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A feed of all posts from all FOS blogs.
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    Last week I had the immense pleasure again of having lunch with Freeman Dyson in Princeton. One of the myriad topics on the platter of intellectual treats on the table was the idea of science as a tool-driven rather than as an idea-driven scientific revolution. The framework was fleshed out in detail by Harvard historian of science Peter Galison in his highly readable book "Image and Logic" and was popularized by Dyson in his own book and article. I wrote a post on that particular paradigm last year.

    Since physics had profited immensely from idea-driven revolutions in the 20th century (most notably relativity and quantum theory) that were enshrined by Thomas Kuhn in his idea of paradigm shifts, it took physicists some time to appreciate how tools like the cyclotron, the cloud chamber, the CCD and the laser have played an equal part in their revolutionary history. But as I told Dyson, chemists on the other hand have absolutely no problem accepting the idea of tool-driven revolutions. Chemistry more than physics is an experimental science where first principles theories are often too complicated to put into practice. Chemists have thus benefited much more from experimental toys rather than fancy theorizing, and in no other case has the ascendancy of such toys been more prominent than in the case of x-ray crystallography and NMR spectroscopy. It's hard to overstate how much these two techniques have revolutionized not just our understanding of the world of molecules but of other domains, like biology and engineering. Last year's Nobel Prize for microscopy was likewise a fitting tribute to the supremacy of tools in chemical and biological research.

    Now a new technique joins the arsenal of structural weapons, and I have little doubt that it too is going to be part of a revolution - cryo-electron microscopy. ACS has a nice article on how much the technique has advanced in the last decade and how prominently it is poised to be applied to structural problems that have been recalcitrant to the old approaches. During the last few years use of the technique has skyrocketed: as this Nature article compellingly describes, cryo-EM can acquire structures of ribosomes in weeks or months that took Nobel Prize-winning scientists years to solve. And as the article says, even this revolution has benefited from a crucial tool-within-a-tool.
    Over the years, gradual progress in computational power and microscope quality has yielded higher and higher resolution structures. Up until the past few years, most cryo-EM structures clocked in at well above 10-Å resolution, about the size of an amino acid. Between 2002 and 2012, only 14 structures determined by EM crossed the 4-Å threshold, dipping a toe in high-resolution territory. But a true breakthrough came in 2012 when a new toy—the direct electron detector—opened the gates, allowing for a flood of high-resolution cryo-EM structures. In 2014 alone, 27 structures have reached sub-4-Å resolution, and scientists keep pushing the boundaries. “The direct electron detector has been the biggest game changer for the electron microscopy field,” says Melanie D. Ohi of Vanderbilt University.
    The direct electron detector joins a long list of specialized instruments like the Bunsen burner, the Kirchhoff spectroscope, the scintillation counter and the Geiger counter, all of which proved to be key appendages of the larger technologies which they were enabling. A good counterpart to the direct electron detector would be the CCD which revolutionized tools like cameras and telescopes and which was awarded a Nobel Prize a few years ago.

    Cryo-EM will almost certainly make a big splash in the world of drug discovery in the upcoming decades. However, better experimental tools alone won't suffice for this revolution. It's sometimes underappreciated how important software and hardware were in enabling the routine application of NMR and crystallography to tough biological problems in drug design. The advent of cryo-EM similarly opens up attractive opportunities for the development of specialized software and hardware that can handle the often fuzzy, low-resolution images coming out of cryo-EM. This will especially be important for multiprotein assemblies like modular enzymes and ribosomes where multiple solutions exist for a given dataset and where computational model building will be paramount. 

    As the technique proliferates, so will the data that it unearths. Someone will have to then make sense of this data, and scientific and financial rewards will await those who have the courage and foresight to found companies making specialized software for analyzing cryo-EM images. The founding of these companies with their custom hardware and software will itself be a paean to the tool-driven revolution in science, in this case one led by the computer. One tool both piggybacking on and enabling another tool, that's how science progresses.

    Added: Here's a nice application of cryo-EM in resolving crystals of the protein alpha-synuclein that are essentially 'invisible'.

    Image source

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  • 09/10/15--13:03: Dear Flat-landers
  • Hello, flat-landers. TPP here in British Columbia, Whistler to be exact. The weather has taken a turn to the sunny side, and right now it's hard to say how much sunshine, clear air, alpine hiking, and mountains a man (or woman) can take. It has been quite awhile since the Phactors were hiking in a high alpine zone, and then it was the Swiss Alps. There are a lot of handsome views, including this one, but they do get so mountainous. Unfortunately this time of year the alpine flora is done flowering but fall color is in fine form. Still some of the scenery is just great. You just can't see something like this in the upper midwest except maybe the the NW most corner of Lincolnland (joking). Sooner or later, our return to the maize and soybean desert will have to occur, but at this point, even though resorty things are now closing down until the snow begins to fall, our departure will not be rushed. The F1 reports that the home area has cooled off and some rain has provided relief to our late summer drought. Maybe it will be safe to return, but not until all the Whiskey Jack (nickname of gray jays) beer is gone. 

