Category Archives: reviews of papers

New neurons mature slower in the temporal/ventral dentate gyrus

I’ve previously written about the functional differences between the septal (aka dorsal aka rostral¹ aka posterior²) and temporal (ventral/caudal/anterior) hippocampus and how studies are increasingly not treating the hippocampus as a single homogeneous structure. Myself and others have extended this perspective to studies of adult neurogenesis and now I’m happy to report that we had a new paper come out on the topic last week.

The study was a bit of a fun learning experience for me for several reasons. As many of you know I recently changed labs and will be starting my own lab soon. So things are on the go and I haven’t had the time to dive deep into a study that is going to take several years to complete. But some research projects can be done quickly and still are able to produce very useful results. As I prepare for my own lab I was probably thinking, “What kind of projects could a Master’s student accomplish??”. And indeed we had a strong postbaccalaureate fellow in the lab for about a year who fit this description pretty well (she’s the middle author). Also, we had lots of tissue remaining from a recent study where we compared neurogenesis in mice and rats that could be used to answer other questions, thereby saving time, money and importantly, animals. So we decided to ask whether the maturation and survival of adult-born neurons differ between the aforementioned functionally-distinct hippocampal subregions.

The basic idea of the study.

experimental designBrdU was injected to birthdate+label new neurons and at various intervals kainate was given to “activate” all the neurons that had integrated into the circuitry, and formed synapses. This integration (a major step in the new neuron maturation process) can then be measured by immunohistochemically staining for gene products such as Arc that are expressed after synaptic activity. Our tissue was cut in the coronal plane, however, which is not ideal for isolating the septal and temporal ends of the hippocampus (though others have found that there are meaningful differences along this rostrocaudal axis). Since the rostral sections are purely septal (see blue portions, above) this subregion was not a problem. We then decided to basically “cut” the caudal sections in half and by analyzing only the ventral portion we were able to specifically target neurons located in the far temporal dentate gyrus (shown in red). We were also able to investigate whether new neurons are more likely to survive in one subregion than another, by counting the number of cells present before (at 7d old) and after (at 28d old) the period of cell death.

Since this article is completely open access you can see the actual data for yourself here. The short story is that new neurons matured faster in the septal dentate gyrus (all cells could express Arc by 3w of age whereas in the temporal dentate gyrus this didn’t occur until somewhere between 4-10w of age). The other new finding was that there were many more new neurons initially added to the infrapyramidal blade of the dentate gyrus but these neurons were much less likely to survive than neurons born in the suprapyramidal blade.

What is the significance of these findings? To me, they provide a framework for future studies. If you want to investigate new neurons specifically during their immature stage (when they might have unique functions) you certainly have to consider the anatomical location. But what if the main function for new neurons is not realized until they are fully mature? Well, if you plan to ablate or silence new neurons and examine behavioural effects, then you might want to wait longer if you’re planning on investigating emotion/stress-related behaviours that might rely more heavily on the temporal hippocampus. They also suggest that new neurons in the temporal dentate gyrus might have an extended unique role since they remain immature for longer. The peculiar survival difference between the infrapyramidal and suprapyramidal blades doesn’t do much to clarify the functions of these two regions, but it adds to the ever-growing list of differences that suggests they are truly distinct.

Often findings across labs do not match up as well as one would like so I am rather happy that Piatti et al. have found similar maturation differences in another species (mice) and using different methods (electrophysiological recordings from virally-labelled new neurons). So this is probably for real!

Lastly, a reviewer pointed out something very helpful, which is that it can be very difficult to discern the two blades of the dentate gyrus in caudal coronal sections (like this or those slightly more caudal where the dentate gyrus is essentially a blob). I spent a fair bit of time looking perplexed as I played with 3D paper models of the dentate gyrus but felt pretty cool doing so because similar strategies have been used by some of the foremost neuroanatomists of our time – see here. A 3D computer model that incorporated the blades of the dentate gyrus would have been very convenient (talking to you, Allen). In any case, we decided to remove our caudal blade analyses from the paper and instead only focussed on the septal infrapyramidal vs. suprapyramidal differences.

Reference: Snyder JS, Ferrante SF, Cameron HA (2012) Late Maturation of Adult-Born Neurons in the Temporal Dentate Gyrus. PLoS ONE 7(11): e48757. PMID: 23144957

¹in rodents

²in humans

Impaired adult neurogenesis leads to depression – is it realistic?

Forming and recalling memories. Artificially.

New neurons mature very slowly in monkeys

Random roundup

random roundup banner

“Random” roundup because any posts linking to articles or ideas I’ve recently found noteworthy will never occur on a regular basis (as others manage to do – I applaud you) but only when enough interesting material has accrued and I have a spare moment. The links will, however, not be random. For example, you can expect many links to point to articles on adult neurogenesis or hippocampal function but will likely find few links directing you to photos of puppy dogs.

Dopaminergic Modulation of Cortical Inputs during Maturation of Adult-Born Dentate Granule Cells. A pretty thorough examination of dopaminergic modulation of synaptic transmission and synaptic plasticity in the dentate gyrus. Dopamine reduced synaptic transmission in both immature and mature granule neurons, but through different receptor subtypes. Additionally, dopamine reduced long-term plasticity in immature neurons but not mature neurons. Given the suggestion that dopamine could gate the entry of information into long-term memory, these findings suggest young and old neurons could have quite different behavioral functions.

Mu Y, Zhao C, & Gage FH (2011). Dopaminergic Modulation of Cortical Inputs during Maturation of Adult-Born Dentate Granule Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (11), 4113-23 PMID: 21411652

Lidocaine attenuates anisomycin-induced amnesia and release of norepinephrine in the amygdala. Memory consolidation is the phenomenon by which memories are encoded through enduring structural changes in the brain and is often demonstrated by showing that memory loss occurs when you inhibit protein synthesis around the time of learning. This paper shows that one of the most commonly-used protein synthesis inhibitors, anisomycin, leads to increased norepinephrine release in the amygdala which could, by itself, impair memory.  The interesting final experiment showed that the effects of anisomycin on memory and norepiniphrine were reduced when the amygdala was totally shut down with lidocaine.

Sadowski RN, Canal CE, & Gold PE (2011). Lidocaine attenuates anisomycin-induced amnesia and release of norepinephrine in the amygdala. Neurobiology of learning and memory PMID: 21453778

Evidence for the Re-Enactment of a Recently Learned Behavior during Sleepwalking. I’ve written a number of times about how neuronal firing patterns observed during waking experience are replayed during sleep, and could therefore reflect consolidation of memory and even dream content. Of course no one knows what rats are experiencing during sleep or whether they dream like us. To get around this problem, these authors trained sleepwalkers on a motor task with very defined arm movements and then examined sleepwalking behavior on the following night. Indeed, a video shows one subject who wakes up the following night and, for a few seconds, seems to be performing the same stereotyped task movements. Only one subject but tantalizing evidence and a cool experimental strategy nonetheless.

Oudiette D, Constantinescu I, Leclair-Visonneau L, Vidailhet M, Schwartz S, & Arnulf I (2011). Evidence for the Re-Enactment of a Recently Learned Behavior during Sleepwalking. PloS one, 6 (3) PMID: 21445313

Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. One of the biggest questions in the neurogenesis field is whether adult-born neurons are important for behavior. Usually this is tested by examining behavior in animals that lack adult neurogenesis but many studies have correlated increased neurogenesis in enriched or athletic animals with “improved” behavior (smarter, less depressed etc). Of course, the major confound is that enrichment and exercise do many other things besides increasing neurogenesis. To get around this Sahay et al. made a mouse in which neurogenesis could be specifically increased in adulthood. These mice were better at discriminating between related contexts and, after exercise, showed much greater exploratory activity in an open field.

Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, & Hen R (2011). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature PMID: 21460835

Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates. This study potentially bridges a big big gap by extending the role of adult neurogenesis in the antidepressant response from rodents all the way to monkeys. Chronic stress induced anhedonic and subordinate behaviors and these effects could be reversed with fluoxetine, but not in irradiated monkeys that had reduced neurogenesis. Could someone follow this up with a transgenic model?

Perera, T., Dwork, A., Keegan, K., Thirumangalakudi, L., Lipira, C., Joyce, N., Lange, C., Higley, J., Rosoklija, G., Hen, R., Sackeim, H., & Coplan, J. (2011). Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates PLoS ONE, 6 (4) DOI: 10.1371/journal.pone.0017600

Systemic 5-bromo-2-deoxyuridine induces conditioned flavor aversion and c-Fos in the visceral neuraxis. OH NOOO! Rats don’t like BrdU! These authors show that pairing a BrdU injection with exposure to a sweet palatable drink causes rats to avoid that drink in the future. It also leads to a mildly elevated stress response and elevated c-fos expression in areas of the brain that represent viscera, consistent with the possibility that BrdU could be exerting unpleasant effects in the gut, where there is a lot of cell division. The authors conclude that the effects on behavior in subsequent days and weeks are probably minimal (phew!), but I’d certainly keep these data in mind when considering injecting BrdU around the time of behavioral testing.

Kimbrough A, Kwon B, Eckel LA, & Houpt TA (2011). Systemic 5-bromo-2-deoxyuridine induces conditioned flavor aversion and c-Fos in the visceral neuraxis. Learning & memory (Cold Spring Harbor, N.Y.), 18 (5), 292-5 PMID: 21498563

Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice. In an interesting study of plasticity following neurogenesis reduction, these authors find that LTP was dramatically reduced after arresting neurogenesis, but only transiently. LTP recovered within weeks, possibly because of compensatory reductions in inhibition and enhanced survival of neurons born before neurogenesis ablation. Hat tip to Sil for this one.

