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Shooting Raw with the Nokia Lumia 1020
1 Image Detail & Noise
|2 Next
Smartphone cameras have improved a great deal over the last couple of years, and those improvements have had a dramatic impact on the market for consumer-level compact cameras. Sales have plummeted as most consumers simply don't see the point of carrying and paying for a compact camera when their smartphone delivers image quality that is beyond what's needed for social sharing and on-screen viewing.
The situation is slightly different in the enthusiast compact space, though. Compact cameras targeted at enthusiast users come with one feature that until recently no smartphone could offer: Raw file capture. The ability to process Raw files and modify shooting parameters after capture on your computer's high-resolution monitor is something many serious photographers don't want to live without.
However, as usual, smartphone manufacturers are moving fast, and in November 2013 Nokia launched the first smartphone with Raw capture: the Lumia 1520. The same feature was made available through a firmware update on Nokia's flagship smartphone, the Lumia 1020. Google also announced the implementation of Raw file capturing capabilities in future versions of Android. So it seems Raw capture is about to become a common feature on smartphones, at least on high-end models.
What does that mean for mobile photographers though? We already had a look at the Nokia 1520's Raw files in our full full review of Nokia's latest model and found the advantages of shooting Raw on the 1520 to be limited. Of course you have the flexibility to modify image parameters such as white balance, sharpness or contrast in post-processing, but it's difficult to squeeze additional detail out of the Raw files and the 1/2.5-inch sensor's limited dynamic range means only very minor shadow and highlight corrections can be applied.
Therefore, we were quite curious to find out how the Lumia 1020's Raw files would fare in processing. In our review we were quite impressed with the phone's JPG output and with its larger 1/1.5-inch imaging sensor. We expect the 1020's sensor to offer more dynamic range than the small-sensor 1520. We installed the Nokia "Black" update on our Lumia 1020 and then went out to take pictures in a variety of light situations. Back in the office we processed them in Adobe ACR to see if they allow for any improvement over the out-of-camera JPEGs.
Image Detail
The JPEG-engines of digital cameras apply detail-smearing noise reduction to the image-data that is captured by the sensor, even at low ISOs. If you need maximum detail in an image and are happy to accept some noise, converting a Raw-file with noise reduction set to zero is therefore a good option. Most Raw-converters will apply some noise reduction, even with the slider in the zero position, but it's still the closest you can get to a noise-reduction-free image.
To find out how much, if any, additional detail you can squeeze out of the Nokia's Raw files we processed a couple of low-ISO files with different noise reduction and sharpening settings in Adobe ACR.
For the first sample we set luminance noise reduction to zero and applied some fine sharpening (Amount 56, Radius 0.8, Detail 41). In the 100% crop of the brickwork below you can see that higher levels of detail can be achieved but the difference will only be visible at a 100% magnification. Apart from the obvious tone curve differences, edge sharpness is better in the converted Raw file and some additional low-contrast detail in the brickwork of the church has been revealed. On the downside you also get noticeably more grain in areas of plain color, such as the sky or the green roof of the building, and the shadows.
In a second step we downscaled the converted Raw image to 5MP in order to compare it to the 5MP JPEG that is captured alongside the DNG file. At the reduced image size the Raw file's grain is almost entirely averaged out but the increase in detail is gone, too. Thanks to Nokia's pretty efficient downscaling algorithm it's almost impossible to see a difference between the 5MP out-of-camera JPEG and our processed image.
Overall, in terms of detail, processing your images is only worth the effort if you are planning on using them at native resolution (the images below were captured separately because the camera can only save a 38MP RAW or a 38MP JPEG along with the usual 5MP JPEG.)
High ISO Noise Reduction
Noise reduction does its job by blurring noise. Some noise reduction algorithms are more intelligent than others but, no matter what camera you are shooting with, noise reduction inevitably also blurs some fine detail. Even with noise reduction "switched off" some of it is applied to your images. Enthusiast compact cameras and digital SLRs at least give you some control over this parameter.
This is not the case for smartphones. You are stuck with the amount of noise reduction that is deemed right by the engineers. On the Nokia Lumia 1020 you can apply your own noise reduction mix by converting the device's DNG files. In this section we are having a closer look at the Nokia's high-ISO Raw files.
When shooting in auto mode the 1020 never really goes higher than ISO 800 and relies on its image stabilization system to get a sharp image. The night scene below was even captured at ISO 640. At this sensitivity some loss of fine detail and grain is visible at 100%, but overall Nokia's full-resolution output still looks pretty good.
When we convert the DNG file with both color and luminance noise reduction set to zero, it becomes clear how much noise is in the image. There is a lot of grain and color blotches, but the image also looks a touch sharper. Increasing the color noise reduction to 25 gets rid of most of the color noise, but preserves most of the detail. However, the 1020's JPEG engine is doing a decent job at higher ISOs and the additional amount of detail you get through Raw processing is limited.
We also produced a "clean" version of the Raw file by setting luminance noise reduction to 45, in addition to the color NR. The end result is not too dissimilar to the out-of-camera JPEG, albeit with a little less sharpening applied.
We went through the same procedure as above with an ISO 1600 DNG file. We had to set the Lumia to manual ISO to make it capture this shot in a dimly illuminated gallery at ISO 1600. As you can see the out-of-camera JPEG is pretty clean, but also a little soft. It's obvious that low-contrast detail is being lost through noise reduction. With all noise reduction set to zero, chroma noise becomes very intrusive - but you can see that some additional low-contrast detail is hiding behind all the noise.
Again, applying some color noise reduction eliminates all the chroma noise and generates an image with good detail but a lot of grain. Reducing the grain by increasing luminance noise reduction makes the image look cleaner, but swallows some low-contrast detail and generates an overall softer look.
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For the more-artistic shots, I enlisted the help of CNET photographer James Martin and CNET camera editor Joshua Goldman, who independently called the Lumia 1020 a "really good smartphone camera" after taking their own rounds of test shots.
To test how well the Lumia 1020 backs up its claims of photog greatness, I shot dozens of pictures with both the Pro Cam app and the native app, using a combination of automatic modes and fancier settings. Full disclosure: I'm a completely casual photographer, so my photos here represent the perspective of an average user. For the more-artistic shots, I enlisted the help of CNET photographer James Martin and CNET camera editor Joshua Goldman, who independently called the Lumia 1020 a "really good smartphone camera" after taking their own rounds of test shots.
Many pictures I took looked fantastic in terms of color, contrast, and detail -- especially fine detail like a visible background cobweb.
What I would use the Nokia raw files for is tonal adjustment. In my previous reply I found highlight recovery was possible but limited. Shadow recovery offers more lattitude but you put up with more noise. However, it's very possible to pull a really good, nicely balances picture out of the dng's.
compared to how much lattitude you have vs a m4/3 raw file? The m 4/3 offers probably 2 stop advantage at either ends, allowing much more extreme push and pulls. So the Nokia dng are limited but there's a lot that can be done within that limit.
being able to REALLY edit the images from a camera phone is a dream come true. it's not always practical to carry around a dslr, but i always have my phone on me. the 1020 is the best solution for my needs, mostly taking notes, and quick snaps, and when i want more, it delivers.
i have yet to use a camera phone that is as capable in the image department, or whose output affords as much editing latitude. i know that the 808 is supposed to outperform the 1020, but i have never seen one in the wild.
Editing on the phone doesn't have a lot to do with shooting raw on the same phone.
DSLRs shoot raw, almost no one wants to edit on a DSLR, and a somewhat bigger smart phone screen isn't a real help.
I frequently edit my RAW files on my Oly E-M1, if I need to extract a quick JPG for sharing online etc.
The oly in camera RAW to JPG allows for basic exposure, contrast, shadow recovery and art filters. One can also crop, reduce red eye, etc during the conversion process.
Also one can edit jpegs. So of course one can edit jpegs from any camera phone. Here I guess the "really" makes your point.
The problem is as I'm sure you know: Editing is not limited to raw. Raw allows much more flexibility, including extraction, but that's only part of editing. So back to "really" suggesting WB, NR tone, etc, but why not just stay "have raws instead of jpegs"?
bigley Ling:
You've made my point, yawn.
No it's not impossible to extract raw files to jpegs on a camera, but it's not the primary method and it's not going to become the primary method.
There may be or may be in the future, I really don't know.