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    A coulpe of abstracts about e-learning:
    This paper presents a new framework for adding semantics into e-learning system. The proposed approach relies on two principles. The first principle is the automatic addition of semantic information when creating the mathematical contents. The second principle is the collaborative tagging and annotation of the e-learning contents and the use of an ontology to categorize the e-learning contents. The proposed system encodes the mathematical contents using presentation MathML with RDFa annotations. The system allows students to highlight and annotate specific parts of the e-learning contents. The objective is to add meaning into the e-learning contents, to add relationships between contents, and to create a framework to facilitate searching the contents. This semantic information can be used to answer semantic queries (e.g., SPARQL) to retrieve information request of a user. This work is implemented as an embedded code into Moodle e-learning system.
    Iyad Abu Doush, Faisal Alkhateeb, Eslam Al Maghayreh, Izzat Alsmadi & Samer Samarah (2012). Annotations, Collaborative Tagging, and Searching Mathematics in E-Learning, arXiv: 1211.1780v1
    As far as Learning Management System is concerned, it offers an integrated platform for educational materials, distribution and management of learning as well as accessibility by a range of users including teachers, learners and content makers especially for distance learning. Usability evaluation is considered as one approach to assess the efficiency of e-Learning systems. It is used to evaluate how well technology and tools are working for users. There are some factors contributing as major reason why LMS is not used effectively and regularly. Learning Management Systems, as major part of e-Learning systems, can benefit from usability research to evaluate the LMS ease of use and satisfaction among its handlers. Many academic institutions worldwide prefer using their own customized Learning Management Systems; this is the case with Moodle, an open source Learning Management Systems platform designed and operated by most of the universities in Sri Lanka. This paper gives an overview of Learning Management Systems used in Sri Lankan universities, and evaluates its usability using some pre-defined usability standards. In addition it measures the effectiveness of Learning Management System by testing the Learning Management Systems. The findings and result of this study as well as the testing are discussed and presented.
    Selvarajah Thuseethan, Sivapalan Achchuthan & Sinnathamby Kuhanesan (2015). Usability Evaluation of Learning Management Systems in Sri Lankan Universities, Global Journal of Computer Science and Technology, 15 (1) arXiv: 1412.0197v2
    And the last abstract about the learning processo in neural network:
    We propose Neural Transformation Machine (NTram), a novel architecture for sequence-to-sequence learning, which performs the task through a series of nonlinear transformations from the representation of the input sequence (e.g., a Chinese sentence) to the final output sequence (e.g., translation to English). Inspired by the recent Neural Turing Machines [8], we store the intermediate representations in stacked layers of memories, and use read-write operations on the memories to realize the nonlinear transformations of those representations. Those transformations are designed in advance but the parameters are learned from data. Through layer-by-layer transformations, NTram can model complicated relations necessary for applications such as machine translation between distant languages. The architecture can be trained with normal back-propagation on parallel texts, and the learning can be easily scaled up to a large corpus. NTram is broad enough to subsume the state-of-the-art neural translation model in [2] as its special case, while significantly improves upon the model with its deeper architecture. Remarkably, NTram, being purely neural network-based, can achieve performance comparable to the traditional phrase-based machine translation system (Moses) with a small vocabulary and a modest parameter size.
    Fandong Meng, Zhengdong Lu, Zhaopeng Tu, Hang Li & Qun Liu (2015). Neural Transformation Machine: A New Architecture for Sequence-to-Sequence Learning, arXiv: 1506.06442v1

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    Today dawned bright and clear in the mountains, and at dawn the temperature was 46 F. And hour later it was 55 F. In another hour it will be 65 F and so on until topping out in the mid-80s. Such are the extremes in temperate mountains this time of year. Just returning from mountain top down to the valley floor yesterday, and the air was noticeably thicker, heavier. Today will probably be our last day suffering in all this clear, clean air. A friend having seen an image much like yesterday's blog said, "Canada is just one big postcard", of course she's never driven to Edmonton. For some fun and amusement, and a bit more, but less vigorous exercise, TPP is thinking about giving an electric assisted bicycle a try. As regular readers know, TPP likes funky bicycles, but has never had the chance to give one of these new electric jobs a try. How about this for an idea? Pick a micro-brewery as a destination, and re-fill a growler so that you can have a fresh cold one when you get back? A man, a plan, Panama! Just for the heck of it, here's another scenery pic from this post-card part of the world. The local whiskey jacks (gray jays) were hanging about hoping for some handouts. Their sense of entitlement is quite amazing.

