstname.lastname@example.com_ > <mailto:firstname.lastname@example.com>> > Date: Wed, October 11, 2017 3:13 pm > To: Duncan Sparrell <email@example.com_ > <mailto:firstname.lastname@example.com>>, "email@example.com_ > <mailto:email@example.com>" > <email@example.com_ <mailto:firstname.lastname@example.com>> > Duncan thanks for the heads up. > > At this point, Ive reviewed a lot of the google document and Im > concerned that we would push for a ballot on such raw text at this point. > > The specification is not at the level it needs to be for a CSD ballot, > in my opinion. > > I suggest we consider resolving a lot more of the content in > question/comments in the google document before spending time on a CSD. > I have not seen resolution of many of the issues to my comments alone > far less anyone elses comments. So therefore in all honesty I couldnt > say I would vote yes for this document as a CSD 1.0. > > Regards > > Allan > > > > *From:*<firstname.lastname@example.com_ > <mailto:firstname.lastname@example.com>> on behalf of Duncan Sparrell > <email@example.com_ <mailto:email@example.com>>* > Date: *Wednesday, October 11, 2017 at 11:45 AM* > To: *"email@example.com_ > <mailto:email@example.com>" <firstname.lastname@example.com_ > <mailto:firstname.lastname@example.com>>* > Subject: *[openc2] Groups - OpenC2 Language Specification uploaded > > /Submitter's message/ > The OpenC2 Language Subcommittee has been reviewing the OpenC2 Language > Specification, which is currently a 150-page google doc > at_https://docs.google.com/document/d/1l7rIZl_I_zZb1FQOMYZkfUI04O7sNasZ-ozUvMn5SMU_ > <https://urldefense.proofpoint.com/v2/url?u=https-3A__docs.google.com_document_d_1l7rIZl-5FI-5FzZb1FQOMYZkfUI04O7sNasZ-2DozUvMn5SMU&d=DwMFaQ&c=jf_iaSHvJObTbx-siA1ZOg&r=k6Q07xZDujljzkKqZUfupXFUDIHGIiq-Sl_u1bw0hyA&m=f0qHldQSCLiCxi5kmsHLFm1LLHlH8pWLiczTVY4RPUU&s=ZnN8-nRIesAUwk17-OzIIxPw5DmNUF8pgBzUjIiG3oM&e=>/. > This gdoc contains both agreed-to text, and text still being debated. > > The attached zip file contains 3 documents which contain the same > 13-page content in 3 file formats (pdf, word, html). It only contains > text that I believe the > Language Subcommittee has reached consensus (but not necessarily > unanimous agreement) on. > > I intend to make a motion at the Oct-18 TC meeting to approve this text > as a Committee Specification Draft (CSD). My intent is to document what > we have reached agreement on, and to draw out any issues we dont > realize we have. Note a CSD is a draft - we will be adding to this > several times before we are ready for publishing as a verison 1.0.0 > Specification. This document contains a lot of boilerplate and the > substantive text is that it contains the list of agreed-to OpenC2 actions. > > The motion will be something along the lines of: > "I move that the OASIS OpenC2 TC approve the OpenC2 Language > Specification, Version 1.0.0, Working Draft revision 03 and all > associated artifacts packaged together in (Link to this page) as a > Committee Specification Draft and designate the PDF version of the > specification as authoritative." > > -- Mr. Duncan Sparrell > > *Document Name*:_OpenC2 Language Specification_ > <https://urldefense.proofpoint.com/v2/url?u=https-3A__www.oasis-2Dopen.org_apps_org_workgroup_openc2_document.php-3Fdocument-5Fid-3D61772&d=DwMFaQ&c=jf_iaSHvJObTbx-siA1ZOg&r=k6Q07xZDujljzkKqZUfupXFUDIHGIiq-Sl_u1bw0hyA&m=f0qHldQSCLiCxi5kmsHLFm1LLHlH8pWLiczTVY4RPUU&s=5QpUhO9AVaa6ttpx8chNT5966h8su-OuDnjyqO7JJjo&e=> > ------------------------------------------------------------------------ > > *Description* > Open Command and Control (OpenC2) is a concise and extensible language to > enable the command and control of cyber defense components, subsystems > and/or systems in a manner that is agnostic of the underlying products, > technologies, transport mechanisms or other aspects of the implementation. _ > __Download Latest Revision_ > <https://urldefense.proofpoint.com/v2/url?u=https-3A__www.oasis-2Dopen.org_apps_org_workgroup_openc2_download.php_61772_latest_oc2ls-2Dv1.0.0-2Dwd03.zip&d=DwMFaQ&c=jf_iaSHvJObTbx-siA1ZOg&r=k6Q07xZDujljzkKqZUfupXFUDIHGIiq-Sl_u1bw0hyA&m=f0qHldQSCLiCxi5kmsHLFm1LLHlH8pWLiczTVY4RPUU&s=_u4-itSNlSIa5eYt6PyqMWiD2aa1hDs0NFc4SL3BOPg&e=>_ > __Public Download Link_ > <https://urldefense.proofpoint.com/v2/url?u=https-3A__www.oasis-2Dopen.org_committees_document.php-3Fdocument-5Fid-3D61772-26wg-5Fabbrev-3Dopenc2&d=DwMFaQ&c=jf_iaSHvJObTbx-siA1ZOg&r=k6Q07xZDujljzkKqZUfupXFUDIHGIiq-Sl_u1bw0hyA&m=f0qHldQSCLiCxi5kmsHLFm1LLHlH8pWLiczTVY4RPUU&s=kUdYz2grr-oQ64jDfpqUH92P5WD91zuu1P9A3x6rKV0&e=> > ------------------------------------------------------------------------ > > *Submitter*: Mr. Duncan Sparrell* > Group*: OASIS Open Command and Control (OpenC2) TC* > Folder*: Working Drafts* > Date submitted*: 2017-10-11 11:44:35 > > > > --------------------------------------------------------------------- To > unsubscribe from this mail list, you must leave the OASIS TC that > generates this mail. Follow this link to all your TCs in OASIS at: > _https://www.oasis-open.org/apps/org/workgroup/portal/my_workgroups.php_ > <https://urldefense.proofpoint.com/v2/url?u=https-3A__www.oasis-2Dopen.org_apps_org_workgroup_portal_my-5Fworkgroups.php&d=DwMFaQ&c=jf_iaSHvJObTbx-siA1ZOg&r=k6Q07xZDujljzkKqZUfupXFUDIHGIiq-Sl_u1bw0hyA&m=f0qHldQSCLiCxi5kmsHLFm1LLHlH8pWLiczTVY4RPUU&s=AX9ldqaUCgDLAPTo59QSRuHSaK0Okd27dle3Hbmcvgw&e=> > > >
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Weston return from Camborne with the points
PUBLISHED: 09:08 11 September 2015 | UPDATED: 09:08 11 September 2015
Copyright Andrew Collins 2014. All rights reserved
Weston returned from Camborne with a hard-fought victory in their opening game of the season.
