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Availability in November
Enjoy some Autumn sunshine (or winter storms!) this November at Pebbles Bed and Breakfast by the Beach. We now have some rooms available 23rd - 30th November. Please ring or email if you're interested in staying at Pebbles Bed and Breakfast for a relaxing holiday by the Beach, a great location for walking the South West Coast Path or just chilling-out and enjoying the view.
Late Availability
Due to a late cancellation we now have the Boat House room available for four nights commencing on the 21st September. Please ring or email if you're interested in staying at Pebbles Bed and Breakfast by the Beach in a Room With A View.
September Availability
We only have very limited availability for this month, we have rooms available on the 6th, 16th, 20th, 27th, 29th & 30th September.
In June we saw Humfrey's two chicks for the first time. Over the last month they have put on a lot of weight and are much larger and noisier! The parents have obviously done a good job in finding food for the little Herring Gulls and today they have fledged and left the nest. Initially this meant clambering around on our conservatory roof but this afternoon they were pottering around the garden.
We wish the two juveniles well...
We now only have two single nights available in July. Limited availability in August. Come and enjoy a short break and experience the stunning sea views from the bedrooms which all overlook Budleigh beach and the South West Coast Path. There are some new and wonderful pebble designs on the beach including this amazing Stegosaurus which you can see from the garden. If you're very lucky you may even catch a glimpse of the Beavers and their new kits on the River Otter (as recently featured on Springwatch on BBC TV), the River Otter is just a short walk from Pebbles Bed & Breakfast.
Single nights are currently available on July 23rd and 31st.
Other dates for longer stays are available in August and September, please ring us or email using the website enquiry form.
Humfrey's Offspring
We had our first sighting today of Humfrey the Herring Gull's chicks. The nest is on one of the flat roofs overlooking the beach. The two chicks are quite demanding and are regularly calling for food from their parents. Humfrey appears to be doing his fair share of looking after the two youngsters who we have called Horatio and Emma.
Herring Gulls normally have one brood consisting of 2 or 3 eggs. The chicks are quite small at the moment but will grow rapidly. It will take about 4 years for the clear grey back and white underside to gradually appear.
Room Availability in June
Rooms available from 27th June, fabulous sea views from your bedroom, delicious Aga cooked breakfast in our conservatory overlooking Budleigh's pebble beach.
Lighthouse Room Availability
Due to a cancellation we have the Lighthouse room available on 4th, 5th & 6th June.
Come and enjoy the panoramic sea view at Budleigh beach and watch the sun setting over the cliffs of the Jurassic Coast from your room at Pebbles Bed and Breakfast.
Since our original blog in May 2014 regarding the discovery of beavers in the River Otter there has been some new and exciting news. For the first time since they were hunted to extinction in the 18th Century, England has a population of wild beavers in East Devon and it looks like they are here to stay! The origin of the beavers in the River Otter is still unknown although it's likely to have been either an escape or a deliberate release from captivity.
When the beavers were first discovered to be breeding in February 2014. Defra announced its intention to capture and remove the animals citing the risk to human health from a tape-worm that European beavers are known to carry, but which is not currently present in the UK. Defra's decision sparked an overwhelming response from local people, with the vast majority showing their support for the beavers to remain.
Natural England (the Government's official advisor on the natural environment) has granted Devon Wildlife Trust a five year licence to monitor the beavers which could mean that they remain in the wild in the long term.
As part of the licence a number of beavers were brought into captivity in order for health checks to be made. This process has been overseen by Defra with expert advice from leading zoological and beaver experts. Having gained a clean bill of health the beavers are now back on the river, a move which signals the start of the five year project in which the animals will be monitored for their impacts on local communities, landscape and wildlife.
The re-release took place on the evening of Monday 23 March 2015.
This was a key moment in the history of modern conservation and has come after months of hard work trying to secure a long term future for the animals.
It's been wonderful seeing the River Otter beavers featured on the BBC tv programme Springwatch 2016.
Evidence of beaver activity can be seen along the River Otter from Budleigh Salterton upstream to Honiton, a distance of around 12 miles. Our most recent sighting of one of the beavers was on Wednesday 8th April. There are footpaths along the river and as our photographs show, good views are possible.
To find out more visit the Devon Wildlife Trust website: www.devonwildlifetrust.org/devons-wild-beavers-appeal
Humfrey the Herring Gull - Update
A number of guests ask how Humfrey our 'resident' Herring Gull is so we thought we should provide an update. We should say that this particular gull was given the name 'Humfrey' by one of our more mischievous regular guests.....
In the summer of 2014 it was clear that Humfrey had somehow sustained a serious injury to his left leg. He was unable to put any weight on it at all, it hung limp while he was flying and obviously made landing very difficult. People were very concerned how he would survive in that condition.
Humfrey regularly perches on our garden walls that border the South West Coast Path overlooking the beach. It was obvious in the summer that he could only stand and land on one leg and he did look as if he was in some discomfort.
The good news was that Humfrey seemed to be able to cope and that he could use his left leg for preening and could also put some weight on it. His leg has definitely improved since 2014, as to whether or not it will heal completely only time will tell. He continues to battle with the other gulls for his fair share of the fish, crab and lobster scraps that the fisherman on the beach discard in the sea. This of course means that Richard still has to gather up the odd crab shell or claw from the lawn.
It's fair to say the that Herring Gulls are not the most popular of our birds but Budleigh wouldn't be the same without its resident population of 'seagulls'.
The RSPB describe Herring gulls as "large, noisy gulls found throughout the year around our coasts and inland rubbish tips, fields, large reservoirs and lakes, especially during winter. Adults have light grey backs, white under parts, and black wing tips with white 'mirrors'. Their legs are pink, with webbed feet and they have heavy, slightly hooked bills marked with a red spot. Young birds are mottled brown. They have suffered moderate declines over the past 25 years and over half of their UK breeding population is confined to fewer than ten sites".
Herring Gulls are in the Red category of conservation importance. Red is the highest conservation priority, with species needing urgent action.
Humfrey has now lost his winter plumage and is looking much smarter with his snow white feathers. It's Springtime and unsurprisingly he has found a mate, so we now have two herring gulls sitting on our garden walls and roofs. We may well hear the pitter patter of tiny webbed feet on our roof before too long.......
Easter Availability
Due to a late cancellation we now have the Lighthouse Room available on the 4th April for 7 nights.
It's not too late to book and enjoy the sea views at Budleigh beach and watch the sun setting over the cliffs of the Jurassic Coast from your room at Pebbles Bed and Breakfast.
A recent guest who stayed at Pebbles the Apartment said "We have had a wonderful time at the beautiful apartment....I have definitely found my bolt hole by the sea."
We have limited availability during March and April including the week commencing 9th March when the Budleigh Food Festival is on and the 8th - 21st April just after the Easter Bank Holiday.
If you'd like to enjoy fabulous sea views from the Juliette balcony overlooking the beach then either ring us on 01395 442417 or complete the website enquiry form. We look forward to hearing from you.
Pebbles the Apartment
We are delighted to announce that Pebbles The Apartment is now available for holiday lets. We welcomed our first guests to the Apartment in late December 2014 and we are very pleased to have a number of bookings for 2015. We already have some excellent reviews on Trip Advisor.
The first floor Apartment has outstanding sea views and overlooks the South West Coast Path, pebble beach and Lyme Bay. Step outside the rear gate and you will be on the Jurassic coast path and Budleigh beach. Open the windows or the French doors and hear the waves and surf breaking on the pebbles.
The accommodation comprises of a light and airy double bedroom with a sea view, a newly fitted separate kitchen and breakfast room with sea view, a separate bathroom with new bath and shower fittings and a lounge with French doors and Juliet balcony overlooking the beach. You really couldn't be closer to the beach!
The Apartment has recently been refurbished to a high standard and is fully double glazed with new furniture and fittings throughout.
Pebbles the Apartment is just a few minutes walk from Pebbles Bed and Breakfast and is available throughout the year for weekly bookings or shorter stays (minimum 3 nights).
If you are interested in renting the Apartment and would like to enquire about availability please either fill in our contact form or call us on 01395 442417.
Please note that Pebbles the Apartment is for adults only, no pets are allowed and we have a strict no-smoking policy.
Parking is available at Pebbles Bed and Breakfast just a short stroll from the Apartment.
We have two rooms available on Good Friday 3rd April and Easter Monday 6th April but only one room available on the 4th & 5th April.
It's not too late to book and enjoy the sea views at Budleigh beach and watch the sun setting over the cliffs of the Jurassic Coast from your room at Pebbles Bed and Breakfast.
This morning guests were treated to the sight of seven Gannets feeding just off the beach in full view from the breakfast conservatory at Pebbles. The Gannets returned on the 12th January in numbers, we counted 21 this time! The Gannet is an unmistakable bird as it's the biggest of all the European seabirds.
The Gannet is a brilliant white bird with black tipped wings, it's wingspan is approximately 6ft or 1.8m. The group of Gannets this morning were behaving typically, circling and diving for fish.
Gannets are regularly seen in groups, they're a social bird and nest in huge colonies usually along cliff edges and steep slopes. We believe the Gannets seen from Budleigh beach nest on the Channel Islands. Their nests usually consist of a pile of seaweed and debris often including plastic rubbish. They will have just one egg and one brood.
They feed by catching fish such as mackerel and pollack underwater diving from height. The Gannet has forward facing eyes and a cushioned head and neck to enable it to spot fast moving fish and dive headlong into the waves to catch them.
These photos were taken by Richard during a visit to the Scilly Islands. One of the best places to see Gannets in the UK is Grassholm, a remote island off the Pembrokeshire coast. The island is a RSPB Reserve.
Christmas Day Swim
Just some of the hardy souls who enjoyed a refreshing dip in the sea on Christmas Day at Budleigh beach. We were lucky that we only had to step outside the back gate to join the crowds of spectators. It was a wonderful atmosphere and a new way for us to spend time on Christmas Day morning! It was great to see the Exmouth Lifeboat crews there supporting the event and putting on a show for everyone.
Amongst the more common wildfowl (such as the splendid Mallard shown above) on the River Otter and on the scrapes adjacent to Budleigh Salterton Cricket Club this afternoon was a female Red Crested Pochard! This is a rarely seen bird in the wild in Britain and was generating quite a lot of interest with local birdwatchers. On the same scape was another unusual bird, a Teal/Wigeon hybrid. More information can be found on the following website:
Numerous Curlew, Shelduck and Wigeon were present, other birds included Heron, Herring Gulls, Black Headed Gulls, Little Egret, Redshank and Reed Bunting.
On the way back to Pebbles we spotted a Black Redstart hopping about on the red cliffs along the seafront promenade, another new bird for the Pebbles birdwatching list.
Late Availability
Due to a late cancellation we have three rooms available for Friday 28th, Saturday 29th and Sunday 30th November. Come and enjoy a short break and experience the stunning sea views from the bedrooms which all overlook Budleigh beach and the South West Coast Path. The heaths just outside Budleigh are also looking stunning in the Autumn sunshine. Other dates are available in December, please ring us or email using the website enquiry form.
November Availability
We have two rooms available for Friday 21st and Saturday 22nd November. Come and enjoy a short break and experience the stunning sea views from the Sail Loft or Boat House rooms which overlook Budleigh beach and the South West Coast Path. We can't guarantee sunshine but we can guarantee spectacular views from your bedroom and breakfast conservatory of the waves crashing on the pebble beach . Other dates are available later in the month, please ring us or email using the website enquiry form.
Pebbles blog
Welcome to Pebbles bed and breakfast blog page.
November 2015