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    The LHCb collaboration is studying the decay of mesons $B$ in order to find some violations in standard model rules. In particular LHCb has measured a particular ratio, named $R (D^*)$, between two decay modes of $\overline{B}^0$ and they find a violation from the standard model prediction that is compatible with other similar measures:

    In the SM all charged leptons, such as taus ($\tau$) or muons ($\mu$), interact in an identical fashion (or, in physicists' language, have the same "couplings"). This property is called "lepton universality". However, differences in mass between the leptons must be accounted for, and affect decays involving these particles. The $\tau$ lepton is much heavier than the $\mu$ lepton and therefore the SM prediction for the ratio $R(D^*)$ is substantially smaller than 1. This ratio is considered to be precisely calculable thanks to the cancellation of uncertainties associated with the $B$ to $D^*$ meson transition.
    But there is another hint of new physics. At the end of July Nature Physics published a new paper from the LHCb collaboration about the possible existence of a new particle:
    The LHCb collaboration published in Nature Physics a paper based on run 1 data which reports the determination of the parameter $|V_{ub}|$ describing the transition of a $b$ quark to a $u$ quark. This measurement was made by studying a particular decay of the $\Lambda_b^0$ baryon. Other measurements of $|V_{ub}|$ by previous experiments had returned two sets of inconsistent results, depending on which method was used to determine the parameter. Theorists had suggested that this discrepancy could be explained by the presence a new particle contributing to the decay process, which affected the result differently, depending on the measurement method. Today's result from LHCb removes the need for this new particle, while the puzzle of why the original sets of measurements do not agree persists.
    where $|V_{ub}|$ is connected to the Cabibbo-Kobayashi-Maskawa matrix.

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  • 09/12/15--16:21: Ducking out the back way
  • Our visit to Whistler ended today, and it was a bit complicated because no one told us about the Vancouver to Whistler bike race today, or what that might mean for people who wanted to got the other direction! Mountain and ocean views are wonderful, but traffic jams suck. So a new plan was devised, exit Whistler to the north, via Pemberton! The drive east up over the mountains was wonderfully scenic, except for the Yellow Arrow bus leading the way. The route is typical of low volume mountain roads, lots of tight turns, up and down, twisting and turning, from the pass following the Duffy Lake road down to the Fraser River valley, then more or less south, twisting and turning along river vallley route. It was very scenic and a fun drive, except for a bit of car sickness from one who doesn't take well to the previous mountain road features. This was not a route for people in a hurry, and it took a couple of hours longer than the regular route being used by the bike race, but driving in the rural Canadian mountains was much better than sitting in a traffic jam. Why waste a couple of hours watching people pedal uphill?  Oh, the day before our bicycle ride was taken on standard person-powered machines so nothing interesting to report on e-bicycles, other than standard bikes will never get TPP to give up his BikeE. Drat. Border crossing took 45 mins. with the usual snotty border agent attitude treating his bosses, citizens of the USA, badly. Grilled a salmon for din-dins.

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  • 09/13/15--05:47: Book report on apples
  • Frazz is one of TPP's favorite comic strips, and today's strip (Sept. 13, 2015) was a classic because it hit TPP right in the wheel house. Caulfield presents a report on apples, and nails it, especially the analysis of the "dreaded, mealy Red Delicious".  This variety happened because of selection on its parent, the Delicous, for better color and especially better storage life. The Delicious was actually a good tasting apple, but it's so rare now only a few apple affectionados still raise this variety. A good old boy in SW Michigan surprised TPP with some Delicious a few years back, although our top 4 list still wouldn't include that variety, it did demonstrate how selection for other characters damaged its taste and texture. 

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  • 09/13/15--15:07: Alexander Gerst's timelapse
  • Watch Earth roll by through the perspective of ESA astronaut Alexander Gerst in this six-minute timelapse video from space. Combining 12 500 images taken by Alexander during his six-month Blue Dot mission on the International Space Station this Ultra High Definition video shows the best our beautiful planet has to offer.
    Marvel at the auroras, sunrises, clouds, stars, oceans, the Milky Way, the International Space Station, lightning, cities at night, spacecraft and the thin band of atmosphere that protects us from space.
    Often while conducting scientific experiments or docking spacecraft Alexander would set cameras to automatically take pictures at regular intervals. Combining these images gives the timelapse effect seen in this video.
    Watch the video in 4K resolution for the best effect and find out more about Alexander Gerst's Blue Dot mission.

    (via ESA)

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    Peter Thiel has some provocative thoughts on biotechnology again, this time in an interview for Technology Review. I had a post earlier about Thiel's view of biotechnology which included some hardheaded, sensible thoughts and some more questionable skepticism. This interview projects a similar combination.