CAMBORNE 21 pts
WESTON 23 pts
WESTON travelled to Cornwall for their first outing in South West One West and came away with a victory after a nail-biting second half which went down to the wire.
The visitors took the lead in the fourth minute through a Glenn Dickson penalty and could have increased their lead in the seventh minute when a scrum inside the hosts 20-metre line led to Dickson ghosting through a gap, only to have the ball dislodged from his hand in the act of scoring.
Weston increased their lead through another Dickson penalty in the 14th minute and looked set to score again, but knocked on near the line. The Camborne line held and in a sweeping move, flanker Sam Matavesi scored near the posts for try that was converted by scrum-half Taron Peacock.
This put the hosts in front for the only time in the game as shortly after, Weston produced a superb passage of play involving captain George Sparks, lock Andrew Glen, scrum-half Hayden Tuttiett, hooker Rich Ford and centre Harry Jones, who combined to put right wing Chris Young over for an excellent score.
This was to prove the last realistic rugby of the first-half, although an altercation led to Glen being yellow carded, along with Peacock from Camborne.
The second half started with a missed penalty for the visitors, but from the resulting drop-out Sparks gathered the ball and released prop Sam Coles, who put Jones away on a mazy run that resulted in the elusive centre crossing for a great try.
Weston could have scored soon after when the industrious Tuttiett retrieved the ball in his own 20-metre area and set off on a long run, which ended in his kick forward being retrieved by the host flanker to avoid a further score.
Camborne were now all over Weston and deservedly cut the lead when centre Ben Jordan scored a converted try, following good pressure from the Camborne forwards.
Weston were up against it, but in the 75th minute, relief came when outside centre Matt Burns intercepted a long pass to race 70 metres for a try under the posts, which was converted by Dickson.
Camborne never gave up and reduced the lead yet again to two points when prop Andrius Zacharovas crossed for another try converted by Peacock. Weston held on, but Camborne looked to have won it only for the score to be ruled out for a double movement.
The final whistle came as a great relief to the visitors, who can take some positives out of this victory as it is probably a game they would have lost last season.
Weston host Coney Hill in their first home game this Saturday, kick-off 3pm.


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Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) expressed at high levels by CD4+ CD25+ CD45RBlow regulatory T cells (Treg) is essential to their homeostatic and immunoregulatory functions. However, its relevance to anti-inflammatory roles of Treg in the context of colitogenic innate immune response during pathogenic bacterial infections has not been examined. We showed earlier in Rag2-deficient 129/SvEv mice that Treg cells are capable of suppressing colitis and colon cancer triggered by Helicobacter hepaticus, a widespread murine enterohepatic pathogen. Using this model, we now examined the effects of antibody blockade of CTLA-4 on Treg function during innate immune inflammatory response. Consistent with our previous findings, we found that a single adoptive transfer of Treg cells prior to infection prevented colitis development despite persistent H. hepaticus infection in recipient mice. However, when infected mice were injected with anti-CTLA-4 antibody along with Treg cell transfer, they developed a severe acute colitis with poor body condition that was not observed in Rag2−/− mice without Treg cell transfer. Despite high numbers of Foxp3+ Treg cells, evident by immunohistochemical analyses in situ, the CTLA-4 antibody-treated mice had severely inflamed colonic mucosa and increased rather than decreased expression levels of cytokines gamma interferon and interleukin-2. These findings indicate that antibody blockade of CTLA-4 clearly abrogates Treg cell ability to suppress innate immune-driven colitis and suggest that Treg cell CTLA-4 cognate interactions may be necessary to maintain homeostasis among cells of innate immunity.
Inflammatory bowel disease (IBD), ulcerative colitis, and Crohn's disease are characterized by chronic and persistent colitis with a relapsing and remitting clinical course. Patients with extended and early-onset colonic inflammation have a heightened risk of developing epithelial dysplasia and intestinal cancer (19, 26, 27). Efforts on modulation of intestinal microflora by antibiotics (10) and probiotics (25) have led to the recognition that enteric bacteria are involved in pathogenesis of IBD. We and others have shown that an enteric pathogen, Helicobacter hepaticus, induces colitis and subsequent colon cancer in 129/SvEv Rag2-deficient mice lacking functional T and B lymphocytes (2, 3, 28). However, immunocompetent wild-type mice of the same genetic background are generally resistant to the proinflammatory effects of H. hepaticus infection (2). These findings suggest that a subset of endogenous lymphocytes have a crucial role in regulating the host innate responses to pathogenic enteric bacteria. Indeed, adoptive-transfer experiments have revealed that a subset of CD4+ lymphocytes with anti-inflammatory roles (CD45RBlow, CD25+, Treg cells) can prevent and/or regulate the colitogenic innate immune responses against H. hepaticus infection (2, 3).