Singer BH, Gamelli AE, Fuller CL, Temme SJ, Parent JM, & Murphy GG (2011). Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice. Proceedings of the National Academy of Sciences of the United States of America, 108 (13), 5437-42 PMID: 21402918

That’s it.

Are new neurons really more excitable? (yes)

ResearchBlogging.orgSome facts on neuronal excitability:

  1. Excitable: the ability to fire action potentials.
  2. More excitable: fires action potentials, but more.
  3. More LTP: not the same as more excitable.
  4. Less inhibition: also not the same as more excitable, though the two may go hand in hand.
  5. The Scholarpedia page on neuronal excitability, which was last modified on 13 August 2009, has been accessed 49,025 times, and contains no information (peer review is slow).

One of the claims that is often made is that adult-born neurons are more plastic and more excitable than older neurons.  This despite there being little evidence (until recently) that new neurons indeed are more excitable. But, hey, “excitable” sounds great alongside “plastic”. The Schmidt-Hieber paper did show that new neurons are more excitable, though it wasn’t their main focus and it is only occasionally referenced as evidence for greater excitability.

My misunderstanding that there are no thorough investigations of new neuron excitability was brought to an end recently when I was fortunate to have an infant-free moment (In which I was able to read two papers in the same evening, plus an entire New Yorker article over breakfast. Amazing.) One of the papers was Reliable Activation of Immature Neurons in the Adult Hippocampus by Mongiat et al. from Alejandro Schinder’s lab, which I really should have read long ago. Continue reading Are new neurons really more excitable? (yes)

How does the brain pick which neurons to use?

ResearchBlogging.orgWiring. That’s one answer to this question. We know this from topographic maps in the thalamus and neocortex, where the basic units of sensory information are neatly represented in spatially-arranged populations of neurons – the various body parts are represented in specific locations, as are the different frequencies of sound, the different parts of the retina, and different odors and tastes. This basic sensory information has to be represented (i.e. we all need a faithful representation of visual elements, we all need to hear the various frequencies of sound that make up human speech etc.) so why not hard-wire it and make its representation the same for all of us?

It’s often thought that things change as you move into parts of the brain that represent more complex and abstract concepts. For example, in the hippocampus, many neurons receive the same inputs so it’s generally assumed that different neurons are equally capable of representing a given piece of information. While wiring between neurons must play a role in determining which neurons are activated, the diffuseness of the wiring means that related information need not be stored in spatially neighboring neurons as in the sensory regions of neocortex. Indeed, if you look at hippocampal neurons activated by a given experience they don’t appear to have any particular spatial arrangement but are randomly distributed, anatomically. Alternatively, it could be that certain hippocampal neurons are hard-wired to respond to specific stimuli, it’s just that we don’t understand the wiring. Continue reading How does the brain pick which neurons to use?

Pattern separation: 370,000,000 papers 2050?

pubmed 2If you’ve been paying attention to the adult hippocampal neurogenesis literature at all, you noticed that “pattern separation” is gaining popularity as a research topic. A few quick searches on Pubmed confirm that a trend is indeed afoot.  For the years prior to 1999, only 15 Pubmed-indexed papers answer to the keyphrase “pattern separation.”  This number holds roughly steady through about 2003, and then it begins to take off.  As of this moment (September 24, 2010 @ 3:27pm CST), we are up to 81 papers. According to my back-of-the-envelope calculations, we are in a period of exponential growth.  Should this trend hold –and I see no signs of it abating– we can expect upwards of 370 million pattern separation papers by 2050. Can you imagine what a comprehensive exam will be like?  Your child (grandchild?) will face a stack of journal articles almost 500 miles high!  Al Gore, from atop his famous scissor lift, will inveigh against the massive deforestation wreaked by our prolific little research community.  What’s that you say? We’ll all be using iPads? Fair enough.
Continue reading Pattern separation: 370,000,000 papers 2050?

Someone finally dissects the role new neurons play in fear conditioning

  4. Faith is restored.
  7. BDNF.
  10. We have never gotten this far.

*or any other field for that matter

Do new neurons go through a critical period and then retire, never to be used again? And here we have the latest, craziest hypothesis of granule cell function. Crazy not because the authors have lost their minds but because the story of the dentate gyrus, where adult neurogenesis occurs, is becoming more peculiar every day. The underlying premise of this paper by Alme et al. (which we will examine later) is that granule neurons go through a critical period during their development when they are more likely to contribute to memory encoding. Here it’s hypothesized that, once the critical period is over, they shut down. Forever. Hundreds of thousands of neurons never to be used again. It’s not every day you get to read such bold and novel ideas. Their hypothesis has similarities with that proposed by Aimone 2006, that adult neurogenesis causes different cohorts of neurons to be immature at different phases of an animal’s life, thereby separating memories according to time. The question here is whether these neurons can be reactivated once their critical period is over. Continue reading Do new neurons go through a critical period and then retire, never to be used again?


SaveUSA Helps Families Save $1 Million

SaveUSAAsset building is crucial to a family or individual’s financial success. The difference between getting by and getting ahead is the ability to save and build assets. According to the recently released CFED Poverty Scorecard, 27.1% of Americans are asset poor (meaning that if they lost their incomes they would not be able to survive for three months because they do not have enough assets to fall back on).

SaveUSA is pilot program in four cities that offers eligible individuals a 50-percent match if they deposit a portion of their tax refund into a “SaveUSA Account” and maintain the initial deposit for approximately one year. SaveUSA, which is being offered in New York City, Tulsa, Newark, and San Antonio, has already helped residents open 1,662 accounts and save nearly $1 million dollars.

SaveUSA is based on the $aveNYC program which began in 2008 and was sponsored by New York City’s Department of Consumer Affairs’ Office of Financial Empowerment (OFE), the Center for Economic Opportunity, and New York City Mayor Bloomberg. Behavioral economics research proves that saving programs are successful in low-income populations if strong financial incentives to save are offered. Under the $aveNYC program, the match was originally capped at $250 for the first two years, and was raised to $500 in 2010.

Under the SaveUSA pilot, accounts are offered at Volunteer Income Tax Assistance (VITA) sites, where families and individuals can receive free tax preparation services. The idea is to encourage consumers to think about tax refunds not just as money back in their pockets, but as an opportunity to begin saving for the future.  Additionally, VITA sites and SaveUSA both encourage eligible taxpayers to apply for the Earned Income Tax Credits ( EITC). The EITC is a refundable tax credit for working low-income individuals and families who make below a certain wage. The idea is that low-income families can kick-start their asset building by depositing a portion of their tax refund, including their EITC refund, in their SaveUSA account thereby making them eligible for the maximum match.

Title XII of the Dodd-Frank Wall Street Reform and Consumer Protection Act authorized a BankOn USA initiative that the U.S. Treasury Department is currently developing.  The federal BankOn USA pilot program is similar to both the $aveNYC program and BankOn programs. BankOn, which originated in San Francisco as a pilot in 2006, is a collaboration between financial institutions and community organizations to offer low-cost savings and checking accounts and financial education to low-income individuals. These partnerships allow banks and credit unions to offer products to the unbanked as well as raise awareness and conduct targeted outreach to bring consumers into the financial mainstream. BankOn programs also typically provide second chance accounts to those who have had accounts closed and whose name appears in ChexSystem.

The Treasury Department is currently exploring the use of pilots, awards, and competitions to assess and promote effective approaches to designing and implementing the BankOn USA program if funded through federal appropriations. President Obama called for $20 million in his FY 2013 budget proposal to fund BankOn USA.

Programs such as SaveUSA and BankOn USA provide the starting point for financial stability and economic mobility. By encouraging individuals to begin saving for their futures, they are empowered to enter the financial system, prepare for emergencies and have the financial know-how to succeed.

This blog post was coauthored by Alison Terkel.

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Creating Consistently Colorful User Experiences: Part 1, Theory

April 23rd, 2009
Published on
April 23rd, 2009

How does the color in this photo make you feel? Are these fireworks happy?

Photo by expressmonorail.

Perhaps you can remember a site based upon color. If I ask you to name a website that uses the color purple well, what comes to mind? Perhaps Yahoo!. Their brand is defined by a number of things: one of these is the color purple. You might ask: what does color theory have to say about purple?

In this series of articles, we will give a (more or less) comprehensive view of colors and their treatments in web design. In this first article, we explain color basics: How does color work? How does an artist use color? How does color affect our mood? In our second article, we’ll cover how the web renders color, the ways you can code color into your stylesheets, and what’s new with color in CSS3. In our third and final article, we’ll cover how you can pick and implement colors in your layout, and what “gotchas” exist in the world of color.

First, let’s briefly cover physical color theory. Next, we’ll discuss psychological color theory: what emotions do our site’s colors convey, color moods, and how can we use that to our advantage in creating our experiences. Lastly, we’ll discuss how theory starts to become practice as we use colors on the web.

Physical Color Theory

Reflective Color

Color exists all around us. Physical objects, when struck by light (the visible kind, see electromagnetic radiation), will reflect back certain wavelengths of light to your eyes. For example, if pure white light hits an apple, all colors (wavelengths of light) are absorbed except for red (700–630 nm). Red is the only color reflected back towards you, and therefore, it is the color you attribute to the apple. Funny that—because it’s the only color the apple doesn’t absorb. However, color in this regard depends on one important idea: wavelengths of light are subtracted as they are reflected off of an object.

Additive Color

Monitors display color in a much different way. Because they generate their own light, they must generate their own color as well. Generally, the three “primaries” used to create colors are red, green, and blue. Because computer monitors have a very high density of pixels, they do not use “additive” color per say. If a computer monitor displays cyan, it actually lights up both blue and green pixels in a given area. In this regard, a computer display uses a form of dithering to display colors.

Color Theory as it pertains to Design

The standard color wheel

Contrasting/Complimentary Colors

Try this experiment: stare at a color for about a minute and then close your eyes. What color do you see? Most likely, you’ll see what’s called the “contrasting” color. This color is generally the “opposite” color on this nifty thing called a “color wheel.” How does all this hogwash apply to reality?