    The interview is really about Thiel's investment in Stemcentrx, a company utilizing our increasing knowledge of stem cell driven tumor evolution to create targeted therapy. As Derek noted in his post on the company it's an interesting approach but there's still a lot of holes that need to be plugged before it becomes reliable. Thiel's own take on the company is unsurprisingly positive, although it's not clear why he thinks the company's approach makes it particularly Thiel-worthy (he is known to be very judicious when it comes to funding startups). He seems to think that Stemcentrx's use of human xenografts in mice is something "very unusual", but I find Thiel's take on this quite unusual since drug discovery scientists have been using human xenografts in mice for decades so it's certainly not a novel idea. Also as Derek says in his post, just because a drug works in human xenografts does not mean it will work in humans.

    The real rub of the matter is Thiel's thoughts on "getting rid of randomness":

    "It’s interesting that a lot of technology outfits are getting into biology. Google has announced a number of plans. You have invested in longevity research. What do you think makes actual programmers want to start programming biology?"
     “The big picture is the question of whether biological science can be transformed into an information science. Can something that seems chaotic, fractal, and generally random be transformed into something more deterministic and more controlled? 
    I think of aging and maybe just mortality as random things that go wrong. The older you get, the more random things happen, the more breaks. If it’s not cancer, you could get hit by an asteroid. So on some level, technology is trying to overcome the randomness that is nature. That is a question on the level of a company. Can you get rid of randomness in building a company? But the philosophical version of the question is whether we can get rid of randomness in its entirety and overcome the randomness that I think of as the evil part of nature.”

    There are a couple of thoughts I have on this. Firstly, biological science has been increasingly transformed into information science for about fifty years now so that's not a brand new development. The problem is that just because it's information science does not mean it's deterministic; Thiel of all people should know how messy, incomplete and random information can be, and unlike him I certainly don’t see randomness as an “evil” (Darwinian evolution, anyone?). And even when the information is available it can be pretty hard to get a handle on it. People who do cheminformatics or bioinformatics for instance are well aware of the kind of false and messy correlations they can find even in information-rich datasets.

    There is no doubt that we can make headway into this problem with better algorithms and computing power, but to believe that somehow injecting enough programmers into biology will enable a quantum leap on the information analysis problem strikes me as a bit naive. Consider Thiel's thoughts on aging: aging is indeed a result of many imperceptible and perceptible random events. But the issue in addressing aging is not the lack of adequate computing approaches that would transform the randomness into predictability. It's the ignorance in understanding the randomness that shackles our ability to understand it in the first place. 

    A good analogy is provided by the random molecules of water molecules in a beaker. We know the movement is random, but we also know enough about this randomness to use the laws of quantum mechanics and statistical thermodynamics to provide accurate and predictable macroscopic descriptions of the random motion. Unlike this scenario, we don't have a complete picture of the randomness in aging (or in cancer for that matter) and we don't know what causes the randomness in the first place. The problem is not one of technology as Thiel seems to think, it's one of basic understanding. It's one of simple ignorance.

    The other peeve I have with thoughts like this is the implicit belief that somehow before the advent of programmers all the scientists working in biotechnology and drug discovery did not have either the ability or the inclination to get rid of randomness (It’s similar to the reaction we have about ‘rational drug design’ – does that mean everyone else was irrational before?). The fact of the matter is that chemists and biologists have been well aware of the randomness in biological systems for decades, and in fact one of the reasons we take random approaches (say phenotypic screening or diverse library design) to try to discover new drugs is precisely because we have studied the randomness and discovered it’s not particularly amenable to more rational approaches. In such cases the trial-and-error process which Thiel dislikes is the rational one; just consider the riches unearthed through pseudo-random directed evolution for instance.

    Sadly Thiel's thinking is not uncommon among technology entrepreneurs and is part of what Derek has called the "Andy Grove fallacy". The Andy Grove fallacy believes that the problem with drug discovery is a lack of technology and computing power; it’s what some people have called “technological solutionism”. But a lack of technology and a lack of basic understanding are two very different things. There is no doubt that we should use all the technology at our disposal to try to make the drug discovery process more rational and amenable to control. But we should also not believe that any particular discipline is going to transform this landscape, especially when we don't even have a good understanding of where its peaks and valleys lie.

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    A friend posted the link to this demonstration, wondering if it was safe. (Do listen to the children in the background - their cries of "kraken" at 1:02 are worth it.  Science is great fun!)

    The caption that came with it noted that it was a mixture of ammonium dichromate ((NH4)2Cr2O)and HgSCN (mercurous thiocyanate).1 Mercury and chromium, probably not something you want to eat I told my friend. The whole thing made me curious, just what were those tentacles come out of the burning pile? And what chemical reactions were driving it?

    It's a coupled set of decomposition reactions. The volcano comes from the decomposition of ammonium dichromate

    (NH4)2Cr2O7(s) → Cr2O3(s)+ N2(g)+ 4H2O(g)

    The reaction produces a lot of heat, which makes the particles being thrown off by the rapid expansion of the two gases (nitrogen and water vapor) glow.

