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1862 David Walley's Hot Springs Resort and Spa
Travel Blogs from Genoa
The adventures of Charlie Flo and Freedom Train
... happened. For a few days we saw over a 100 hot air balloons lift up into the air. And airplanes race by in groups of about 10.
Friday night.
We decided to go hiking early that morning. Charlie Flo cancelled his date and we both scrambled to get our weekend errands done before heading off into the woods.
The plan was to hike 25 miles of the Rim to Reno trail to the top of the 10,800 ft Mt Rose.
A half hour before our ride was scheduled to come we ...
Three Rivers, CA to Topaz Lake, NV
I've completed day two of my cross country motorcycle trip. Today I rode from Three Rivers, CA to Topaz Lake, NV via Sequoia National Park and the Sonora Pass which is in the Stanislaus National Forest via route 108 which is just north of Yosemite.
At 0630 I headed north east from three rivers to the entrance of sequoia national park. The giant sequoias are about 18 miles up one of the most challenging roads I've ever tackled on ...
Leaving Yosemite heading to the oasis of Tahoe
... equipment to help with the fire and they had set up areas to inform people about the fire on the side of the road. They had blocked off all the little parking spots on the side of the road where you would normally take photos of the park for safety reasons but people were still stopping right on the road to take photos of all the black trees. Madi wondered what had happened to all ...
Smoke gets in your eyes
Started out as a bright sunny day. By one pm the area is covered in a pall of haze and smoke from a huge fire in the Yosemite area. It's around 200 miles south of here but you can smell smoke and there are bits of ash in the air. The sun ...
Round the Lake
Weather still clear and hot. So dull.
Went for drive round Lake Tahoe past Emerald Bay. Very pretty. Had a lovely lunch at the West Bay Inn which sits on the lake edge. Could have stayed all day. Plans for next few days include paddle steamer trip on the water. Yesterday went on a cable car trip up Heavenly Mountain. The second part was a chair lift to the top ...
Historical Traveler Reviews 1862 David Walley's Hot Springs Resort and Spa Genoa
True Piece of Americana - Enjoy, Relax
Walley'sIts wonderful - its away from the world, but still close to so many things.....Lots of fun.First, the spa. First, they are mineral baths (natural). The swimming pool is wonderful and warm. Very nice and fun. Families were having fun here; adults could sit in the mineral baths and soak away their troubles. The greatest thing is looking up at the High Sierra Mountains - what a view. It is wonderful, relaxing, and truly beautiful spot. Some of the reviews have complained about the "spa" - its because they cannot bare to look up and see the beautiful mountains; the wonderful view of the valley; and the wonderful cheerfulness of the place. Its great.In terms of the rooms - they're nice condo style with a nice fireplace; nice porches; and nice beds. The best thing is the large jet tub where you can relax again after a wonderful day of gambling, mountain biking, crusing Lake Tahoe, hiking, skiiing, mountain biking; and about anything else you can think of.The greatest thing about Walleys' is you can bring your "refreshments" to your condo and have a very luxurious but inexpensive vacation. If you decide however to take advantage of the wonderful buffets, lunches, brunches, etc - then you can dine on site or take a very short drive to the Lake Tahoe area, Carson City, or for an hour drive Reno. Wonderful location...quiet to get away from it, but within a short drive to all the action.Its also historic - which brings a lot of enchantment to this vacation.
My wife and I stayed here for a week in July 2003. When we arrived we realized there was a wedding that weekend. Staff seemed frantic and unorganized. When we finally got our room, it was a little dissapointing. There was obvious wear and tear. I was there on a time share exchange, we have a 5 star time share, this was deifnitely not comparable. In July it is over 100 degrees everyday day and still fairly warm at night. Two nights the air conditioning went out in the whole building, once for about 4 hours. Also the hot springs seemed old and in need of some touch up. These may be some random occurances, but by the sound of the other reviews this resort needs some work. Proceed with caution. The nicest facet we experienced was the restaurant. The food was superb. As far as the surrounding area, your only hope is Lake Tahoe which is a solid 25 minute drive over the mountain. A little sketchy after dark.
Sooooooooo relaxing
Have spent several weeks, Summer, Spring, and Fall and truly love this place. Warm water pools most relaxing but if you want some action Tahoe only 20 minutes away, or Carson City. And there's workout places on site. Sitting on the deck and watching the wildlife and birds passing by in the Carson River Valley Reserve is so great. Very nice room with great tubs. Not crazy about DW's Restaurant, only negative. Nearby golf courses are excellent. Enjoyable drive there on Hwy 88.
Save Your Money and Don't Go
Terrible Terrible TerribleI had gone to South Lake Tahoe for a little R&R and found that over the mountains (in the Nevada valley) there were a variety of locations with mineral waters for soaking also offering spa services (massages, facials, etc.). I'd picked up a variety of brochures and called around and was told by David Walley's they were "five star" with an excellent facility. The brochure looked excellent.
Lights, Signs and Mirrors
We vacationed at Walley's the week of August 23, 2003. There are no signs to indicate "this is the place". Nor are there any lights at night to show you the road into the complex. Believe me it is dark out there around the mountains. Once we drove into the complex we had no idea where the check-in ofice was. We had to ask some people walking down on the sidewalk. The first room we got (for 4 people) was nice but the sofa bed was unbelievably flat and uncomfortable. However we did complain to the manager and she got us into another building. It still had a sofa bed but it was much more comfortable. It was beautiful and quite cozy. Our balcony was long and able to hold all four of us. Our view was the mountains and the wet lands. A babbling brook ran past our balcony but then on the third day everything shut down for repairs. The brook dried up and algea appeared. The restaurant was great but we had to give up our first born to pay for the meal. It was very, very, expensive. Bring a mirror with you because if one person is using the bathroom there is no mirror in the other portion of the apartment.
Time Share Tour a Hoax
My boyfriend and I went for a timeshare tour and our accomodations ended up being in a motel instead of the reserved hotel, the spa services advertised in the pamphlet they sent us were not available and there was a lack of usable assistance from the booking company.
A classic case of "you get what you pay for" or in this case not pay for.
After a 4 hour drive we were more than dissapointed on our Labor Day Vacation.
Disappointing Visit
We visited Walley's on June 21 2003. What was to be my surprise birthday present was something less than enjoyable at Walley's. My girlfriend scheduled a 1pm massage and a 3pm facial massage for me with Walley's staff. When we arrived, there were alot of timeshares sales persons driving clients all over the property in golf carts. The hotsprings was packed with potential clients and guests. The atmosphere was something like a "cattle-car loading operation". The check-in desk told me to be upstairs in only a little white robe at 1pm for my massage. I did so, and sat there for a half hour until someone figured out that Walley's had changed my massage to 2pm ! It was grerat sitting there for the half hour -with only the little white robe on for nothing. We then attempted to obtain something to eat at their Deli cafe. There too, throngs of people and timeshare clients were overwheling the cafe staff. We received our meal 45 minutes after ordering, not allowing time for my 2pm massage. Just proir to eating I went to the desk and asked for a refund for the massages. The front desk ckerk denied the refund and any wrongdoing with our scheduled massage time. I insisted to speak with the manager - and she kindly refunded our reservations in full. Ok, it ruined our day and we got over it. We won't go back because Walley's has become too impersonalized - and too much like a cattle- herding operation for it's timeshare business. We heard other guests complaining of the same.
It was our second visit and the hot springs pools are as wonderful as the last time. I wish they would have stayed the way they were before, though. They used to have four cottages that could accomidate six partys and it made it very comfortable. Now in addition to the cottages, there are two LARGE hotels on property and it seemes busy now. Our cottage was wonderful and right across from the pools. Which, actually was the best place on the property. We will make sure to stay there again on our next visit.
Walley's Hot Springs - Where the Entire Family Can Have an Exceptional Vacation
The moon rises over the Sierras. You turn to your wife who is relaxing in the hot tub next to you. Your children are swimming in the 80 degree swimming pool. You tell your wife: Its a wonderful night. All is well here at Walley's in Nevada.
Best Spa in United States-Sierras
Soaking in a hot tub - relaxing in mineral pools -and then you look up and there is the Mighty Sierra. Gorgeous mountains - big beautiful blue sky. You look around and everyone is smiling and enjoying the spa facilities. It is so relaxing and so quiet and so soothing.


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Grand Targhee Resort
Travel Blogs from Jackson
Day 7 - On to Grand Teton NP
... to speed on open roads with no one around you. Well it was 65-70 the whole last 4 hours to Grand Teton.