However it's not clear that you understand that jpegs can also be edited, so "edit" is not a word one uses when talking about raws. But yes I missed your point because I ignored the preposition "from". And I already acknowledged this point above.
yeah.. that's what i had gathered.. but it took a while for a raw editor to appear on ios, so.. while i'm not holding my breath, i'm not giving up hope that there will be one, yet.
no problemo buddy, it's easy to get swept up in the moment, especially when reading about the things one is passionate about. As of this moment, i have yet to settle on an in camera jpeg editor, for my 1020, mostly because the nokia jpeg engine itself is decent enough for snaps, and i'm not into 'apping' images. Also, the built in edit funtionality of the nokia software lacks considerably.
the lack of apps for windows platform is heavily documented though, so, i kind of expected to wait, going in.
I edited a Lumia 1020 RAW sample, is there a place to post it? I've never posted a pic on connect.dpreview.com, I don't know if it's possible or if I should post it on dpreview.com Thanks.
Samsung are just about to release the S5 with a new 16mp ISOCELL sensor so let the camera phone battle begin.
if anything i feel phones can be a good testing points for sensor improvements before putting them in actual cameras
So is your thinking that the Samsung S5 must have raw because Android 4.4 can shoot raw?
Possible, but I'm not sure that's the case. Could be a hack a few months after the phone ships, I guess.
Still no OIS! >:-(
Ok, Nokia raw gives slightly better DR but slightly grainier/noisy look than Nokia jpeg, it's a trade off. But how about technically comparing it to an ordinary DSLR or M4/3? I can't imagine people suddenly shedding their cameras for Nokia phones even as hobbyists. Another gimmick for wannabes.
I'm sure NOKIA isn't trying to make people stop buying SLRs and CSCs.
Smart phones are so good now as phones and phablets that people chose their phones on things like screen quality, physical size, robustness, photo quality ect. Also there is a huge compact camera market that can be eaten into
It may be a little gimmicky but the smartphone market is very competitive and everyone is looking for a way to differentiate. Based on their recent offerings it appears that Nokia is focused on sparking the interest of people more into photography than the average smartphone user. While it would be interesting to see a side by side of these RAW files verses those of APS-C or m4/3 cameras a better comparison would be against enthusiast compact cameras with similarly sized sensors.
"Ok, Nokia raw gives slightly better DR but slightly grainier/noisy look than Nokia jpeg, it's a trade off."
But what processing did you do to the raw from the Nokia? Raw processing has many different variables.
Also, why cite camera types with much bigger sensors?
An interesting exercise but the only benefit I can see from shooting RAW is a slight improvement in DR.
at the very least it is very useful for white balance corrections too. But a lot about images is somewhat a matter of personal taste...tonality, colors, contrast etc...you can modify all these parameters to your liking. It's not only about "optimizing" IQ, it's more about optimizing them for your taste.
true, although one assumes the auto white balance to get it right first time, to alleviate having to correct it post.
The raw ability is useful already because of the 1020's lousy auto white balance. Everything else is a bonus.
By shooting raw you ensure your photos' image quality can improve over time because you can always process them again with the latest and the greatest raw converter.
I understand raw capability should made it more attractive to serious users. But wouldn't a serious raw user conclude that to get better quality, one needs to use a camera to take pictures?
I agree with AbrasiveReducer. RAW on the phone is just a marketing. This trick works especially on those, who doesn't know what is RAW.
Even if it is marketing tactic (like the megapixel wars of mid-2000s) the fact of the matter is those who can/will use it are going to benefit from it. Due to the ultra competitive nature of the smartphone industry I'm sure all flagship smartphones will offer this within 2 years (probably less). That competition will lead to better sensors and RAW files so the "serious users" need not worry if they don't always have their primary/walk-around camera with them.
Phone camera's are pretty good these days, and with RAW support it just adds flexibility especially at times when one does not have their camera at their disposal
Its good to have options, but, i dont bother with RAW on sensors smaller than APSc. At that point, you are just shooting for fun and need convenience more than absolute image quality.
Put another way, if you do care enough about image quality to shoot RAW.. why bother with anything less than APSc.
Jogger is likely one of those types who thinks it's easy to to adjust colour+WB starting with a jpeg and propounds the argument that smaller sensors are noisy no matter what and noise reduction is the only reason to shoot raw.
Is there a download link for these DNGs?
Thank you.
how long is the shot to shot in raw?
Where's Apple?
I would say that balance purple in the sondra is created when the sondras is changed too but can be corejir in Photoshop, balace of color+sondras to the maquenta put Green
what about switching off autocorrect? ;) maybe we would understand and reply to your "sondras"... :)
Options are always better than no options. It looks like you can squeeze out a little, maybe even a lot depending on how much you value extra detail and flexibility. That sky in the shot with the building is horrendous in JPEG. If I had the option, I'd always shoot with RAW knowing at the minimum I can squeeze out a JPEG of the same quality.
With that said, imaging on the smartphone is going nowhere until we can figure out how to either increase the size of the sensors or there's a breakthrough in sensor technology.
Why is it for ???? Want to take a real photo ? Sony RX100 or something like that ! Don´t waste your time.
And I called home and asked my wife to send me the RX100 somehow, since I only had my old cellphone with me and found some nice places worth a shot or two. But I had to wait a few hours...
Thanks Lars for the article and the examples.
Since my Lumia 1020 offers RAW ... I'm using it. In most cases I use it, because I don't have the ability, like with iPhone apps, to set a a bright and a dark point for exposures. So I often underexpose my images to have details and no clipping in the brightest areas.
This ends up having some noise in the dark parts of an image when I raise the exposure in the dark parts in ACR.
The Nokia 1020 often tends to have vertical banding in the noise when I do that, but TOPAZ DeNoise is perfect for that, because it has a specialized setting for the vertical banding.
The JPGs out of the Nokia are very good, but since it is possible I prefer using the DNG files.
There is very little to be recovered on those RAW files since the scene's DR is too much for any camera (maybe except for FF).
Anyway, the article above limited itself to 5MP output making it seem that RAW is useless.
I'm always amazed how well lightroom works with my 808 jpegs. It almost (not quite) feels like working with a RAW file. Has anyone else had that experience and how does working with the 808 JPEG files compare to the 1020 RAW files?
Yes. I had the exact same experience using my 808 JPEGs with LightRoom. A LOT of head space is left there, especially when capturing at good/decent light with -0.3 EV set...
To me Out of Camera JPEGs have more contrast in the noise tests and not much, enough, details recovered when using manual noise reduction. With the ACR sharpening you do get a bit more details but it's obviously lost if not used at full 38 MP resolution so not much use other then landscapes. The lack of highlights and even little shadow detail recovery is very disappointing and in my opinion the largest usefulness of Raw makes little to no point in shooting other then JPEG.
I would have liked to see a comparison of manual crop processed RAW to a JPEG zoomed in to maximum to see if we can get more details and better noise when we lose that 38 MP to 5 MP with no down sampling.
If they would recover some more highlights and and shadows in jpeg already like Sony with the automatic dynamic range optimizer RAW becomes more and more useless. I shoot jpegs on all my Sony cameras and if I didn't make really big mistakes in exposure (which thanks to EVF almost never happens) I always like the output. Fuji has the same approach. In camera correction and good jpeg processing, good enough even for professionals.
I really don't see a big market/need for RAW editors for mobile devices
In my opinion, the jpegs are superior. Why bother with raw in this case? There's little or no improvement at all.
based on what I can see from the crops, the out of camera JPG is superior to ACR converted raw with noise reduction. ACR without noise reduction is sharper and has more details than out of camera JPG but then the result seems rather noisy.
Be aware that the 1020's ISO 1600 may be close to ISO 400 on comparable cameras.
Noting that I don't have a camera of any sort on my phone, it's a phone, I too think the jpegs are better than the conversions overall. I'm sure that some minor tweaking with the backlight adjustment in PhotoScape, my default simple and easy to use PES, would bring out similar detail in the "horse tail" image, if editing on my PC. Analysing and editing images like this to a micro level, quickly reaches the point of diminishing returns IMO. So much so that you can easily get to the point where you give up, start over, and get an acceptable result with just a couple of clicks.
I have allready pretty much experience with developing 1020 DNG pictures. I agree in general with the conclusions of this review but like to remark that in ACR you can pull out details from the highlights when you capture your shots at minus 0.7 stop. Of course you should be carefull not to crank up the shadows too much in ACR.
You like in-phone JPEG processing better than the author's.
The tiny gain in DR is priceless. I love it! Thanks for the review.
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Rolex is the most famous luxury watchmaker in the world. They launched the perfect timepiece for yachting professional : The Rolex Yacht-Master II. Featuring the worlds first programmable countdown function with its automatic movement. It is water resistant up to 100m, functions also include hours, minutes and small seconds. Essential Watches are not Authorized dealer of all these brands, but we give "unworn condition" of all these watches. You will get 1 year warrenty on all the unworn conditioned watches.