    The heat then triggers the decomposition of the mercury compound:

    2 Hg(SCN)2(s) → 2HgS + 4CS2 + carbon nitrides

    The erupting tentacles are an example of intumescence2, a property of mercury thiocyanates noted long ago by the venerable Friedrich Wöhler3. It's a well known demonstration, often called Pharaoh's Serpents. Many material intumesce when heated, and thus produce their own insulation.  Some passive fire protection systems rely on this property of polymers, by which they essentially rapidly produce their own insulating layer upon heating, or by swelling up to block air ducts to prevent smoke and other gases from spreading too quickly through a ventilation system.

    It works with mercuric thiocynate as well (Hg(SCN)2) — by some accounts even better — and better yet if you toss a bit of potassium nitrate and a bit of fuel in the form of sugars. In other bits of historical trivia, the mercuric thiocyanate was originally made by the aptly named Otto Hermes. The sale of mercuric Pharaoh's Eggs ceased after some kids ate them with deleterious (fatal) effects.

    If you just want to see the snakes minus chromium salts or mercury - try this demonstration based on calcium gluconate instead or check out pyrotechnic expert Tenney Davis suggestions in the Journal of Chemical Education.

    1.  From the Latin verb "to swell" — related to thumb and tuber (as in root vegetables like potatoes)

    2.  The chemist who showed in 1828 that compounds made by nature do not have some "vital essence" that distinguishes them from the same structure crafted by a chemist from inorganic (never living) materials.  Something the Food Babe and hawkers of 'bioidentical' hormones do not get.

    Read more:

    Brian Clegg at Chemistry World.  A paper on the demonstration from Journal of Chemical Education in 1940, by Tenney Davis of MIT who taught courses in explosives way back when ($).

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    Watching ABC's World News Tonight this week, I saw an impressive-looking ad for a pill that claimed to improve memory and cognition. The ad showed several adults, all looking very happy, presumably because they didn’t forget where they left their keys. In appearance, it looked like many of the drug ads that run on the evening news in the U.S. these days.

    The ad described a product called Prevagen, which is sold as a supplement, not a drug. This is a critical distinction: supplements are almost completely unregulated, unlike real drugs. The FDA isn’t allowed to regulate supplements and their claims, thanks to Congress and the 1994 DSHEA law.

    I was curious about what this memory pill could be. The Prevagen ad, website and packaging make a number of very strong claims, scientifically speaking. The biggest claim is that Prevagen improves memory*, something pretty much everyone would like. The website also includes the more specific claim that “Prevagen can improve memmory within 90 days.*” The package adds that Prevagen “supports healthy brain function*, [a] sharper mind*, and clearer thinking.*"

    How can they make these claims if they aren’t true? Simple: every claim has a little asterisk (*) next to it. If you scroll all the way to the bottom of the Prevagen webpage, you’ll find what that means:
    “*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.”
    Behind this blanket escape clause, supplement makers hide all kinds of unsupported claims. Thus Quincy Biosciences–Prevagen's manufacturer–can state that “Prevagen significantly improves learning,” add the asterisk, and voila! the FDA can’t touch them, as long as they don't make a claim to cure a specific disease.

    And by the way, they also claim that “Prevagen improves the quality of sleep.*” There’s that asterisk again.

    So what is Prevagen? It’s a pill that contains a protein called apoaequorin, which is found in a species of jellyfish that glows in the dark. These jellies produce two proteins, apoaequorin and green fluroescent protein (GFP), that help them fluoresce. It’s an amazing biological system, and the three scientists who discovered GFP were awarded the 2008 Nobel Prize in chemistry.

    How (you might be wondering) this can be sold as a dietary supplement? After all, we don’t eat apoaequorin, and isn’t a supplement supposed to be related to something we normally eat? It sounds more like a drug. The FDA agrees with me–I’ll get to that below.

    Despite Quincy Bioscience’s claims, I see no reason why eating this protein would have any effect at all on brain function. First of all, it’s not even a human protein, so it's unlikely to work in humans. Second, even if it did work in humans, eating it would not deliver it to our brains, because it would be almost certainly be broken down in the stomach. And third, the connection between this protein and memory is complex, so simply having more of it is not likely to improve memory.

    Prevagen isn’t cheap, either. If you order direct from the company, a month’s supply of pills will cost you $66 with shipping. There’s even an “extra strength” version, though I cannot see how twice as much of an ineffective pill will be twice as effective. On the other hand, two times zero does equal zero.