Treg cells express constitutively on their surface high levels of cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4; CD152) in addition to the costimulatory molecule CD28 (23). Although both CTLA-4 and CD28 can bind to B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells (APCs) with varying affinity, the balance of dual signals delivered to T cells regulates the extent of their activation and subsequent immune response. In comparison, CTLA-4 shows higher affinity for both B7 molecules over CD28 and plays a dominant inhibitory role in limiting T-cell proliferation and interleukin-2 (IL-2) production. Moreover, CTLA-4-mediated suppression in part is thought to be accomplished by competing for stimulatory signals of CD28 (12, 14, 24). Read et al. have shown that in vivo administration of anti-CTLA-4 antibody blocks the suppressor function of CD4+CD25+ Treg cells on colitis induced in wild-type mice by the adoptive transfer of CD45RBhigh effector T cells from syngeneic or B7-1/B7-2/CTLA-4 triple-deficient mice (22). These data suggested that anti-CTLA-4 antibody interfered with CTLA-4/B7 costimulatory signals between Treg cells and APCs but not those between effector T cells and APCs. Despite blocking of CTLA-4 on Treg cells, anti-CTLA-4 antibody treatment did not eliminate Treg cells or their peripheral development, accumulation, or suppressor function (22). In other studies, modification of CTLA-4 signaling failed to alter Foxp3 expression in vitro (11). However, the relevance of CTLA-4 to the Treg anti-inflammatory function or their ability to regulate innate immune response against bacterial infection has not been examined before. We hypothesized that blockade of CTLA-4 on Treg cells affects their ability to suppress innate immune inflammation in Rag2-deficient mice. To examine this possibility, we administered CTLA-4 antibody to H. hepaticus-infected 129/SvEv Rag2-deficient mice with or without addition of Treg cells, monitored their persistence in vivo, and assessed the outcome of CTLA-4 blockade on the gut innate immune inflammatory response and dysplasia.
Mice and bacteria.Rag2-deficient and wild-type mice on a 129/SvEv strain background were obtained from Taconic Farms. All mice were housed in Association for Assessment and Accreditation of Laboratory Animal Care-approved facilities. The mice were free of known murine viruses, Salmonella spp., Citrobacter rodentium, ecto- and endoparasites, and murine Helicobacter spp. Experimental mice dosed with H. hepaticus were housed separately in a biocontainment area of the animal facility. H. hepaticus (strain 3B1; ATCC 51449) (6) was grown under microaerobic conditions, prepared, and confirmed pure as described previously (2, 6).
Adoptive transfer of Treg cells and antibody treatment.CD4+ lymphocytes were isolated from spleens of wild-type littermates by using magnetic beads (Dynal Biotech USA, Oslo, Norway) and then sorted by high-speed flow cytometry (MoFlow2) to obtain purified populations of CD4+ CD25+ CD45RBlow lymphocytes (∼96% pure) as described previously (2). The purified Treg calls from Helicobacter-free 129/SvEv donors were injected into syngeneic Rag2-deficient mice intravenously in the retro-orbital sinus with 3.0 × 105 cells/animal suspended in 0.2 ml of media. Three days later, mice were dosed with either H. hepaticus (2.0 × 107 bacteria/animal) or sham media every other day for a total of three doses. Treg recipient mice underwent a 2-week administration with either purified hamster anti-mouse CTLA-4 monoclonal antibody (UC10-4F10-11) or hamster control immunoglobulin at a dose of 100 μg/animal/day intraperitoneally. The administration of antibody started at 1 day before or 4 weeks after Treg transfer. The mice were euthanized 6 weeks after the last dose of anti-CTLA-4 antibody, or otherwise euthanized when the mice developed severe diarrhea and lost up to 20% of their initial body weights. A cohort of aging 129Sv/Ev Rag2-deficient mice remained untreated and served as controls. At the end of these experiments, samples of colon, cecum, ileum, duodenum, stomach, liver, and spleen were harvested at necropsy. Experimental infection of mice was confirmed in cecum samples by using H. hepaticus-specific primers (8). Helicobacter-free status was also confirmed in controls.
Histological evaluation.Histological findings were evaluated as described previously (2). Briefly, samples of the colon, cecum, ileum, duodenum, stomach, and liver were fixed in formalin, embedded in paraffin, and stained with hematoxylin and eosin. Lesions were scored by a pathologist blinded to sample identity. The colonic and cecal lesions were scored on the basis of size and frequency of inflammatory lesions on a scale of 0 to 4 with ascending severity (grade 0, none; 1, minimal; 2, mild; 3, moderate; and 4, severe). Epithelial dysplasia and neoplasia were graded using a scale of 0 to 4 based on a recently described scheme (2) (grade 0, normal; 1, mild dysplastic changes; 2, low-grade adenoma/dysplasia; 3, high-grade adenoma/dysplasia, carcinoma in situ, or intramucosal carcinoma; and 4, invasive carcinoma). The data were compiled from two replicate experiments.
Immunohistochemistry.After deparaffinization, formalin-fixed sections were antigen retrieved with pepsin (Zymed, San Francisco, CA) for 10 min at 37°C and labeled with rat monoclonal antibody recognizing mouse antigen (Foxp3; BD Pharmingen, San Diego, CA). Primary antibody binding was detected with species-appropriated biotinylated secondary antibodies (Sigma Chemical Company), streptavidin peroxidase, and 3,3-diaminobenzidine (Vector Laboratories, Burlingame, CA). Immunohistochemical assays were performed on an automated immunostainer (i6000; Biogenex, San Ramon, CA).
Detection of cytokine mRNA and bacterial DNA.Segments (5 ml) of distal and proximal colon, cecum, terminal ileum, and spleen were collected and snap-frozen in liquid nitrogen. According to the manufacturer's instructions, RNA was extracted by using TRI-Reagent RNA isolation reagent (Sigma-Aldrich). Quantitative PCR was performed using TaqMan gene expression assay kits (Applied Biosystems) to analyze mRNA expression of gamma interferon (IFN-γ), IL-2, IL-10, Foxp3, and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) in a ABI Prism sequence detection system 7700 (Applied Biosystems) (4). The expression levels of target mRNA were normalized to micrograms of mouse chromosomal DNA, whose quantities in the samples were measured with 18S rRNA gene based primers and probe mixture (Applied Biosystems), as described previously (4, 8).
Statistical analyses.Analyses of histological scores and bacterial DNA and expression levels of mRNA were performed by using a Mann-Whitney U nonparametric test and unpaired t test. Group differences of body weight changes were analyzed by analysis of variance.