Rolex Yacht-Master-II Watches | Essential-Watches.comPosted by essentialwatch1 69 days ago (http://www.essential-watches.com)
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Tried to push on to 50K words tonight and end the NaNoWriMo marathon. Wasn't going to happen, life getting in the way and all. One more day, 1245 words to go. Totally need a break from the novel when this is over.
Thoughts, Words, Expression, Articles.
action-adventure historical fiction
Canadian. Gen Y. Opinionated.
Give me a sentence. I'll write you a story.
The writer gives life to a story, the reader keeps it alive.
Musings of a writer, teacher, and student of this remarkable universe.
Jesus, the only security in life
Poetry. Lyrics. Emotions.
It's time to get hella serious about writing!
Asla İdeallerinden Vazgeçme Asla! Never Give Up Your İdeals Never!
Writer, Editor, Bridget Jones Enthusiast
Beauty & Creativity
Has a Mom from Indonesia (Taiwanese Aboriginal Descent), a Dad from America, and a Heart from Writing


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Of what use is philosophy for organizing information? Philosophers aim to clearly articulate problems and possible solutions to those problems. Insofar as any kind of practice is problem-driven, philosophical investigation of those problems can improve understanding and help guide practice. Philosophy does not provide solutions, but it can help practitioners understand their problems better, and it can potentially help them avoid wasting time on nonsolutions.
Furner's (2010) survey of the intersection of philosophy and information studies highlighted several areas of philosophy relevant to and potentially useful for organizing information. Here I focus on an area of philosophy left out of that survey: the philosophy of history. I believe that the philosophy of history is broadly relevant to organizing information. But I have chosen to narrow my focus to a single theoretical idea from the philosophy of history, the idea of colligation. The idea of colligation both clarifies the present understanding of, and suggests possible futures for, the practice of organizing information. If my argument is persuasive, I hope that it will lead to further engagements between the theory and practice of information organizing and the philosophy of history.
The philosophy of history is a rich and varied field. It overlaps with other subdisciplines of philosophy including metaphysics, epistemology, and other meta-disciplinary philosophies such as the philosophy of science and the philosophy of literature. It is also highly interdisciplinary, so much so that some of its most important contributors do not even identify themselves as philosophers, much less philosophers of history (Tucker, 2009). These contributors include philosophically oriented historians who have examined the conceptual underpinnings of their own practice, and literary critics interested in understanding history as a genre of literature.
Rather than attempt to summarize this deep yet fragmented tradition here, I sketch a broad description, before turning to the more specific question of how the idea of colligation is relevant to organizing information. For a general introduction to the field, the article in the Stanford Encyclopedia of Philosophy (Little, 2011) is quite good. The articles in Blackwell's Companion to the Philosophy of History and Historiography (Tucker, 2009) provide a more in-depth survey of past and current issues in the field. Older anthologies of classic works in the field, including Gardiner's Theories of History 1959) and Meyerhoff's Philosophy of History in our Time (1959), can also be useful.
Philosophers of history seek to elucidate the concepts and assumptions implicit in historians' work that usually go unreflected upon by historians themselves. As a systematic examination of historical discourse, philosophy of history is useful for analyzing (the discipline of) history as an information domain (Hjørland & Albrechtsen, 1995). Philosophers of history have examined issues such as how historians turn documents surviving from the past into evidence, how historians make judgments of relevance or significance, the structure and logic of historical explanations, the semantics of historical narrative, the overlap of historiography with the social sciences, the relation of history to cultural memory, and so on. Much of this work is directly relevant to the design and study of organizing systems to support or provide access to historical research, yet few scholars or practitioners of information organizing seem to be aware of it. The exceptions, such as Helen Tibbo in her (1993) work on providing access to historical literature, have demonstrated how the philosophy of history can significantly enrich understanding of the problems of organizing information.
One such problem that has received considerable attention from theorists of information organizing as well as philosophers is the problem of "aboutness." Deciding what a text or other resource is "about" is the central problem of subject analysis. Analytic philosophers have mainly focused on the aboutness of individual sentences (Furner, 2010, pp. 183–185), which is not the most useful angle for organizing information. Philosophers of history, on the other hand, are concerned with the aboutness of whole texts: "The general problem of how complex texts as a whole may account for some part or aspect of the world, may well be best exemplified by historiography" (Ankersmit, 2009, p. 201). This problem is the focus of the theory of colligation and colligatory concepts.


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Recent Movie Reviews
The Takamori Legend
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ninjas ,samerrais ,bloody bits nuff said
Fallen Angel: Teaser
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perfect keep up the good work
movie like guality no flaws execept when you zoomed up on the front when she was running she looked funny. guts were realilistic spatters on the guys visor when he died were top notch if i was a legitimate critic i would give this tailer 2 THUMBS WAY UP AND TOES
The Stick Slayer Slayer
Rated 4 / 5 stars
showed some effort
pretty good on the slayer slayer's moves and animation but the sticks and the other slayer felt that the animation was a tiny bit rushed. even tho they showed no battle damage and needed fighting and blood shedding between the main characters fighting reminded me of those times of me watching hours of dbz (moment of reflecting time...). it was also funni and entertaining.nice sound at battles but note that the clash sequence was way too long between the sword and the pencil. but seeing it was a parody you set it at preety high standards. you spent alot of well spent time on the slayer slayer but not a much on the real slayer and even less on the sticks. I would like to see more of the S3 in the future with more diversity,charecters(the S3 FIGHTING HIS BROTHER??!!) , back rounds(i liked the moving red clouds), AND more action , GOOD JOB
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great sonic game
smooth animation and gameplay
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way 2 hard
its 2 challenging 4 me and the graphiks suck,but great style and concept.
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Sweetness Dude
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Complete feeds, floating sticks for koi, goldfish and other cyprinids kept in garden ponds. Thanks to their special structure the sticks do not sink to the bottom. The feed for the fish is a food right from the nutritional point of view, aiming to satisfy their energy needs. It has got an adequate fiber to ensure healthy digestion.
Ideal for goldfish, koi carp, bleak, tench.


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Jeff Jacobson
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Trail To-Do ListView all 4
4.8 mi 7.8 kmCDT: Schultz Saddle to Johnson Lake (MT Sec. 14)
Hamilton, MT
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18.9 mi 30.4 kmCDT: Chief Joseph Pass to Schultz Saddle (MT Sec. 13)
Salmon, ID
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33.6 mi 54.1 kmPioneer Loop National Recreation Trail #750
Butte-Silver Bow (Balance), MT
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16.7 mi 26.9 kmCurly Lake
Whitehall, MT
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This trail is trashed by motorized trail users. The climb up from curly creek was a good challenge. Motorized use of the trail has resulted in very exposed rocks and roots making it a challenging and fun technical climb, BUT the way down from the summit is totally trashed by moto use. So sad. The trail is eroded, rocks are painfully loose and every switchback is like a sand pit. Our group of 4 with two very experienced riders all felt that trail was trashed.
84 days ago
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When comparing Day of the Tentacle Remastered vs Broken Age, the Slant community recommends Day of the Tentacle Remastered for most people. In the question"What are the best point and click adventure games on PC?" Day of the Tentacle Remastered is ranked 2nd while Broken Age is ranked 8th. The most important reason people chose Day of the Tentacle Remastered is:
The game has a cartoon art style as well as animation that is meticulously detailed without taking shortcuts like reusing frames when a unique one would work better. The game also plays like a cartoon as well, with the same silliness and gags that you would expect from a classic episode of Loony Tunes.
Ranked in these QuestionsQuestion Ranking
Pro Timeless cartoony art style
The game has a cartoon art style as well as animation that is meticulously detailed without taking shortcuts like reusing frames when a unique one would work better. The game also plays like a cartoon as well, with the same silliness and gags that you would expect from a classic episode of Loony Tunes.
Pro Time travel makes you think 4 dimensionally
The major unique gameplay mechanic in DOTT is time travel, which lends much more depth to puzzles. Instead of dealing with one linear feeling storyline, there are 3 different time periods that interact with each other making for more unique gameplay and allows you to attempt many different puzzles in parallel which can interact with each other through the passing of time.
Pro Ridiculous puzzles
DOTT's puzzles are a bit more out there than your typical adventure game flair, but while they'll leave you scratching your head, when you solve them, you wont just feel accomplished, but it will also be hilarious.
Pro Filled with humor
The game often uses gags and jokes that call back to the first time they were told in the game making for a game that points out its own humor through the process of inside jokes to the player. This gives an inclusive feeling to the player, that they are part of the game.