Ok so as you approach the western part of the state the mountains start coming into view and when you first glimpse the Grand Tetons - WOW - what a sight: Magnificent! Awesome! Big and impressive! Too bad the sky is overcast as it is somewhat hard to make out a lot of details. Hopefully tomorrow will be much clearer. On to the trails and scenic ...
Wyoming, Wyoming! Land of the sunlight clear!
... New Roman", Times, serif; font-size: 14px;">Shinin' down bright as can be
Up on the hill there's a coyote singin'
A Song of Wyoming for me
The exciting afternoon with the lake.
... was no current them we swam to a place that had a really strong current and I struggled to get to the rocks but I did it. We had to grab the rocks but the current was to strong. I had to let go. We floated with the current happily but then we realized that our stuff was the other way. We had to swim all the way back. As we were climbing out Emma dislocated her toe!! Jordan had to come down and fix it. By then I was really shivering ...
Day 24 - Jackson
The Plan - there is no plan What really happened - from our room you can see a ski lift modified to take bikes. Various people are going up the lift and riding down on specially made bike trails. This has captured the imagination of Andy and the boys and they are keen to try it out. Whilst I am not a very good cyclist I will try anything once and I am convinced that it can't be that hard by the number of five ...
Snake river & another severe thunderstorm warn
On the way we saw historic snake river, with stretches of white water. We saw people rafting down the white water. At one point we wen saw an almost vertical raft! That was breathtaking! We also saw some frontier towns along the way. We also many interesting life saw animal figures at many interesting places. ...


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This message board is only an archive. Click here to go to the current message board.
Originally Posted by AnnaMarie I wanted to get a real tree once, but finding a good strong stand for it was difficult and expensive. We have a beautiful artificial. We no longer use the boxes and boxes of decorations we collected and made over the last thirty years. this tree only gets birds and a squirrel. That sounds lovely. If I did that here, between the dogs and the cat I might not have a tree left!! It would be hunting time!! I have a hard enough time with them almost knocking it over every time they try to get under it!!
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Shrimp Stew Recipe
"Here in the Northwest, we have a seemingly endless supply of seafood, so we're always searching for creative new recipes," reveals Renton, Washington cook Jennie Benjaminson. "This thick hearty stew was a big hit."
- 1 small onion, chopped
- 2 garlic cloves, minced
- 1-1/2 teaspoons olive oil
- 1-1/2 cups diced fresh tomatoes
- 1/2 cup tomato sauce
- 4-1/2 teaspoons minced fresh dill or 1 teaspoon dill weed
- 1 teaspoon Dijon mustard
- 1/2 teaspoon honey
- 1/4 teaspoon salt
- 1/2 pound cooked medium shrimp, peeled and deveined
- 1/2 cup crumbled feta cheese
- 1/2 cup minced fresh parsley
- In a large saucepan, saute onion and garlic in oil for 5 minutes. Stir in the tomatoes, tomato sauce, dill, mustard, honey and salt. Bring to a boil. Reduce heat; simmer, uncovered, for 10 minutes. Add the shrimp, cheese and parsley; simmer 5 minutes longer. Yield: 2 servings.
Originally published as Tomato-Dill Shrimp Stew in Cooking for 2
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She is not posing, yet I am drawing her figure, as she leans on the windowsill, looking out
with crossed elbows for balance faded jean legs close together under unbuttoned shirt, gentle curves
Her hair trails her shoulders, unkempt and windblown a barometer of her relaxation
She is not posing, yet my pencil embraces her shape; every beautiful imperfection.
for my favorite ninjagirl
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What can I do to block a 2 story building that is being built right behind my house?
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What can I do to block a 2 story building that is being built right behind my house?We just moved into this new neighborhood 10 months ago. Behind us was commercial property with a few 1 story buildings that we could not visibly see from the ground. 4 months into living here, a contractor started breaking ground for what is now going to be a huge 2 story warehouse with the loading dock right at our back fence. The building is set so far back from their road, that their back wall is about 15 feet from our fence! it's unbelievable how close it is. I blocks about 75% of our view from our patio and is almost taller than the power lines that run across the back of the community. I have a 15 foot utility easement to make things worse. That's half of my yard! Any ideas of what i could build or plant to help block this horrible view?
Asked By: jeepchickie77 - 9/15/2007
Best Answer - Chosen by Asker
Obviously a fence would be impractical and cost prohibitive. But a natural fence, now there's another idea. Pine trees were suggested, and for the most part, that's not a bad choice, but they don't grow too fast, and could potentially take up more of your yard because of the spread when mature...
Answered By: danmancc - 9/15/2007
Additional Answers (3)
Plant a bunch of pine trees. They are providing a very effective fence on 2 sides of my property right now. After the pine trees grow tall and you can see underneath them, plant some bushes in front of them. Then you will see a wall of green instead of the building. It will take a few years to get to the height...
Answered By: Gypsy Girl - 9/15/2007
i wouldn't suggest pine trees (they drop sap, pine cones and pine needles) but maybe another deciduous tree. oak or maple. depends on where you live. bamboo is a fast growing, tall plant that will help.
Answered By: redgator40 - 9/15/2007
I agree with the gentlemen. Planting poplar might do it for you. They grow fast and will provide a nice shady area. But, caution if you are allergic to pollen. This tree is not for you. They give out a light puffy seed .(almost like dandelions). Tough on the allergies.
Answered By: lakesider - 9/15/2007
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Mumbai top spot for NRIs
Dubai, June 3, 2013
Mumbai has remained a favourite among non-resident Indian (NRI) property buyers with 31 per cent of the UAE based NRIs choosing to invest in the city, according to a survey.
The survey was conducted by Sumansa Exhibitions, organisers of the Indian Property Show, scheduled to be held from June 20 to 22 at Dubai World Trade Center.
In second spot is Bangalore with 22.63 per cent (up by 5 per cent from last time) preferring to invest in the coming three to six months. Chennai takes the third place with 17.92 per cent, whereas Pune at 15.35 per cent takes fourth position and Delhi goes down to fifth at 10.23 per cent.
Navi Mumbai, Cochin, Gurgaon, Hyderabad and Coimbatore are among other preferred cities for property purchase.
NRIs are interested in buying residential apartments, both for own use as well as for investment purpose, the survey said.
"Despite being the 'highly un-affordable' place, even for the upper middle income group back home, Mumbai has become a top choice for NRIs in the UAE for investment in the real estate sector. The expansion of cities and the development of new areas such as Wadala and Chembur are revising the price appreciation for Mumbai in a range of 125 per cent -133 per cent between 2013 -2017," said Sunil Jaiswal, CEO.
"This huge upward swing of Mumbai property price appreciation is based on its primary location, proximity to workplaces and upcoming key projects like Eastern Freeway project and Monorail. Also, Navi Mumbai is enthralling with lots of opportunities for new homebuyers. Localities like Ulwe and Kalamboli are promising with immense benefit from the upcoming rail network in the region. Our survey actually points out that Mumbai is looked for quick Capital appreciation whereas Bangalore is more for ownership and better lifestyle," he added.
Around 14,000 NRIs across UAE participated in the survey which was conducted to understand the reason of buying property in India, preferred cities for investment, type of property, time frame to buy, budget and finances planned. - TradeArabia News Service
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Ripoff Report | Complaints Reviews Scams Lawsuits Frauds Reported
Showing 1-2
Date | Title City, State | ||
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2, Report #927374 Aug 14 2012 08:43 PM | Sobe Threads They stole $170 from me, I placed a order for bracelets they sale online and never received the jewelry or my refund!! Shreveport, California Author: Inkster, Michigan ORGANIZED CRIME: Sobe Threads Shreveport, California |


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Fine-point pen with square holder provides a safe, secure pen that won't dry out and prevents the growth of odor-causing bacteria and fungus on the pen's surface - protecting both you and your customers. The Wedgy Secure pen contains specially formulated, fraud-resistant ink that helps prevent identity theft and check washing. Black ink ballpoint writes easily - even on thermal paper. Long-lasting EPA and FDA-approved antimicrobial technology is designed to inhibit bacterial and fungal growth on the pen's surface. The virtually indestructible coil ensures that the pen stays in place. The adhesive square base mounts easily to any clean, dry surface. Plastic coil extends to 5' and coils back to less than 6".


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Fred Smith - vs. Pershing
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This white speaker from Sony is wireless with bluetooth connection for around the house music. It also has an Audio-Line jack so you can play your music directly.