CTLA-4 blockade abolished the Treg suppression of H. hepaticus-induced colitis.Rag2-deficient 129/SvEv control mice, free of H. hepaticus, showed no evidence of colitis (Fig. 1A and 2) during the course of the study. H. hepaticus infection in a cohort of mice, housed in a separate location, led to moderate to severe typhlocolitis and epithelial dysplasia by 8 weeks postinfection (wpi), as shown in Fig. 1B. Furthermore, H. hepaticus infection initially caused a delay in body weight gain (50% [6 of 12 mice]) immediately after bacterial inoculation, but thereafter the animal's body weight recovered steadily (data not shown). Inflammation was not evident in the ilea, duodena, stomachs, or livers of the infected mice (data not shown). A group of H. hepaticus-infected mice (n = 11) that subsequently received CD4+ CD25+ CD45RBlow cells by adoptive transfer showed no signs of disease and had very little inflammation in their colons, a finding consistent with our prior data on Treg-mediated amelioration and colonic lesions (Fig. 1C). Also, the Treg-recipient mice showed no loss in their body weights unlike their infected counterparts that did not receive Treg cells. To examine the effect of CTLA-4 blockade on the colitis-protective function of Treg cells, anti-CTLA-4 antibody was administered to a group of infected mice (n = 7) that had earlier received Treg cells. Surprisingly, despite their circulating Treg cells, mice injected with CTLA-4 antibody developed a rapidly progressive wasting condition with bloody diarrhea starting as early as 1 wpi. The CTLA-4 antibody regimen could not be continued beyond 2 weeks due to the rapidly deteriorating clinical condition of the mice. The body weight loss continued even after the end of anti-CTLA-4 administration. Although 7 of the 11 mice injected with anti-CTLA-4 regained their body weight to their initial body weight by 4 weeks after the last injection, these mice showed signs of profound colitis, 6 weeks after the last dosing with anti-CTLA-4. The inflammation was characterized by discontinuous and patchy infiltration of mononuclear cells, neutrophils, and eosinophils with severe epithelial dysplasia (Fig. 1D). The remaining four anti-CTLA-4-treated mice (4 of 11) had to be euthanized due to poor body condition by 5 wpi. These mice, too, exhibited severe inflammation and transmural ulcers in the colon (Fig. 1E). Interestingly, despite severe colitis, anti-CTLA-4-administered mice showed no significant levels of inflammation in the ileum, duodenum, stomach, or liver (data not shown). There was no significant difference in the number of H. hepaticus organisms/μg of mouse bowel DNA between the infected Treg recipients that were treated with control immunoglobulin G (IgG) (5.8 × 105 [5.3 × 102 to 1.2 × 108]; median [range]) versus those treated with anti-CTLA-4 (3.1 × 104 [3.6 × 102 to 8.6 × 109]).
Histologically, the inflammatory response characterized by mononuclear and polymorphonuclear cells was observed in the colon and cecum. To quantify the severity of inflammation among different groups of mice, the extent of inflammatory cell infiltration and epithelial dysplasia was evaluated in the distal, middle, and proximal colons and ceca of mice by two veterinary pathologists blinded to sample identity, according to the method described previously (2). Clearly, as shown in Fig. 3, the mice infected with H. hepaticus had higher levels of inflammation and epithelial dysplasia in their colons and ceca. Mice that received adoptive transfer of Treg cells showed significantly lower (P < 0.05) overall inflammation scores in colon, despite small foci of inflammatory cells seen occasionally in few sections of the infected mice that were transferred with Treg cells. Suppression of inflammation mediated by Treg cells was more complete in colon than in cecal tissue. Finally, the extent of inflammation in both colon and cecum was significantly higher after anti-CTLA-4 treatment in mice infected with H. hepaticus-infected group that had also received Treg cells compared to infected control mice that did not receive Treg cells. A longer observation period is needed to determine whether mice undergoing treatment with anti-CTLA-4 antibody have a similar trend toward increased epithelial dysplasia.
CTLA-4 antibody required Treg cells to promote inflammation in H. hepaticus-infected mice.The findings of increased colon pathology and rapid onset of clinical disease in H. hepaticus-infected Treg recipient mice administered with anti-CTLA-4 antibody were unexpected. These signs or lesions observed only in the infected Treg recipients administered anti-CTLA-4 antibody but not control IgG suggest that CTLA-4 blockade of Treg cells had clearly mediated enhancement in disease pathology. It is possible that CTLA-4 antibody could induce alteration in the phenotypic and/or functional profile of Treg cells in vivo in the context of inflammation, as shown by Poutahidis et al. (20). To test the requirement for bacterial challenge, Treg recipient mice maintained under H. hepaticus-free conditions were administered the antibody. Administration of anti-CTLA-4 to the uninfected mice did not induce lower bowel lesions (Fig. 1F and 2), nor did it alter their body weight (data not shown). To determine whether effects of anti-CTLA-4 required Treg cells during the course of infection, we injected anti-CTLA-4 into H. hepaticus-infected Rag2-deficient mice without the addition of Treg cells. Anti-CTLA-4 alone did not significantly accelerate the inflammation (Fig. 1G and 2) or affect body weight in H. hepaticus-infected Rag2-deficient mice. These findings confirmed that H. hepaticus infection, Treg cells, and CTLA-4 blockade were all essential to exacerbate clinical disease. These findings also further excluded the possible role for antibody contaminants such as endotoxin in this process.
Previously, we have shown that Treg cells once transferred persist and retain their ability to suppress colitis for several weeks. However, it was unclear whether CTLA-4 blockade at 4 weeks after Treg cell transfer and infection still affected their suppressor function. Thus, we administered CTLA-4 antibody (n = 6) or control IgG (n = 6) separately to two groups of H. hepaticus-infected Treg recipients starting at 4 weeks after Treg transfer and monitored their body condition and development of clinical disease. The mice receiving anti-CTLA-4 later in the course of infection failed to gain body weight, and this late intervention was still effective at abolishing the Treg suppressive effect on inflammation in the colon for an additional 6 weeks after the final dose of anti-CTLA-4 (data not shown).