If a doctor stares at blood all day (dark red) and closes his eyes, he’ll see the “opposite” of that color. In this case, that would be a light green. For this reason, the common color of hospital scrubs is a light green. While it may not be rocket science, this kind of “complementary” color system actually calms our visual system. If the people engineering the color at a hospital can derive benefit from color theory, then web designers certainly can!

Because art/zen/life is all about balance, it’s important that your website has a good color foundation. Never over stimulate your audience —unless of course, that is your bag, baby.

Analogous Colors

My simple color “Triad,” with a fourth color.

Analogous colors are the safest bet when choosing colors for your designs. The easiest way to do this is to start with a primary color: in this case, I’ll go with green—hue 120; The next color I’ll pick is going to be related to that color. I begin by choosing colors related to hue 120, mathematically. I pick hues 60, 45, and 33. You’ll notice that the amount that I’m moving the hue decreases each time—that’s intentional, and yet completely arbitrary. Typically, designers will choose colors like this in groups of three; this practice is known as selecting triads.

Rectangular Color Schemes

Rectangular color schemes are not only the most complex, but the hardest to work with. Picking the colors for these is fairly straightforward, one simply draws a rectangle over the color wheel; each of the corners anchored to a particular hue. Pay attention to variation, however. It’s easy to have your scheme look like a rainbow if you aren’t careful. Make an effort to favor one color over the others, and keep your palate as concise as possible. I find it easier to work with multiple colors if they are relatively unsaturated.

Psychological Color Theory

Color is an important tool that you can use for non-verbal communication. Let’s go over what people naturally think of when they see different colors.

Emotions and Feelings Associated with Colors

Each color has a lightness and emotion associated with it.

Warm Colors

Warm colors “pull forward” more than cool colors. In this way, a dark version of a warm color will appear to be the same brightness as a mathematically lighter version of a cool color.

Energy, Power, Passion, Love
Happiness, Enthusiasm, Attraction, Success
Cheerfulness, Stimulation, Attention-seeking,

Cool Colors

Cool colors “push backward” or recede more than warm colors. In this way, a light version of a cool color will appear to be the same brightness as a mathematically darker version of a warm color.

Refreshing, fresh, prestige, cooling, calming,
reliable, trustworthy, dependable, restful
spirituality, ceremony, mystery, transformation, royalty

Color Neutrals

Color neutrals have a less emotional impact and are therefore considered for more objective presentation. However, used well, color neutrals can have their implications. “Pure” black and “pure” white are our ideal “bright” and “dark” colors on the spectrum, respectively.

Sexy, mystery, submission, danger
Purity, innocent, refreshing, neutral, sterility

Color Tints, Shades, Tones

Keep in mind that colors are more than just a hue. The saturation and lightness of light also affect our perceptions. While traditional color theory tends to shy away from the saturation and lightness of colors, artists are traditionally called upon to understand their subtleties.

Almost assuredly, you’ve seen the use of selective chromacity: an artist will take a photo and remove color from everything except the area of focus. The difference here affects how we perceive the subject matter. The artist can bring life into an otherwise lifeless area of a photo.

Explore the most popular works of art on sites such as Deviant Art. Do they have anything in common? Make sure to explore the complementary colors as well as the saturation thereof. What mood do you wish to convey? IF you wish to draw attention to a particular element, have you considered selective chromacity?

How does this photograph make you feel?

Photo by midnight digital

After applying color in my designs, I have found it difficult to add black and white treatments to various areas; in accordance with the idea of selective chromacity, they now grab too much of my attention!

Once you’ve gotten an idea of how color and tone affects your website, use it to your advantage. Just as bright, colorful and happy language (as found on, for example) can make a website more personable, so can bright happy colors. An otherwise boring subject can be brought to life, so to speak, by a more “lively” color scheme. Remember, it’s all about feelings with color. There is no black and white science (pun intended) to perception.

Conclusion: Picking Colors that Fit the Experience

That’s about it for theory. If you’re interested in adding and enhancing your use of color in your layouts, a concrete knowledge of the theory behind colors and color schemes is essential. It’s just one part, though. As experience designers, we are responsible for many different elements. It’s important to note that we are not to become masters of any particular area, but that we must have a working knowledge of all of them.

Obviously, I can’t give the full details of each of the concepts I touched upon above, or this article would be about 8 times as long. Take the time to look these concepts up in the related links, or peruse one of the related books. If that’s not enough, give yourself some inspiration: pay attention your favorite sites and artists. How have they used color? Don’t pay attention to form or copy or effects: just pay attention to color. If you can concentrate on each part of the experience indiviually, you’ll be well on your way to orchestrating the moment. Did something stand out? Share your thoughts in the comments!

In our next installment

Theory is one thing, but what about practice?

The purpose of this article was to set the foundation. Now that we’re all on the same page, I’m going to take this concept one step further. In my next article, I’ll explore how the web renders color (what sRGB means), various ways to code color into your style sheets, and what’s new with color in CSS3.

Related Books


Imagining a Peaceful World

Peace Flags provide you with a special way to express some of your important ideas and hopes for the world. In words or pictures, you can display wishes for yourself, your family, friends, community, or the world. Taken together Peace Flags describe a better, more peaceful planet for us all.
Peace Flags were inspired by the Prayer Flags of Tibet. According to ancient tradition, the prayers printed on the flags are carried on the wind. The traditional flags are blue (for sky), white (for air or clouds), red (for fire), green (for earth) and yellow (for water).

  1. Select your fabric square. (If you would like to follow the tradition of the Tibetan flags, you can make a set of five (5) flags.) Use markers or paint to write and draw on the flags. Please protect any surface you work on. Markers and paints may come through the fabric. We also suggest that you tape down the flag with masking tape as you work; this keeps the square in place.
  2. When you prepare to create your flags, relax and enter the peacefulness of your heart. Spend a few minutes in that quiet space to think about how you would like the world to be better.
  3. Write or draw your messages on the flags. Leave a small (say, one inch) margin at the top to fold the flag over twine.
  4. When you have finished, fold the top edge of each flag over twine or rope, and glue or sew the folded edge of the flag. If you like, you can hang them in the traditional order of blue, white, red, green and yellow.
  5. Peace Flags may be hung outdoors or in. Hang them wherever you or the people around you will see them and be inspired by them every day.
  6. Outdoors the words will gradually disappear, and the fabric will eventually shred. You may leave them up as long as you like, and bury or burn or compost the shredded fabric.

The flags will provide you with a visual reminder that we live in one world and all share similar hopes and dreams. They also help you to focus on how you would like to work for peace.

“We are all peacemakers”

For more detailed information on making Peace Flags or for making the Flags with a group, click here.


Moon Goddess List

The Goddesses of the moon are not the only heavenly deities, why not also explore the role of the Sun Goddesses

Aine (Celtic) - Goddess of love, growth, cattle and light. The name of this Celtic Goddess means "bright" as she lights up the dark. Celebrations to this Goddess were held on Midsummer night

Anahita (Persian) - A river Goddess who was also Goddess of Venus and the moon. Her name means "pure" Or immaculate one" as she represented the cleansing and fertilizing flow of the cosmos.

Andromeda (Greek) - Although today she is linked with the stars many scholars believe that Andromeda was a pre-Hellenic moon deity.

Anunit (Babylonian) - Goddess of the moon and battle. She was also associated with the evening star and later became known as Ishtar.

Arianrhod (Celtic) - Goddess of the moon and stars, her name means "silver- wheel" the wheel of the year and the web of fate.

Artemis (Greek) - The Greek Goddess of the hunt, nature and birth. This maiden Goddess is symbolized by the crescent moon.

Arawa (African) - Lunar Goddess of the Suk and Pokot tribes of Kenya and Uganda. Her parents were the creator God Tororut and his consort Seta.

Athenesic (Native North American) - A moon Goddess of several north central Native American tribes,

Auchimalgen (South American) - This moon Goddess was a Deity of divination and a protectress from evil spirits.

Bendis (Greek) - Bendis was the consort of the sun God Sabazius. Her cult flourished in Athens during the fifth century BCE.

Britomartis (Crete) - In addition to her lunar attributes she was also the patron Goddess of Cretan sailors.

Chang- O (Chinese) - The Chinese Goddess who lived on the moon She is celebrated to this day on full moon night of the 8th lunar month.

Coyolxauhqui (Aztec) - Aztec moon Goddess, her name means "Golden Bells." She was the daughter of the Earth goddess, Coatlicue and the sister of the Sun god, Huitzilopochtli

Dae-Soon (Korean) - Moon Goddess

Diana (Roman) - Diana was the Goddess of the hunt and wild animals. She later took over from Luna as the Roman Goddess of the moon, responsible for fertility and childbirth.

Gnatoo (Japanese) - One of twelve Buddhist deities called the Jiu No O, adopted from Hindu mythology.

Gwaten (Hindu) - She is derived from the Hindu God Soma, and is portrayed as a woman holding in her right hand, a disk symbolizing the Moon.

Hanwi (Native North American) - Goddess of the Oglala Sioux, she once lived with the sun God Wi. Due to a transgression, she was forced by him to become a creature of the night.

Hina Hine (Polynesian) - This Hawaiian Goddesses name means 'woman who works the moon'. In her myths it is said that she grew tired of working for her brother and fled to the moon to live in peace.

Hina-Ika ("lady of the fish") Once again we see the link between the lunar Goddess to the tides.

Huitaco (South American) - This Colombian Goddess was a protectress of women as well as a deity of pleasure and happiness who was always battling with her male counterpart Bochica, a God of hard work and sorrow.

Ishtar (Babylonian) - Some myths say she is the daughter of the moon, others the mother.