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Eldridge Holmes
Eldridge Holmes
New Orleans soul singer Eldridge Holmes was born in Violet, Louisiana in 1942 -- according to an article on the Funky 16 Corners website, circa 1962 he began collaborating with producer Allen Toussaint, making his debut on Toussaint and Joe Banashak's Alon label with the single "Poor Me." The energetic "Begging for Your Love" soon followed, and with 1963's "I've Got to Keep on Trying," Holmes veered into country-soul territory. None of his Alon efforts generated any commercial interest, however, and after two more singles for the label, "Popcorn Pop Pop" and "Emperor Jones," Holmes left the label to hone a smoother, more urbane soul sound that would blossom on 1964's "Gone Gone Gone," the first of two Toussaint co-writes that he recorded for the Washington, D.C.-based Jet Set label. After the follow-up "Humpback" failed to ignite a new dance craze as hoped, Holmes signed with another of Toussaint's labels, Sansu, to release 1965's "Without a Word," his most elegant outing to date; conversely, his second Sansu side, "Beverly," was his funkiest side yet, but despite the elasticity of his vocal and songwriting prowess, Holmes remained little known even in the Crescent City until his next single, 1967's "Where Is Love," issued on Toussaint's Deesu imprint. A major local favorite, the record was licensed for national distribution on Decca but went nowhere, nor did the follow-up, a cover of Lee Dorsey's "Working in a Coal Mine." Decca dropped Holmes soon after, and in 1969 he resurfaced on Deesu with "The Book," a blistering funk effort featuring the instrumental backing of the Meters; a sublime reading of Tim Hardin's "If I Were a Carpenter" appeared soon after, and with "Lovely Woman," a nod to the sweet soul of his Jet Set output, Holmes left Deesu for good. He next turned up on Atco with 1970s "Pop Popcorn Children," recorded with the Meters during their Look-Ka Py Py sessions; it was his lone effort for the label, and in 1972 Holmes reunited with Toussaint for the Wardell Quezergue-arranged "Love Affair," the first-ever release on the fledgling Brown Sugar label, and the singer's final recording. He went on to work as a bus driver, nursing assistant, and mechanic prior to his death from heart disease in 1998. ~ Jason Ankeny, Rovi
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Scotland will vote in 2014 whether to split off from England and the rest of the United Kingdom. Scottish nationalists argue that Scotland would be better off alone.
Ending Britain's 306-year rule would allow Scotland to reverse generations of economic mismanagement and free its lawmakers to boost economic growth, say Scottish nationalists campaigning to split from the UK.
Independence would not only bring the long-standing and sometimes-troubled union to an end, but allow tax cuts and investment focused on boosting exports to spur growth on the Scottish side of the border.
In an attempt to sour support for independence ahead of a Scottish referendum in September 2014, Britain's rulers have issued a flurry of warnings in recent months about the dangers of Scotland scrapping its union with England.
Scotland, according to the British government, would have trouble keeping the pound; its economy would be dangerously exposed to the vicissitudes of the oil market and its banking sector would be vulnerable to a Cyprus-style debt crisis.
But the Scottish government hit back at those gloomy views with a report entitled "Scotland's Economy: The Case for Independence" which said years of shoddy London policies had cost Scotland 19,000 new jobs and hampered growth for decades.


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Sen. Carl Levin might like pie, but surely not served this way. The Michigan Democrat was listening to a question at constituent meeting in the town of Big Rapids on Monday when a woman struck him in the face with a pie.
Ahlam M. Mohsen, 22, of Coldwater, Mich., will be arraigned Tuesday, the AP reports, after being held without bond on a felony charge of stalking and misdemeanor counts of assault and disorderly conduct.
Mohsen told the Big Rapids Pioneer she hoped "to send a message that liberals and Democrats are just as implicated in the violence [of war] as the Republicans."


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In vivo positioning and covalent modifications of nucleosomes play an important role in epigenetic regulation, but genome-wide studies of positioned nucleosomes and their modifications in human still remain limited.
This paper describes a novel computational framework to efficiently identify positioned nucleosomes and their histone modification profiles from nucleosome-resolution histone modification ChIP-Seq data. We applied the algorithm to histone methylation ChIP-Seq data in human CD4+ T cells and identified over 438,000 positioned nucleosomes, which appear predominantly at functionally important regions such as genes, promoters, DNase I hypersensitive regions, and transcription factor binding sites. Our analysis shows the identified nucleosomes play a key role in epigenetic gene regulation within those functionally important regions via their positioning and histone modifications.
Our method provides an effective framework for studying nucleosome positioning and epigenetic marks in mammalian genomes. The algorithm is open source and available at http://liulab.dfci.harvard.edu/NPS/ webcite.
Chromatin structure widely manifests itself in various aspects of mammalian development and disease. The key structural element of chromatin is the nucleosome, which consists of an octameric histone core wrapped by 146 bps of DNA [1]. Nucleosomes play two major roles in epigenetic regulation of gene expression. The first is to limit DNA accessibility to cellular machinery [2-5] through specific positioning of nucleosome core particles, which can be remodeled in an ATP-dependent manner. The second is to regulate transcriptional activities through covalent modifications (e.g. methylation, acetylation and phosphorylation) of the tails of four core histone types H2A, H2B, H3 and H4 [6-9]. Therefore, characterizing the global locations and modification marks of positioned nucleosomes is a crucial step towards unraveling the mechanism of epigenetic regulation in eukaryotes.
High-throughput mapping of positioned nucleosomes has been conducted in yeast [10,11] and selected human promoters [12] using high resolution tiling microarrays. Several studies have also profiled genome-scale histone modification marks using Chromatin ImmunoPrecipitation (ChIP) coupled with microarrays (ChIP-chip) [8,13-15], although only one study in yeast [7] mapped the modifications at nucleosome resolution. Recent developments in high-throughput sequencing techniques offer a promising alternative to microarrays in analyzing genome-wide nucleosome positioning and histone modifications. Barski et al. [16] used Solexa to conduct nucleosome-resolution ChIP-Seq of twenty different histone methylation marks as well as H2A.Z in human CD4+ T cells, although the analysis in that study was performed at a much lower resolution than offered by the data. Recently, the same group also sequenced MNase-digested nucleosomes and performed ChIP-Seq of eighteen histone acetylation marks [17,18]. As an extension of their histone methylation study, they attempted to reveal the effects of nucleosome positioning [17] and combinatorial patterns of histone modifications on gene activity [18] separately. However, genome-wide studies of positioned nucleosomes coupled with histone modifications in human still remain limited.
We thus developed a novel computational framework for analyzing histone modification ChIP-Seq data at nucleosome resolution in a global scale. By combining the sequenced tags from all histone methylation ChIP-Seq data [16] and employing signal processing techniques, we comprehensively identified modified positioned nucleosomes in functionally important regions and revealed their distribution throughout the human genome. Through subsequent statistical modeling, we were then able to assign histone methylation marks to each positioned nucleosome in CD4+ T cells, revealing the key roles of nucleosome positioning and modifications in epigenetic gene regulation.
Identification of positioned nucleosomes with epigenetic marks from ChIP-Seq
The dataset from Barski et al. contains one ChIP-Seq profile for each histone modification studied in CD4+ human T cells, totaling 185.7 million 25 nt tags that are uniquely mapped to the human genome [16]. Despite Solexa technology's unique ability to sequence millions of tags from each sample, most locations in the human genome still lack enough coverage from a single sample alone to allow an accurate identification of positioned nucleosomes. To overcome this difficulty, we combined all 185 million ChIP-Seq tags in our search for positioned nucleosomes. Each Solexa sequencing tag of 25 nt represents one end of a ChIP-DNA fragment, corresponding to approximately 150 nt long mono-nucleosomal DNA resulting from MNase digestion. Therefore, we extended each sequenced tag to 150 nt in the 3' direction to represent a whole mono-nucleosome. This method of combining ChIP-Seq tags from 21 different histone modifications and extending each tag increased the original sequence data from individual sample by approximately 100-fold (approximately 21- and 6-folds from tag combination and extension, respectively) and provided over 10-fold non-redundant genome coverage (since all Solexa tags are uniquely mapped to the genome), sufficient to identify positioned nucleosomes.