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Online multiplayer
This game is playable online.
PixelJunk Monsters!
Take on the role of Tikiman and protect your hut of helpless babies from waves of incoming monsters; build weapon towers to defend...Genre: Turn-based, Strategy
Crossfire Extended Release1.9.0 (28 Jan 2014)
Crossfire Extended Release is a 2D python based non-proprietary (GPLv2) graphical medieval fantasy roguelike RPG with a multiplayer focus.Genre: Role-playing
Infinite Pixels
by Somniare0.5.0 (9 Jan 2014)
Infinite Pixels is an exploration, survival sandbox game.Genre: Role-playing
Voxelands24 Aug 2015)
Voxelands is a sandbox construction game based on Minetest, which was inspired by earlier "voxel world" games such as Infiniminer.Genre: Adventure, Role-playing
Six Wheels and a Gun24 Jan 2013)
Using an exceptional physics simulation, S.Genre: Shooter, Simulation
OpenDungeons0.6.0 (8 Sep 2015)
OpenDungeons is an open source, real time strategy game sharing game elements with the Dungeon Keeper series and Evil Genius.Genre: Construction and management, Strategy
by TreehouseTest build (7 Jan 2014)
Dethroned is an action real-time strategy game about three factions, their kings and their champions with a competitive gaming ingredient.Genre: Strategy
Steam Squad30 Mar 2014)
Steam Squad - turnbased wargame, which takes place during the First World War, in an alternate universe.Genre: Turn-based, Strategy
ChaosEsque Anthology27 Nov 2015)
ChaosEsque Anthology is a first person shooter.Genre: Shooter, Action
by Artplantfrequently updated
Entropy is a sandbox science fiction MMOG with a strong focus on freeform gameplay and large-scale space combat, and is available right...Genre: MMO, Action
Warspear Online
by AIGRIND LLCfrequently updated
Create a Hero and battle monsters in a classic 2D MMORPG that has gained popularity with millions of players worldwide! In Arinar,...Genre: MMO, Adventure, Role-playing

subset: commoncrawl


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Inicio, duración y término de la estación lluviosa en cinco localidades de la costa ecuatoriana
Zambrano, E.
Hernández, F.
Refereed StatusNon-Refereed
MetadataShow full item record
El objetivo de este trabajo es llegar a definir el inicio, término y duración de la estación lluviosa, mediante el análisis de datos de precipitación a fin de usar los resultados como fechas atribuibles a los cambios de estación climática presentes en la costa ecuatoriana......The parameter that remarks the change of the climatic season in Ecuador is precipitation, which at the beginning or end is not continuous; this work defines the beginning, duration, and end of the rainy season in five towns of the Ecuadorian coast, located along the central and southern coast. Daily precipitation data obtained from the Hydrographic and Oceanographic Information System of INOCAR is analyzed since 1975 until 2005. The criterion to define the beginning and duration of the rainy season is based on the analysis of pentads. This is and adaptation of the methodology proposed by Alfaro (1998). If at least, are rains during three consecutive pentads, the date is marked as the begin of the rainy season; if there are no registries of rain in 3 consecutive pentads is defined as ending of rainy season, normally expected to be in April. Results show a regularity in the beginning, and, and duration dates being affected from time to time by the variability of El Niño-a. As main conclu.....


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On Tuesday, the Obama Administration reached an agreement with wildlife advocates that would require the Interior Department to extend protection to a number of threatened species. If approved, the deal would make 2018 the deadline to set additional protections for 757 plant and animal species, including the Miami Blue butterfly, Pacific walrus and the wolverine.
Some species in the deal have been have been on a candidate list for protection since 1973, shortly after the passage of the Endangered Species Act. The new deal includes 258 of those candidates, as well as 499 new flora and fauna species.
According to Kieran Suckling, executive director of the Center for Biological Diversity, the group which filed the petition, "We're dealing with the ultimate stakes of life and death with this settlement. If these 757 species had to wait much longer, many of these would go extinct as well."
The Fish and Wildlife Service will review the species in the act. "This work plan will allow the service to more effectively focus our efforts on provifing the benefits of the ESA to those imperiled species most in need of protection," said service director Dan Ashe.
About China DeSpainChina DeSpain is a San Antonio-based writer and blogger. She loves pop culture, animal rights, health and fitness, international travel, books and wigs. Follow China on Twitter: @ChinaDeSpain
View all posts by China DeSpain →
3 Responses to Obama Administration Reaches Agreement with Wildlife Advocates
Enjoying our new blogger, China DeSpain – looking forward to reading more.
Great news! It's about time they started addressing all those animals on the waiting list.
This is a great start! If this goes thru I will Be very happy for our animals! I helped protect New England cottontail habitat as a volunteer for a while (they are on the list) and they need this protection!
This still has to be approved (thru a Federal judge), and if it does, Congress has thru 2018 to mull greater protections. The House Republican proposed budget ( for the DOI) BLOCKS any new listings on the Endangered Species Act. I actually wonder how this will sit with the USDA's Wildlife Services agency that is currently tasked with killing animals (like wolves and in the name of population control).