    I wrote to ask the president of Quincy Bioscience, Mark Underwood, if his company is claiming that Prevagen will provide any benefits to people suffering from dementia or Alzheimer’s. He didn’t answer that question, but he did respond that “our scientific basis for the claims we make related to Prevagen are on pretty solid ground.” He was careful to qualify this first, though, writing that
    “Prevagen is intended to assist people with mild memory issues related to aging. Prevagen is not a pharmaceutical, nor is it approved by the FDA for the treatment of any neurodegenerative disease (Alzheimer’s, Parkinson’s, etc.).  We do not wish to confuse mild memory loss related to aging with Alzheimer’s disease or dementia in our advertising.”
    I also asked Underwood if he could provide any peer-reviewed studies supporting his company's claims. He sent me several studies, but none of them was peer-reviewed: they include company-sponsored studies that are unpublished, and one published abstract from 2011, in the Journal of Alzheimer’s and Dementia. Abstracts, though, are not peer-reviewed: they are short summaries typically presented in oral form at conferences, and sometimes published (as this one was) in special supplements to journals. This abstract seems to be the basis of the claim on Prevagen’s website that “Prevagen was tested in a large double-blind, placebo-controlled study using computers to assess brain performance. 218 adults over 40 years old participated in the three month study. Prevagen significantly improved learning and word recall.*” (Note the asterisk again.)

    Prevagen’s claims should be easy to test. If Prevagen really does improve memory, then it would be relatively cheap to run large, well-controlled studies on randomized subjects, and I’d expect to have seen multiple studies published since 2011. But because Prevagen is being marketed as a supplement, Quincy Bioscience doesn’t have to prove anything. They just have to be careful not to cross the line in their advertising.

    I asked Ted Dawson, the Abramson Professor of Neurodegenerative Diseases at Johns Hopkins School of Medicine, what he thought of Prevagen’s claims.
    “It is hard to evaluate Prevagen as to the best of my knowledge there is no peer-reviewed publication on its use in memory and cognition,” said Dawson. “The study cited on the company’s web site is a small short study, raising concerns about the validity of the claims.” 
    Treating dementia, Alzheimer’s, Parkinson’s, and other age-related brain disorders is truly difficult. If you want to see what real scientists (not supplement maker) are doing to try to stave off or cure dementia, here’s a short video narrated by Dr. Dawson:

    Dr. Mark Sager, a scientist at the Wisconsin Alzheimer’s Institute and a Professor at the University of Wisconsin, has been quoted saying that he does not recommend Prevagen “primarily because there’s no evidence that it does any good.” He recommends adopting a Mediterranean diet instead, which does have some scientific evidence to support it.

    I’m not the first person to raise questions about Prevagen. In 2012, a class action lawsuit was filed against them in California, in which the plaintiffs argued that the Prevagen didn’t work and that the advertising campaign was false and misleading. Earlier this year, another class action lawsuit against Quincy Bioscience argued that Prevagen’s active ingredient, apoaequorin, "is completely destroyed by the digestive system.” And in 2012, the FDA sent Quincy Bioscience a warning letter (see it here), pointing out that the company was marketing Prevagen as a drug, not a supplement. The FDA stated that:
    "Apoaequorin is not a vitamin, mineral, amino acid, herb or other botanical, or dietary substance for use by man to supplement the diet ... nor is it a combination of dietary ingredients. Therefore, the synthetically produced apoaequorin used in your Prevagen products is not a dietary ingredient as defined in section 201(ff)(1) of the Act.... Accordingly, your Prevagen products could not be marketed as dietary supplements even if they were intended only to affect the structure or function of the body and not for use in the cure, mitigation, treatment, or prevention of disease."
    Somehow, though, Quincy continues to sell Prevagen as a supplement. Their website claims they are the #1 selling brain health supplement in the U.S. today.

    The appeal that Prevagen is making to consumers is a very old one: basically, they want you to think that if a protein is used in your brain, then eating that protein will make your brain healthier (even though apoaequorin is not a human protein). By this argument, I could package up hundreds of different proteins (perhaps thousands–the brain is a complex organ) and sell them as “brain food” This simplistic principle has been used for centuries in folk medicine: it’s the reason why some people think that eating the body parts of bears and tigers will make them more virile. But eating tiger organs doesn’t make you more like a tiger. It's a form of magical thinking, and there's simply no science to support it. In short, it's just wrong.

    Human health isn’t that simple. You don’t acquire the properties of the food you eat. Eating chicken won't make you fly, and eating tuna won't make you a fast swimmer. Eating jellyfish proteins (Prevagen's main ingredient) won't improve your memory, nor will it allow you to emit green fluroescent light. There's no magic brain food, or supplement, that will make you smarter. But you can be a tiny bit richer by not spending your money on ineffective supplements.

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    Amphiascus sp., copyright Alexandra.

    The animal shown in the image above is a member of Amphiascus, a cosmopolitan genus of about thirty known species of benthic harpacticoid copepods. Amphiascus is a genus of the family Miraciidae; in older texts, you will find it referred to the Diosaccidae, but this family is now regarded as a synonym of the former. Miraciids are somewhat elongate harpacticoids generally with a fusiform body shape and females with paired egg sacs; as with other copepod taxa, their specific characterisation depends on fairly fine characters of the appendage setation (Willen 2002). Wells et al. (1982) placed Amphiascus in association with a group of related genera in the miraciid family tree on the basis of its retention of a fairly extensive setation on the pereiopods, two inner setae on the endopod of pereiopod II in females, and two articulated claws on that segment in males. However, the proposed phylogeny of Wells et al. provides no apomorphies for Amphiascus itself, implying that it is characterised only by plesiomorphies relative to related genera.