The collection of extended sequence tags can be regarded as a random sampling of modified nucleosomes in the human genome. In this view, given the almost periodic nature of nucleosome locations, the length of each tag can be actually shortened based on the intuition offered by the Nyquist-Shannon sampling theorem [19] from signal processing. The theorem states that for a correct pattern reconstruction, the sampling frequency must be at least twice the maximum frequency of the signal of interest. In our context, the statement roughly implies that the tag length should be at most half the nucleosome length. Motivated by this principle, we took only the middle 75 nt sequences of all extended tags as inputs to our nucleosome identification algorithm. As shown in Figure 1A, keeping only the central 75 nt gave better resolution of nucleosome positioning than the full 150 nt. Using tag lengths shorter than 75 nt increases noise although it may give a sharper nucleosome positioning signal (Figure S1 in Additional file 1). After the tag extension, wavelet denoising was first applied to reduce the genomic background noise and smooth the sequencing tag counts across the genome. Laplacian of Gaussian (LoG) technique was then used to globally identify peaks of qualifying width (80–250 nt) as positioned nucleosomes (see Methods).
Additional file 1. Supplementary materials. This file includes seven supplementary figures and two supplementary tables: Figure S1. Nucleosome positioning signal after extending each tag to 150 nt in the 3' direction and taking the middle 75 nt (A), 45 nt (B), and 25 nt (C). Figure S2. Genomic distribution of identified positioned nucleosomes under different p-value cutoff. Figure S3. Percentage of DNase I HS sites of human CD4+ T cell containing identified positioned nucleosomes. Figure S4. Correlation between histone modification profiles at the same nucleosome loci. Figure S5. Co-occurrence of different histone modification pairs on the same positioned nucleosome loci under different cutoffs for histone modification assignment. Figure S6. Enrichment of co-occurrence of histone modification pairs on adjacent positioned nucleosome loci. Figure S7. Poisson-based p-values vs. FDR (q-value). Table S1. The ChIP-Seq tag number, modified nucleosome number, percentage of tags located in modified nucleosomes, ChIP-Seq efficiency and modification type for each histone modification. Table S2. Number and distribution of identified positioned nucleosomes under different p-value cutoff.
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Figure 1. Genome-wide identification of positioned nucleosomes from ChIP-Seq data. (A) An example showing the workflow from sequencing tags to assigned modified nucleosomes: ChIP-Seq tags for all the available histone modifications in CD4+ T cell (shown tags for four representative marks, with arrows in each indicating its strand orientation) are combined; each tag is extended towards 3' to 150 nt (legends on the right denote tag count); taking the middle 75 nt of all the extended tags provides better signal resolution; wavelet denoising smoothes the signal; LoG identifies peaks as positioned nucleosomes; histone modifications are assigned to individual identified nucleosomes. (B) Examples of peaks with unbalanced tag counts. Narrow regions A and B were repeatedly sequenced, creating the four flanking peaks with unbalanced tag counts between plus (pink) and minus (blue) strands as shown in the pie charts. They might arise from repetitive sequences in unsequenced or unannotated genome regions, thus were removed from further analysis.
Most detected peaks had similar numbers of tags from plus and minus strands, since double stranded DNA fragments are equally likely to be sequenced from either direction. However, some peaks had significantly unbalanced tag counts (i.e., the number of tags from one strand was more than 4-fold higher than that from the other strand). Examples of this phenomenon are shown in Figure 1B, where hundreds of tags were aligned to very narrow regions A (27 nt) and B (33 nt). Extending the tags in the 3' direction to 150 nt and taking the middle 75 nt created two separate peaks flanking A (peaks 1 and 2) and B (peaks 3 and 4), thus creating unbalanced tag counts between plus and minus strands for those peaks. It is worth noting that both regions A ('ggtctagaatggaatggaaagaatgga') and B ('atacaatcgattggaatcgaatggaatggaagg') are near the centromere and both contain the repeated sequence 'tggaa', which is a type of common sequence repeats found near human centromeres [20]. Although the sequences of both regions A and B are uniquely mapped to the current version of human genome assembly (NCBI Build 36.1 or UCSC Hg18), it is possible that they occur in multiple copies near or within the centromeres, which may not have been yet fully sequenced and annotated. To avoid any complications arising from repeat sequences, we thus regarded the detected peaks with unbalanced tag counts as unreliable and discarded them from further analysis. This procedure removed 5% of the peaks, and the remaining 438,652 peaks were retained as confident positioned nucleosomes in CD4+ T cells.
Based on the ChIP-Seq tags for individual histone methylations, we assigned histone methylation marks to each identified nucleosome (see Methods). 99.97% of the positioned nucleosomes had one or more kinds of histone modifications, with an average of 4.4 modifications per nucleosome. Table S1 in Additional file 1 listed the numbers of modified positioned nucleosomes for each histone modification. In Table S1 in Additional file 1, we also classified the 21 ChIP-Seq histone modifications into three types: active marks (related to active genes [16] or active enhancers [8]), repressive marks (related to inactive genes [16] or heterochromatin [21]), and moderate marks (no clear preference between active and inactive genes [16]). The genome locations of identified positioned nucleosomes and their histone modification profiles are available at http://liulab.dfci.harvard.edu/NPS/Result/ webcite.
Distribution of modified positioned nucleosomes
While the identified positioned nucleosomes with histone modifications were modestly correlated with chromosome length (R2 = 0.443, Figure 2A), they had a much stronger correlation with gene density (R2 = 0.817, Figure 2A). This observation suggested biological functions of modified positioned nucleosomes in controlling gene activities. In addition, we found that 22% of the identified positioned nucleosomes appeared in promoters within 2.5 kb of transcription start sites (TSSs) – 6.8 times more than would be expected by random chance (~1 positioned nucleosomes per kb). Similarly, 54% were located in genes (defined as the region from 2.5 kb downstream of the TSS to the transcription end site, Figure 2B) – 1.6 times more than expected by chance. The remaining 24% of positioned nucleosomes often appeared far away from genes, with an average distance to the nearest TSS of 110 kb. Surprisingly, 76% of these distal positioned nucleosomes contained the transcriptional promoter signature H3K4me3 or enhancer signature H3K4me1/2 [8], indicating those nucleosomes may reside in functionally important regions and participate in the regulation of enhancers, repressors and insulators, or may lie near unannotated genes in the genome. In order to test the robustness of our observations, we used different p-value cutoffs for nucleosome identification. Although the number of identified nucleosomes varies with the cutoff, the general genomic distribution of identified nucleosomes is not affected (Table S2 and Figure S2 in Additional File 1).
Figure 2. Genomic distribution of identified positioned nucleosomes. (A) Correlation of identified positioned nucleosomes on each chromosome with chromosome length and gene density. (B) Genomic distribution of identified positioned nucleosomes. (C) PhastCons conservation scores are lower at center-aligned positioned nucleosomes, and higher at flanking linker regions, regardless of whether nucleosomes occur in genes, promoters or intergenic regions.
Sequences in nucleosome free regions have been found to be more evolutionarily conserved than nucleosome-occupied regions in both yeast genome [10] and human promoters [12]. We calculated the average phastCons conservation scores [22] for all detected positioned nucleosomes in CD4+ T cells and their nearby linker regions. Positioned nucleosomes in genes, promoters and intergenic sequences all have lower sequence conservation than their flanking linker DNA (Figure 2C). The linkers might be conserved because they harbor cis-acting elements to interact with trans-acting factors.
DNase I hypersensitive (HS) sites are regarded as containing a mixture of regulatory cis-elements. A recent study to map DNase I HS regions in CD4+ T cell discovered that only 2% of the genome is HS, with an average size of 634 nt [23]. We observed that 30% of our identified positioned nucleosomes were located in the DNase I HS regions. In addition, modified positioned nucleosomes were detected in 45% of all DNase HS regions, and in 99% of high confidence HS regions (DNase I HS quality score > 3, Figure S3 in Additional file 1). These observations suggest an epigenetic mechanism of modified positioned nucleosomes in establishing and maintaining functionally important regulatory regions in the human genome.
Nucleosome function in gene regulation
Nucleosomes are believed to play an important role in gene regulation by controlling the accessibility of DNA to trans-acting factors [2,24] and modulating the structure of chromatin [25]. We examined nucleosome positioning relative to the binding sites of CTCF [16], which is the only trans-acting factor (besides PolII) in human CD4+ T cells with available genome-wide binding locations. Aligning the nucleosome data at CTCF sequence motifs if one was present [26] or at the centers of CTCF ChIP peaks otherwise, we observed strong positioned nucleosome patterns (Figure 3A–B). The center of CTCF binding showed strong depletion of nucleosomes, flanked by two equally well-positioned nucleosome peaks on both sides. Six out of the nine active marks were enriched in both flanking nucleosomes, suggesting a coordinated function of active histone marks to regulate nearby cis-regulatory sites. We observed stronger H3K4me3 at positioned nucleosomes near CTCF binding sites in promoters (Figure 3A) than in intergenic regions (Figure 3B), and the converse for H3K4me1, agreeing with known chromatin signatures of transcriptional promoters and enhancers [8], respectively. Our observation of nucleosome positioning and histone modification around CTCF binding sites is similar to a recent observation by Fu et al. [27]. In their paper, Fu et al. used the overall tag enrichment of nucleosome sequencing tags [17] around CTCF binding sites, while we took advantage of histone methylation ChIP-Seq data to infer positioned nucleosomes and then displayed the modification profile of identified positioned nucleosomes around CTCF binding sites.