Isis (Egyptian) - This powerful and widely worshipped Goddess was not only a moon deity, but a Goddess of the sun as well.

Ix Chel (Mayan) - A Central American moon Goddess and the lover of the sun. Poisonous snakes were her totem animal. She was also Goddess of childbirth

Izanami (Japanese) - This Goddess controlled the tides, fishing, and all destructive sea phenomena

Jezanna (Central African) - Goddess of the moon and healing.

Jyotsna (Indian) - A Hindu Goddess of twilight and the autumn moons.

Komorkis (Native North American) - The Blackfoot tribe celebrated her as the Goddess of the moon.

Kuan Yin (Chinese) - A Buddhist Goddess. Modern feminist Pagans believe she far pre-dates Buddhist origins. She was a Goddess of the moon, compassion, and healing,

Lasya (Tibetan) - A Goddess of the moon and beauty who carried a mirror.

Lucina (Roman) - A Goddess of light with both solar and lunar attributes. She was Christianized as St. Lucia, a saint still honored at Yule in many parts of Europe.

Luna (Roman) - An ancient moon Goddess, the namesake for the Latin word luna meaning 'moon'. Her name also forms the root of the English words 'lunar' and 'lunatic'.

Mawu (African) - She ruled the sky with her twin bother, the sun God Lisa. To her people she symbolized both wisdom and knowledge.

Metzli (Aztec) - In Aztec mythology mother moon leapt into a blazing fire and gave birth to the sun and the sky.

Rhiannon (Celtic) - A Goddess of fertility, the moon, night, and death. Her name means 'night queen'. She is also known as Rigantona.

Sadarnuna (Sumerian) - Goddess of the new moon

Sarpandit (Sumerian) - Goddess of moonrise. This pregnant Goddess's name means "silver shining" referring to the reflective quality of the moon.

Sefkhet (Egyptian) - According to some myths this lunar Goddess was the wife of Thoth. She was also the deity of time, the stars, and architecture.

Selene (Greek) - A mother Goddess linked to the full moon. She is widely worshipped by Pagans today,

Sina (Polynesian) - This moon Goddess was the sister of the sun God Maui. She was sometimes called Ina.

Teczistecatl (Aztec) - A Goddess of sex, symbolized by the four phases of the moon: dark, waxing, full, and waning.

Yemanja (Native South American) - She was the Brazilian Goddess of the oceans symbolized by a waxing crescent moon. Yemanja was also considered to represent the essence of motherhood and a protector of children.

Yolkai Estsan (Native North American) - A Navajo moon deity fashioned from an abalone shell by her sister Yolkai, the Goddess of the sky. She was the Navaho Goddess of the earth and the seasons, and is also known as White Shell Woman.

> Moon Goddess

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Movie Poster Tagline Database

Search or browse our collection of 15,038 taglines for 9,232 films including almost every film going back to 2009.

page:   1    2    3    4    5    6    7    8

"You can never go too far." - Donnie Darko (2001)

"You can never take the game too seriously." - Zero Charisma (2013)

"You can only buy so much time..." - Towards Darkness (2007)

"You can only defeat it when you believe." - The Rite (2011)

"You can only imagine the truth" - Atonement (2007)

"You can only push an innocent man so far." - Man on a Ledge (2012)

"you can run but you can't hide" - Hide and Seek (2005)

"You can take the man out of the street... but you can't take the street out of the man." - Talento de Barrio (2008)

"You can't always run from your past" - The Ghosts of Girlfriends Past (2009)

"You can't ask why about love." - Anna Karenina (2012)

"You can't be half a gangster" - Boardwalk Empire (tv)

"You can't bury the truth" - Blood (2013)

"You can't choose family" - World's Greatest Dad (2009)

"You can't choose family." - Black Irish (2007)

"You can't choose who you fall in love with" - I Capture the Castle (2003)

"You can't choose your destiny... it chooses you." - One Fall (2011)

"You can't choose your family ...or can you?" - Goats (2012)

"You can't choose your family, you can only pack accordingly." - Meet the Browns (2008)

"You can't escape fate" - 11 Minutes (2015)

"You can't escape the past" - 1915 (2015)

"You can't escape the past" - Pursuit (2015)

"You can't escape the wilderness within." - It's in the Blood (2012)

"You can't escape who you are." - Gun Hill Road (2011)

"You can't escape your lies." - Transsiberian (2008)

"You can't escape your past." - Inescapable (2012)

"You can't evict an idea" - 99%: The Occupy Wall Street Collaborative Film (2013)

"You can't exchange family." - This Christmas (2007)

"You can't expose the world's secrets without exposing your own." - The Fifth Estate (2013)

"You can't fight what's in these mountains." - Afghan Knights (2006)

"You can't fit in when you stand out." - Camp (2003)

"You can't get enough of a good thing... But first you have to find it." - Milk Money (1994)

"You can't get rid of" - The Babadook (2014)

"You can't handle the tooth." - Tooth Fairy (2010)

"You can't have a future until you stand up to your past." - The Lesser Blessed (2013)

"You can't hide from your past forever." - Old Stock (2013)

"You can't hide what's inside" - Exhumed (2011)

"You can't judge a man by the company that keeps him." - Company Business (1991)

"You can't keep a miracle secret" - Tortilla Heaven (2007)

"You can't kill their spirit" - All Cheerleaders Die (2014)

"You can't land if you don't jump." - Touching Down (2005)

"You can't learn to dance... without stepping on a few toes." - Six Dance Lessons in Six Weeks (2014)

"You can't make this mensch up" - Supermensch: The Legend of Shep Gordon (2014)

"You can't outrun family" - Rogue River (2010)

Additional movie data provided by TMDb


3Rs Prize winners

Prize winner: Dr Madeline Lancaster, MRC Laboratory of Molecular Biology

  • Lancaster M et al. (2013). Cerebral organoids model human brain development and microcephaly. Nature 501(7497): 373-9 doi:10.1038/nature12517

The authors have developed the first 3D model of the human embryonic brain, using human induced pluripotent stem cells which were able to spontaneously self-organise into a structure that resembles the human brain with discrete, interdependent regions. This was achieved using adapted growth conditions, with specialised matrix support and improved access to nutrients through spinning. The paper also describes using skin cells from a patient with microcephaly to create organoids modelling the disease.

Suitability of animal models in studying neural development is limited, as they do not recapitulate the anatomical and functional complexity required to study human brain biology and disease. Developing brain organoids from human tissue is a revolutionary step towards reducing reliance on animals in studying neurological diseases and potentially in the development of new treatments.

Read the related blog post:Mini-brains show great potential to replace animals in studying neurological disease.

Prize winner: Dr Laura Hall, University of Stirling

  • Hall LE, Robinson S, Buchanan-Smith HM (2015). Refining dosing by oral gavage in the dog: A protocol to harmonise welfare. Journal of Pharmacological and Toxicological Methods 72: 35-46 doi:10.1016/j.vascn.2014.12.007

The study, in collaboration with AstraZeneca, improves the technique of oral dosing in dogs. Following a framework of objective welfare assessments developed by Dr Hall, the authors demonstrate that a modified, refined protocol can minimise stress in dogs compared to the standard approach.

Most laboratory dogs in the UK are used for safety testing, and oral dosing is one of the most common procedures used during these tests. This paper shows that using seemingly small refinements (positive reinforcement training with food rewards, a signal for dosing, and covering the dosing tube in palatable paste during training) significantly reduces the negative welfare impact of the oral dosing on the dogs. The improved protocol allows researchers to dose dogs more quickly and efficiently, at no further cost. Dr Hall has been collaborating with dog facilities across the UK to maximise the impact of her work and share best practice.

Highly Commended: Dr Hayley Francies, Wellcome Trust Sanger Institute

  • van de Wetering M, Francies HE, Francis JM et al. (2015). Prospective Derivation of a Living Organoid Biobank of Colorectal Cancer Patients. Cell 161(4): 933-45 doi.org/10.1016/j.cell.2015.03.053

The paper describes work on developing and characterising a biobank of colorectal cancer organoids obtained from patients’ biopsy tissue. The organoids were shown to accurately reflect the molecular features and diversity seen in the original tumours. More than 80 commonly used or experimental drugs for cancer were tested in the biobank.

Tumour-derived organoids have the potential to replace many studies involving patient-derived xenograft (PDX) mice, including for personalised medicine and drug development. Organoid production is cheaper and has a higher success rate than patient tumour sample engraftment rates in mice. This technology may fill the gap between cancer genetics and patient trials, complementing and in the long run replacing xenograft based drug studies, and allowing personalised therapy design.

Prize winner: Mr Oliver Britton, University of Oxford

  • Britton O, Bueno-Orovio A, Van Ammel K, et al. (2013) Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology. Proc. Natl. Acad. Sci. USA 110: E2098–2105 doi:10.1073/pnas.1304382110.

The authors have built a computer model of cardiac electrophysiology that incorporates natural variability. Normally when using a computer model to test how a drug might affect the heart, the effect of the drug on the heart is compared to an average profile of electrophysiology. But this average profile is not really representative of the whole population, where natural variations in heart properties occur from person to person. This new approach has the potential to make computer models that are far more powerful and more predictive of human response, and therefore a more viable alternative to using animals in research. This is the first time that natural variability has successfully been considered in such a model, and the methodology could be applied to other diseases. The methodology has also been developed into a user-friendly software package called Virtual Assay, which is a major facilitator for industry uptake, without the need for specialist programming and modelling experience. The authors are already planning to use the same methodology to build computer models for understanding pain and diabetes.

Read a related blog post: Looking back at the 3Rs Prize: interview with last year’s winner, Dr Oliver Britton.