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Denise Richards wants to end custody of Charlie Sheen and Brooke Mueller's children
After taking responsibility for her ex-husband and his (other) ex-wife's twin sons back in May, Denise Richards has written to the Los Angeles County Department of Children and Family Services requesting that another caregiver for Bob and Max replace her, according to TMZ. Richards' letter the the DCFS reportedly details violent behavior on the part of the 4-year-old boys, whom she allegedly says seemed to get worse after visiting their mother, Brooke Mueller, who spent time battling a drug addiction in rehab this past spring. The boys' alleged violence has reportedly been aimed at Richards' daughters and family dogs.
Sheen, meanwhile, has been on a public tirade against Mueller, talking trash on Twitter and to whichever press outlets will listen about her drug problems, and calling her a variety of unprintable names. Mueller reportedly plans to hold him in contempt of court over his outbursts, as their 2011 divorce settlement mandated that he not discuss her substance abuse issues in the press.
© 2015 Whalerock Industries


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AF mode in the X100 menu
Started Feb 8, 2012 | Discussions thread
Shop cameras & lenses ▾
Regular Member • Posts: 371 • Gear list
AF mode in the X100 menu
Feb 8, 2012
My AF mode was greyed out until I reset the camera. I assume it was because of the way I had my camera set up but not sure what the cause was. I know someone in this forum will have re answer.
Christine Edwards's gear list:Christine Edwards's gear list
Sony RX1 Ricoh GR Leica M9 Fujifilm X-Pro1 Olympus OM-D E-M5 +14 more
Fujifilm FinePix X100
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jjl2u - You struck out again and have been kicked out of the game for arguing with the umpire. David kennedy will remain exactly where he is as CEO of Rareco and continue building the South Africa operation he was appointed to do. I did not say he will be the CEO of GWMG, all I stated he is one of the key personnel and part of the expertise that "nebbya" so eloquent characterized that is needed by any successful enterprise.. Much more informative that your repetitive rhetoric.


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- Filed Under
The Corning Area Chamber of Commerce will host a grand reopening and ribbon-cutting ceremony at 10 a.m. July 9 at AIM Independent Living Center's Chemung location at 650 Baldwin St. in Elmira NY 14901
AIM Independent Living Center's Elmira Office is transitioning from the current Elmira location at 1316 College Ave. to the Economic Opportunity Program Inc. building.
AIM will officially be in the EOP building starting next week. The AIM Elmira phone and fax numbers will remain the same. Phone: (607) 733-3718. Fax: (607) 733-0180. ...


text: Meta Battle Subway PokeBase - Pokemon Q&A Login Register All Activity Questions Unanswered Tags Users Ask a Question Rules Chat Does Poison touch negate the other status the attack could cause? 1 vote Example: Toxicroak with Poison touch uses Ice-punch. Does Ice-punch still have a 10% chance of freezing the target as well as the 30% chance of poison? or does it only have the 30% Poison chance? poison-touch asked Mar 14, 2012 by Speed freak Please log in or register to add a comment. Please log in or register to answer this question. 1 Answer 4 votes Best answer Yes, it still has the 10% chance of freezing, its just you would have to be extremely lucky to get a freeze. 9/10 Poison touch would have already poisoned the foe. answered Mar 14, 2012 by Saz Please log in or register to add a comment. Related questions What is the difference between the Abilities Poison Point and Poison Touch? Stench or Poison Touch for Muk? What happens if a Pokemon with Poison Touch uses a move with a chance with poisoning? What are all the status moves that cause Poison, Burn, Frozen, Paralysis and Sleep? Ability probability question Does poison touch stack up with poison jab so it would become 50% instead of 20% and 30%? Does poison touch make poison jab more likely to poison? How to beat Pokemon which cause status problems? Useful Meta Posts How to change your username How to add a user avatar Why was my post hidden? The points system Question etiquette Flags vs Downvotes Anime FAQ


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Sealy Posturepedic Hybrid Kingsthorne Plush Mattress
A Sealy Posturepedic Hybrid Mattress Kingsthorne Plush delivers the perfect combination of comfort and support with a half foam and half springs design. Reduce tossing and turning with gel memory foam, which cradles and supports you as you sleep.
Price is for MATTRESS ONLY. Bed set and foundation in images are sold separately.$1,499.00 - $2,998.00$2,598.00
Beautyrest Black Kingston Hybrid Pillow Top MattressA restful night's sleep is an essential part of a healthy lifestyle. Recharge your human battery with the Beautyrest Black Kingston Hybrid Pillow Top Mattress. This top of the line mattress features Micro Diamond Infused AirCool Memory Foam that helps conduct heat away from the body and aid in temperature management.$2,649.00 - $5,298.00
Sealy Posturepedic Sedgebrooke Plush Pillow Top Mattress
The Sealy Posturepedic Gel Sedgebrooke Plush Euro Pillow Top mattress combines multiple inches of SuperSoft foam and a plush euro pillow top to create a luxurious sleep experience. A full layer of gel memory foam and individually encased titanium alloy Apex innersprings provides back-aligning support and lasting durability.
Price is for MATTRESS ONLY. Bed set and foundation in images are sold separately.$2,699.98
Beautyrest Recharge 1000 Pillow Top Mattress
The Beautyrest Recharge World Class Plush Pillow Top offers body conforming support with 1000 density Beautyrest Pocketed Coil springs and relaxing comfort with a 2" plush comfort foam pillow top. GelTouch and AirCool foam helps to relieve pressure points on your body so you can wake up feeling recharged.
Price is for MATTRESS ONLY. Bed set and foundation in images are sold separately.$1,724.99 - $3,499.98$2,899.98


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Some Critical Reflections on Activism and Sudan: A Reply to Monim
Dear Monim,
I have long argued that humanitarians and human rights activists should embrace critical self-reflection including acknowledging their mistakes (see my piece, originally entitled "Writing rights and getting it wrong". So I welcome the change to debate–though not, of necessity, on everything. Monim puts his finger on two closely-related key issues, which […]Continue Reading →
Alex de Waal: the Rebirth of a Principled Activist?
Whenever Alex de Waal publishes analysis or reflections, Sudanese intellectuals and activists, and the concerned international institutions and individuals, give it priority attention. The last week of April and first week of May 2013 were for me remarkable weeks, watching de Waal coming with two articles, re-positioning himself as an advocate for "principled" activism […]Continue Reading →
I am a freelance writer and editor who has lived and worked off and on in central Africa for 25 years. I am writing to call your attention to this week's Congressional hearing on Dodd-Frank 1502. Held by the Monetary Policy and Trade subcommittee of the House Financial Services Committee, the hearing examined the unintended […]Continue Reading →
In Defense of International Activists
I am responding to your two posts, about activism and the review of John Young's book The Fate of Sudan.
Defining activism, you believe one of the main tasks of activists is to challenge […]Continue Reading →
Patrick Karuretwa is the Defense and Security Advisor to the President of Rwanda and a Fletcher alumnus.
As I read Professor Alex de Waal's perceptive piece on "Reclaiming Activism," I thought I should not miss this opportunity to, for once, disagree with one of the few "experts on Africa" I have always had genuine […]Continue Reading →
Reclaiming Activism
Reclaiming Activism
For most of my adult life I introduced myself as an "activist" first and a writer, researcher, or practitioner of humanitarian action or peacemaking second. Then, about seven or eight years ago, I became rather uncomfortable with the word. Not because I had diluted my personal commitment to working in solidarity with suffering […]Continue Reading →
Tagsadvocacy Africa African Union arms trade atrocities AU book review Bosnia Burma conflict data Democratic Republic of Congo Drugs Egypt Eritrea Ethiopia gender genocide Getting Somalia Wrong? human rights memorial illicit trade Indonesia intervention Iraq justice Libya Mali mediation memorialization new wars Olympics peace political marketplace Re-Framing the Debate responsibility to protect Somalia South Africa South Sudan sports Sudan Syria trafficking Uganda UN Unlearning violence Zenawi