Figure 3. Positioning and modification patterns of nucleosomes around cis-acting elements in CD4+ T cell. (A) CTCF binding sites at promoters and (B) intergenic regions, aligned by CTCF sequence motif (if present) or by peak-center (if absent). The y-axis denotes the average number of positioned nucleosomes for each binding site. Nine active histone modifications are ordered by ChIP-Seq efficiency as in Table S1 in Additional file 1, and shown at peak locations. Inactive marks are absent in positioned nucleosomes around CTCF binding sites, DNase I HS regions, and TSSs, thus are not drawn here. Colors indicate the proportion of positioned nucleosomes carrying a particular histone mark (key on the bottom). (C) DNase I HS sites in promoters and (D) in intergenic regions. (E) TSS of expressed genes and (F) unexpressed genes.
DNase I HS sites are regarded as containing a mixture of regulatory cis-elements and are thus expected to exhibit nucleosome depletion similar to trans-acting factor binding sites. We examined the nucleosome profiles around DNase I HS sites [28] by aligning those regions by their peak summits, and we indeed found nucleosome depletion at the DNase I HS sites, flanked by two strong nucleosome positioning peaks (Figure 3C and 3D). Furthermore, while the nucleosome occupancy on both sides of DNase I HS sites is relatively lower than that of CTCF binding sites, the flanking nucleosomes showed similar histone modification profiles as in the case of CTCF binding regions.
There have been several studies using tiling arrays to investigate nucleosome positioning in yeast and human promoters [7,10-12]. Similarly, a recent study [29] revealed the promoter nucleosome architecture by separating the + and - strands of H3K4me3 and H2A.Z ChIP-Seq tags [16]. Here we examined the average number of positioned nucleosomes in the promoters of 4,517 expressed genes (Figure 3E) and 8,906 unexpressed genes (Figure 3F), obtaining much stronger nucleosome patterns than all previous studies in humans. For both expressed and unexpressed genes, the average number of positioned nucleosomes showed strong depletion approximately 50 nt upstream of TSS, although the depletion for unexpressed genes was weaker. The nucleosome signal gradually decreased as it oscillated away from TSS, but we could still clearly delineate five peaks downstream of TSS and at least two peaks upstream.
Detailed histone modification profiles on positioned nucleosomes near TSSs revealed interesting patterns, some of which could not be observed previously without the map of nucleosome-resolution modifications (Figure 3E). First of all, despite the fact that a decreasing number of genes contained a positioned nucleosome as the distance to TSS increased, the proportion of positioned nucleosomes carrying the H3K4me3 mark was constantly high. Three active marks (H3K4me1, H3K4me2, and H3K9me1) were rarely present at +1 nucleosome, but increased both upstream and downstream. Two other active marks H4K20me1 and H2BK5me1 were absent from upstream positioned nucleosomes, but showed increasing presence downstream from TSS. Since the function of H2BK5me1 mark was previously unknown and H4K20me1 was known as a transcription elongation mark in mammalian cells [30], we speculate that H2BK5me1 may also be a transcription elongation mark. In contrast, the active variant H2A.Z had high occupancy upstream and decreasing presence downstream. No H3K27me1, H3K36me3, repressive, or moderate marks appeared in positioned nucleosomes near TSS.
Surprisingly, these modification patterns were almost identical between expressed and unexpressed genes (Figure 3E–F). This observation suggests that a subset of genes with undetectable transcripts not only contain positioned nucleosomes near TSS, but also carry the identical histone modifications as expressed genes. Since the elongation mark H4K20me1 was present downstream of TSS and so was the proposed elongation mark H2BK5me1, despite being slightly weaker than in expressed genes, it was likely that these genes were actually transcribed but quickly degraded.
Several studies reported that certain histone modifications tend to occur in groups [7,9,14,31]. We also examined the histone modification co-occurrence patterns at nucleosome resolution, and we observed that active and repressive marks occurred mutually exclusively in the same nucleosomes (Figure S4 in Additional File 1). In order to test the robustness of our observations, we used different p-value cutoffs for assigning histone modifications. Although the number of nucleosomes with histone modifications varies, the general trend of correlation between histone modification profiles is not affected (Figure S5 in Additional File 1). We also found that adjacent nucleosomes avoided sharp transitions between active and repressive histone modifications and, instead, tended to carry the same or similar modifications (Figure S6 in Additional File 1). Our observations are supported by two recent publications [18,32]. Wang et al. combined the histone acetylation and methylation ChIP-Seq data to observe that certain histone modification marks tend to be grouped for activating gene expression [18]. Furthermore, Yu et al. used a Bayesian network to infer the relation between histone methylation marks and gene expression [32].
With the availability of commercial high-resolution tiling microarrays and high-throughput sequencing technologies, tremendous progress has been made towards understanding epigenetic regulation of gene expression. Nonetheless, studies on positioned nucleosomes with histone modification profiles at nucleosome resolution are still limited in human. We developed a signal-processing approach to identify positioned nucleosomes from existing histone methylation ChIP-Seq data and determined the histone modification states of each identified positioned nucleosome in CD4+ human T cells.
Despite the extensive scale and fine resolution of our analysis, our study did face potential biases and drawbacks. First, it will miss positioned nucleosomes that lack the particular set of histone modifications investigated by ChIP-Seq. In fact, we might even miss some modified nucleosomes if ChIP-Seq for the mark (e.g. repressive mark H3K9me3) is not sequenced deep enough. However, the identified positioned nucleosomes from ChIP-Seq appeared predominantly at functionally important regions. When compared with a recent study that sequenced over 150 million nucleosomes in CD4+ T cells [17], our nucleosome positioning signals from ChIP-Seq data not only agreed with their results, but also yielded much stronger and distinct nucleosome patterns in functionally important regions (Figure 4), thus greatly facilitating the identification of positioned nucleosomes in such regions. Moreover, while nucleosome sequencing is becoming popular in smaller model organisms [33,34], the size of the mammalian genome requires extensive sequencing coverage at a substantial cost. Thus, our method of utilizing nucleosome-resolution histone modification ChIP-Seq data provides an alternative solution to identifying positioned nucleosomes in functionally important regions and, at the same time, can also provide information about the histone modification status of individual nucleosomes. As ChIP-Seq data on additional histone modifications under the same cell condition become available, this analysis could be repeated to generate an increasingly complete and accurate nucleosome map of functionally important regions.
Figure 4. Comparison of nucleosome positioning signals of histone methylation ChIP-Seq data and nucleosome sequencing data in functionally important regions. Examples comparing nucleosome positioning signals from ChIP-Seq and nucleosome sequencing at regions around CTCF binding site (A), DNase I HS site (B) and TSS (C). The nucleosome positioning signal of methylation ChIP-Seq (combining 21 types of histone modifications) is shown in red color; while that of nucleosome sequencing is shown in blue color. Each tag is extended towards 3' to 150 nt and taken the middle 75 nt to generate the positioning signals; wavelet denoising was used to smooth the signals. The black profiles under the nucleosome positioning signals of methylation ChIP-Seq and nucleosome sequencing indicate a CTCF binding site (A), DNase I HS site (B), and the promoter of C2CD2 (C), respectively.
Second, ChIP-Seq tags that were not uniquely mapped to the genome were discarded, so our approach will miss some regions with segmental duplication and repeat elements. Repeat sequences currently pose serious challenges to understanding the human genome and will require further novel advances in experimental and computational techniques. Third, the ChIP-Seq data [16] used in this study lacked a proper control sample, which ideally should be prepared from naked genomic DNA digested with MNase, size-selected and sequenced. Such a control sample could greatly benefit our analysis and improve the accuracy of our identified nucleosomes. For example, we could use it to eliminate false positives that might arise from unannotated repetitive sequences in the genome and Solexa sequencing bias (e.g. more tags in GC-rich regions). In addition, although we computationally calculated the false discovery rate (FDR) for positioned nucleosome identification from Poisson-based p-values, we could empirically estimate a more reasonable FDR of our approach that considers potential ChIP-Seq bias by comparing the numbers of peaks identified from ChIP and control.