    The title of this post refers to the circumstances surrounding the discovery of a relatively recently described Amphiascus species, A. kawamurai Ueda & Nagai 2005. In the cultivation in Japan of nori, the edible alga used (among other things) in wrapping sushi rolls, the conchocelis phase of the life cycle is grown on oyster shells in outdoor tanks of seawater (like many algae, nori goes through an alternation of generations, with its life cycle including two very distinct forms; as well as the familiar large flat alga, the life cycle of nori includes a small filamentous shell-boring stage, initially mistaken for a distinct organism and called Conchocelis). Unfortunately, the oyster shells may also become overgrown with diatoms, retarding the growth of conchocelis. As a result, nori growers may be required to laboriously scrub the shells of diatoms several times over the conchocelis growth period. However, it was noticed in Ariake Bay in Kyushu that some form of copepod would sometimes appear in the nori tanks, presumably brought in with seawater from the bay. When this copepod was present, it would graze on the diatoms, reducing the need for other controls. Study of the nori-tank copepod revealed it to be a previously undescribed species, revealing once more that even the species we are not aware of have the potential to directly improve our lives.


    Ueda, H., & H. Nagai. 2005. Amphiascus kawamurai, a new harpacticoid copepod (Crustacea: Harpacticoida: Miraciidae) from nori cultivation tanks in Japan, with a redescription of the closely related A. parvus. Species Diversity 10: 249–258.

    Wells, J. B. J., G. R. F. Hicks & B. C. Coull. 1982. Common harpacticoid copepods from New Zealand harbours and estuaries. New Zealand Journal of Zoology 9 (2): 151–184.

    Willen, E. 2002. Notes on the systematic position of the Stenheliinae (Copepoda, Harpacticoida) within the Thalestridimorpha and description of two new species from Motupore Island, Papua New Guinea. Cah. Biol. Mar. 43: 27–42.

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    As Nobel season dawns upon us, Stu Cantrill points me to an endlessly interesting link on the Nobel website which lists nominating information for various scientists up to 1964 (names of nominees and nominators cannot be revealed for 50 years). Since many more deserving scientists never win the prize compared to those who do this list makes for especially readable material.

    For instance Carl Djerassi who never won the prize was nominated three times (only until 1964 though, so he was likely nominated many more times after that). In the peace category Franklin Roosevelt was nominated 5 times. And Lise Meitner was nominated 47 times without winning in both the physics and the chemistry categories.

    The astonishing statistics are for everybody's favorite chemistry demigod R B Woodward. Woodward was nominated a record 92 times from 1937 until 1965 when he finally won. What's even more stunning though is the year of his first nomination - 1937. That can't be quite right since Woodward was 20 years old then and about to finish his PhD at MIT. Interestingly there is no name in front of the nomination so this could be a mistake. But there's little doubt that nominating even the precocious Woodward at age 20 would have been premature to say the least (Note: Woodward famously finished both college and graduate school in four years and had to drop out for one semester for neglecting other subjects). 

    The more authentic nomination still comes in 1946 when he was still only 29: this time he was nominated along with his colleague Bill Doering by the astronomer Harlow Shapley. The nomination was clearly for the Woodward-Doering breakthrough synthesis of quinine. After 1946 Woodward was nominated pretty much every single year by multiple people. In fact looking at the list what's astonishing is how he didn't win the prize until 1965.

    You can have more fun looking at the list and especially searching for other famous chemists who should have gotten a Nobel Prize but who never did. For instance Gilbert Newton Lewis is widely considered to be the greatest American chemist to have never won, and he was nominated 41 times so one wonders what exactly kept him from being on the list. C K Ingold, one of the fathers of physical organic chemistry, also never won and he was nominated 63 times. On the other hand, Robert Robinson with whom Ingold enjoyed a friendly rivalry was nominated 51 times but actually won.

    Another interesting fact to be gained from the database is the number of times a particular Nobel Laureate nominated another scientist. In what is a testimony to his well-known generosity of spirit for instance, Niels Bohr nominated other scientists 25 times (this included multiple nominations for Lise Meitner who unfortunately never won). 

    Woodward on the other hand nominated someone only once - Linus Pauling in 1949. Interestingly, Woodward had tried to apply for an instructorship at Caltech in 1942 when Pauling was the chairman of the department but as the letter below indicates, Pauling didn't seem too interested; one wonders how the course of American and Caltech chemistry would have been had both Woodward and Pauling reigned over the world of chemistry from the same department.