CTLA-4 blockade led to inflammation in colon despite accumulation of Foxp3+ cells.The findings that CTLA-4 blockade abrogated the anti-inflammatory function by Treg cells suggested that their colitis-protective role depends on signaling via CTLA-4. To localize and confirm the presence of Treg cells, staining for Foxp3, a marker specifically expressed by CD25+ Treg cells, was undertaken. As shown in Fig. 3 and 4, Foxp3+ cells were evident throughout the gastrointestinal tissues in H. hepaticus-infected Treg recipient mice. As expected, Rag2-deficient mice, whether infected or uninfected, had no Foxp3+ cells. Notably, the extent of infiltration by Foxp3+ cells was higher in Treg recipient mice that were subjected to the CTLA-4 blockade regimen (Fig. 3). There was increased expression of Foxp3 evident in colons in situ; however, Foxp3+ cells in the mucosa of ceca, ilea, duodena, and stomachs of the mice injected with anti-CTLA-4 were comparable to those of mice treated with control immunoglobulin (Fig. 4). Foxp3+ cells in lymph nodes adjacent to colons and stomachs were also observed in anti-CTLA-4-administered mice (data not shown). The immunohistochemical findings matched the quantitative analysis of Foxp3 using real-time PCR assays, which indicated that colonic Foxp3 expression was increased in Treg cell recipient mice given anti-CTLA-4 (Fig. 3E and F). Foxp3 mRNA expression levels were low in the ceca, ilea, and spleens and unaffected by CTLA-4 administration (Fig. 4Q, R, and S).
CTLA-4 blockade led to increased IFN-γ and IL-2 but not IL-10 expression in colon of H. hepaticus-infected Treg recipient mice.To further elucidate the basis for loss of disease suppression in mice given anti-CTLA-4, we measured IFN-γ, IL-2, and IL-10 expression levels in the colon, cecum, and spleen tissues. As shown in Fig. 5, H. hepaticus infection led to an increase in IFN-γ expression in the colon, cecum, and spleen. Suppression of IFN-γ and other cytokines was evident in corresponding tissues from mice that received Treg cells. In contrast, however, CTLA-4 blockade resulted in a remarkable increase of IFN-γ mRNA expression especially in the colon. In contrast, IL-2 expression in the colons, ceca, and spleens of Rag2-deficient mice was unaffected by H. hepaticus infection or the addition of Treg cells since Rag2-deficient mice lack functional lymphocytes that are a major source of IL-2, and the adoptively transferred Treg cells at best produce only small quantities of IL-2 (1, 5, 7). Administration of anti-CTLA-4 antibody resulted in higher levels of IL-2 expression in colon tissues compared to cecal tissues from H. hepaticus-infected Treg recipient mice. Expression levels of IL-10, a key immunoregulatory cytokine expressed by cells of both innate and acquired immunity, were elevated after H. hepaticus infection in the colon, cecum, ileum, and spleen. Neither the adoptive transfer of Treg cells nor CTLA-4 blockade affected IL-10 expression in these tissues.
The profound influence of CTLA-4 on T-cell immunity has been known for over a decade; however, the precise roles played by this molecule continue to emerge. Evidence that CTLA-4-deficient mice die by 3 to 4 weeks of age from extensive lymphoproliferative disease, along with immune-mediated damage to multiple organs, indicates its essential role in negative regulation of the CD4+ helper T-cell compartment. That blockade of CTLA-4 on CD25+ Treg cells abrogates their homeostatic role on helper T cells, as demonstrated in the CD45RBhi T-cell transfer mouse model, highlights its role in the suppressor function of regulatory T cells. However, the relevance of CTLA-4 to the suppressor function of regulatory T cells in isolation, when inflammation is generated by cells of innate immunity, has not been examined until now. Growing attention to roles of microbiota and chronic inflammation in initiating and sustaining cancer development led us to test the outcome of CTLA-4 blockade on the development of bacterially triggered colitogenic inflammatory response and dysplasia in a well-characterized Rag2−/− murine model.
Our previously established model of innate immune-driven colitis triggered by H. hepaticus made it feasible to test the relevancy of CTLA-4 on Treg functions in the absence of other lymphocytes. We find that CTLA-4 blockade clearly disables the anti-inflammatory functions of Treg cells. Interestingly, CTLA-4 antibody administration in H. hepaticus-infected Treg recipients led to an acute colitis and clinical disease that was more severe than innate immune-driven colitis alone. One possible explanation is that adoptively transferred cells included incompletely differentiated CD4+ cells that assumed a proinflammatory phenotype in the absence of suppressive functions by Treg cells. Even small numbers of non-Treg CD4+ cells present during adoptive transfer may expand rapidly in a Rag2-deficient host. An alternative is that CTLA-4 blockade stimulates cells of innate immunity to increase production of proinflammatory cytokines. The observation that disruption of Treg cell function, in this case blockade of CTLA-4, induces a proinflammatory phenotype in mice raises the possibility that CTLA-4 blockade may predispose to the development of inflammation-associated cancer, as previously described in mice with Treg cells lacking IL-10 (20). When extrapolated to lymphopenic human subjects, these data suggest that CTLA-4 blockade or dysfunction of any remaining lymphocytes may exacerbate ongoing inflammatory responses and precipitate acute clinical disease.
In the present study, adoptive transfer of Treg cells into Rag2−/− mice suppressed the induction of IFN-γ in response to H. hepaticus. In these Rag2−/− mice, H. hepaticus infection induced expression of a key inflammatory cytokine, IFN-γ, that was correlated with a severe inflammatory host response. Although Treg cells showed strong suppression of IFN-γ, CTLA-4 blockade resulted in abolishment of Treg suppression on IFN-γ expression and the induction of colon-specific pathology. Histopathology resembled features of colitis induced in Rag2−/− mice after transfer of naive CD4+ CD45RBhigh T cells (15). The finding that Foxp3+ cells were evident only in inflammatory foci in the gastrointestinal tract and only after bacterial challenge matched findings of Poutahidis et al. (20). Localization of Treg cells in the gastrointestinal tract matched the expectation that Treg cells traffic and function in the periphery in active inflammatory foci.