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Respond to Review of El Piano - York
by Beckylovesfood
Review: Came here for dinner on my Birthday, we ordered a platter and when it arrived it had a couple of candles in which was so nice! I was so impressed because they put the food in front of us and my meat eating hubby actually looked excited to eat. Normally I have to drag him to places and he politely eats but I really think he enjoyed it! It was the first time we have ever got to share anything too! (BIG bonus!) Oh and he has never enjoyed cabbage before but he was happily eating the mexislaw! The staff were all really nice and the food was good. The bonus for me is that it is gluten free and as I am not so good with gluten I could happily eat everything including puddings without worrying. We ate there the next night and also bought one of their beautiful rugs which are so soft under your feet by the way. Thanks El Piano for a lovely couple of evenings, you made my week!
Posted by Magdalena, owner on Tuesday, July 23, 2013
Lovely to hear that you BOTH enjoyed the food...The EL PIANO YORK cooks are really great...many years of experience between them and AMAZINGLY they still love to go to work each day and DO IT ALL OVER AGAIN...
As for the carpets, they are made in Spain by friends of ours, recycled fibres and machine washable I still have three which I bought nearly 20 years ago. The trick is to not let them get too dirty and wash them regularly.
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After a fantastic opening earlier this month with great critical reviews as the cherry on top, Guardians of the Galaxy proved to be a win for Marvel. Of course, being the superhero nerd I am, I went and saw it opening night. Superhero-Nerd-Me loved the action, tech, and comedy while E-Learning-Nerd-Me spent the entire movie whispering loudly to my poor friend (and everyone within a 4 seat radius) that Star-Lord is a total autodidact!
Just as a quick reminder, autodidacts are fabulously awesome people who love learning and teaching themselves new things. Star-Lord probably turned to autodidactism more out of necessity than a pure love of learning, but he still dances to sweet '80s music and refers to 'The Legend of Kevin Bacon' from Footloose – so he retains the awesome factor, in my opinion. Check out these instances that proved Star-Lord AKA Peter Quill caught the autodidact bug.
Musical Tech Prowess
26 years after being abducted from Earth as a child by 'space pirates', Peter still listens to music on the same
walkman from the same audio cassette with the same headphones. It is probably safe to assume that in all his struggles and travels from planet to planet, Peter's beloved music system broke down from time to time. Considering that he likely didn't have contact with too many Earthlings, he had to figure out how to fix everything himself. The key words here being: 'figure out how'. Plus, I don't know of any battery from the '80s that would still have enough juice to power a tape player after 26 years – so Peter probably had to engineer a replacement power source on his own. Conclusion: Autodidact.
Bonus: Peter's ship, The Milano, had a cassette player and speakers installed. Considering we don't make extraterrestrial spaceships here on Earth (at least not to the knowledge of us ordinary folks), he probably installed that himself too.
The Ultimate Linguist
Here on Planet Earth, we have hundreds of different languages – sometimes dozens within the same country. Unless every being on every planet except Earth exclusively speaks English, there were probably several different languages that Peter had to learn in order to jump from world to world and continue to communicate with ease. Considering the fact that he grew up around pirates, there probably weren't too many maternal figures or teachers around to teach Peter – which means that he largely picked that up on his own too.
When he left Earth, Peter was definitely more than 8 or 9 years old – well past the threshold where humans can pick up languages extremely rapidly. The fact that he picked them up so well at his age points to his fantastic self learning skills as well.
So You Think You Can Dance?
Well you don't have much on Star-Lord, the Amazing Dancing Alien! Kids don't have fully developed motor skills – that's a well known fact that explains why kids are usually not the best dancers. That's also why it is so extraordinary that Peter left Earth as a child, didn't have access to Terran movies or culture, but picked up how to dance (albeit '80s style) completely on his own based solely on 26-year-old memories. He beat his ultimate nemesis in the movie by distracting him through a dance off !
Imagine what he would have been able to do on Earth with access to a dance teacher and pop culture. Granted, becoming known as a Guardian of the Galaxy is a pretty cool title, but the Next Michael Jackson would have been pretty spectacular too.
If you think Star-Lord is an ultimate autodidact, check out Groot! He learned to dance as a baby:
Images from: Marvel Comics and Marvel Cinematic Universe


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BNS Body Classes Updated to Version 0.4
= Version 0.4 =
* Released December 2012
* Added conditional check on `option_classes`
* Added generic (sample) calendar extension
* Added more common dates: Valentine's Day, St. Patrick's Day, April Fool's Day, Halloween, Remembrance Day
* i18n updates
* Prepared for extension plugins
* Refactored options to more appropriate naming conventions
* Updated descriptions and FAQ to reflect new features
BNS Body Classes changelog
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Tag: UpdateBNS Add Style Retired
It is with a heavy heart that I am retiring, for the first time, one of my plugins. Although BNS Add Style served its purpose when I wrote it, there are simply too may other good options to choose from that are being actively supported and improved whereas this plugin was not seeing the attention […]
Share this:Pinup Meets Grunge Updated to Version 2.2
Mostly minor items were addressed but the latest review of Pinup Meets Grunge should now better meet the WordPress Theme Review Requirements and Recommendations even if it still remains under suspension for Adult Content(?!) You can download this version from its GitHub repository here. Enjoy! Related posts: Ground Floor Updated to Version 2.1 Desk Mess […]
Share this:BNS Login Version 2.3.3
Just a quick update … this plugin just seems to do what it needs to do and not much more ever really get requested or considered to be added to it. That being the case, this plugin will also most likely be moving to a twice yearly release; unless, of course, a great idea comes […]
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Ronda Rousey discusses why she gave Miesha Tate the bird at the L.A. stop on the UFC world tour, TUF 18, why Tate will lose Armenian fans after TUF airs, if she was bothered by her fight being bumped watch video >>
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http://prommanow.com -- ProMMAnow.com reporter Daniel Theodore had to face up to some of his past comments regarding Miesha Tate as the UFC women's bantamweight contender calls him out. Dan sets the watch video >>
August 1, 2013 UFC women's bantamweight champ Ronda Rousey and challenger Miesha Tate continue their intense rivalry sitting face to face in the Sportscenter studio to talk about their upcoming remat watch video >>
UFC 168: Miesha Tate versus Ronda Rousey! Whose Hotter! Who Wins! watch video >>
Miesha updates us on the next season of TUF and her rivalry with Ronda Rousey! watch video >>
Former UFC champion Anderson Silva discusses his first fight against Chris Weidman, how he still wants to fight Roy Jones Jr., his conversations with Dana White about a potential Jones Jr. fight, wh watch video >>
For more log onto http://www.fighthubtv.com Like us:http://on.fb.me/xWRC1f follow us:http://bit.ly/wACkIv videos uploaded daily! Subscribe: http://goo.gl/vnzIb Michael Mardones speaks with Ryron Gra watch video >>
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During the UFC 168 conference call, Anderson Silva, Chris Weidman, Ronda Rousey and Miesha Tate discussed their upcoming fights next Saturday night. Subscribe to our channel for more MMA videos! Cli watch video >>


text:
2002 Jeep Liberty • 6 cylinder • 85,000 miles
2002 jeep liberty. Can not get the power steering pump to stop leaking after installation of the pump, hose with the o ring.
please advise
please advise
December 8, 2010.
December 8, 2010.
Have you replaced the O-ring? Have you checked to make sure there are no marks on the hose itself where it attaches?
Dec 8, 2010.
Dec 8, 2010.
Serpentine belt broke due to tensioner bearing freezing. Drove it for another 4 minutes and stopped before it reached max temperature/redline. It was stopped in a bad area, so waited ...
1 answer • 1998 Buick Regal • 45,000 miles
I have a 2005 Honda Civic Hybrid. The issue I have is the power steering. I haven't done anything to the car yet. I onl looked at te manual to see if I need to change the liquid but ...
5 answers • 2005 Honda Civic Hybrid • 112,000 miles
1999 Ford Taurus mileage: 120,000. Is replacing the power steering hoses very difficult?
1 answer • 1999 Ford Taurus • 120,000 miles
Power steering went out but why won't the fluid stay in
1 answer • 2002 Chevrolet Impala • 138,000 miles


text:
What a waste of milk and of money, and what a stinky, sticky mess!
If the goal was to make water reflect more light, why would they not just add something harmless and cheap to water?
I think you are wrong...but I don't know for sure. It would not be the first time Hollywood did something idiotic.


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December 1, 2015
LUBBOCK (June 24, 2013)--Authorities Monday in Lubbock identified three people killed in what police described as a murder-suicide arising from a domestic dispute as Jack Alexander Bridges, 17, Kayla Ann Lewis, 19, and Mark Antonio Reyes, 20.
Bridges and Lewis were found dead Sunday morning at a home in Lubbock and Reyes' body was found later at another residence.
Investigators think Reyes shot the two teenagers and then later killed himself after a dispute at Lewis' home.
A 5-month-old baby was found unharmed at the residence where Reyes' body was discovered.
The infant, who's believed to be Lewis' child, was placed in state custody.
Click Here to access the online Public Inspection File
Viewers with disabilities can get assistance accessing this station's FCC Public Inspection File by contacting the station with the information listed below. Questions or concerns relating to the accessibility of the FCC's online public file system should be directed to the FCC at 888-225-5322, 888-835-5322 (TTY), or email@example.com.