Pro Classic pixel graphics still available
For purists or those that would like to see how the original looked, there is a graphical setting to switch to the original graphics.
Pro Completely new re-drawn graphics
In order to update the game for modern hardware, the graphics have been entirely re-drawn from scratch for HD displays. This makes for a much improved experience in the graphical department that sees a classic improved for modern use. Luckily the new graphics still exude the excellence of the original, meaning there is no loss of quality or feeling of the game.
Pro Polished art design
The graphics, music and voice acting are all top notch. Considering the amount of money this game made through its Kickstarter, it is no surprise the extent of the polish of the game.
Con No hints
There is no in-game hint system to help them when they run into the few unintuitive puzzles, meaning the player will either have to tough it out, or consult an online guide. Both of which can be immersion breaking and disrupts the flow of enjoyment of the game.
Con Some puzzle solutions can be a stretch
Most of the puzzles in the game make sense, with item combinations that one can usually think about coming to a useful conclusion. But some of the puzzles take this a step too far and are not as logical in their conclusions, this can be frustrating for the player and may turn some people off of the game.
The second act of the game has an increasingly incoherent story that explains very little of what is going on. Considering the first act ends with a cliffhanger and many questions to be asked, to see the second half explain almost none of it makes for a frustrating story.


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A product page for the lonf-expected tablet was temporarily listed on the Google Play store a few days ago, claiming the second-generation Nexus 10 would go on sale Nov. 21. However, Google has since deleted the page from its website.
The story was first revealed by Ubergizmo, but the tech web blog has since removed the article about the released date of the tablet.
It's still known a bit about Nexus 10 — though a recent leak revealed that the tabley will come with the same 2560 x 1600 resolution display, a quad-core Qualcomm Snapdragon 800 CPU and 3GB of RAM.
The new device was rumored to run Android 4.4 Kit Kat, the latest version of the populat operating system that is now available for most other Nexus tablets.
As The International Business Times informs, the Google Nexus 10 is originally priced $399 for the 16GB wifi model and Staples' discount will bring it down to $349. The 32GB model costs $499 and will now cost $449.
The tablet launch is predicted to be held alongside with some other major news of the Internet searching giant, however, with Google reportedly planning to shedlight on some important changes on the way tablet apps are discovered and displayed on company's Google Play.
Two weeks ago Google unveiled its latest flagship Android smartphone, the 5in Nexus 5 that comes running the next iteration of Android 4.4 "Kitkat".
Google developed the device in partnership with LG, which is the slimmest, fastest Nexus phone yet. The screen offers 445 ppi, while the device measures 69.17×137.84×8.59 mm and weighs 130g.
The smartphone features a 4.95-inch, 1,920-by-1,080 full HD IPS Corning Gorilla Glass 3 display with 445 pixels per inch. It runs a 2.3GHz Qualcomm Snapdragon 800 chip, 450MHz Adreno 330 GPU.
The phone comes loaded with the new version of Google's operating system — 4.4, nicknamed KitKat — which will also become available for some other Android phones.
The Nexus 5 includes a 1.3-megapixel front-facing camera and 8-megapixel rear shooter with optical image stabilization.
With a 2,300 mAH battery, Google promised up to 17 hours of talk time, 300 hours of standby, 8.5 hours of Internet time on Wi-Fi and 7 hours on LTE. If you need more, the Nexus 5 includes built-in wireless charging support.
Speaking of Android Kit Kat which will probably be featured on the Nexus 10, Android chief Sundar Pichai said: "The first thing you'll notice about KitKat is we've made the experience much more engaging: the book you're reading, the game you're playing, or the movie you're watching—now all of these take center stage with the new immersive mode, which automatically hides everything except what you really want to see."
Google is known for naming its mobile software after different types of desserts. Past names have included Cupcake, Donut, Honeycomb, Jelly Bean and now KitKat. Earlier this year the tech giant and Nestle struck a marketing deal naming the new software after the candy bar.


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The recently developed DNA microarray technology provides a powerful and efficient tool to rapidly compare the differential expression of a large number of genes. Using the DNA microarray approach, we investigated gene expression profiles in cultured human aortic endothelial cells (HAECs) in response to 24 h of laminar shear stress at 12 dyn/cm2. This relatively long-term shearing of cultured HAECs led to the modulation of the expression of a number of genes. Several genes related to inflammation and EC proliferation were downregulated, suggesting that 24-h shearing may keep ECs in a relatively noninflammatory and nonproliferative state compared with static cells. Some genes were significantly upregulated by the 24-h shear stress; these includes genes involved in EC survival and angiogenesis (Tie2 and Flk-1) and vascular remodeling (matrix metalloproteinase 1). These results provide information on the profile of gene expression in shear-adapted ECs, which is the case for the native ECs in the straight part of the aorta in vivo.
- DNA microarray
- endothelial cells
- gene expression
- shear stress
the regulation of gene expression in physiological and pathophysiological conditions is a fundamental problem in health and disease. With conventional molecular biological or biochemical approaches, studies on regulation of expression can be conducted on only a small number of the genes. Advances in molecular genetics and computational biology have led to the development of innovative methods to analyze differential gene expression profiles. DNA microarray technology represents a powerful tool for rapid, comprehensive, and quantitative analysis of gene expression profiles of normal/disease states and developmental processes (44, 45). This technology has been successfully applied to studies in many conditions, e.g., gene expression of yeast cell cycle regulation, human breast cancer development, human inflammatory diseases, and the transcriptional program of human fibroblasts in response to serum stimulation (22, 26, 38, 48).
Hemodynamic forces regulate the structure and function of the blood vessel wall. The endothelial cells (ECs) lining the blood vessels are exposed to the shear stress resulting from the tangential forces exerted by blood flow. Previous in vitro and in vivo findings have shown that a sudden onset of shear stress activates EC signaling pathways and modulates EC gene expression (for review see Refs. 5, 7, 19, 24). In these studies, the flow-modulated genes have been investigated mainly by using Northern blotting to detect the expression of mRNA, and the translated proteins have been detected by the use of immunoblotting, enzyme-linked immunosorbent assay (ELISA), or radioimmunoassay (RIA). There have been efforts to compare the shear stress-induced gene regulation by using the differential display strategy (3, 50). Although differential display is useful for the identification of shear-stress-responsive genes, it can only cover a limit number of genes, with laborious procedures and relatively low reproducibility. The DNA microarray technology provides an efficient tool to rapidly compare the differential expression of a large number of genes in a single test, and this is ideally suited for studying the pattern of gene expression in ECs induced by various experimental conditions (4).
There is increasing evidence that the gene expression induced by laminar shear stress is time dependent. The sudden application of shear stress to ECs previously in static culture causes the transient activation of a large number of genes, but most of these genes become downregulated during the sustained application of shear stress, e.g., for 24 h (5). In the current study, we used the DNA microarray technology to investigate the EC gene expression profiles in response to 24-h shear stress. The aims are to confirm and expand previous knowledge with this relatively new technology for the elucidation of the genomic programming of shear-adapted ECs.
Cell culture.
Human aortic endothelial cells (HAECs) derived from an adult female donor were obtained from Clonetics (San Diego, CA) and cultured in Endothelial Cell Growth Medium-2 (EGM-2) supplemented with 2% FBS, hydrocortisone, human fibroblast growth factor-β (hFGF-β), vascular endothelial growth factor (VEGF), R3-insulin growth factor (R3-IGF-1), ascorbic acid, human epidermal growth factor (hEGF), GA-1000, and heparin (Clonetics). To maintain the same culture environment, the flow experiments (Shear stress experiments, below) were performed by using the same culture medium as in the static culture, with the aim of avoiding the possible effects of growth factors on gene expression. Cell cultures were maintained in a humidified 95% air-5% CO2 incubator at 37°C. All cells were cultured to passage 3 and kept frozen in liquid nitrogen. The cells were then thawed and further cultured for two more passages to obtain sufficient cells for each experiment. All experiments were conducted with HAECs in passage 5.
Shear stress experiments.
A flow system was used to impose shear stress on cultured ECs as described by Frangos et al. (15). In brief, a 10 × 8-cm glass slide seeded with a confluent monolayer of HAECs was mounted in the flow channel created by sandwiching a silicone gasket between the glass slide and an acrylic plate, with inlet and outlet for exposing the cultured cells to the shear stress imparted by flow. The channel has dimensions of 0.25 mm in height, 6 cm in width, and 7.5 cm in length. A laminar shear stress of 12 dyn/cm2 was generated by the flow resulting from a hydrostatic pressure difference between two reservoirs. This level of shear stress is encountered under physiological conditions in the straight part of the aorta and frequently used to study the effects of shear stress on ECs. The flow system was kept at 37°C and ventilated with 95% humidified air and 5% CO2. The same batch of HAECs at passage 5 was used for three independent shear experiments.
cDNA labeling, microarray, hybridization, and imaging.