Recent studies have shown that CD4+ Treg cells are also increased in inflamed mucosa during IBD (16) and in H. pylori-infected gastritis patients (21), even though these cells express Foxp3 and retain their suppressor capacity ex vivo (16). Thus, uncontrolled inflammation in IBD may be unrelated to a failure of Treg to localize in affected tissue but rather due to a defect in the ability of Treg to function properly in the inflammatory microenvironment. Our data implied that the disruption of CTLA-4 costimulatory signal may be involved in the impaired Treg functions and may play a role in the pathogenesis of inflammatory diseases. It is possible that, as a consequence of CTLA-4 blockade, CD28-dominant signal stimulates innate immunity to produce proinflammatory cytokines. CD28 costimulation can deliver stimulatory signals not only to T cells to proliferate but also to dendritic cells to promote proinflammatory cytokine production, such as IFN-γ and IL-6 (17, 18, 29). Treg cells with insufficient CTLA-4 may stimulate innate immune cells to increase inflammation in order to promote bacterial clearance during an acute bacterial infection.
Recent studies have shown that APCs have an ability to produce IL-2 in response to bacterial stimulation (9). However, H. hepaticus infection alone was not sufficient to induce IL-2 expression in colon of Rag2-deficient mice. The addition of anti-CTLA-4 to H. hepaticus-infected Treg recipients resulted in a remarkable increase of IL-2 expression in colon, even though donor Treg cells are typically unable to produce IL-2 (1, 7). Interestingly, IL-2 production was increased after H. hepaticus infection only in the colon and not in the cecum or the spleen. Further studies of the effect of CTLA-4 signaling on IFN-γ and IL-2 regulation are required but will be challenging because ex vivo data may not always reliably parallel relevant pathogenic in vivo events.
An unexplained finding is the inconsistency between inflammatory cell infiltrates and gene expression observed in the ceca of H. hepaticus-infected Treg recipient mice at 8 wpi. Despite cellular infiltration in ceca of some Treg cell recipient mice, IFN-γ transcription in the ceca was consistently suppressed after Treg cell transfer. One possible explanation for the discrepancy between gene expression and pathology is that ceca exhibited discontinuous inflammation that was misrepresented in our assays. Discontinuous inflammation in the appendiceal orifice is often noted in IBD patients, but its presence does not correlate with clinical activity (13). Another explanation for the mismatch between IFN-γ and IBD is that eventual suppression of histopathology may temporally lag behind suppression of cytokine transcriptional levels (i.e., taking 12 weeks instead of 8 weeks after infection). Indeed, we previously reported that Treg cell transfer had statistically lowered the inflammation scores but did not completely eradicate IBD in H. hepaticus-infected mice at 12 wpi. In those studies, a subset of Treg recipient mice infected with H. hepaticus had localized inflammation (2). Further analysis of histological and immunological responses in the appendices of humans and ceca of mice in the progressions of IBD is warranted.
Finally, it remains to be determined how IL-10 relates to CTLA-4 in this setting. IL-10 is an anti-inflammatory cytokine that counter-regulates IFN-γ and other proinflammatory cytokines during the development of IBD. Treg cells collected from IL-10-deficient donors, such as Treg cells undergoing blockade of CTLA-4, are incapable of inhibiting colitis triggered by H. hepaticus (3) in Rag2−/− mice, and similarly develop severe colitis only after bacterial infection (20). In the present study, however, IFN-γ expression was independent of IL-10 expression, suggesting that the CTLA-4-mediated Treg mechanism may be separate from IL-10-mediated functions of Treg cells in this setting.
In summary, these data provide evidence that blockade of CTLA-4 on Treg cells clearly abrogates their suppressive function on colitis induced by H. hepaticus in Rag2-deficient mice. A better understanding of immune regulation involving CTLA-4 and cells of innate immunity will be required as trials with human anti-CTLA-4 antibodies progress into a clinical setting.
We thank Kathy Cormier, Chakib Boussahamain, Kristen Clapp, and Juri Miyamae for technical assistance.
This study was supported by NIH grants R01CA67529 (J.G.F.), R01DK52413 (J.G.F.), R01CA108854-01A1 (S.E.E.), and P30-ES02109 (J.G.F. and S.E.E.).
- Received 2 May 2008.
- Returned for modification 22 July 2008.
- Accepted 18 September 2008.
↵▿ Published ahead of print on 29 September 2008.
Editor: J. L. Flynn
- American Society for Microbiology


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Evan Zaloudek
The SDM team is proud to work with Evan Zaloudek and his parents to create advertisements showcasing his many successes at NSBA and AQHA competitions. Evan is one of the talented riders that participate in showmanship competitions across the Midwest with Partners for Progress. In the past, SDM has done numerous graphic design assignments for Partners for Progress, including calendars, event invites, logo modification, signage, and more.
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Pedal, Paddle, Hike, Drive: 5 Top Coast Trails
There's good news for Live Culture Coast travelers passionate about wild places and classic Oregon coast scenes—you know, the arch rocks and sea stacks, gold-sand beaches, rivers, and forests. Over the past few years, Southern Oregon Coast communities have been hard at work creating the kind of world-class trails that give hikers, bikers, and paddlers up-close-and-personal access to the best of Southern Oregon Coast's wild places.
There's more good news: Make the trip to southern coast for Live Culture Coast this fall (October 18-27, 2019) and you just might have a few trails and beaches all to yourself. Why is that? The Southern Oregon Coast is a bit farther afield; as such it receives fewer visitors compared to Oregon's central and north coasts. (In spite of the fact the coast's so-called "banana belt" is warmer and sunnier than coastal points north.)
The five trails below, both new and known, get you out and exploring what is fast-becoming one of the greatest outdoor recreation destinations on the whole West Coast.
TRAIL #1 Wild Rivers Coast Scenic Bikeway
What—Oregon had the first Scenic Bikeway program in the country—and one of the best routes begins in the fishing town of Port Orford. The Wild Rivers Coast Scenic Bikeway threads 61 miles of bikeable routes, including a 17-mile stretch along the Wild and Scenic Elk River.
Good for—Bikers of every ability. Choose your own itinerary by keeping it local and close to town, spinning a few east miles to Paradise Point State Recreation Area, or trying for all 61 miles in a single day.