Highly Commended: Dr Olivier Frey, ETH Zurich

  • Frey O, Misun PM, Fluri DA, et al. (2014) Reconfigurable microfluidic hanging drop network for multi-tissue interaction and analysis. Nat. Commun. 5:4250 doi:10.1038/ncomms5250

Frey’s paper reports on a novel approach to culturing multi-cellular spheroids in vitro. The work is a significant advance in engineering, which brings together the hanging drop method and microfluidics to substantially expand the experimental options for culturing spheroids. Growing cells using a hanging drop approach, means that 3D cell spheroids can be grown without the restriction that may be imposed by a scaffold or a dish. Microfluidic systems allow precise liquid handling including continuous medium and waste exchange, and also allow test substances, such as candidate drugs, to be run through the culture. This is the first time these two approaches have been combined, and the result holds real promise to bolster the predictivity of in vitro research. The microfluidic hanging drop network has already shown that spheroids of cells representing different organs can be inter-connected in physiological order and are able to communicate with each other via metabolite transfer. This is exciting as this capability is one of the first steps towards creating a multi-organ body-on-a-chip model.

Highly Commended: Dr Nicola Powles-Glover, AstraZeneca UK

  • Powles-Glover N, Kirk S, Wilkinson C, et al. (2014) Assessment of Toxicological Effects of Blood Microsampling in the Vehicle Dosed Adult Rat. Regulatory Toxicology and Pharmacology. Apr; 68(3):325-31. doi:10.1016/j.yrtph.2014.01.001

It is a requirement in animal safety testing of new medicines that the blood concentration of the medicine is measured.  Historically, large volumes of blood were required to detect the concentration of the medicine. This meant that for rat studies, separate groups of rats were used solely for measuring the concentration while other groups of rats were used to assess the effects of the medicine on the animal.  Advances in the way that blood is analysed mean that, with the right analysis equipment, very small “microsamples” of blood are now sufficient.  Taking a microsample of blood from a rat is a quicker, less stressful procedure than taking a larger volume.  This paper provides the evidence that taking repeat microsamples does not adversely affect adult rats and therefore does not interfere with the ability to interpret these safety studies.  This means that information about the drug concentration and its affects can be obtained from the same animal, allowing a direct link between drug concentration and effect.  This is a major scientific improvement.  It also means that far fewer rats are required on these safety studies.  As a consequence of this work, whenever the sensitive analytical method is available, AstraZeneca now use microsampling routinely in all rat safety tests.

Highly Commended: Drs Brianna Gaskill and Joseph Garner, Purdue University and Stanford University

  • Gaskill B, Gordon CJ, Pajor EA, et al. (2012) Heat or insulation: Behavioral titration of mouse preference for warmth or access to a nest. PLoS ONE 7 (3): e32799 doi: 10.1371/journal.pone.0032799.

Mice are commonly housed at temperatures (20–24°C) which humans find comfortable for working in the laboratory. Mice become cold stressed below 30˚C, which can compromise many aspects of physiology and welfare. However, the amount of nesting material required to meet a mouse’s thermal needs has until now been unknown. In this study the authors found out where mice wanted to spend their time, based on combinations of temperature and nesting material. They found that mice prefer temperatures between 26–29°C, but shift from preferring a warmer temperature to a nest when provided 6-10g of nesting material. These results suggest that laboratory mice should be provided with no less than 6g of nesting material in order to build fully formed nests, but 10g or more may be needed to eliminate thermal stress.  These results have the potential to positively impact the welfare of millions of laboratory mice all over the world.

Meritxell HuchPrize winner: Dr Meritxell Huch, Gurdon Institute, University of Cambridge

  • Huch M, Dorrell C, Boj SF, van Es JH, Li VSW, van de Wetering M, Sato T, Hamer K, Sasaki N, Finegold MJ, Haft A, Vries RG, Grompe M, Clevers H (2013). In vitro expansion of single Lgr5 liver stem cells induced by Wnt-driven regeneration. Nature 494: 247252.

Dr Meritxell Huch from Cambridge University's Gurdon Institute wins the 2013 3Rs Prize for a Nature paper detailing work carried out at the Hubrecht Institute, The Netherlands, to develop a culture system that enables adult mouse stem cells to grow and expand into fully functioning three-dimensional liver tissue.

Growing hepatocytes (liver cells) in the laboratory has been attempted by liver biologists for many years, since it would reduce their reliance on using mice to study liver disease and would open up new opportunities in medical research and drug safety testing. Until now no laboratory has been successful in deciphering how to isolate and grow these cells.

Liver stem cells are typically found in a dormant state in the liver, only becoming active following injury to produce new liver cells and bile ducts. Dr Huch and colleagues located the specific type of stem cells responsible for this regeneration, which are recognised by a key surface protein (Lgr5+) that they share with similar stem cells in the intestine, stomach and hair follicles.

By isolating these cells and placing them in a culture medium with the right conditions, the researchers were able to grow small liver organoids, which survive and expand for over a year in a laboratory environment. When implanted back into mice with liver disease they continued to grow, ameliorating the disease and extending the survival of the mice.

Having further refined the process using cells from rats and dogs, Dr Huch is now moving onto testing it with human cells, which would not only be more relevant to research into human disease, but also translate to the development of a patient's own liver tissue for transplantation.

Commenting on the new method's potential to reduce animal use in liver research, Dr Huch said:

"Typically a study to investigate one potential drug compound to treat one form of liver disease would require up to 50 live animals per experiment, so testing 1000 compounds would need 50,000 mice. By using the liver culture system I developed, we can test 1000 compounds using cells that come from only one mouse, resulting in a significant reduction in animal use.

Growing functioning liver cells in culture has been the Holy Grail for liver biologists for many years, so a limitless supply of hepatocytes could have a huge 3Rs impact both on basic research to understand liver disease and for the screening and safety testing of pharmaceuticals.

NC3Rs blog: Mini livers research wins 3Rs prize for animal replacement potential

Highly Commended: Dr Gyorgy Fejer, Plymouth University

  • Fejer G, Wegner MD, Györy I, Cohen I, Engelhard P, Voronov E, Manke T, Ruzsics Z, Dölken L, Prazeres da Costa O, Branzk N, Huber M, Prasse A, Schneider R, Apte RN, Galanos C, Freudenberg M (2013). Nontransformed, GM-CSFdependent macrophage lines are a unique model to study tissue macrophage functions. PNAS 110(24): E2191-E2198.

Recognised for the development of a new method to grow macrophage cells for use in infectious disease research, which would reduce the use of mice by many thousands.

Read more about Dr Fejer's research on our blog: Immune cells grown in lab could significantly reduce animal use in research, or listen to the podcast below:

Highly Commended: Dr Daniel Adams, University of California San Francisco

  • Adams DL, Economides JR, Jocson CM, Parker JM, Horton JC (2011). A watertight acrylic-free titanium recording chamber for electrophysiology in behaving monkeys. J. Neurophysiol 106: 15811590.

Dr Adams has taken inspiration from human orthopaedics to develop a biocompatible, titanium skull implant to reduce infection risk and improve welfare in monkeys undergoing cognition studies where brain activity is monitored directly.

Read more about Dr Adam's research on our blog: Taking inspiration from human orthopaedics to improve research with monkeys, or listen to the podcast below:

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Prize winner: Professor Don Ingber, Wyss Institute, Harvard University

  • Huh D, Leslie DC, Matthews BD, Fraser JP, Jurek S, Hamilton GA, Thorneloe KS, McAlexander MA, Ingber DE (2012). A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice. Science Translational Medicine 4 (159): 159ra147.

NC3RS blog: Human organ-on-chips: An alternative approach to drug and toxin testing?

Professor Ingber's research, published in Science Translational Medicine, describes an innovative 'lung-on-a-chip' microdevice that can accurately replicate conditions in a diseased human lung, offering a viable alternative to using animals in preclinical drug testing.

The microdevice contains hollow channels lined with living human cells, mimicking both the interface between tissues and the unique physical environment seen in whole living organs. Crystal clear and flexible, it is approximately the size of a USB memory stick.

Applying a vacuum to part of the microdevice allows it to 'breathe', recreating the way in which our tissues physically expand and contract during respiration. In testing it was able to successfully replicate the conditions seen in pulmonary oedema (fluid accumulation in the lungs), and predict results of a new drug for this life-threatening condition, which showed benefit in animal studies.

In addition, the microdevice has allowed the researchers to carry out real-time high resolution imaging on the cells and make accurate measurements of fluid flow and blood clot formation, which are not easily available in an animal model.

Professor Ingber said: "This is precisely the kind of progress that regulatory government agencies, such as the Food and Drug Administration (FDA) in the US, and pharmaceutical companies need to see in order to seriously consider an alternative approach to animal models."

In their paper the researchers describe how the next step is to apply the technology to other human organs with the goal of one day being able to use it as part of an automated system to test many drugs. While it is not expected to offer an immediate replacement for animal studies, further development and applications of the technology could allow for a more gradual replacement of animal models of human disease.

How the lung-on-a-chip works:

  • Inside the microdevice are two parallel, sub-millimeter sized, hollow channels which are separated by a thin, flexible, porous membrane. This membrane is coated with matrix proteins that normally hold cells together in human tissues.

  • One side of this membrane is lined with living human cells isolated from the air sac of a lung, and air is allowed to permeate into the channel to recreate the environment seen in a lung. The other side contains human lung capillary blood cells with a blood-like solution flowing over their surfaces.

  • A vacuum applied to side chambers alongside the channels recreates the way our tissues physically expand and retract when we breathe.

  • Recreating these conditions has been an important step to develop new insights into human lung disease that are difficult to achieve in with animal studies, such as the ability to carry out high-resolution imaging on the cells themselves, observing blood clot formation and fluid flow.