text:
Page 1
Candida albicans Strain-Dependent Virulence and
Rim13p-Mediated Filamentation in
Experimental Keratomycosis
Bradley M. Mitchell,1,2Tzu G. Wu,1Beth E. Jackson,1and Kirk R. Wilhelmus1
PURPOSE. To compare the virulence of wild-type Candida al-
bicans strains in a murine model of corneal candidiasis and to
investigate the role of fungal filamentation in disease progres-
METHODS. Scarified corneas of immunocompetent or cyclo-
phosphamide-treated BALB/c mice were topically inoculated
with one of three human isolates of C. albicans, a homozygous
mutant of the pH-dependent filamentation gene rim13 or a
mutant reference strain control. Mock-inoculated eyes served
as negative controls. Corneal disease was categorized daily for
8 days with quantitative fungal culturing of eyes at 6 hours, 1
day, 4 days, and 8 days after infection and histopathologic
examination at 1 day and 4 days after infection.
RESULTS. Corneal disease severity differed significantly among
wild-type strains (P ? 0.02). The rim13–/–mutant Tn7-rim13
was fully attenuated, whereas the mutant control DAY286 was
fully virulent. Pretreatment of mice with cyclophosphamide
increased susceptibility to wild-type C. albicans and partially
rescued the attenuated phenotype of the genetically deficient
rim13–/–fungal mutant. All strains replicated with similar ki-
netics in vitro, and wild-type strains had similar clearance from
infected eyes. Histopathologic findings correlated with disease
CONCLUSIONS. Wild-type strains of C. albicans that differ signif-
icantly in ocular pathogenicity correlate with the ability of
yeast to produce pseudohyphae and hyphae and to invade
corneal tissue. Full attenuation of the fungal rim13–/–mutant is
the first direct demonstration of a hyphal morphogenesis-re-
lated gene as a specific virulence factor for C. albicans during
corneal infection. (Invest Ophthalmol Vis Sci. 2007;48:
774–780) DOI:10.1167/iovs.06-0793
Candida albicans is found on the ocular surface of up to one
third of otherwise healthy persons.1–4Although this fungal
species is typically commensal, severe ocular disease develops
under certain conditions. How this shift to pathogenic invasion
occurs is still unclear, but the transition is finely balanced and
genetically regulated.5Fungal mechanisms crucial for mucosal
and systemic infection by C. albicans include adherence, ger-
mination, production of extracellular proteinases and phos-
pseudohyphae and hyphae.6–9Previous work has suggested
that the conversion to filamentous forms contributes to ocular
virulence of C. albicans.10,11
Environmental cues such as pH12,13influence filamentation
growth of Candida, Saccharomyces, and Aspergillus through
a conserved alkaline-response pathway.14,15Mutant strains un-
able to grow at a given pH in vitro are less capable of infecting
selective sites in vivo.16,17This system, called the RIM101
pathway or the PacC pathway, depending on fungal genus,18is
governed by the zinc finger–containing transcription factor
Rim101p/PacC.15,19–21In acidic conditions, Rim101p is full-
length and inactive, whereas in neutral to alkaline conditions
its C-terminal portion is cleaved, resulting in activation of the
protein that regulates gene expression.22–24Several gene prod-
ucts are required for this proteolytic processing, including
Rim8p/PalF, Rim9p/PalI, Rim13p/PalB, Rim20p/PalA, and
Rim21p/PalH.24,25Rim13p/PalB is a calpain-like protease that
cleaves the C-terminal glutamate-aspartate-rich domain of
Rim101p during activation.18
Because of the complex life cycle of fungi, investigating the
pathogenesis of oculomycosis requires in vivo models that
allow high reproducibility and sensitive quantitation.10,11,26–28
This study compared the degrees of virulence of three different
C. albicans wild-type strains in mice and evaluated the contri-
bution of the RIM101 signal transduction pathway.15,20,21Our
findings provide direct evidence for the importance of filamen-
tation in keratomycosis and demonstrate that a morphogenesis-
related fungal gene is a specific virulence factor for C. albicans
during corneal infection.
switchingfrom yeaststo
Fungal Cultures
Three wild-type strains of C. albicans originally isolated from human
infection, a Tn7 transposon mutant, and a mutant control reference
strain were evaluated. Strain VE175 is a corneal isolate that has been
used to induce experimental keratomycosis in rabbits.29Strain B311
(ATCC 32354; American Type Culture Collection, Rockville, MD) is an
isolate that is highly virulent in mice when injected intravenously30and
that causes ocular disease in mice after corneal inoculation.11Strain
SC5314 has been used extensively for genetic studies of C. albicans
and experimentally causes corneal disease in rabbits.29,31Strain Tn7-
rim13 is a homozygous mutant with a transposon insertion at position
239 of the rim13 coding sequence18that was transformed into strain
BWP17,15a derivative of strain SC5314, as part of a homozygous
insertion mutant library.32The mutant control reference strain
DAY286 has a Ura?Arg?His?genotype and was created by the trans-
formation of strain BWP17.15
All yeast strains were grown on Sabouraud dextrose agar (Difco,
Detroit, MI) for 3 days at 25°C. For corneal inoculation, the yeasts were
harvested and diluted in sterile phosphate-buffered saline (PBS) to yield
From the
Cullen Eye Institute, Department of Ophthalmology, and the2Depart-
ment of Molecular Virology and Microbiology, Baylor College of Med-
icine, Houston, Texas.
Supported by a clinical investigator award (EY00377), cooperative
agreement (EY09696), and core grant (EY02520) from the National Eye
Institute; a senior scientific investigator award and grant from Research
to Prevent Blindness, Inc.; the J. S. Abercrombie Foundation; the Retina
Research Foundation; and the Sid W. Richardson Foundation.
Submitted for publication July 12, 2006; revised September 5,
2006; accepted December 1, 2006.
Disclosure: B.M. Mitchell, None; T.G. Wu, None; B.E. Jackson,
None; K.R. Wilhelmus, None
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked "advertise-
ment" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: Kirk R. Wilhelmus, Department of Oph-
thalmology, NC-205, Baylor College of Medicine, 6565 Fannin, Hous-
ton, TX 77030; email@example.com.
1Sid W. Richardson Ocular Microbiology Laboratory,
Investigative Ophthalmology & Visual Science, February 2007, Vol. 48, No. 2
Copyright © Association for Research in Vision and Ophthalmology
Page 2
1 ? 105or 1 ? 106colony-forming units (CFU)/5 ?L inoculum based
on optical density (OD) at 600 nm and using a conversion factor of 1
U OD600equal to approximately 3 ? 107CFU/mL based on Saccharo-
myces33and confirmed for Candida.11For the in vitro growth kinetics
study, yeasts were collected from the agar plates and diluted in Sab-
ouraud dextrose broth (Difco).
Adult female BALB/c mice (Harlan Sprague-Dawley, Houston, TX) were
used at 6 to 8 weeks of age. A subset of mice was pretreated 5 days, 3
days, and 1 day before corneal inoculation with intraperitoneal injec-
tions of cyclophosphamide (Sigma, St. Louis, MO) at 180 mg/kg body
weight, as previously described.11This regimen and dose of cyclophos-
phamide results in severe immunosuppression and induces a biological
effect within ocular tissues.11Mice were anesthetized and corneally
scarified as previously described.11Five microliters (1 ? 105or 1 ? 106
CFU) inoculum of C. albicans was applied to the scarified corneas.
Mice that were scarified and received mock inoculation with sterile
PBS served as negative controls. All animals were treated in accordance
with the ARVO Statement for the Use of Animals in Ophthalmic and
Vision Research, and the protocols were approved by the Baylor
College of Medicine Institutional Animal Care and Use Committee.
In Vitro Growth Kinetics
One thousand CFU of each C. albicans strain were inoculated into 2
mL Sabouraud dextrose broth and incubated at 27°C with continuous
rocking for 7 days. Two milliliters mock-inoculated Sabouraud dex-
trose broth served as a negative control. Results of two independent
experiments performed in triplicate were averaged. The broth was
sampled at 6, 9, 22, 34, 50, 76, 96, and 168 hours after inoculation for
in vitro growth by measuring the OD600and using the conversion
factor of 3 ? 107CFU/mL per 1 U OD600.11,33Statistical analyses were
determined with Student's t test.
Clinical Scoring
All mice were monitored daily for corneal involvement for up to 8 days
postinoculation (p.i.). The severity of keratomycosis was scored with
the aid of a dissecting microscope. A grade of 0 to 4 was assigned to
each of three criteria: area of opacity, density of opacity, and surface
regularity.11,28Scores from each category were tallied daily for each
eye to yield a possible total score of 0 to 12. A total score of 1 to 5 was
categorized as mild eye disease, a total score from 5 to 9 was consid-
ered moderate, and a total score greater than 9 was considered se-
vere.11Results were evaluated for statistical significance by the
Kruskal-Wallis one-way analysis of variance on ranks. Pairwise multiple
comparison procedures included the Dunn method and the Tukey test.
Quantitative Isolate Recovery
Mice were killed and eyes were enucleated at 6 hours, 1 day, 4 days,
and 8 days p.i. and were processed for microbial culturing. Eyes from
infected and mock-infected mice were individually ground in a frosted
glass grinder, as previously described.11A 0.5-mL homogenate aliquot
was fourfold serially diluted in Sabouraud dextrose broth containing
chloramphenicol 50 ?g/mL and incubated at 27°C. After 4 days of
incubation, the last blank in the serial dilution that had visible yeast
growth was recorded as the titration end point and then was examined
by subculture and microscopy. Results were analyzed with Student's t
Mice used for histologic examination were killed, and the eyes were
enucleated at 1 day and 4 days p.i. Eyes from C. albicans–infected and
mock-infected mice were formalin-fixed, paraffin-embedded, and sec-
tioned at a thickness of 8 ?m for histologic study. Sections were
deparaffinized and stained with Grocott methenamine silver (GMS;
Richard-Allan Scientific, Kalamazoo, MI) or periodic acid-Schiff (PAS;
In Vitro Growth Kinetics of Wild-type
C. albicans Strains
To determine whether inherent growth differences existed
among the strains of C. albicans, the growth rates of strains
VE175, B311, and SC5314 were evaluated in vitro. The overall
growth kinetics of the three different strains was similar, with
all three strains demonstrating similar lag, log-growth, and
plateau phases (Fig. 1). Mock-inoculated negative control cul-
tures remained negative for growth throughout the 7-day
study. The results suggested that all three strains replicated at
similar rates under controlled in vitro conditions and that no
strain demonstrated an apparent growth advantage or disad-
Visual Examination of Keratomycosis in Mice
Infected with Wild-type C. albicans Strains
After the inoculation of 1 ? 106CFU of C. albicans, mice were
visually evaluated daily for 8 days and scored for corneal in-
volvement (Fig. 2). Mice infected with strain VE175 developed