Three independent sets of experiments were performed, each consisted of an experiment with HAECs subjected to 24-h shear stress and a paired control experiment with HAECs kept under static condition for 24 h. In each experiment, the total RNA was isolated by using STAT60 total RNA purification reagent (TEL-TEST "B"). The cells were lysed in phenol-containing STAT60 solution and centrifuged. The RNA-containing aqueous phase was isolated, and 0.6 vol of isopropanol was added to precipitate RNA. Thirty micrograms of total RNA was subjected to reverse transcription (RT) reaction and [33P]dCTP labeling using an Atlas Pure Total RNA Labeling System (Clontech). The 33P-labeled cDNA was hybridized to Atlas Human Cancer 1.2 arrays at 68°C for 16 h, followed by washing once in 2× SSC/1% SDS at 68°C for 30 min and three times in 0.1× SSC/0.5% SDS at 68°C for 30 min. The hybridized array was then exposed to Phospho Storage Screen (Molecular Dynamics), and the images were analyzed and quantified by using an AtlasImage 1.01 software (Clontech) to quantify the intensity of each of the 1,185 spots. The Atlas 1.2 array was chosen because it contains many genes involved in growth, proliferation, cell cycle regulation, cell structure remodeling, and inflammatory responses, as well as signal transduction, which were the functions of interest in our investigation. Furthermore, it does not require too much RNA for the hybridization and it is relatively inexpensive.
Data analysis and statistics.
Each Atlas 1.2 array consists of four separate filters. Two filters from each set were used to perform the experiments reported in this study, one for static condition and another for 24-h shearing; the other two filters were used for other experiments. A total of three sets of filters were used, thus providing three sets of experimental data, each with a static and a shear experiment from the same set of filters. The background was determined from the intensity reading around the spotted areas by using the AtlasImage Software and subtracted from the reading of the spot. Comparisons were made between the static and shear filters from the same set; the results obtained from each filter were normalized by using the mean intensity as the reference, i.e., global normalization. The normalized results of the sheared and static filters from the same set were used to calculate the ratio for each gene in each set. The ratios for each gene from three independent experiments (i.e., for the three sets of filters) were used to perform paired Student's t-test to assess the significance of the difference of the mean ratio from unity. A P value of 0.05 or lower was taken to indicate a statistically significant difference of the shear/static ratio from unity. No normalization was performed between filters. The shear/static ratios are reported as means ± SE.
RT-PCR was carried out by using the following procedures. For RT reaction, 5 μg of total RNA and 0.5 μg of oligo(dT) in 20 μl diethyl pyrocarbonate-H2O were incubated at 70°C for 5 min, and cooled slowly at room temperature for 10 min. To synthesize the first-strand cDNA, 2.5 μl of 10× first-strand buffer, 0.5 μl of RNase inhibitor (40 U/μl), 1 μl of 100 mmol/l dNTPs, and 0.5 μl of Moloney murine leukemia virus reverse transcriptase (50 U/μl) were added. The samples were incubated at 37°C for 1 h, and then at 90°C for 5 min to stop the reaction. Volumes of 0.1 or 0.5 μl of each RT reaction were mixed with 50 μl of a PCR mixture containing 1× PCR buffer (GIBCO BRL), 1.5 mmol/l MgCl2, 200 μmol/l dNTPs, 30 pmol each of 5′ and 3′ primers, and 2.5 U of Taq DNA polymerase (GIBCO BRL). The PCR reaction was carried out by heating for 3 min at 94°C, followed by 20 to 35 cycles of denaturation (94°C, 45 s), annealing (range from 55 to 60°C, 45 s), and extension (72°C, 1 min), and subjected to final extension for 10 min at 72°C using a Primer 96 thermocycler (MHG Biotech). The PCR products were analyzed by 1% agarose gel electrophoresis. Because of variations in the abundance of mRNA of different genes in the cell, the PCR cycles and titrations of RT reaction were varied to ensure that the PCR reaction was in the linear range.
Northern blot analysis.
The microarray results were selectively confirmed by Northern blot analysis. The cDNA fragments of the selected genes were used as probes labeled with [32P]dCTP by random primer labeling. Northern hybridization was performed according to standard protocol (43). Twenty micrograms total RNA from static or sheared samples was electrophoresed on a formaldehyde-containing 1.5% agarose gel. The RNA was transferred to a nylon membrane for hybridization with the 32P-labeled cDNA. The hybridized RNA was detected by autoradiography.
The results of statistical analysis showed that 125 genes have a significant difference (P ≤ 0.05) between the sheared and static samples (Table 1). Among these 125 genes that showed a statistically significant difference, none increased to threefold or higher, and two decreased to one-third. One gene increased to more than twofold, and 18 decreased to one-half. Fifteen genes increased to 1.5-fold or more, and 53 genes decreased to 1/1.5 (i.e., 0.67) or less. A feature of this study is that statistical analysis is performed to assess the significance of the difference, rather than using an ad hoc ratio such as twofold or threefold as a cutoff threshold. The use of a "fold of change" as a cutoff becomes necessary in the absence of statistical evaluation. It is also to be noted that, by taking the mean values from three experiments, the range of changes in the present study tended to be smaller than those in which a single experiment was performed. Another reason for fewer genes to show modulations at 24 h is that shear stress causes many genes to be transiently activated and then returned to the baseline level with sustained shearing (5).
The results on some of the genes that show a statistically significant difference between the sheared and control samples are discussed below according to their functional categories.
Shear stress regulates the expression of genes related to inflammation.
Exposure of ECs to proinflammatory cytokines [such as interleukin-1 (IL-1) and tumor necrosis factor (TNF)] results in the modulation of "prothrombotic-proinflammatory" program (31, 32). In the current microarray study, several proinflammatory and prothrombotic genes were significantly downregulated by 24-h shear stress, including MYD88 (0.37 ± 0.15, an adapter protein essential for signaling via the IL-1 receptor), CD30 ligand (0.44 ± 0.12, a member of the TNF superfamily and an inducer for T-cell proliferation), and platelet basic protein (0.47 ± 0.06, PBP, a chemokine for neutrophils and monocytes). Using RT-PCR analysis (Fig. 1A), we confirmed the decreased expressions of MYD88, CD30 ligand, and PBP genes in response to 24-h shear stress. The downregulation of MYD88 has been confirmed by Northern blotting (Fig. 2). In addition, we found that the expression of IL-1 receptor antagonist protein (0.51 ± 0.10), thymus-expressed chemokine (0.54 ± 0.07), IL-14 (0.64 ± 0.08), and IL-15 (0.67 ± 0.06) were also downregulated in response to 24-h shear stress, although to lesser degrees than the other cytokines mentioned above. The expression of other cytokines-related genes showed no significant change in response to 24-h shear stress. The only inflammation-related gene that showed an upregulation in response to 24-h shear stress is the IL-13 receptor gene (1.85 ± 0.21). It is interesting to note that IL-13 receptor and its ligand IL-13 have been implicated in anti-inflammatory responses (31, 51).
Shear stress regulates the expression of genes related to EC cell proliferation.
DNA microarray results indicate that most of the genes encoding cell cycle regulation proteins, such as cyclins A, B, and D, and most cyclin dependent kinases, were not significantly modulated by the 24-h shear stress. However, 24-h shear stress did cause significant increases in the G1/S-specific cyclins C (1.88 ± 0.08) and E (1.78 ± 0.18). Several EC growth factors were significantly downregulated by 24-h shear stress; these include bone morphogenetic protein 4 (BMP4, 0.36 ± 0.14), transforming growth factor-β2 (TGF-β2, 0.42 ± 0.05), hepatoma-derived growth factor (HDGF, 0.48 ± 0.08), and FGF6 (0.54 ± 0.09).
Shear stress regulates the expression of genes related to EC remodeling.
Shear stress plays an important role in modulating EC morphology, cytoskeleton, and extracellular matrix (ECM) remodeling (7). In our microarray study, a few cytoskeleton- and ECM-related genes were downregulated by the 24-h shearing, e.g., cytokeratin 4 (0.34 ± 0.04), cytokeratin 2E (0.37 ± 0.10), microtubule-associated protein (0.53 ± 0.11), laminin-α4 (0.54 ± 0.08), and integrin subunits β3 (0.54 ± 0.06) and α7b (0.55 ± 0.08). The expression of matrix metalloproteinase-1 (MMP1 or interstitial collagenase) was significantly upregulated (2.77 ± 0.35) in response to the 24-h shear stress, and this was confirmed by RT-PCR and Northern blotting (Figs. 1B and 2). The expression of MMP3 has been shown to be regulated in parallel to MMP1 in many different experiment settings (33, 34). However, the 24-h shearing did not affect the expression of MMP3 (0.94 ± 0.23) nor the metalloproteinase inhibitors TIMP1 (1.04 ± 0.14) and TIMP2 (0.81 ± 0.05).