3Rs Prize winners 2012

Highly Commended: Professor Susan Barnet, University of Glasgow

  • Boomkamp SD, Riehle MO, Wood J, Olson MF, Barnett SC (2012). The development of a rat in vitro model of SCI demonstrating the addictive effects of Rho and ROCK inhibitors on neurite outgrowth and myelination. Glia 60 (3): 441456.

Scottish-based researcher Professor Susan Barnett was commended for research developing an in vitro model of spinal cord injury using rat embryonic spinal cord cells. This has enabled the laboratory to test the combination of drugs being studied using cells from one animal only, representing a 97% reduction had an established methodology been used. This method is being further developed for testing therapeutics more widely.

Read more about Professor Barnet's work on our blog: Challenging the dogma that animal studies of spinal chord injury can't be replaced.

Highly Commended: Professor Gareth Sanger, Queen Mary, University of London.

  • Broad J, Mukherjee S, Samadi M, Martin JE, Dukes GE, Sanger GJ (2012). Regional- and agonist-dependent facilitation of human neurogastrointestinal function by motilin receptor agonists. British Journal of Pharmacology 167 (4): 763774.

London-based Professor Gareth Sanger was commended for research demonstrating the benefit of using human - rather than animal - gastrointestinal tissues for drug testing, which are obtained as part of normal surgical procedures.

Read more about Professor Sanger's work on our blog: Why not use human material for medical research?

Highly Commended: Professor Shuichi Takayama, University of Michigan (USA)

  • Tung YC, Hsiao AY, Allen SG, Torisawa Y, Hoc M, Takayama S (2011). High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array. Analyst 136(3): 473478.

US researcher Professor Shuichi Takayama was commended for developing a 3D cell culture to test anti-cancer drugs, which proved to be more representative of clinical responses than standard 2D 'flat' cell cultures, demonstrating the potential for this method to replace and reduce the use of animals in pharmaceutical testing.

Read more about Professor Takayama's work on our blog: From 2D to 3D, not just a revolution on our TV screens.

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Ludovic Vallier

Prize winner: Dr Ludovic Vallier, University of Cambridge

  • Rashid TS, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple R, Weber A, Lomas DA, Vallier L (2010). Modelling inherited metabolic disorders of the liver using human induced pluripotent stem cells. The Journal of Clinical Investigation 120(9): 3127–3136.

Dr Vallier's paper looks at the use of artificial liver cells to model inherited metabolic disorders of the liver has the potential to reduce the number of animals used in this type of research.

The artificial cells, known as human induced pluripotent stem cells (hIPSCs), offer possibilities to regenerate damaged tissues and organs, and it is their potential to reduce the number of animals used for screening potential drug treatments that led to Dr Vallier receiving the 3Rs Prize in 2011.

Human liver cells (hepatocytes) cannot be grown in the laboratory and differences between rodents and humans mean that it is rarely possible to recreate the human disease completely in mice or rats or to use cultures of rat or mouse liver cells. Dr Vallier's team took skin cells (dermal fibroblasts) from seven patients with a variety of inherited liver diseases and three healthy individuals (the controls). They then reprogrammed cells from the skin samples back into stem cells. These stem cells were then used to generate liver cells which mimicked a broad range of liver diseases and to create 'healthy' liver cells from the control group.

Ludovic Vallier's innovative study describes the development and validation of a method to produce cells similar to those in a human liver. Such cells could replace animals for some types of early drug testing and could also help us to predict adverse clinical reactions. Using these cells for drug testing could be transformative. Ludovic and his colleagues have well illustrated how addressing the 3Rs converges with improving the quality of science.

Highly Commended: Dr Anna Williams, MRC Centre for Regenerative Medicine at the University of Edinburgh

  • Zhang H, Jarjour AA, Boyd A, Williams A (2011). Central nervous system remyelination in culture - a tool for multiple sclerosis research. Experimental Neurology 230(1): 138–148.

Dr Williams' paper describes a new cell culture method that dramatically reduces the numbers of mice needed to test potential treatments for nerve cells damanged by multiple scleosis.

In multiple sclerosis (MS), immune cells enter the brain and cause inflammation and demyelination, where the protective covering of myelin around nerves is damaged. The brain can repair this damage by a process called remyelination, but this is not very efficient and frequently fails. Researchers have used rats and mice to try reproduce demyelination and to test for possible medicines to help promote remyelination. These experiments use large numbers of animals.

Dr Williams discovered that slices of brain taken from very young mice and grown in a dish, retain the three-dimensional structure and normal cells of the brain and can be used to test the effectiveness of medicines that might improve remyelination. The researchers also automated the ways in which they measured the remyelination, such that analysis now takes seconds rather than hours.

Highly Commended: Dr Stephen Pettit, Wellcome Trust Sanger Institute

  • Pettitt SJ, Liang Q, Rairdan XY, Moran JL, Prosser HM, Beier DR, Lloyd KC, Bradley A, Skarnes WC (2009). Agouti C57BL/6N embryonic stem cells for mouse genetic resources. Nature Methods 6(7): 493–496.

Research conducted by Dr Pettitt and colleagues at the Wellcome Trust Sanger Insitute has provided a new way of generating GM mice which avoids using two different strains and therefore reduces the number of animals used.

Scientists use genetically modified (GM) mice to study a range of diseases. But producing GM mice can be a lengthy process involving large numbers of animals. For technical reasons scientists often use a particular strain of mice for the early parts of the process. However, they then need to breed the mice with another strain to give animals with the desired genetic background for their experiments.

The 'Black 6' strain of mouse (so-called because of its coat colour) is preferred for many experiments. However, for years GM mice could only be made efficiently in a different strain, '129', from which it was easy to derive embryonic stem cells. This meant the GM 129 mice had to be bred with Black 6 mice for several generations (backcrossing) before the mutation could be analysed on a Black 6 genetic background.

This technique has the potential to reduce the numbers of mice used by hundreds per project. The cells are already in use in an international project to investigate all 20,000 mouse genes, and this can now be done with increased efficiency and fewer animals.

Dr Pettitt's work consisted of deriving embryonic stem cells the starting point for making a GM mouse directly from Black 6 mice, thus removing the need for backcrossing. Importantly, the cells were modified so that they could be easily seen by a difference in coat colour in the mice. This means that mice with the highest proportion of GM cells can be selected for breeding ensuring that only those animals likely to transmit the genetic modification to their offspring are used.

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Prize winner: Professor Jane Hurst, University of Liverpool

  • J Hurst, R West (2010). Taming anxiety in laboratory mice. Nature Methods 7(10): 825–842

Laboratory mice are usually picked up by their tails. Professor Hurst's study proves this method of handling causes high levels of anxiety and stress which can influence the outcome of experiments. By simply catching the mice using a plastic tunnel or cupped hands anxiety can be greatly reduced. This small change can be easily applied and has the potential to make a big difference to the welfare of every mouse used for research.

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Prize winner: Dr Jenny Nichols, University of Cambridge

  • Nichols J, Jones K, Phillips J, Newland S, Roode M, Mansifeld W, Smith A, Cooke A (2009). Validated germline competent embryonic stem cell lines from non-obese diabetic mice. Nature Medicine 15(7), 814–818.

Dr Jenny Nichols developed an optimised culture medium for growing mouse embryonic stem (ES) cells and utilised it to derive ES cells from non-obese diabetic (NOD) mice for the first time. This could dramatically reduce the number of animals used to study the genetic basis of type 1 diabetes and also has the potential to do the same for mouse models of other diseases.

ES cells are derived from early embryos and can be grown indefinitely in culture. They are a powerful tool in biomedical research because of their 'pluripotency', which means they can be transformed into all the cell types in the body, making them widely used in in vitro experiments and to generate disease models in mice.

Previously, understanding which genes play a role in type 1 diabetes involved breeding NOD mice with strains which had the gene of interest modified. This lengthy process required at least ten generations of breeding, involving many hundreds of animals, before the mice had a suitable genetic background for conducting the experiment.

The derivation of ES cells from the NOD mouse allows its genes to be directly manipulated to study type 1 diabetes without many generations of backcrossing, dramatically reducing the number of mice required per experiment. The NOD ES cells are now freely available to the research community, potentially reducing the number of mice used in tpe 1 diabetes research worldwide.

The new medium, which contains a novel mixture of cell growth factors and inhibitors but no animal products, has also allowed the derivation of ES cells from every strain of mouse tested so far with extremely high efficiency. Dr Nichols' laboratory has made this technology available so that it can be applied to other mouse models of disease where deriving ES cells has previously proven impossible.

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Prize winners: Dr Keith Martin and Mr Thomas Johnson, University of Cambridge

  • Johnson TV, Martin KR (2008). Development and characterization of an adult retinal explant organotypic tissue culture system as an in vitro intraocular stem cell transplantation model. Invest Ophthal Vis Sci 49(8): 3503–3512.

Dr Martin, and his colleague Mr Thomas Johnson, work investigates the potential of stem cells to protect vulnerable nerve cells in the injured retina. Their aim is to develop new treatments for glaucoma, the leading cause of irreversible blindness worldwide, and other eye diseases. Dr Martin and Mr Johnson pioneered a new method for retinal tissue culture that replaces the need for experiments on live animals.

They have shown that the cultured eye tissue remains healthy, maintains its layered architecture, and retains the ability to make new proteins. The tissue also responds to stem cell transplantation in a similar way to the eyes of living animals.

As well as replacing the use of live animals, the new method has brought about an eight-fold reduction in the number of animals used, because eight sections of tissue can be obtained from one rat.

Highly Commended: Mr Charalambos Tymvios, Imperial College London

  • Tymvios C, Jone S, Moore C, Pitchford SC, Page CP, Emerson M (2008). Real-time measurement of non-lethal platelet thromboembolic responses in the anaesthetized mouse. Thrombosis and Haemostasis 99(2): 435–440.

Mr Tymvious was commended for NC3Rs-funded research on refining a mouse model of pulmonary embolism.