only mild keratomycosis by 24 hours p.i. that became signifi-
cantly less severe by day 8 (day 1 vs. day 8; P ? 0.001). Mice
infected with strain B311 developed moderate keratomycosis
on day 1 that persisted through day 4 (day 1 vs. day 4; P ? 0.7)
but that became less severe on and after day 5 (day 1 vs. day 5;
P ? 0.04). Mice infected with strain SC5314 also developed
moderate keratomycosis, but corneal involvement remained
moderate to severe through day 8 (day 1 vs. day 8; P ? 0.9). As
previously reported,11all mock-infected corneas had mild sur-
face irregularities and swelling at 6 hours after the corneal
scarification procedure but regained the normal appearance of
a naive eye within 24 hours and then remained unchanged.
Mice infected with strain B311 had significantly more disease
VE175, B311, and SC5314. One thousand CFU of each cultured Can-
dida albicans strain were inoculated into Sabouraud dextrose broth
and monitored for growth for 7 days by optical density at a wavelength
of 600 nm (OD600). Mean OD600measurements (? SD) of six samples
from two independent experiments are plotted. The lowest points
plotted on the graph represent the optical density of the broth used as
diluent and for blanking the spectrophotometer.
In vitro growth kinetics of Candida albicans strains
IOVS, February 2007, Vol. 48, No. 2
Candida Virulence in Keratomycosis 775
Page 3
than mice infected with strain VE175 from day 1 through day
4 (P ? 0.001). However, disease with strain B311 improved
from day 5 through day 8 and became similar to disease with
strain VE175 (P ? 0.2 for day 5 through day 8). Corneal disease
with strain SC5314 was significantly greater than that caused
by strain VE175 at all time points (P ? 0.001). Representative
findings from day 4 and day 8 are shown in Figure 3.
Quantitative Isolate Recovery of C. albicans
To correlate visible eye disease to fungal load within ocular
tissues, mouse corneas were scarified and individually infected
with 1 ? 106CFU of one of the three C. albicans strains or
were mock-infected and analyzed by end point titration at 6
hours, 1 day, 4 days, and 8 days p.i. As shown in Figure 4, the
rates of fungal clearance in mice were similar among the three
strains at all time points evaluated (P ? 0.1). Strains VE175,
B311, and SC5314 were cleared from ocular tissues with sig-
nificantly fewer organisms recovered from the infected cor-
neas on day 8 compared with day 1 (P ? 0.009 for all three
strains). No C. albicans was recovered from mock-infected
corneas at any time.
Histopathology of Mouse Eyes Infected with Wild-
type C. albicans Strains
Histologic examination of infected eyes harvested 1 day and 4
days p.i. revealed invading yeasts in the corneal epithelium and
the stroma. Corneas of infected animals showed epithelial
thickening and varying degrees of stromal edema and inflam-
mation. Massive hyphal formation was present in the cornea 1
day p.i. for strain SC5314 (Fig. 5A), but the yeast form was
predominant 4 days p.i. The yeast form and some pseudohy-
phae were typically seen in VE175-infected animals, with the
infection primarily more superficial and affecting the corneal
epithelium and anterior portion of the stroma (Fig. 5B). Neu-
trophilic infiltration and edematous corneal stroma were prom-
inent in corneas infected with strain SC5314, less severe with
strain B311, and minimal with strain VE175 at 4 days p.i.
Mock-infected eyes did not show signs of infection or inflam-
strains VE175, B311, and SC5314. Immunocompetent BALB/c mice
were mock-infected or infected with 106CFU of C. albicans and
visually evaluated for their corneal involvement for 8 days. Mock-
infected corneas received sterile PBS and served as controls. A total
score less than 5 was categorized as mild disease, from 5 to 9 was
considered moderate, and greater than 9 was severe. Each point rep-
resents the mean score (? SD) of 9 to 48 eyes.
Severity of murine keratomycosis induced by C. albicans
murine keratomycosis induced by C.
albicans strains VE175, B311, and
SC5314. Corneas of immunocompe-
tent BALB/c mice were mock-in-
fected or infected with 106CFU C.
albicans and were photographed 1
day, 4 days, and 8 days after inocula-
tion. Representative
Clinical progression of
776 Mitchell et al.
IOVS, February 2007, Vol. 48, No. 2
Page 4
mation but did have residual microscopic epithelial changes
from the initial scarification procedure.
Evaluation of Rim13p for C. albicans Virulence
during Corneal Infection
To exclude any inherent growth differences for the homozy-
gous rim13–/–mutant Tn7-rim13 or its mutant-control refer-
ence strain DAY286, growth rates were evaluated in vitro and
compared with those of SC5314. The overall growth kinetics of
Tn7-rim13 and DAY286 were similar to those of SC5314, with
no significant difference at any of the growth phases (Fig. 6).
Mutant strains replicated at similar rates under controlled in
vitro conditions, and no obvious growth advantage or disad-
vantage occurred compared with the wild-type strains used in
the studies.
To determine the potential contribution of Rim101p-medi-
ated filamentation on the virulence of C. albicans during cor-
neal infection, Tn7-rim13 and DAY286 were compared with
their progenitor wild-type strain SC5314. After inoculation of
1 ? 106CFU of each strain on the scarified corneas of immu-
nocompetent mice, eyes were observed daily for 8 days and
were scored for corneal involvement (Fig. 7). DAY286 induced
severe keratitis indistinguishable from that caused by strain
SC5314 throughout the 8 days of observation. Tn7-rim13 was
fully attenuated, which caused only slight corneal opacity at
day 1 that resolved by day 2 and remained clear through day 8.
Differences in disease severity between Tn7-rim13 compared
with SC5314 and DAY286 were significantly different (P ?
Histopathologic evaluation 1 day and 4 days p.i. of eyes
from immunocompetent mice infected with 1 ? 106CFU of
strains DAY286 and Tn7-rim13 correlated with disease severity
(data not shown). Similar to SC5314, DAY286 infection re-
sulted in invading yeasts in the corneal epithelium and the
stroma, epithelial thickening, and varying degrees of stromal
edema and inflammation. Neutrophilic infiltration and edema-
tous corneal stroma were also prominent in corneas infected
with strain DAY286. Hyphal formation was present in the
cornea 1 day p.i., but the yeast form was predominant at 4 days
p.i. Eyes infected with Tn7-rim13 were essentially histologi-
cally normal except for an occasional adherent yeast form and
mild epithelial changes from the initial scarification procedure.
Effect of Systemic Immunosuppression on
Experimental C. albicans Keratitis
Immunosuppression increases the susceptibility of the host to
infection and increases keratitis severity.11,34To evaluate the
effect of immunosuppression on the attenuated phenotype of
the rim13 mutant, immunocompetent (Fig. 8A) or cyclophos-
phamide-treated mice (Fig. 8B) were infected with 1 ? 105
CFU of strains Tn7-rim13, DAY286, or SC5314 and were mon-
itored for 8 days. SC5314 and DAY286 induced moderate
keratitis in immunocompetent mice that began resolving on
day 4 and subsided to mild disease on the final days of the
study. At no time was disease severity between these two
strains significantly different (P ? 0.13). Eyes exposed to Tn7-
rim13 remained disease free, which was significantly different
from keratitis caused by SC5314 and DAY286 (P ? 0.01).
Pretreatment of mice with cyclophosphamide increased cor-
neal disease severity, resulting in mean disease scores in the
severe range for SC5314 and DAY286 at all time points during
the 8-day evaluation. Immunosuppressive treatment partially
restored virulence to strain Tn7-rim13, resulting in mean dis-
C. albicans wild-type strains SC5314 and VE175. Mouse corneas were
mock-infected or infected with 106CFU of C. albicans and enucleated
1 day and 4 days later. Paraffin-embedded eyes were sectioned at a
thickness of 8 ?m and stained with PAS. Representative findings 1 day
after infection are shown. (A) In SC5314-infected eyes, abundant fungi
and corneal edema were evident in both the epithelium (E) and the
corneal stroma (S). Pseudohyphae and hyphae were the predominant
fungal forms. (B) VE175-infected eyes showed significantly fewer or-
ganisms and less edema and neutrophilic inflammation relative to
SC5314-infected eyes. Budding yeasts (arrows) were the predominant
fungal forms. Original magnification: (A) ?200; (B) ?400.
Histopathologic views of murine keratomycosis induced by
albicans from infected corneas. Corneas of immunocompetent BALB/c
were mock-infected or infected with 106CFU of C. albicans strain
VE175, B311, or SC5314 and analyzed by end point titration at 6 hours,
1 day, 4 days, and 8 days after inoculation. Mock-infected corneas
received only sterile PBS. Culture-positive end points were converted
to CFU, and the mean (? SD) of six eyes per time point are plotted.
The lowest points plotted on the graph represent the lower limit of
detection by the assay.
Quantitative isolate recovery of three different strains of C.
IOVS, February 2007, Vol. 48, No. 2
Candida Virulence in Keratomycosis 777
Page 5
ease severity that increased to moderate levels, peaked at 3
days p.i., and resolved to mild levels with only slight corneal
opacity. Even with the elevation in disease severity of cyclo-
phosphamide-treated mice infected with Tn7-rim13, the mean
degree of eye disease was significantly less than that observed
for strains SC5314 and DAY286, except at day 3, the peak of
corneal involvement (P ? 0.036).
Candida keratitis is an opportunistic infection.35C. albicans
can be acquired as the result of eye trauma or surgery, and it is
an occasional contaminant encountered by corneal transplant
recipients,36bandage contact lens wearers,37and patients with
chronic ocular surface disease.38Experimental murine kerato-
mycosis is a reliable mammalian system for understanding the
pathogenesis of human ocular infection.11This model allows
quantitative assessment of disease severity and is suitable for
comparing virulence differences among fungal strains and mu-
Specific virulence factors involved in C. albicans corneal
infection are unknown but may be similar to mechanisms
controlling candidal adherence and invasion during candidiasis
of other organs and tissues.39Phenotypic switching—the abil-
ity of yeasts to form filamentous cells—is a crucial step in
dissemination and infection. O'Day et al.29correlated C. albi-
cans hyphal penetration with corneal disease severity in a
rabbit model, and we recently reported an association between
hyphal and pseudohyphal forms of C. albicans with more
severe corneal disease in immunosuppressed mice.11
In the present study we used a murine model to compare
the corneal pathogenicity of three wild-type strains of C. albi-
cans, a pH-mediated filamentation gene mutant, and a mutant
reference strain control using clinical, microbiologic, and his-
topathologic methods. These C. albicans strains caused kera-
tomycosis with different degrees of severity, suggesting that, as
in systemic and other mucosal infections, C. albicans uses
virulence factors during corneal infection.