We developed a novel computational framework and efficiently identified over 438,000 positioned nucleosomes coupled with histone modifications in functionally important regions of the human genome. These nucleosomes are not evenly distributed across the genome: more than 75% are near genes, and the remaining ones far away from TSSs are likely around distal cis-regulatory elements such as enhancers and insulators. Our analysis of nucleosome positions and modifications near TSS, CTCF binding sites, and DNase I HS sites strongly support the dual role of nucleosomes in epigenetic regulation. First, chromatin structure at cis-regulatory elements may be controlled by histone modifications to recruit chromatin-associated proteins and maintain an open state, as supported by our analytical result that active and repressive marks do not occur together in the same or adjacent nucleosomes. Second, nucleosomes may be remodeled, exposing DNA binding sites to a variety of cellular machineries for transcription.
The work flow is divided into two major components: nucleosome position detection and histone modification assignment to positioned nucleosomes (Figure 1).
Nucleosome Position Detection
Nucleosome-level ChIP-Seq tags from all histone modifications were combined to provide enough genome coverage. Each 25 nt tag was extended to 150 nt in the 3' direction, and the middle 75 nt was used for nucleosome position detection. We then modified an approach that was applied to nucleosomes on tiling microarrays [12] to analyze the pre-processed data from ChIP-Seq. First, genomic regions with sparse tags (defined as fewer than 3 tags per kilobase (kb)) were discarded. The remaining regions were subjected to wavelet denoising to reduce the background noise in ChIP-Seq data. In this study, we chose coiflet4 as wavelet and scaling functions and performed decomposition at level two. Coiflet4 is suitable because its morphological characteristics are similar to the nucleosome peak shape [12]. Denoising at level two removed most high frequency noises, and further denoising appeared to deform the true peak shapes. We selected minimization of Stein's Unbiased Risk Estimate (SURE) and soft thresholding for estimating the threshold and filtering the signal, respectively [35,36]. SURE combined with soft thresholding is known to be suitable for denoising data containing edges (discontinuities), and matches well with our peak detection algorithm which perceives the edges as boundaries of positioned nucleosomes.
The peak detection algorithm calls peaks using LoG method, a combination of Gaussian window smoothing and Laplacian edge detection. Gaussian smoothing with an envelope size of 30 nt (which enabled us to achieve the best performance in peak detection in this study) was first adopted to further reduce the noise, then Laplacian edge detection was applied to find the inflection points of peaks in the data. The peaks detected by LoG were filtered based on the following criteria. First, the peak width should be between 80 and 250 nt. Second, the p-value of each peak was estimated as the probability that the same or larger number of tags can accumulate within the peak region by chance using Poisson approximation, and peaks with p-value greater than 10-5 were discarded, which corresponds to 0.014% of FDR estimated by using a bootstrapping-based method [37] (Figure S7 in Additional file 1). Finally, for each peak, the number of tags from one strand should be less than four times that from the other strand.
Histone modification assignment for nucleosomes
After positioned nucleosomes were detected as described above, the sequence tags were regrouped into different types of histone modification. The p-value of a particular histone modification at a positioned nucleosome was calculated based on the tag count of that histone modification in the nucleosome region using Poisson distribution, similar to the method mentioned above. A histone modification was assigned to the nucleosome if its tag count p-value in the region was less than 10-3.
The nucleosome-resolution (MNase digestion) ChIP-Seq Solexa tags for 20 types of histone methylation and histone variant H2A.Z as well as the ChIP-resolution (sonication) ChIP-Seq data for CTCF and Pol II in human CD4+ T cell [16] were downloaded from http://dir.nhlbi.nih.gov/papers/lmi/epigenomes/hgtcell.html webcite. The gene expression profiles of CD4+ T cell were obtained from SymAtlas [38]. CTCF ChIP peaks were detected using MACS [39].
Software implementation
The software for positioned nucleosome identification from ChIP-Seq data is implemented in Python and publicly available at http://liulab.dfci.harvard.edu/NPS/ webcite. The algorithm also works to detect positioned nucleosomes from nucleosome sequencing experiments (without ChIP). It requires two input files: a ChIP-Seq tags file (BED format) and a user-defined parameter file (TXT format). The users can easily set their own parameters other than the ones suggested above by editing the parameter file. The output of the software is a tab-delimited format file containing the chromosomal coordinates and p-values of the detected nucleosomes. In this work, the software processed 185 million Solexa tags within five hours on a Linux computer (CPU speed: 2 GHz).
ChIP: chromatin immunoprecipitation; LoG: Laplacian of Gaussian; TSS: transcription start sites; HS: hypersensitive; FDR: false discovery rate; SURE: Stein's Unbiased Risk Estimate.
Authors' contributions
XSL, YZ and HS conceived the project and wrote the paper. YZ, HS and JSS designed the algorithm, performed the research and implemented the software, with the assistance of YL. All authors read and approved the final manuscript.
We thank Myles Brown, Kevin Struhl, Keji Zhao, Jérôme Eeckhoute, Mathieu Lupien, Dustin Schones and Wei Li for their insightful discussions and critical readings of this manuscript. The project was partially funded by NIH grant HG004069-02. JSS was supported in part by the Martin A. and Helen Chooljian Membership in Biology.
Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ: Crystal structure of the nucleosome core particle at 2.8 A resolution.
Nature 1997, 389(6648):251-260. PubMed Abstract | Publisher Full Text
Lu Q, Wallrath LL, Elgin SC: Nucleosome positioning and gene regulation.
J Cell Biochem 1994, 55(1):83-92. PubMed Abstract | Publisher Full Text
Workman JL, Kingston RE: Alteration of nucleosome structure as a mechanism of transcriptional regulation.
Annu Rev Biochem 1998, 67:545-579. PubMed Abstract | Publisher Full Text
Chromosome Res 2006, 14(1):5-16. PubMed Abstract | Publisher Full Text
Langst G, Becker PB: Nucleosome remodeling: one mechanism, many phenomena?
Biochim Biophys Acta 2004, 1677(1–3):58-63. PubMed Abstract | Publisher Full Text
Rando OJ: Global patterns of histone modifications.
Curr Opin Genet Dev 2007, 17(2):94-99. PubMed Abstract | Publisher Full Text
Liu CL, Kaplan T, Kim M, Buratowski S, Schreiber SL, Friedman N, Rando OJ: Single-nucleosome mapping of histone modifications in S. cerevisiae.
PLoS Biol 2005, 3(10):e328. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, Barrera LO, Van Calcar S, Qu C, Ching KA, et al.: Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome.
Nat Genet 2007, 39(3):311-318. PubMed Abstract | Publisher Full Text
Kurdistani SK, Tavazoie S, Grunstein M: Mapping global histone acetylation patterns to gene expression.
Cell 2004, 117(6):721-733. PubMed Abstract | Publisher Full Text
Yuan GC, Liu YJ, Dion MF, Slack MD, Wu LF, Altschuler SJ, Rando OJ: Genome-scale identification of nucleosome positions in S. cerevisiae.
Science 2005, 309(5734):626-630. PubMed Abstract | Publisher Full Text
Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP, et al.: Genome-wide maps of chromatin state in pluripotent and lineage-committed cells.
Nature 2007, 448(7153):553-560. PubMed Abstract | Publisher Full Text
Ozsolak F, Song JS, Liu XS, Fisher DE: High-throughput mapping of the chromatin structure of human promoters.
Nat Biotechnol 2007, 25(2):244-248. PubMed Abstract | Publisher Full Text
Pokholok DK, Harbison CT, Levine S, Cole M, Hannett NM, Lee TI, Bell GW, Walker K, Rolfe PA, Herbolsheimer E, et al.: Genome-wide map of nucleosorne acetylation and methylation in yeast.
Cell 2005, 122(4):517-527. PubMed Abstract | Publisher Full Text
Bernstein BE, Kamal M, Lindblad-Toh K, Bekiranov S, Bailey DK, Huebert DJ, McMahon S, Karlsson EK, Kulbokas EJ, Gingeras TR, et al.: Genomic maps and comparative analysis of histone modifications in human and mouse.
Cell 2005, 120(2):169-181. PubMed Abstract | Publisher Full Text
Bernstein BE, Humphrey EL, Erlich RL, Schneider R, Bouman P, Liu JS, Kouzarides T, Schreiber SL: Methylation of histone H3 Lys 4 in coding regions of active genes.
Proc Natl Acad Sci USA 2002, 99(13):8695-8700. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K: High-resolution profiling of histone methylations in the human genome.