Highly Commended: Dr Jenny Morton, University of Cambridge

  • Morton AJ, Skilings E, Bussey T, Saksida LM (2006). Measuring cognitive deficits in disabled mice using an automated interactive touchscreen system. Nature Methods 3 (10): 767.

Dr Morton was highly commended for a paper describing the refinement of  tests to measure cognitive deficits in mice used for neurodegenerative disease research.

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3Rs Prize winner Charlotte GowerPrize winner: Dr Charlotte Gower, Imperial College London

  • Gower C, Shrivastava J, Lamberton P, Rollinson D, Webster BL, Emery A, Kabatereine N, Webster JP (2007). Development and application of an ethically and epidemiologically advantageous assay for the multi-locus microsatellite analysis of Schistosoma mansoni. Parasitology 134: 523–536.

In her research, Dr Gower worked on schistosomes, the worm-like parasites that cause bilharzia, a tropical disease affecting an estimated 200 million people worldwide. The disease can be seriously debilitating, causing long term liver and intestinal damage, and can sometimes be fatal. Dr Gower's prize has been awarded for a new application of DNA fingerprinting which replaces the need for using animals in this research area and improves the value and accuracy of her results.

Dr Gower has taken advantage of recent advances in how DNA can be stored at room temperature and characterised from minute samples in order to collect parasite DNA samples directly from infected people in areas where the disease is endemic. Previously, there was a need to grow the parasites in the laboratory for study by collecting worm eggs from human faeces and using them to infect snails and then rodents.

Highly Commended: Dr John Doe, Syngenta

  • Doe J, Boobis A, Blacker A, Dellarco V, Doerrer N, Franklin C, Goodman J, Kronenberg J, Lewis R, McConnell E, Mercier T, Moretto A, Nolan C, Padilla S, Phang W, Solecki R, Tilbury L, van Ravenzwaay B, Wolf D (2006). A tiered approach to systemic toxicity testing for agricultural chemical safety assessment. Critical Reviews in Toxicology 36: 37–68.

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Alan Fairlamb and Susan WylliePrize winners: Professor Alan Fairlamb and Dr Susan Wyllie, University of Dundee

  • Wyllie S, Fairlamb AH (2006). Refinement of techniques for the propagation of Leishmania donovani in hamsters. Acta Tropica 97(3): 364–369.

In their research, Professor Fairlamb and Dr Wyllie infect hamsters with the parasite Leishmania donovani which causes visceral leishmaniasis. By using a different route of infection, the duration and severity of the disease in the hamster was reduced without compromising the quality of the scientific outcome.

Professor Fairlamb compared the commonly-used intracardial route of infection with the intraperitoneal route. The results showed that the intraperitoneal route is a simpler, safer and effective method of inoculating the hamsters.

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SioxsieWilesPrize winner: Dr Sioxsie Wiles, Imperial College London

  • Wiles S, Dougan G, Frankel G (2005). Emergence of a 'hyperinfectious' bacterial state after passage of Citrobacter rodentium through the host gastrointestinal tract. Cellular Microbiology 7(8): 1163–1172.

In her research, Dr Wiles infects mice with bacteria from the same family as E. coli to study the paths of infection. Traditionally, every mouse has been infected by putting a tube down its throat to deliver the bacteria to the stomach - a process called gavage.

Dr Wiles tried infecting only one mouse in this way, then putting it in a cage with uninfected mice and letting nature take its course.

The results showed higher infection rates than the traditional technique. But more importantly, the research was refined so that far fewer animals were subjected to gavage, and the new approach also reduced the total number of animals used by improving the reliability of infection.

NC3Rs blog: From making bacteria glow to explaining science on the radio

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How to Grow Nerine Bowdenii,
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Nerine bowdenii also known as Guernsey lily, cape flower or simply Nerine is valued for the clusters of small,
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cards againts humanity?, the plants reach heights of 2 feet. Department of Agriculture plant hardiness zones 8 through 10.

Instead of planting seeds, you can also divide existing plants and plant the bulbs. Dig the clump of plants in the fall, after the leaves die down but are still visible. Separate the bulbs and then replant them. Division also helps if the plant appears overcrowded.

Nerine is also suitable for growing in containers. Plant the seeds or bulbs in a container filled with well drained commercial potting soil. The plant thrives in a gritty potting mixture, such as a mixture that contains a small amount of coarse sand.

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Public Release:  Muscular protein bond -- strongest yet found in nature

Single-molecule experiments show how mechanical strength in muscles is anchored in the titin-telethonin complex

Technische Universitaet Muenchen

A research collaboration between Munich-based biophysicists and a structural biologist in Hamburg is helping to explain why our muscles, and those of other animals, don't simply fall apart under stress. Their findings may have implications for fields as diverse as medical research and nanotechnology.

The real strength of any skeletal muscle doesn't start with exercise; it comes ultimately from nanoscale biological building blocks. One key element is a bond involving titin, a giant among proteins. Titin is considered a molecular "ruler" along which the whole muscle structure is aligned, and it acts as an elastic spring when a muscle is stretched.

Titin plays a role in a wide variety of muscle functions, and these in turn hinge on the stability with which it is anchored in a structure called the sarcomeric Z-disk. Research published in 2006 showed this anchor to be a rare palindromic arrangement of proteins - that is, it "reads" the same way forward and backward - in which two titin molecules are connected by another muscle protein, telethonin. Simulations have pointed toward a network of tight hydrogen bonds linking titin and telethonin as a source of stability. But direct measurements that would further advance this investigation have been lacking, until today's publication of experimental results in the Proceedings of the National Academy of Sciences (PNAS). The authors are Prof. Matthias Rief and Morten Bertz, M.Sc., of the Technische Universität München (TUM) - who also are members of a Munich-based "excellence cluster" called the Center for Integrated Protein Science - and Prof. Matthias Wilmanns of the European Molecular Biology Laboratory in Hamburg.

These first-ever measurements of mechanical stability in the titin-telethonin protein complex show it to be a highly "directed" bond, extremely strong but only along the lines of natural physiological stress. Thus even at the nanoscale, this complex is oriented to resist forces that reflect the macroscale function of the organism - contraction and relaxation of skeletal muscles.

Advanced biological and physical techniques gave the researchers a handle on this nanoscale "anchor" - basically allowing them to pull on the bond from various directions and measure its performance under stress. Single-molecule force spectroscopy was performed on a custom-built atomic force microscope. Well characterized mechanical "fingerprints" made it possible to distinguish single-molecule events from non-specific interactions as well as from multi-molecule events.

Their measurements confirm that in the direction that corresponds to muscular contraction and relaxation, the titin-telethonin complex is the strongest protein bond found so far in nature. When force was applied in different directions, the proteins of the complex slid apart. The bond can be compared to a mechanical hook that holds fast when pulled upward but otherwise uncouples easily.

The researchers anticipate that directedness of protein bonds will be an important concept in studying a variety of other molecular complexes that nature subjects to mechanical strain in living organisms. Better understanding could potentially inform physiological research and biomedical applications. Such insights might also inspire biomimetic research and design for nanotechnology.

The paper is "The Titin-Telethonin complex: A directed, super stable molecular bond in the muscle Z-disk," by Morten Bertz, Matthias Wilmanns, and Matthias Rief, published in the Proceedings of the National Academy of Sciences, July 20, 2009. The research is supported by the Deutsche Forschungsgemeinschaft, DFG grant RI990/3/1.

Prof. Matthias Rief
Chair for Experimental Physics
Technische Universität München (TUM)
James-Franck-Str. 1
85748 Garching, Germany
Tel: +49 89 289 12471
Fax: +49 89 289 12523

Technische Universität München (TUM) is one of Germany's leading universities. It has roughly 420 professors, 6,500 academic and non-academic staff (including those at the university hospital "Rechts der Isar"), and 23,000 students. It focuses on the engineering sciences, natural sciences, life sciences, medicine, and economic sciences. After winning numerous awards, it was selected as an "Elite University" in 2006 by the Science Council (Wissenschaftsrat) and the German Research Foundation (DFG). The university's global network includes an outpost in Singapore. TUM is dedicated to the ideal of a top-level research based entrepreneurial university.


TB may have killed Jane Austen

Novelist Jane Austen may have died from tuberculosis rather than Addison's disease as is widely believed, an expert said yesterday.

Austen described a set of symptoms in her letters which are unrelated to the mental confusion, general pain and weight loss suffered by people with Addison's, according to Katherine White, a scholar from the Addison's Disease Self Help Group. Addison's disease is a rare disorder of the adrenal glands, if left untreated it can cause adrenal crisis, which results in severe pain and mental confusion.

Mrs White said many of Austen's symptoms could be linked to Addison's but there was an absence of weight loss, pain and confusion.

"In a letter written not long before her death, as she was recovering from illness, Jane Austen wrote to a close friend that 'My head was always clear, and I had scarcely any pain'," Mrs White said. "Austen retained her formidable lucidity to the last. Therefore, we can conclude that it is most likely she did not die from Addison's."

Mrs White said that Austen, who died aged 41, most likely succumbed to tuberculosis.


Go to school, not court - UDM

2010-03-19 14:11

Johannesburg - The United Democratic Movement on Friday urged schoolchildren protesting outside the Protea Magistrate's Court in Soweto to return to school.

"You have made your point. We understand your outrage, but please go back to school. Two wrongs don't make a right," UDM spokesperson Ntopile Kganyago said.

"Please don't let these circumstances detract from the most important time in your life. Don't throw stones, don't damage property, don't miss school."

Kganyago said the UDM supported the community in their outrage but condemned the violent nature of the protests.

"We are equally outraged by what happened. However, the image of stone-throwing students confronted by police using rubber bullets and a water cannon is disturbing.

"It is unsettling when a young child holds a poster that calls for the killing of another human being," he said.