Corneal disease caused by candidal strain SC5314 was sig-
nificantly more severe than that caused by strain B311 or
VE175. Histologic analysis further indicated that strain SC5314
was more invasive than the other two strains, with fungi
penetrating more deeply into the corneal stroma. These results
are consistent with previous results from the rabbit model.10
By the fourth day of experimental infection, the amounts of
pseudohyphae, severe stromal edema, structural destruction,
Tn7-rim13, and DAY286. One thousand CFU of each cultured C. albi-
cans strain were inoculated into Sabouraud dextrose broth and mon-
itored for growth for 7 days. Optical density measurements were
converted to CFU/mL, and the mean (? SD) of six samples from two
independent experiments are plotted.
In vitro growth kinetics of C. albicans strains SC5314,
cans strains SC5314, DAY286, and Tn7-rim13 at 1 ? 106CFU. Immu-
nocompetent BALB/c mice were mock-infected or infected with 106
CFU of C. albicans and evaluated for 8 days. Each point represents the
mean score (? SD) of 5 to 18 eyes.
The severity of murine keratomycosis induced by C. albi-
strains SC5314, DAY286, and Tn7-rim13 at 1 ? 105CFU. Immunocom-
petent BALB/c mice (A) or mice pretreated with cyclophosphamide
(B) were mock-infected or infected with 105CFU of C. albicans and
evaluated for 8 days. Each point represents the mean score (? SD) of
17 to 35 eyes from immunocompetent mice and three to five eyes from
cyclophosphamide-treated mice.
Severity of murine keratomycosis induced by C. albicans
778Mitchell et al.
IOVS, February 2007, Vol. 48, No. 2
Page 6
and inflammation were more evident in corneas infected with
strain SC5314 than in those infected with strain B311 or
The greater virulence of strain SC5314 was not caused by an
inherently accelerated rate of replication because all three
strains had similar in vitro growth kinetics. Colonization factors
mediating adherence are also unlikely to explain the corneal
virulence of C. albicans because, at early stages of infection,
similar numbers of viable organisms were recovered from in-
fected corneas. Fungal clearance from the murine cornea was
also similar for all three wild-type strains. This disparity be-
tween in vivo growth and clinical and histopathologic severity
was also found in experimental C. albicans keratitis of rab-
bits.10Our results and those of O'Day et al.29show that though
the fungal load may be partially indicative of microbial repli-
cation and clearance, it is inadequate for predicting the disease
severity or invasiveness of the infecting organism.
Based on previous reports28,29and our current findings
from studies using the wild-type strains of C. albicans, we
speculate that the virulence factors involved in regulating phe-
notypic switching contribute to fungal penetration into the
corneal stroma and account for differences in disease severity.
Virulent strains SC5314 and B311 are induced to filament in
vitro by growth at pH 8, but the less virulent strain VE175 fails
to filament (data not shown). A shifting corneal microenviron-
ment around colonizing yeasts could induce the candidal
Rim101 pathway.40Genetically regulated fungal filamentation
would facilitate stromal invasion and trigger an inflammatory
We previously showed that host factors, including immune
status and genetic background, contribute to the outcome of
murine keratomycosis caused by C. albicans11and Fusarium
solani.28Our current results are an extension of these findings.
Pretreatment of mice with cyclophosphamide resulted in more
severe disease for wild-type and mutant strains of C. albicans.
Immunosuppressive treatment restored virulence partially, but
not completely, to the rim13 mutant, suggesting that host
factors and infecting pathogen factors influence disease profile.
Our current findings demonstrate that various strains of C.
albicans have inherent differences in pathogenic potential.
Furthermore, our studies using a homozygous rim13 mutant
provide direct evidence that filamentation is important for C.
albicans virulence during corneal infection and indicate that a
hyphal morphogenesis-related gene is a virulence factor for
fungal keratitis. The pronounced attenuation observed for
strain Tn7-rim13 is consistent with the role of fungal filamen-
tation in candidiasis and supports the concept of developing
therapeutic approaches targeting the Rim101 signal transduc-
tion pathway. The experimental murine keratomycosis model
will be useful for continued investigation of virulence factors
mediating fungal infection of the eye.
The authors thank Denis M. O'Day for providing stocks of the VE175
and SC5314 strains of Candida albicans and Aaron P. Mitchell and
Michael C. Lorenz for providing the DAY286 and Tn7-rim13 fungal
1. Hammeke JC, Ellis PP. Mycotic flora of the conjunctiva. Am J
Ophthalmol. 1960;49:1174–1178.
2. Ainley R, Smith B. Fungal flora of the conjunctival sac in healthy
and diseased eyes. Br J Ophthalmol. 1965;49:505–515.
3. Kercher L, Wardwell SA, Wilhelmus KR, Mitchell BM. Molecular
screening of donor corneas for fungi before excision. Invest Oph-
thalmol Vis Sci. 2001;42:2578–2583.
4. Wu T, Mitchell B, Carothers T, et al. Molecular analysis of
the pediatric ocular surface for fungi. Curr Eye Res. 2003;26:
5. Whiteway M, Oberholzer U. Candida morphogenesis and host-
pathogen interactions. Curr Opin Microbiol. 2004;7:350–357.
6. Kumamoto CA, Vinces MD. Contributions of hyphae and hypha-
co-regulated genes to Candida albicans virulence. Cell Microbiol.
7. Niewerth M, Korting HC. Phospholipases of Candida albicans.
Mycoses. 2001;44:361–367.
8. Schaller M, Borelli C, Korting HC, Hube B. Hydrolytic enzymes as
virulence factors of Candida albicans. Mycoses. 2005;48:365–377.
9. Yang YL. Virulence factors of Candida species. J Microbiol Im-
munol Infect. 2003;36:223–228.
10. O'Day DM, Head WS, Robinson RD, Yang R, Shetlar D, Wang MX.
Contact lens-induced infection—a new model of Candida albi-
cans keratitis. Invest Ophthalmol Vis Sci. 1999;40:1607–1611.
11. Wu TG, Wilhelmus KR, Mitchell BM. Experimental keratomycosis
in a mouse model. Invest Ophthalmol Vis Sci. 2003;44:210–216.
12. Penalva MA, Arst HN Jr. Regulation of gene expression by ambient
pH in filamentous fungi and yeasts. Microbiol Mol Biol Rev. 2002;
13. Davis D. Adaptation to environmental pH in Candida albicans and
its relation to pathogenesis. Curr Genet. 2003;44:1–7.
14. Tilburn J, Sarkar S, Widdick DA, et al. The Aspergillus PacC zinc
finger transcription factor mediates regulation of both acid- and
alkaline-expressed genes by ambient pH. EMBO J. 1995;14:779–
15. Davis D, Wilson RB, Mitchell AP. RIM101-dependent and-indepen-
dent pathways govern pH responses in Candida albicans. Mol
Cell Biol. 2000;20:971–978.
16. Ghannoum MA, Spellberg B, Saporito-Irwin SM, Fonzi WA. Re-
duced virulence of Candida albicans PHR1 mutants. Infect Im-
mun. 1995;63:4528–4530.
17. De Bernardis F, Muhlschlegel FA, Cassone A, Fonzi WA. The pH of
the host niche controls gene expression in and virulence of Can-
dida albicans. Infect Immun. 1998;66:3317–3325.
18. Li M, Martin SJ, Bruno VM, Mitchell AP, Davis DA. Candida
albicans Rim13p, a protease required for Rim101p processing at
acidic and alkaline pHs. Eukaryot Cell. 2004;3:741–751.
19. Porta A, Ramon AM, Fonzi WA. PRR1, a homolog of Aspergillus
nidulans palF, controls pH-dependent gene expression and fila-
mentation in Candida albicans. J Bacteriol. 1999;181:7516–
20. Wilson RB, Davis D, Mitchell AP. Rapid hypothesis testing with
Candida albicans through gene disruption with short homology
regions. J Bacteriol. 1999;181:1868–1874.
21. Porta A, Wang Z, Ramon A, Muhlschlegel FA, Fonzi WA. Sponta-
neous second-site suppressors of the filamentation defect of
prr1Delta mutants define a critical domain of Rim101p in Candida
albicans. Mol Genet Genomics. 2001;266:624–631.
22. Lamb TM, Xu W, Diamond A, Mitchell AP. Alkaline response genes
of Saccharomyces cerevisiae and their relationship to the RIM101
pathway. J Biol Chem. 2001;276:1850–1856.
23. Diez E, Alvaro J, Espeso EA, et al. Activation of the Aspergillus
PacC zinc finger transcription factor requires two proteolytic
steps. EMBO J. 2002;21:1350–1359.
24. Lamb TM, Mitchell AP. The transcription factor Rim101p governs
ion tolerance and cell differentiation by direct repression of the
regulatory genes NRG1 and SMP1 in Saccharomyces cerevisiae.
Mol Cell Biol. 2003;23:677–686.
25. Xu W, Mitchell AP. Yeast PalA/AIP1/Alix homolog Rim20p associ-
ates with a PEST-like region and is required for its proteolytic
cleavage. J Bacteriol. 2001;183:6917–6923.
26. Oji EO. Development of quantitative methods of measuring anti-
fungal drug effects in the rabbit cornea. Br J Ophthalmol. 1981;
27. O'Day DM. Orally administered antifungal therapy for experimen-
tal keratomycosis. Trans Am Ophthalmol Soc. 1990;88:685–725.
IOVS, February 2007, Vol. 48, No. 2
Candida Virulence in Keratomycosis779
Page 7
28. Wu TG, Keasler VV, Mitchell BM, Wilhelmus KR. Immunosuppres-
sion affects the severity of experimental Fusarium solani keratitis.
J Infect Dis. 2004;190:192–198.
29. O'Day DM, Head WS, Csank C, et al. Differences in virulence
between two Candida albicans strains in experimental keratitis.
Invest Ophthalmol Vis Sci. 2000;41:1116–1121.
30. Hasenclever HF, Mitchell WO. Production in mice of tolerance to
the toxic manifestations of Candida albicans. J Bacteriol. 1962;
31. Lo HJ, Kohler JR, DiDomenico B, Loebenberg D, Cacciapuoti A,
Fink GR. Nonfilamentous C. albicans mutants are avirulent. Cell.
32. Davis DA, Bruno VM, Loza L, Filler SG, Mitchell AP. Candida
albicans Mds3p, a conserved regulator of pH responses and viru-
lence identified through insertional mutagenesis. Genetics. 2002;
33. Treco DA, Winston F. Growth and manipulation of yeast. In:
Ausubel FM, Brent R, Kingston RE, eds. Current Protocols in
Molecular Biology. New York: John Wiley & Sons; 2003:13.2.
34. Negrete-Urtasun S, Reiter W, Diez E, et al. Ambient pH signal
transduction in Aspergillus: completion of gene characterization.
Mol Microbiol. 1999;33:994–1003.
35. Ritterband DC, Seedor JA, Shah MK, Koplin RS, McCormick SA.
Fungal keratitis at the New York Eye and Ear Infirmary. Cornea.
36. Merchant A, Zacks CM, Wilhelmus K, Durand M, Dohlman CH.
Candidal endophthalmitis after keratoplasty. Cornea. 2001;20:
37. Iyer SA, Tuli SS, Wagoner RC. Fungal keratitis: emerging trends and
treatment outcomes. Eye Contact Lens. 2006;32:267–271.
38. Tanure MA, Cohen EJ, Sudesh S, Rapuano CJ, Laibson PR. Spec-
trum of fungal keratitis at Wills Eye Hospital, Philadelphia, Penn-
sylvania. Cornea. 2000;19:307–312.
39. Molero G, Diez-Orejas R, Navarro-Garcia F, et al. Candida
albicans: genetics, dimorphism and pathogenicity. Int Microbiol.
40. Bensen ES, Martin SJ, Li M, Berman J, Davis DA. Transcriptional
profiling in Candida albicans reveals new adaptive responses to
extracellular pH and functions for Rim101p. Mol Microbiol. 2004;
41. Villar CC, Kashleva H, Mitchell AP, Dongari-Bagtzoglou A. Invasive
phenotype of Candida albicans affects the host proinflammatory
response to infection. Infect Immun. 2005;73:4588–4595.
780Mitchell et al.
IOVS, February 2007, Vol. 48, No. 2