Shear stress regulates the expression of genes related to signal transduction.
Shear stress, like chemical stimuli, induces many signaling pathways in ECs to modulate vascular biology (7). Our microarray expression study has shown that 24-h shear stress causes the selective modulation of a few signaling molecules. Two endothelium-specific receptor tyrosine kinases were significantly upregulated, i.e., Tie2, which is angiopoeitin-1 and -2 receptor (1.90 ± 0.01), and Flk-1/KDR, which is VEGF receptor 2 (1.51 ± 0.02). These increases were confirmed by RT-PCR analysis (Fig. 1C). Tie2 and Flk-1 have been shown to play important roles in vasculogenesis during embryonic development and the subsequent angiogenesis (14, 39). Endothelin-3 was downregulated by 24-h shear stress (0.52 ± 0.11).
The expression of caveolin-1, another signaling molecule, was significantly downregulated (0.42 ± 0.04) after 24 h of shearing, and this was confirmed by the RT-PCR analysis and Northern blotting (Figs. 1C and 2).
Other genes affected by 24 h of shear stress.
As shown in Table 1, the expression of several transcription- and metabolism-related genes was also modulated by 24-h shear stress, with most of them being downregulated. In addition, 24-h shear stress also modulated the expression of genes involved in RNA splicing (suppressor for yeast mutant, arginine/serine-rich splicing factor 8), protein translation and transportation (RNA binding protein PPTB-1, elongation factor 2, importin α3), development (lunatic fringe), and redox response (glutathione-S-transferase homolog, glutathione synthase), as well as some genes with unknown functions.
DNA microarray provides a powerful and efficient tool by which to compare the differential expression of a large number of genes in a single reaction and enables a systematic analysis of cellular responses of gene programming to experimental conditions. The results of DNA microarray studies not only provide quantitative information on genomic programming, but also allow the deduction of information on relevant cellular functions for the pursuit of in-depth studies on selective genes. The information on cardiovascular gene expression profile obtained from DNA microarray studies can direct our attention to previously unknown or ignored genes for the performance of further analysis to decipher their potential functions. Such investigations can lead to new experimental analysis to unravel the complex regulatory mechanisms in physiological and pathophysiological conditions.
Fluid shear stress exerts many effects on vascular ECs and plays an important role in maintaining the homeostasis of blood vessels. It has been shown that shear stress modulates the expression of EC genes encoding growth factors, adhesion molecules, coagulation molecules, chemoattractants, proto-oncogenes, and vasoactive substances (5, 7). For example, the platelet-derived growth factors (PDGFs), intercellular adhesion molecule-1, monocyte chemotactic protein-1 (MCP-1), and c-fos genes are all transiently upregulated by shear stress (23, 35, 42, 46). However, most of these studies reported the effects of short-term shear stress, which are different from those of longer periods of shearing. We have performed some preliminary studies using the same Atlas 1.2 Cancer array, on the short-term (1 h) effect of shear stress on gene expression profile. The results show an induction of genes such as PDGF A, PDGF B, EGF, tissue plasminogen activator (tPA), c-jun, and c-fos at this early time point, as previously reported in the literature. In addition, genes such as IL-1, IL-6, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and actin did not show a modulation by shear stress, as found in previous studies on individual genes.
Prolonged shearing can decrease EC turnover, including cell proliferation and apoptosis (1, 11, 12, 29). Since relatively long periods of shearing is more relevant to the flow condition in the athero-resistant, straight parts of the arterial tree, the current study focused on the effects of 24-h shear stress on the gene expression profiles in HAECs. The aim is to elucidate the genomic programming of ECs in response to sustained shear stress.
Long-term shear stress decreases EC DNA synthesis and arrests EC cell cycle at G1/G0 phase (6, 10, 29, 36). One of the mechanisms for the shear stress-induced EC arrest was through the posttranslational modifications of Rb and p53 (29). Indeed, the transcription levels of Rb and p53 were not affected in our DNA microarray study. Our findings that 24-h shear stress downregulates the expression of many cell proliferation genes, notably the genes related to growth factors (e.g., BMP4, TGF-β2, HDGF, and FGF6), suggest that autocrine/paracrine mechanisms may be involved in the shear stress-induced EC growth arrest.
Two EC survival genes, Tie2 and Flk-1, are upregulated by the 24-h shear stress. Tie2 has been shown to be expressed not only in embryonic vasculogenesis and subsequent angiogenesis, but also in the entire adult vasculature (arteries, veins, and capillaries). It has been suggested that Tie2 plays an important role in the maintenance of the normal function of the adult quiescent vasculature (53). Both Tie2 and Flk-1 are connected with the downstream phosphatidylinositol-3-kinase (PI3K)/Akt survival pathway (18, 27). Thus the increased expressions of Tie2 and Flk-1 in response to 24-h shear stress may enhance the activity of their downstream PI3K/Akt pathway to promote EC survival.
Our findings of the downregulation of a number of inflammatory genes, including MYD88, CD30 ligand, PBP and several cytokines, indicate that shear stress may antagonize inflammatory responses through such gene modulation. Activation of the IL-13 pathway has been shown to decrease the expression of pro-inflammatory cytokines and chemokines (51). Therefore, the upregulation of the IL-13 receptor in response to 24-h shear stress also would lead to an anti-inflammatory action. Cytokines-mediated activation of ECs in many physiological or pathophysiological processes may enhance the interaction between EC and immunocompetent cells (e.g., monocytes) and lead to the disorganization of EC cell junctions to increase the passage of macromolecules such as low-density lipoprotein (LDL) (8, 9, 52). By decreasing inflammatory responses, shear stress could prevent the induction of the atherogenic "prothrombotic-proinflammatory" program and promote the normal function of ECs as a permeability barrier and nonthrombogenic surface lining the vascular wall (32).
In vivo and in vitro studies have suggested that shear stress promotes angiogenesis (2). In the current study, several lines of evidence are consistent with this concept. First, as mentioned above, 24-h shear stress upregulates the endothelium-specific Tie2 and Flk-1 receptor tyrosine kinases, which play crucial roles in both vasculogenesis and angiogenesis (14, 39). Second, the expression of MMP1 is upregulated in response to 24-h shear stress. Collagen is a major secreted ECM protein in the blood vessel. The degradation of collagen by MMP1 may initiate and promote angiogenesis (21, 25). Third, the expression of caveolin-1 is downregulated by 24-h shear stress. It has been shown that angiogenesis inducers [VEGF, basic FGF, hepatocyte growth factor (HGF)] cause dramatic reduction of the caveolin-1 mRNA level in human umbilical vein ECs (HUVECs) and that angiogenesis inhibitors block the VEGF-mediated downregulation of caveolin-1 (30).
Consistent with the current microarray result of the downregulation of caveolin-1 by 24-h shear stress, we have also found that immunostaining of caveolin-1 in cultured bovine aortic ECs decreases upon 24-h shear stress (S. Li and S. Chien, unpublished results). Caveolin-1 is the essential component for assembling the plasma membrane caveolae structure, which has a lipid-ordered membrane domain mainly composed of cholesterol and sphingolipids and has a rich content of signaling molecules (47). It has been proposed that the caveolae function as signaling centers or scaffolds for the preassembly of signaling complexes and the cross talk between various signaling pathways (47). Caveolin-1 also plays an important role in the interaction and recruitment of signaling molecules (37). The decreased expression of caveolin-1 in response to 24-h shear stress may lead to the decreases of caveolae structure and preassembled signaling complexes on the EC surface. Consequently, this could keep ECs in a less active state in their response to various forms of stimuli.
Long-term exposure of ECs to shear stress has been shown to cause the elongation and alignment of ECs along the flow direction, with rearranged microfilaments and focal adhesion sites, attenuated cortical F-actin, and enhanced central stress fibers (20, 28). Our microarray results showed that the expression of the majority of cytoskeleton- and ECM-related genes was not affected by 24-h shear stress. It is likely that shear stress induces cytoskeleton and ECM reorganization at the protein level, rather than the transcription level. Another possibility is that after 24-h exposure to shear stress, ECs have already adapted to the shearing condition, and the remodeling events have subsided. Our results did show the downregulation of a few genes encoding cytoskeleton/ECM proteins and integrins by 24-h shear stress. It remains to be established whether the downregulation of these genes plays a role in the shear stress-regulated EC remodeling.