Cell 2007, 129(4):823-837. PubMed Abstract | Publisher Full Text
Schones DE, Cui K, Cuddapah S, Roh TY, Barski A, Wang Z, Wei G, Zhao K: Dynamic regulation of nucleosome positioning in the human genome.
Cell 2008, 132(5):887-898. PubMed Abstract | Publisher Full Text
Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, Cui K, Roh TY, Peng W, Zhang MQ, et al.: Combinatorial patterns of histone acetylations and methylations in the human genome.
Nat Genet 2008, 40(7):897-903. PubMed Abstract | Publisher Full Text
Oppenheim AV, Schafer RW: Prentice-Hall. Englewod Cliffs, New Jersey: Prentice-Hall Inc; 1989.
Prosser J, Frommer M, Paul C, Vincent PC: Sequence relationships of three human satellite DNAs.
J Mol Biol 1986, 187(2):145-155. PubMed Abstract | Publisher Full Text
Kouzarides T: Chromatin modifications and their function.
Cell 2007, 128(4):693-705. PubMed Abstract | Publisher Full Text
Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, Clawson H, Spieth J, Hillier LW, Richards S, et al.: Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.
Genome Res 2005, 15(8):1034-1050. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Boyle AP, Davis S, Shulha HP, Meltzer P, Margulies EH, Weng Z, Furey TS, Crawford GE: High-resolution mapping and characterization of open chromatin across the genome.
Cell 2008, 132(2):311-322. PubMed Abstract | Publisher Full Text
Anderson JD, Widom J: Sequence and position-dependence of the equilibrium accessibility of nucleosomal DNA target sites.
J Mol Biol 2000, 296(4):979-987. PubMed Abstract | Publisher Full Text
Li B, Carey M, Workman JL: The role of chromatin during transcription.
Cell 2007, 128(4):707-719. PubMed Abstract | Publisher Full Text
Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI, Green RD, Zhang MQ, Lobanenkov VV, Ren B: Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome.
Cell 2007, 128(6):1231-1245. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Fu Y, Sinha M, Peterson C, Weng Z, Van Steensel B: The Insulator Binding Protein CTCF Positions 20 Nucleosomes around Its Binding Sites across the Human Genome.
PLoS Genet 2008, 4(7):e1000138. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Boyle AP, Davis S, Shulha HP, Meltzer P, Margulies EH, Weng Z, Furey TS, Crawford G: High-resolution mapping and characterization of open chromatin across the genome.
Cell 2008, 132(2):311-322. PubMed Abstract | Publisher Full Text
Schmid CD, Bucher P: ChIP-Seq Data Reveal Nucleosome Architecture of Human Promoters.
Cell 2007, 131(5):831-832. PubMed Abstract | Publisher Full Text
Vakoc CR, Sachdeva MM, Wang H, Blobel GA: Profile of histone lysine methylation across transcribed mammalian chromatin.
Mol Cell Biol 2006, 26(24):9185-9195. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Schubeler D, MacAlpine DM, Scalzo D, Wirbelauer C, Kooperberg C, van Leeuwen F, Gottschling DE, O'Neill LP, Turner BM, Delrow J, et al.: The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote.
Genes Dev 2004, 18(11):1263-1271. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Yu H, Zhu S, Zhou B, Xue H, Han JD: Inferring causal relationships among different histone modifications and gene expression.
Genome Research 2008, 18(8):1314-1324. PubMed Abstract | Publisher Full Text
Valouev A, Ichikawa J, Tonthat T, Stuart J, Ranade S, Peckham H, Zeng K, Malek JA, Costa G, McKernan K, et al.: A high-resolution, nucleosome position map of C. elegans reveals a lack of universal sequence-dictated positioning.
Genome Res 2008. PubMed Abstract | Publisher Full Text
Shivaswamy S, Iyer VR: Stress-dependent dynamics of global chromatin remodeling in yeast: dual role for SWI/SNF in the heat shock stress response.
Mol Cell Biol 2008, 28(7):2221-2234. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Donoho DL, Johnstone IM: Adapting to Unknown Smoothness via Wavelet Shrinkage.
Journal of the American Statistical Association 1995, 90(432):1200-1224. Publisher Full Text
Donoho DL: De-noising by soft-thresholding.
Information Theory, IEEE Transactions on 1995, 41(3):613-627. Publisher Full Text
Storey JD, Tibshirani R: Statistical significance for genomewide studies.
Proc Natl Acad Sci USA 2003, 100(16):9440-9445. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, et al.: A gene atlas of the mouse and human protein-encoding transcriptomes.
Proc Natl Acad Sci USA 2004, 101(16):6062-6067. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nussbaum C, Myers RM, Brown M, Li W, et al.: Model-based Analysis of ChIP-Seq (MACS).
Genome Biol 2008, 9(9):R137. PubMed Abstract | BioMed Central Full Text


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Telltale Games making Wallace & Gromit? Someone's been reading my wish list again. While there are some snags here, there's nothing that can stop this game from being great fun to play.
Let's let the biggest problem into the wild then, the one that might put off some Wallace & Gromit fans but still isn't in any way as bad as it sounds - or rather, as he sounds. Peter Sallis, the traditional voice of Wallace, does not voice the character in Telltale's Game.
This isn't as bad as you might expect, since his replacement is Aardman's own Sallis stand-by impersonator Dan Whitehead, and he's often a dead ringer for the aging Last of the Summer Wine star.
Often, but sadly, not always. Still, this is hardly Telltale's fault, and Whitehead's not a bad substitute, but the problem is that he's so quiet. He's often drowned out by the background music, making joke-spoiling subtitles a must. Consequently it makes his Wallace voice seem decidedly unemotional in some the more high-tension scenes.
While we're on the subject of sound, another quibble is the rather simplistic, yet confusing, options menu. There are no separate volume controls for sound effects, music and voices like there are in most games, instead there's just one big pointless volume control (we do have those on our speakers, you know, guys). So the music can occasionally get too loud and cloud even the other actors' voices out.
Telltale are aware of this and will hopefully fix it later, but for now it's a problem. The options menu also makes no obvious mention of saving, and it took me a while to track down the function.
All that said, the rest of the sound is perfect. The other voice actors are all proper English folk, not Americans-doing-English as some may have feared, and all perform their characters perfectly. The classic Wallace & Gromit theme tune by Julian Nott makes a proud appearance, and the rest of the music is all Telltale veteran Jared Emerson-Johnson's work and up to his usual high standards.
Speaking of the characters, they're a suitably eclectic bunch with plenty of foibles, quirks and downright insane moments. Consequently they fit well into Aardman's Northern universe. It's a slight pity that the town's policeman is now PC Dibbins rather than Curse of the Wererabbit's fantastically named PC Mackintosh, but as he was voiced by comedy legend Peter Kay he was probably either busy or out of Telltale's price range. Dibbins is a really excellent replacement, though.
As far as returning characters, if you're expecting Hutch or Shaun to turn up you'll be disappointed, although there are plenty of references to the animations and a mechanical 'character' popping for a quick cameo. There's nothing related to A Matter of Loaf and Death however, as this presumably takes place before the universe-shattering events of that recent story.
I hate saying too much about the story, but here Wallace & Gromit are in the honey business and have to get a big order ready, before everything goes wrong of course.
Nothing really unpredictable happens (especially if you've seen the plot-spoiling trailer), but it's all carried over with such charm and fun that it's hard not to love it. I could say the same about all the Wallace & Gromit films incidentally, so the game's still spot-on.
Another area I was slightly worried about was the difficulty, since the game had to appeal to both 'hardcore' gamers and Wallace & Gromit fans. Thankfully the puzzles are arguably the most perfectly realised Telltale have ever made, managing to both be easy yet sometimes tricky to work out.
I can guarantee that you will overlook something critical at some point, then find yourself searching for an answer that's been right in front of you all the time. I know I did. I even had to use the hints at one point, which work just fine too.
Gameplay, unlike Telltale's other duo Sam & Max, alternates between control of Wallace and Gromit. Wallace is a very traditional adventure-gaming character, making comments about everything, but Gromit is refreshingly different as he never says a word.
Just like in the films, Gromit's expression is everything. His animation is absolutely perfect (and this goes for all the other characters too). It's just a shame that there's a large portion of the game where Gromit doesn't accompany Wallace. Never mind, it probably works better because of this.
I really cannot overstate how well Telltale has captured the world of West Wallaby Street. They've even made loads of little bee-based puns for the bookshelf titles. While there are quibbles, most of them will probably get ironed out, especially as the series goes on.