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(2 of 2 customers found this review helpful)
excellent buy
By Big Daddy
from Lacey, WA
About Me Avid Do-It-Yourselfer
Best Uses
Comments about Pipe Taps 6 Pc:
I bought this set mainly because I only needed the 1/2-14 NPT tap, these will easily tap cast iron and fast too they cut clean and smooth with minimal effort and definatly an awesome buy
Bottom Line Yes, I would recommend this to a friend
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(1 of 1 customers found this review helpful)
Creat your own Couplings!
By Expopro
from Cuauhtemoc, Chihuahua, MEXICO
About Me Professional
This is a great set. Will save you money when you create your own couplings and taps on pipe and some tube (not all tubes work).Stick to schedule 80 pipe or tube whether PVC or cast iron. You can go down to schedule 40 on cast iron pipe, but the thicker the wall the better for your taps. The disadvantage I see is a lack of instruction manual on what kind of pipe and tubes these items can work with, but aside from that, they're great for creating your own couplings of the desired length you need them.
(4 of 4 customers found this review helpful)
Don't waste your money! ! ! ! ! ! ! !
By Ern
from Coarsegold, CA
Only about of an hour buying these taps, I tried to redress threads on an ell that I accidently cross treaded the pipe into. It turns out the cast pipe ell is much harder than the taps and instead of cutting new threads, it stripped all the cutting threads off the tap. I've only been a machinist for 45 years, so I think I still know how to thread pipe and fittings. This set of taps are only good for pipe made of jelly or maybe PVC won't strip them. If your doing a home plumbing project, go buy a tap the size you need that I know will cost as much as this set. You will get what you pay for if you buy these!
Bottom Line No, I would not recommend this to a friend
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