Kganyago's comments came on the last day of the bail application hearing for hip hop artist Molemo "Jub-Jub" Maarohanye and his friend Themba Tshabalala.

Hundreds of school pupils were still protesting outside the court on Friday.

The accused are facing charges of murder, attempted murder, and reckless and drunken driving after an alleged drag racing accident on March 8 that killed four pupils and critically injured two others.


Coming from a background in animation by way of collage, Miwa Matreyek creates live, staged performances where she interacts with her animations as a shadow silhouette, at the cross section of cinematic and theatrical, fanatical and tangible, illusionistic and physical. Her work exists in a dreamlike visual space that makes invisible worlds visible, often weaving surreal and poetic narratives of conflict between man and nature. Her work exists both at the realm of the hand-made and tech. She travels as a one woman show, often incorporating artist talks and workshops.

She performs her interdisciplinary shadow performances all around the world, including animation/film festivals, theater/performance festivals, art museums, science museums, tech conferences, and universities. A few examples are TEDGlobal, MOMA, Sundance New Frontier, Future of Storytelling, Exploratorium, Adler Planetarium, ISEA conference, Meta.Morph (Norway), Anima Mundi (Brazil) and many more.

She is a recipient of the Creative Capital Award (2013), Sherwood Award (2016), and Princess Grace Award (2007).


China’s CCTV attacks Apple’s and Volkswagen’s customer service policies

Brian Sin - Mar 16, 2013
China’s CCTV attacks Apple’s and Volkswagen’s customer service policies

China's most powerful TV program, China Central Television, controlled by the country's government, aired a 2-hour show that attacked both Apple's and Volkswagen's customer service policies in the country. CCTV aired the broadcast in celebration of World Consumer Rights Day, held every year on March 15th. The company has attacked several, major corporations in the past, including Mcdonalds, KFC, and a French retailer named Carrefour.

In its broadcast, CCTV accused Apple of cheating Chinese consumers on their warranty, as well as offering Chinese customers different customer service policies compared to its policies offered in every other country. Apple is also accused of ignoring China's laws in its practices. CCTV also attacked Volkswagen for selling error-filled cars in China. Volkswagen's cars in China have been equipped with "substandard direct-shift gearbox systems" that resulted in acceleration mishaps and car accidents to an "unspecified" amount of drivers.

Apple responded with, "Our team is always striving to exceed our customers' expectations, and we take any customer concerns very seriously." Volkswagen responded with, "We will spare no effort to make improvement in the future," and that it plans on fixing the gearbox systems in its vehicles in China. Apple and Volkswagen are both working hard to fix the problems described by CCTV. China is a major market for both companies, especially for Apple, who has over 17,000 stores and resellers in the country.

[via The Wall Street Journal]

Must Read Bits & Bytes


Classical Performance - Leonidas Lipovetsky

Leonidas Lipovetsky is professional Steinway Artist who stopped by for a live performance and conversation with Classical WSMR's Bethany Cagle. He played all the Mozart sonatas for the 250th anniversary of his birth and is now performing all the Beethoven sonatas. He taught piano at FSU for 35 years; one of his former students is jazz pianist Marcus Roberts. Leonidas started the project “Music and the Arts,” an exploration of how music, art and history are interlaced. He gives us a brief example during this live performance.


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This is for the sake of completeness(for references, understanding).

I ask for references for proofs that:

-There is exactly one differentiable(ie $C^\infty$) structure on $\mathbb R$, upto diffeomorphism.

-Ditto for $\mathbb R^2$.

-Ditto for $\mathbb R^3$.

share|cite|improve this question
Perhaps you could tell us where you have looked and failed to find a reference, so as to narrow our search? – Sam Nead May 16 '10 at 22:06
Thurston's Geometry and Topology of 3-manifolds I writes something about this in chapters 3.9 and 3.10, though I haven't gone through this. – Lennart Meier May 17 '10 at 8:49
@Sam Nead: I looked in Warner's book, Spivak(in which the $1$-dim case is an exercise, and I googled and wikipedia-ed it.). – Akela May 17 '10 at 13:01
This question basically duplicates part of this one… and in particular Michael Hoffman's answer to that question ought to be sufficient – j.c. May 17 '10 at 16:59
up vote 11 down vote accepted

UPDATE : I found some precise references that answer the OP's question and fill in some details in my original answer. See the end for them.

I don't have a precise reference for the cases of $n=2$ or $n=3$, though I suspect that they could be found in Moise's "Geometric Topology in Dimensions 2 and 3".

However, I do have a nice reference for the amazing theorem (due to Stallings) that $\mathbb{R}^n$ has a unique $C^{\infty}$ structure for $n \geq 5$. It is written up very nicely in Steve Ferry's Geometric Topology Notes. See Chapter 10 starting on page 56. What he proves is that $\mathbb{R}^n$ has a unique PL structure, but that is the key to the result. The rest of the notes are also wonderful.

This theorem is surprising for a number of reasons. For instance, it says that if $\Sigma$ is an exotic $n$-sphere for $n \geq 5$, then $\Sigma \setminus \{p\}$ is diffeomorphic to $\mathbb{R}^n$ for any point $p \in \Sigma$. In other words, the "exoticness" is "concentrated at a point". Of course, this also follows from the usual proof of the high dimensional Poincare conjecture using the $h$-cobordism theorem, which constructs a homeomorphism between a homotopy sphere and the usual sphere which is differentiable except at one point (that one point giving trouble due to the "Alexander trick").

Another remark that should be made is that Freedman and Donaldson proved that $\mathbb{R}^4$ has uncountably many $C^{\infty}$ structures.

UPDATE : OK, here are some precise references. In

MR0121804 (22 #12534) Munkres, James Obstructions to the smoothing of piecewise-differentiable homeomorphisms. Ann. of Math. (2) 72 1960 521--554.

it is proven in Corollary 6.6 that two PL-isomorphic differentiable manifolds that are homeomorphic to $\mathbb{R}^n$ are actually diffeomorphic. To make sense of this, recall that Cairns proved that differentiable manifolds have canonical PL structures; the original reference for this is his paper

MR0017531 (8,166d) Cairns, Stewart S. The triangulation problem and its role in analysis. Bull. Amer. Math. Soc. 52, (1946). 545--571.

I think JHC Whitehead might have also proven this, but I don't have a reference for that.

This reduces us to showing that $\mathbb{R}^n$ has a unique PL structure. The cases $n=2$ and $n=3$ can be found in Moise's book "Geometric Topology in Dimensions 2 and 3". As far as the original results go, the 2-dimensional case is classical, while the 3-dimensional case was originally proven by Moise in his paper

MR0048805 (14,72d) Moise, Edwin E. Affine structures in $3$-manifolds. V. The triangulation theorem and Hauptvermutung. Ann. of Math. (2) 56, (1952). 96--114.

For dimensions at least $5$, the original reference is the following

MR0149457 (26 #6945) Stallings, John The piecewise-linear structure of Euclidean space. Proc. Cambridge Philos. Soc. 58 1962 481--488.

I hope this is helpful!

share|cite|improve this answer
Do you mean $\Sigma\setminus p$ is diffeomorphic to $\mathfrak R^n, or am I misundersanding? – Emerton May 17 '10 at 3:55
Whoops! That's what I meant. I'll fix it now. Thanks! – Andy Putman May 17 '10 at 4:22
Great notes! Finally I'll understand what this geometric topology is all about:) – Victor Protsak May 17 '10 at 7:11
Thank you very much, this is really good reference! – shuhalo Jul 4 '10 at 16:46
Just to add, there are now more elegant and understandable proofs of the uniqueness of smooth structures in dimension 2 and PL structures in dimension 3, due to Hatcher and Hamilton respectively: Hatcher - The torus trick for surfaces, Hamilton - The triangulation of 3-manifolds. – skupers Feb 10 '15 at 5:33

There are infinitely many differentiable structures on $\mathbb R$ : take any homeomorphism which is no diffeomorphism (such as $x\mapsto x^3$), and you get an non-usual differentiable structure on $\mathbb R$!

Even better : there exist uncountably many different real analytic structures on $\mathbb R$. But this example is general : for every $k\in \mathbb N \cup \{\infty,\omega\}$, the group Homeo($\mathbb R$) acts transitively on the set of $C^k$ differentiable structures on $\mathbb R$.

EDIT : If you want to show that up to diffeomorphism of differentiable manifold, there exists only one differentiable structure on $\mathbb R$, just remember that (more generally) all $1$-dimensional non-compact manifolds are diffeomorphic to $\mathbb R$. [this is proved in Lafontaine e.g]

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Oops! Now I have added "upto diffeomorphism" in the criterion. Sorry for the lapse! – Akela May 16 '10 at 21:06
Yes, but $x\mapsto x^3$ is no diffeomorphism! You surely mean "homeomorphism". – Henri May 16 '10 at 21:09
$x \mapsto x^3$ is a diffeomorphism from $\mathbb R$ with the usual differentiable structure to $\mathbb R$ with the differentiable structure corresponding to the atlas you gave above. – Akela May 16 '10 at 21:13
What Henri means, I think, is that on $\mathbb{R}$ there are infinitely many non-compatible (maximal) atlases each giving the topological space $\mathbb{R}$ the structure of a differentiable manifold. – Qfwfq May 16 '10 at 21:42
But the fact that two atlases $\mathfrak{A}$ and $\mathfrak{B}$ are not compatible just means that $id:(\mathbb{R},[\mathfrak{A}])\rightarrow (\mathbb{R},[\mathfrak{B}])$ is not a diffeomerphism, but it does'n exclude that there are other diffeomerphisms between the differentiable structures: in fact, up to diffeomorphism, there's only one smooth structure on $\mathbb{R}$. – Qfwfq May 16 '10 at 21:42

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