Still, we'll still be left with Dan Whitehead as Wallace. For some this will be unforgivable, and others will wish that Telltale had hired someone who sounded a little less like Sallis but could emote more and talk louder. I can get over this, but you'll have to make up your own mind as a consumer.
I can't take anything away from the rest of the game, however. It's a wonderful adventure, a perfect Wallace & Gromit yarn, and I honestly can't recommend it highly enough. While I've had moans about previous Telltale games, they've surpassed my expectations this time round.
If you can live with the faux-Wallace, I suggest you buy Fright of the Bumble Bees at once. If Telltale can keep up this quality, we're looking at some Aardman-rivalling stories coming up.
Fans should love it, but straight Telltale fans might find the script much less laugh-out-loud funny than Sam & Max, Strong Bad or even Bone. It beats A Vampyre Story, however (non-Telltale but a close stable-mate).
There, the review's over and I didn't once use the word "cracking". I feel proud.
Chris Capel
Avalanche have teamed up with SEGA to produce a digital release.
Tomb Raider creators Square Enix has released the first in a series of Survival Guides for the upcoming title.
ZombiU has been pipped as one of the Wii U's flagship games as it encompasses the upgraded power of the console from its predecessor, it's GamePad compatible and you won't find it anywhere else.
The last flurry of releases before Christmas is more of whimper than a bang - Mass Effect Trilogy is the only notable release.


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Slideshow posted in Entertainment News | Monday, January 11, 2010
48 of 62: This Oct. 23, 1965 file photo shows "Daniel Boone" star Fess Parker, left, and his stand-in Carol Lynton. Parker died of natural causes at his Santa Ynez home on Thursday, March 18, 2009. He was 85. (AP Photo)


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The recent release of Fable Anniversary and the general rise in the popularity of high-definition makeovers in recent years got me thinking; are HD remakes of video games really necessary?
Tag Archives: Xbox
Microsoft Looking Into Cheaper Digital Games
Microsoft's Major Neslon chimed in on a Reddit thread, saying that competitive digital pricing is indeed on the agenda for Microsoft's market place.
Xbox One Sells Over 3 Million Units in 2013
Debuting worldwide on the 22nd of November, Microsoft's Xbox One released following severe criticism and apparent lack of interest. In spite of many gamers voicing their preference of Sony's PlayStation 4, Microsoft announced that they sold 2 million consoles in 18 days, breaking their personal records.
Max: The Curse of Brotherhood Review
Max: The Curse of Brotherhood is the latest game to be released for the Xbox One. The latest game in the Max series by Press Play has us back in control of Max as he is trying to rescue his brother Felix from the evil Mustachio. We travel through lands filled with monsters, lava pits, crocodiles, raging rivers and other perilous obstacles that pose a threat to Max throughout his journey.
Why I Love: FIFA 14 Career Mode
If you were to create a poll regarding gamer's favorite modes in the FIFA games, I've no doubt that Ultimate Team would end up at the top of the list with the most amount of votes. The majority of FIFA players love trading cards, building up their own teams and opening packs, but there are those of us who would rather play another mode like Career. I'm part of the latter group, and after picking up a discounted copy of FIFA 14 on Xbox Live leading up to Christmas, I thought I'd express my thoughts on why Career mode is so great.
Why Should You Be Excited About Valve's Steam Machine?
Valve's upcoming gaming console/ PC hybrid, the 'Steam Machine' is set to be released next year, and is currently undergoing a beta test with 300 machines equipped with an assortment of specifications being sent out over the past few weeks to a select group of testers. With that in mind, here are a few reasons to get excited about Valve's first venture into console gaming.
Dead Rising 3 Operation Broken Eagle DLC Revealed
Capcom has announced Operation Broken Eagle, an upcoming DLC content update for their Xbox One launch title Dead Rising 3. It will be the first episode in the Untold Stories of Los Perdidos.
Free & Paid DLC Is Coming To Ryse: Son of Rome
Microsoft has announced that both free and paid DLC will be coming in the near future for their Xbox One launch title Ryse: Son of Rome.
Castlevania: Lords of Shadow 2 Box Art
Konami has revealed the box art for their upcoming game Castlevania: Lords of Shadow 2, which is currently slated to launch early next year. The company made the reveal on Twitter by posting images of what the game case will look like for both PlayStation 3 and Xbox 360 versions of the game.
Microsoft Employee's Recieve Exclusive Xbox One
Unnamed IGN sources have leaked an employee exclusive Xbox One.
(Picture VIA IGN)
Looking at the console you can see the 'I MADE THIS' next to the disc drive(which is pretty sweet). and do I even have to mention the whiteness? if only the kinect matched.
Several sites have reached out to Microsoft asking if they can buy the (employee) exclusive xbox one. Apparently they don't understand the word employee. or exclusive.


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I cant get it to work.
This is a discussion on Celeste Bluetooth 4.3.1 working ! within the iPad Hacking forums, part of the Apple iPad Discussions category; I cant get it to work....
I cant get it to work.
Originally Posted by MAcsure
All my friends used to call me Sharky. you can call me that. My other nickname is YoungOne.
Well i have tried... Alternate methods.... (don't kill me Marie) but i think i will just go for it and spend the $10 for it in cydia. I really want it. I take so many pictures with my phone because it has an AMAZING camera, but i want to get them to iPad to enjoy them without firing up my silly windows computer.
Young One, is there a specific reason why you want to use Bluetooth to send the images? Because if using wifi were an option, then Photo Sync would be a better and cheaper option. It's $1.99 and let's you send images directly from an iPhone to iPad. It doesn't even require a jailbreak
Or "Photo Transfer App" does both wifi and Bluetooth. I use it all the time.
15" MacBookPro with Retina Display 16GB 3.4GHz i7 256GB | iPad4 WiFi 32GB 6.1.2 (evasi0n) | iPad3 4G 64GB 6.1.2 (evasi0n) | iPad2 3G 64GB 5.1.1 (redsn0w) | iPad1 3G 64GB 4.3.3 (jbme) |
iPhone5 32GB 6.1.2 (evasi0n) | iPhone4S 64GB 5.1.1 (absinthe) | iPhone4 32GB 7.0b2 (stock) | iPhone3G 16GB 3.1.3 (jbme) | iPod Classic 6G 160GB (stock) | AppleTV 2G 5.0.2 (seas0npass)
Please review the hacking section rules and our main rules before posting!
Photo sync works with Bluetooth as well, device to device, device to pc etc....also another great investment would be the iPad camera connection kit, especially if you're jailbroken!!
Last edited by Frenchroll; 05-19-2011 at 12:43 PM.
I bought Celeste off of Cydia **** EDITED ****. Photo transfer app is ok, but only works for apple phones. I use my casio G'zOne for pictures for the iPad 1.
But still on 4.3.1.
Last edited by f4780y; 05-19-2011 at 03:54 PM. Reason: discussion of piracy is forbidden - read the rules!
Now really confused. So which do I need now. I want to transfer files ( pic, phone video, etc ) from any phone ( nokia, iPhone, Ericsson etc.Originally Posted by Higrab
I this celeste app would do that all,Are you guys saying there's alternative ?
Sent send from iPad using iPF
64GB WiFi/3G iPad running iOS version 4.3.3, boring and safe.
Hi frenchy, what you mean by another great investment would be the cck,, ..... Jail broken.... What am I missing out on, since I is free alreadyOriginally Posted by Frenchroll
Sent send from iPad using iPF
64GB WiFi/3G iPad running iOS version 4.3.3, boring and safe.
I dont have an iphone.Originally Posted by DontUnderstandMyIpad
I REALLY want celeste!


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I have been lifting for about 3 years now and have never gone to a competitive stage with it. I don't really have the genetics to be a bodybuilder but I have always been naturally lean. I've really...
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No, as they try to keep this a Question and Answer site only. But you can talk some with people through comments. I don't think they will ever change their format as this type of question has been asked for years. They want to be different from Facebook, Twitter, and the rest. No, they will keep it as it is : Questions and Answers. You could write to them in the suggestion area and say something about it. Can't hurt to try !
they should have something like that
but thats why they have comments
I think we all agree that they should have some sort of chatting with some restrictions.
please ask.com!!! "don't change a thing"...;-)
Yes, ask.com has indeed "thought about" this concept. They regularly have surveys of members to ask their opinion about the website and this idea in particular.
The answer in the surveys has, to this point, always been - NO!
No. Ask.com was never intended to be a social site. Although, I can say I have met most of my friends here, I still try not to use it as a social site.