Where—There are numerous access points, but Port Orford is the bikeway's official hub. You can access detailed info on the whole bikeway (or send the route to your mobile device) by heading to the Oregon Scenic Bikeways page of RidewithGPS.
Bike Service—For bike rentals, maps, insider intel and more, get yourself to Pineapple Express Adventure Rides in Port Orford. You can also get repairs and info from South Coast Bicycles in nearby Bandon.
TRAIL #2 Samuel H. Boardman State Scenic Corridor
What—The Samuel H. Boardman State Scenic Corridor runs along Hwy 101 for 12 jaw-dropping miles. It's a must for travelers to the area. Sea stacks galore, secluded beaches, forests that meet the sea—and trails both easy and challenging. Numerous viewpoints also make Oregon's wild coast accessible to those with limited mobility.
Good for—Everyone! Car travelers have plenty of viewpoints for gazing and there are trails for hikers of every ability.
Where—The Samuel H. Boardman State Scenic Corridor Runs lies between the towns of Gold Beach and Brookings. Multiple viewpoints on Hwy 101 are well-signed—and often are the locations of trailheads that lead to the Oregon Coast Trail. OregonHikers.org has detailed hike guide for an 8-mile route from North Island to Arch Rock.
TRAIL #3 Oregon Coast Trail
What—This long-distance super trail runs for 425 along the Pacific Ocean, from the mouth of the Columbia River to the California border—but don't let the length deter you. Much of the trail is the beach itself, and the Southern Oregon Coast boasts some of the most scenic sections (think haystack rocks dramatic bays and forests that reach the ocean edge). Access points are numerous and within easy reach.
Good for—Hikers of all levels. The hardest part is simply picking which section to experience.
Where—To find an access point that works for your trip, a great place to start are the easy-to-use maps from the Oregon Coast Trail Foundation which lay out the trail section by section. Each map has critical wayfinding information about tides, stream crossings and other hiker notes.
Get Maps/ Intel—The Crissey Field Welcome Center near the California border is one-stop-shopping for travel advice and tourism resources, including trail recommendations.
TRAIL #4 Whiskey Run Mountain Bike Trails
What—A mountain biking must. Eighteen miles (and counting) of professionally built trails that undulate through a section of Coos County Forest that once was actively logged. Cross-county terrain ranges from beginner to expert, from rollers to easy climbs to bracing downhill. The trails are well-marked by level and length, making Whiskey Run among the most user-friendly mountain bike trail systems in the state. Here you'll find classic Oregon landscapes—towering trees filter light to a salal- and fern-covered forest floor laced with streams and freshets.
Good For—Families and riders of all levels. Thanks to pro trail-makers Ptarmagin Ptrails and IMBA, all routes are well-marked and easy to follow. Signage, benches, parking areas, and land use provided by Coos County Forestry
Where—Coos County Forest, between Coos Bay and Bandon. Map your way to the Whiskey Run Bike Trail parking here.
Rent a Bike/ Bike Service— Do check out the Whiskey Run Trail system online before you head out. For rentals, maps, guided rides, insider intel and more, get yourself to Pineapple Express Adventure Rides in Port Orford. (The shop also offers private mountain biking lessons.) You can also get repairs, spares, tune-ups, and info from South Coast Bicycles in nearby Bandon and Moe's Bike Shop in North Bend.
TRAIL #5 Coquille River Water Trail
What—Some day, the Coquille River Water Trail may stretch for 41 miles along the Coquille River from Myrtle Point to Bandon. Today, kayakers can paddle some of the best spots, such as the Bandon Marsh U.S. National Wildlife Refuge. During fall and spring, tens of thousands of shorebirds stop at the refuge to feed in eel-grass beds and shores tidal salt marsh—it's a literal wildlife riot.
Good for—Paddlers of all levels.
Book a Trip/Get a Guide—A Coquille River Water Trail Guide is in the works, but South Coast Tours in Gold Beach is both a wealth of paddling information and runs regular paddle excursions to the lower reaches of the Coquille. And Coos Boat Tours gives a 2 hour Coquille River round trip tour from Bandon to Bear Creek


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Family History Consultants
The Key to Successful Family History Programs
What We Will Discuss Today
1. Consultants and the Church Handbook. 2. Consultants' Primary Responsibilities. 3. Additional Ways to Serve. 4. How to Help Members. 5. Help for Consultants.
Purpose of Family History
"If temple ordinances are an essential part of the restored gospel, and I testify that they are, then we must provide the means by which they can be accomplished. All of our vast family history endeavor is directed to temple work. There is no other purpose for it. The temple ordinances become the crowning blessings the Church has to offer." (Gordon B. Hinckley, "New Temples to Provide 'Crowning Blessings' of the Gospel," Ensign, May 1998, 87)
Consultants Help Members
"You can start searching in the first few generations going back in time. From that you will identify many of your ancestors who need your help. Someone in your own ward has been called to help you prepare those names for the temple." (Henry B. Eyring, Ensign, "Hearts Bound Together," May 2005, 79)
consultant.familysearch.org Register Online
Family history consultants are encouraged to register online at: consultant.familysearch.org
By registering, you get:
Why Register? By registering, you get: Access to online training for family history consultants. updates and information for family history consultants. Early access to new systems, such as the new FamilySearch, when they become available.
Online Training Online training lessons on the Church's Internet Learning System.
Revised Church Handbook
In 2006 the Church Handbook of Instructions: Book 2, Section 9, was revised.
Revised Church Handbook
The revision simplified the family history organization in stakes and wards. The handbook describes the essential role of family history consultants in the basic family history program of the Church.
Key to a Successful Program
The key to a successful family history program is family history consultants who meet with members individually to help them begin and continue their family history.
Family History Consultants
Primary Responsibilities
Consultants' Primary Responsibilities
Reach out to members of the ward a few at a time, so that over time all members have the opportunity to participate in some element of family history. Focus on individuals and families suggested by the priesthood executive committee and the ward council. Help new members identify ancestors and go to the temple soon after their own baptism to be baptized and confirmed for their ancestors.
1. Consultants Reach Out Consultants are encouraged to reach out to all members in the ward, a few families at a time, to help them begin or expand their family history efforts.