In the current study, MMP1 is the only cytoskeleton/ECM-related gene significantly upregulated by 24-h shear stress. There is evidence that MMP1 may be involved in EC migration and wound healing. Shear stress can enhance EC migration and wound healing in both animal studies and cell cultures (40, 49, 54). MMP1 has been shown to promote wound healing by facilitating keratinocyte migration over the collagen-rich dermis during re-epithelialization (16). Hence, the increase in MMP1 expression by shear stress would be beneficial for EC migration and wound healing. In addition, Tie2 and Flk-1 have been connected to the PI3K signaling pathway, which not only plays a role in cell survival, but also is involved in cell migration. PI3K has been shown to be upstream of the Rho family small GTPases (13, 16). Through its regulation of Rho family GTPases, PI3K affects actin polymerization and focal adhesion formation and consequently influences cell migration (41). Taken together, the upregulation of MMP1, Tie2, and Flk-1 could be synergistic in promoting EC migration and wound healing under long-term shear stress.
There had been relatively little information on the effects of prolonged shear stress on gene expression. During the revision of this manuscript, the report by Garcia-Cardena et al. (17) was published to provide for the first time extensive information on the modulation of EC gene expression by 24-h shearing. They also found that the majority of the gene expression remained unchanged after 24-h laminar shear stress. They reported a set of experiments that consisted of control, laminar shear, and turbulent flow; no statistical analysis was given in the report. A number of the genes that showed a twofold change in Ref. 17 in response to laminar shear were not present in the microarray used in the present study. For example, the genes related to nitric oxide synthase-associated regulatory factors, which are important to understanding vascular tone regulation and other functions, were not present in the Atlas filter. Some of the genes, however, were common to both studies. Laminar shear stress (24 h) caused an increase of MMP1 in both studies. Rb binding protein 2, FGF receptor 3 precursor, CRM1 protein, and BRCA2 decreased in both studies. Thus some of the changes in gene expression are in the same direction, but others are not. By using a twofold change as a criterion, Garcia-Cardena et al. (17) found a shear-induced upregulation of fibronectin precursor, thioredoxin reductase, osteonectin, and protein tyrosine phosphatase. In the present study, however, these genes either did not show a statistically significant change.
In comparing the results of these two studies, we must note several differences in materials and methods. Garcia-Cardena et al. (17) used HUVECs, whereas we used HAECs derived from an adult female donor. The difference in the origin of cells and also the use of growth factors at various concentrations may contribute to differences in expression of genes. As mentioned above, the gene list used as probes were different between the two studies, and even genes with the same name may have different portions of the sequences. Garcia-Cardena et al. (17) used a microarray with a large number of genes to conduct a set of experiments on control, laminar flow, and disturbed flow, whereas we used a much smaller microarray but performed statistical assessment of significance of differences on three sets of experiments on laminar flow and control. These differences in materials and methods, may contribute to the discrepancies in the results obtained in the two studies. With the DNA microarray technology being in its early development stage, there is a need to conduct and report results under different conditions, but each one must be clearly documented for future data mining and bioinformatic analysis.
In the living cardiovascular system, the shear condition may be the normal situation and the absence of shear may be the pathological situation. Thus the straight part of the aorta, which is continuously exposed to laminar shear stress, is generally spared from atherogenesis; in contrast, areas with disturbed flow or low flow are the areas with predilection. It is interesting that Garcia-Cardena et al. (17) found similar gene expression patterns for disturbed flow and static condition, both being different from 24-h laminar flow. Therefore, although this report uses the static value as a control, perhaps one should take the view that the results obtained under shear are the reference and the absence of shear represents a deviation from the norm.
We investigated the effects of 24-h shear stress on gene expression profiles of cultured HAECs by using the microarray technique. We report that 24-h shear stress significantly modulates EC gene expression related to inflammatory cytokines, cell proliferation, ECM/cytoskeleton remodeling, and signal transduction. The results suggest that relatively long-term shear stress inhibits EC turnover and inflammatory responses, thus keeping ECs in a relatively noninflammatory and nonproliferative state to maintain their normal function as a permeability barrier and nonthrombogenic surface. Our results also provide evidence that 24-h shear stress promotes angiogenesis, EC remodeling, and migration, which would facilitate vascular formation and remodeling. (For detailed information and databases of the current study, please refer to the Supplementary Material1 for this article, published online at the Physiological Genomics web site.)
This work is supported by National Heart, Lung, and Blood Institute Grants HL-19454, HL-62747, and HL-64382 (to S. Chien), by HL-56707 and HL-60789 (to J. Y-J. Shyy), by National Institute of Environmental Health Sciences Superfund Grant ES-10337, and by a gift from the Cho Chang Tsung Foundation of Education.
↵1Supplementary Material to this article is available online at http://physiolgenomics.physiology.org/cgi/content/full/7/1/55/DC1.
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).
Address for reprint requests and other correspondence: S. Chien, Dept. of Bioengineering and the Whitaker Institute of Biomedical Engineering, Univ. of California, San Diego, Mail code 0427, 9500 Gilman Dr., La Jolla, CA 92093-0427 (E-mail: schien{at}bioeng. ucsd.edu).
- Copyright © 2001 the American Physiological Society


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Embassy stories, books, poems, and more
3 results
Related Tags:embassy, art, centre, consulate, curator, detective, ecoterrorism, environment, equestrian, estuary, explosion, iceland, journey, museum, norway, nubian, old embassy, racism, rats, seattle, sinister, tigers, underground, van gogh
Short Story / Mystery and Crime
July 10, 2012
Det. Michael LaTour, recently fired from the Seattle Police Dept., teams up with an attractive museum curator to uncover and thwart an art theft ring. Read More
Short Story / Action and Adventure
February 20, 2011
The American Embassy in Ecuador has been blown up by a groups of terrorists. Sarah and Brian attend to the injured while CIA agent George investigates the incident. Who blew up the Embassy and why did they do it? Read is rivetting story to find out. this story was brought… Read More
Tags: environment, explosion, centre, equestrian, embassy, estuary, ecoterrorism
August 06, 2008
This is only PG because I know some quite young people can be every easily scared, and a lot of people don't like rats. Originally this was started as a joke with a few friends, but then I used it for school work as well and I am generally quite… Read More
Tags: journey, sinister, rats, old_embassy, embassy


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Serves: 10
Time to make: 30 mins, plus overnight drying
Total cost: $0.60 / $0.06 per serve
1 cup icing sugar
4 teaspoons trim milk
1/2 teaspoon green food colouring (optional)
1/4 teaspoon peppermint essence
extra 1/3 cup icing sugar, for dusting (do not mix it with the rest)
Step 1 Mix icing sugar, milk, food colouring (if using) and essence until they stick together. Add more milk if the mixture is too powdery. Add more sugar if it's too moist.
Step 2 Dust the kitchen counter and rolling pin with icing sugar. Roll the mixture until it's as thick as your little finger.
Step 3 Dip the cutter in icing sugar and cut out small shapes (circles work best). Rework the scraps until all the mixture is used.
Step 4 Set peppermint creams on wax paper to dry overnight. The following morning, turn them over to dry the underside.


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Monday, January 28, 2008
Fritz the Cat
Fritz the Cat has been one of my very favorite movies for years. It's got so many pluses that make it worth watching again and again. It's got fascinating animation which is beyond cartoonish in its intermittent psychedelic sequences. It's got a great soundtrack. It's got a great story that is both comedic and moralistic (sort of), especially for a film that actually became the first animated motion picture to receive an X rating. Therefore, like most of the content on Cultarama, it really shouldn't be shown to kids, even if it is animated. It also received the honor of becoming the first independent film to gross over a million dollars. The character of Fritz the Cat was actually a character created by Robert Crumb who's "Keep on Truckin'" logo became part of the 60's. In fact the entire movie really captures the feel of the late 60's which is when it was being made, despite a 1972 release. Robert Crumb never gave the producers of the movie any rights or permissions to use his characters and actually sued to have his name removed from the credits. Crumb even went so far as to kill off Fritz the Cat in his comics so as to discourage another film. It didn't work, a sequel named "The Nine Live of Fritz the Cat" was released the following year. The story takes us through Fritz's adventures as he strolls through the major themes of the late 60's... orgies, drugs, religion, music, activism, etc. Even though it's rated X doesn't mean it's a porno, and especially by today's standards, far from it. It's just a great adventure story told by one of the most suave cool cats you'll ever meet. Plus a myriad of other colorful characters. All animals of course, but appropriate animals (cops are pigs, black people are crows, shady activists are lizards, Jews are old lions, the list goes on and on). This is a true classic and doesn't just deserve to be watched, it demands to be owned. It just made it to DVD so you have no excuse not to go out and get your copy!! An interesting side note to this movie is towards the end of the film when the activists are plotting to "make a statement" (blowing something up, I think). The makers of the movie invited real militants and activists into the recording studio and just recorded whatever they talked about. This actual dialogue recording was edited and used as the dialogue of the shady activists in the movie.