1. Reach Out to Members The objective is that every member or family in the ward should be contacted by a family history consultant.
Be proactive! Don't wait for members to call you!
1. Reach Out to Members Be proactive! Don't wait for members to call you! Some members may be hesitant to approach you themselves to ask for help. Members will usually respond positively to a personal invitation from a family history consultant to help them get started.
Where possible, visit with members in their homes.
1. Reach Out to Members Where possible, visit with members in their homes. Members usually will have information available in their home to help them get started.
2. Focus Efforts As you reach out to members, focus particularly on individuals and families suggested by the priesthood executive committee and the ward council.
2. Focus Efforts Contact these individuals and families and visit with them as soon as possible. Report to the high priests group leader on your success in contacting these members and the help you have provided.
3. Help New Members Meet with new members of the Church soon after their baptism to introduce them to the principles of family history and temple work. Help these new members identify ancestors and go to the temple to be baptized and confirmed for them.
3. Help New Members New members who have experienced the Spirit when they were baptized usually are excited to provide the same opportunity for their ancestors. Having the opportunity to go to the temple and perform ordinances for their ancestors can bring great strength to new members.
Family History Consultants
Additional Opportunities to Serve
Family History Consultants
The scope of the family history consultant calling has been expanded to include, when assigned: Serving in a family history center. Providing training to those with family history callings in the stake.
Teach Family History Classes
You may be assigned by the bishopric, to teach family history classes during Sunday School or other times.
Serve in a Family History Center
You may be assigned by the bishopric or high priests group leader to serve in a family history center supported by the stake.
Provide Family History Training
One or more family history consultants may be assigned by the high council adviser to provide family history training to those with family history callings in the stake.
Help Ward Leaders Teach
Help priesthood and auxiliary leaders teach lessons on temple and family history work. For example: Quorum and auxiliary lessons. Fifth Sunday presentations. Home, family, and personal enrichment nights. Ward firesides.
Help Youth Help youth complete family history activities to fulfill requirements for Duty to God, Scouting, and Personal Progress awards. Help youth and their families find the names of ancestors who need ordinances they can take on temple excursions.
Promote FamilySearch Indexing
FamilySearch Indexing is an excellent way for members, including youth, to become involved in family history. See
Help Missionaries The missionary guide, Preach My Gospel, discusses how missionaries can use family history to interest their contacts in the gospel. Family history consultants may be asked to "provide an initial search of family roots" for missionary contacts.
Help Members
Help Members Many members have had little experience with family history. Members have a variety of family history needs. Most can be successful if they receive individual help.
Help Members Those you help may be:
Life-long members who have assumed that a relative has taken care of their family history. Young families busy with Church callings, work, and children. New, enthusiastic converts. Mature members with stacks of paper genealogical forms. Not interested in doing family history right now.
Help Members Pray for inspiration and discernment to understand members' family history needs and how you can help. The Spirit is essential in the work of family history consultants.
Ask questions to understand how you can help them. For example:
Help Members Ask questions to understand how you can help them. For example: How can I help you? What are you hoping to accomplish? What family history work have you done before? What experience have you had using FamilySearch?
Help Members Members often need encouragement to begin or continue their family history. Be positive and supportive. Help members step-by-step, at their own pace. Prayerfully consider their needs and how you might help. "Lead me, guide me, walk beside me."
What are some ways you as a family history consultant could help:
Discussion What are some ways you as a family history consultant could help: A young couple busy with work, Church assignments, and raising children? A newly baptized, enthusiastic member of the Church? A less-active member whom the high priests group leader has asked you to contact and provide family history help?
What are some ways you as a family history consultant could help:
Discussion What are some ways you as a family history consultant could help: An elderly member who has stacks of old family history forms and doesn't know what to do with them? A life-long member and priesthood leader who has assumed that a relative has done his family history?
Help for Family History Consultants
Where can I get help? Help for Family History Consultants
Doctrine, leadership, and direction
Help for Consultants Priesthood Leaders Family & Church History Dept. Consultant Doctrine, leadership, and direction Training and knowledge
Guidance from Priesthood Leaders
Help for Consultants Guidance from Priesthood Leaders
Guidance from Priesthood Leaders
Under the direction of the bishopric, the high priests group leader coordinates temple and family history work in the ward. Where there is no high priests group leader, a member of the elders quorum presidency fills this role.
Guidance from Priesthood Leaders
The high priests group leader: Recommends individuals to be called as family history consultants. Ensures that enough consultants are called to meet the needs of the ward. Supervises family history consultants.
Guidance from Priesthood Leaders
The high priests group leader may provide consultants the names of individuals and families to contact.
Guidance from Priesthood Leaders
The high priests group leader reports to the bishopric on temple and family history activities Including reports on the individual work by family history consultants with members.
Guidance from Priesthood Leaders
Family history consultants should: Seek counsel and direction from the high priests group leader. Provide the high priests group leader a monthly report of their service.
Discussion What are some things a family history consultant could report to the high priests group leader?
Support from the Family and Church History Department
Help for Consultants Support from the Family and Church History Department
Resources Family and Church History Department provides publications and other resource materials.
Basic Resources A Members Guide to Temple and Family History Work. (34697) Church Handbook of Instructions: Book 2, Section 9. (35709) How Do I Start My Family History? (32916) Temples of the Church of Jesus Christ of Latter-day Saints. (35863) Training for Family History Leaders DVD. ( )
FamilySearch Support The Church has established FamilySearch Support to help consultants answer family history questions. FamilySearch Support missionaries and staff are located worldwide. FamilySearch Support uses an online system to track and to find the answers to family history questions.
FamilySearch Support Consultant has question or problem Telephone
FamilySearch Support Contact FamilySearch Support at: (North America) Through FamilySearch, Product Support, Ask a Question and a Support Representative.
Headquarters Support Headquarters Support at Church headquarters provides technical help to family history consultants and FamilySearch Support worldwide.
Family History Helps Members
"Family history work of Church members has a refining, spiritualizing, tempering influence on those who are engaged in it. They understand that they are tying their family together, their living family here with those who have gone before." (Boyd K. Packer Ensign, "Your Family History: Getting Started," Aug 2003, 17)
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