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The Baker Group
Week in Review: December 6, 2013
Surprises to the upside are almost always well received. Like getting a Baker's dozen at the Crispy Creme, or finding a good parking spot downtown. [Last] week's slate of economic releases contained a few upside surprises of its own. Nothing quite on the same order as discovering there's an extra glazed donut in the box, but still some pretty good news. [Friday] morning, in the Bureau of Labor Statistics' monthly employment report, we learned that the Unemployment Rate fell to 7% from October's 7.3%. That's a five year low.
MBS Market Strategies
Week in Review: August 23, 2013
It might very well be that the most significant, market-moving event of the week actually happened last month. With [last] Wednesday's release of the FOMC's minutes from their July meeting, the Fed disappointed many, if not most, market participants who thought they would be getting some clarity about Chairman Bernanke's tapering intentions. Well, if they'd been thinking, they wouldn't have thought that.
Week in Review: August 6, 2013
Edward Snowden is not the only one for whom [last week] was a big week. For those not seeking political asylum, [last] week was filled with market-moving statistics and events. Just [Friday] morning, the always much anticipated Employment Report from the Bureau of Labor Statistics (BLS) was unleashed on a marketplace expecting to see a 185k increase in Non-Farm Payrolls. What they got was a less-than-robust gain of 162k new jobs along with a downward revision of last month's figure. The 195k jump in new jobs that was reported in July was actually only 188k.
Special Baker Group Report
Information received since the Federal Open Market Committee met in June suggests that economic activity expanded at a modest pace during the first half of the year. Labor market conditions have shown further improvement in recent months, on balance, but the unemployment rate remains elevated. Household spending and business fixed investment advanced, and the housing sector has been strengthening, but mortgage rates have risen somewhat and fiscal policy is restraining economic growth.
Week in Review: July 26, 2013
With [Friday] morning's release of the University of Michigan's Index of Consumer Sentiment showing a rise to 85.1 from 83.9, one wonders if survey takers might have taken a detour around Detroit. Apart from the financial maladies that plague that beleaguered municipality, a rosier outlook was also manifested by the 8.3% rise in New Home Sales, which more than made up for the 1.2% decline in Existing Home Sales. As far as prices are concerned, the FHFA House Price Index rose by .7% in May.
Week in Review: July 23, 2013
In his two days of Congressional testimony this week, Fed Chairman Ben Bernanke, excluded from Fifth Amendment protection, used the legislative forum to continue to downplay the perception that it is the FOMC's intention to begin a "tapering off" of their $85B monthly bond purchases. Mr. Bernanke took the opportunity to assure market participants that monetary policy will be "highly accommodative for the foreseeable future." The question then becomes, just how far can Ben foresee? He also reiterated that the future direction of monetary policy is not...
Week in Review: July 12, 2013
For those who were lucky enough to be a teenager during the 70's, you may recall the urban myth surrounding everybody's favorite rock band, Led Zeppelin. It was rumored that if one played "Stairway to Heaven" backwards, at high speed, hidden messages could be detected. Well, coming from one who tried to find those hidden messages, they were never discovered and all I succeeded in doing was scratching up my favorite album. Now, I realize that some readers won't know what a record album is, but that's beside the point.
Week in Review: June 28, 2013
From a galloping horse, one might be hard pressed to see what Ben Bernanke and Paula Deen have in common. Both, it seems, have had difficulty lately in being understood by their respective followers. For Ms. Deen, the problem may lie with her message; for Mr. Bernanke, the problem may lie with his audience. Ben's audience, which is pretty much everybody, seems to have heard things that were never actually said. So, it's been an interesting week as a veritable Murderer's Row of Fedspeakers have gone to great lengths to clarify the Chairman's previous clarification.


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If you haven't checked out Inside the Exorcist, now's the time. The series is in the top 10 on Apple Podcasts (as of this writing). And it's a solid #1 in the Movie/TV category. And it has been getting some glowing reviews, including this one from the movie/TV industry publication Indiewire: So listen here and subscribe. And please take a few moments to give the series a rating on Apple Podcasts or wherever you consume your podcast content. As you know, these efforts help surface the show to more listeners. … [Read more...]
Tag: mark ramsey
Hear "Inside The Exorcist" Today!
Today is the day. It's the day that the first two episodes of my new series for Wondery, Inside the Exorcist are released. Drop whatever you're doing and subscribe here. Why should you listen? Because the series is really, really good. And because if you enjoyed my previous series, Inside Psycho, you're going to like this one even more. This is the kind of audio that helped make radio famous once upon a time. And today it's driving new interest in the on-demand category. Inside The Exorcist is a 7-part deep-dive into the backstory of the people who made the classic The … [Read more...]
Media Unplugged: Apple's TV Strategy Revealed
Apple's TV strategy revealed! And... Video wins online - but where's the money? Plus, rants and raves about Dyson's move into electric vehicles, the scale of Amazon's investment in Alexa, 12 questions that will change your life, and my own new podcast about the people and the making of the movie The Exorcist. It's episode 72 of Media Unplugged with branding authority Tom Asacker and media strategist Mark Ramsey. Listen as we go inside media to reveal the ugly truth! Click the play button below: And if you're reading this by email, click here for the audio. Sample and … [Read more...]
AM Radio: With Friends Like This…
Everybody loves AM radio, right? Everybody needs AM radio, right? Hmm. Maybe not. Imagine a world where a new auto model dispenses with AM radio, but even so experiences blockbuster consumer demand. Of course, I'm talking about Elon Musk's forthcoming Tesla Model 3: Elon Musk, during a conference call hosted by Goldman Sachs a few days ago, articulated that annual demand for the Model 3 could eventually surpass 700,000 units. As a point of reference, the cumulative number of Model 3 reservations currently checks in at more than 500,000, an impressive figure to say the least. "We … [Read more...]
Introducing The Amazing New Podcast: "Inside The Exorcist"
I was floored by the amazing reception to Inside Psycho a few months ago, and I am now very proud to introduce to you my second collaboration with incomparable audio designer Jeff Schmidt and the terrific folks at Wondery: Inside The Exorcist. This project has been months in the making and I can honestly say I am as proud of it as anything I have ever done. Listen (if you dare) and I think you'll hear some of the most compelling audio you will ever hear. That's how good I think this is, and I hope you agree. The teaser launches today and the series kicks off on October 10, just in … [Read more...]
Radio's Streaming Effort May Be Screwed – Part 2
Yesterday I published a piece that argued two things: First, the decline in streaming for broadcast radio stations is real - it's a trend, not a blip. Second, that decline has consequences not only for your streaming strategy but also for the strategy of spreading your radio brands across every new platform under the sun ("Alexa, I mean you!"). So what do you do? Here's what I think you have to do. And not just you, but everyone who comes at digital from a place that has not, until recently, been digital: You have to start over. Imagine the consumer at the center of the content … [Read more...]
Radio's Streaming Effort May Be Screwed – Part 1
It's one of the most disturbing results from the recent Triton streaming audio trends report, and most broadcasters are looking the other way. This is the picture I'm talking about: The charts show year-over-year streaming listening growth for pureplays (e.g., Spotify, Pandora, etc.) and for broadcasters. And it clearly shows two things: Pureplay listening is rising rapidly – it's up more than 16% overall year-over year; meanwhile streaming listening to broadcast brands – the very same radio stations that almost everyone listens to for at least some time in an average week – is … [Read more...]
Media Unplugged: Amazon is Promising the NFL what Nobody Else Can
Amazon is promising the NFL what nobody else can. And... Apple wants James Bond. Plus, rants and raves about a terrific new promotional app from TV's The Walking Dead for Mountain Dew, the myth that the radio industry needs less regulation, and the strange phenomenon of "free range trees." . It's episode 71 of Media Unplugged with branding authority Tom Asacker and media strategist Mark Ramsey. Listen as we go inside media to reveal the ugly truth! Click the play button below: And if you're reading this by email, click here for the audio. Sample and subscribe to Media … [Read more...]