    Source: Angew. Chem. Int. Ed. 2007, 1378

    In any case, the nomination website makes for very intriguing browsing with which you can play around for a long time. The one thing it makes clear is what we already know - that the number of outstanding Nobel-caliber scientists who will never win the prize far outweighs the number who actually do. That fact should put the nature of the prize in the right perspective.

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  • 09/16/15--04:55: Cox's Orange Pippin
  • Perhaps you have never heard of or seen this apple: Cox's Orange Pippin. TPP just finished eating one, the first in a great many years and it did not disappoint. The orange pippin is simply one great tasting apple, a wonderful, juicy, sweet-tart flavor with a bit of citrus, a hint of banana and other fruity undertones. This apple sets a standard against which the taste of other apples is judged. This is a heritage variety that originated in the UK and introduced in 1825. Now it is seldom grown except by apple affectionados, so it was quite a surprise to find a bin of them in a supermarket in northern Washington state. They are not a particularly showy apple, at first mostly greenish with a streaky reddish blush and of medium size. As the ripen the green becomes yellow and reddish blush develops to produce an orangy-red color. TPP just read that something like 90% of agricultural biodiversity has been lost in the last 100 years. According to the Apples of New York (1905) 1600 varieties of apple were being grown at the time. Wonder how many varieties are commercially grown now? Wonder how many of those varieties have ceased to exist? Do you think 160 varieties are being grown there now? At least Cox's Orange Pippen has survived and you can buy the trees from many  nurseries. This image came from Van Meuwen's nursery.

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  • 09/16/15--05:10: Pretty, but toxic, mushroom
  • This is an easy mushroom to identify, Amanita muscaria, the fly agaric. They are big (the cap can easily be 15 cm in diam when spread) and very handsome, and a large number of them were arising in a grove of trees with which  the fungus has a mycorrhizal association. The red-orange-yellow cap flecked with white patches is very distinctive. The rest of the mushroom is white and although not seen here, a skirt-like veil surrounds the stem and the stem sits in a basal cup. The spore color is white although you should not judge this by the gill color. They are very toxic and while they have been used as a hallucinogen in some cultures, and maybe even worshiped as the god Soma, they are way too toxic to experiment with although as can be seen in the picture, some one took a nibble. These were near a walking path, but plants let alone fungi just don't register with most people. They missin' out. 

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    For several months I've been stalling on a relatively simple project whose completion would let us submit a nice paper.  This is the missing step in an undergraduate Honours student's project; I wrote about her project and what I need to do here.

    1. Starting with a circular plasmid containing the short 'Toxin' and 'Antitoxin' genes, I'll use inverse PCR to amplify a linear fragment that lacks most of the coding sequences of the Antitoxin gene.
    2. I'll also amplify (or find) a SpcR cassette.
    3. I'll ligate these two molecules together to create a circular plasmid with the SpcR cassette replacing the Antitoxin gene.  I could do this by blunt-end ligation (what the Honours student originally did) or do it as the student originally planned, using conventional ligation of 'sticky ends' generated by digesting both fragments with a restriction enzyme whose site is present at all the ends (she designed it into the primers).  I think she changed her plan because our stock of this enzyme was inactive.
    4. I'll use this plasmid (linearized by cutting somewhere in the vector) to transform the bacterium Actinobacillus pleuropneumoniae to SpcR.
    5. I'll use PCR of chromosomal DNA from the new resistant transformant to check that the original antitoxin gene has been replaced by the SpcR cassette.
    6. Next I'll do a transformation assay on this mutant to see if its competence has changed, with the wildtype and toxin mutant as positive controls.

    Step 1 actually requires that I get off my butt and:

    1. Resuspend the primers at the appropriate concentration of TE (or water?).  (Check with the grad student.)
    2. Find the PCR reagents. (Ask the grad student).
    3. Find the template.  (Find info provided by Honours student before she left.)
    4. Learn how to run the PCR machine (Ask the grad student.)

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    So what's this kid doing in the high school auditorium after school?  He's drilled holes and put pipes into a cooler, there's some kind of heating device or trigger. Wires.  And it looks like a boat load of some sort of chemical in that bowl that he's dumping in there.  And then...and it shoots out some kind of gas.  Kids scream. The gas begins to cover the stage.

    "What's happening?" wants to know the teacher who hears the commotion from the hallway.  "I'm testing a fog machine I built for the class play."

    Yes, at first glance the situation looks potentially perilous.  But a quick question, followed by a bit of common sense and the teacher is reassured that all is well.

    Now that everyone is sure that there is no bomb, what should happen to the kid?

    A.  Pull the child into the principal's office and demand that he sign a statement admitting his guilt.

    B.  Call the police, who will arrest him and charge him with building an explosive device.

    C. Call the police, who will arrest him and charge him with building a "hoax bomb"

    D. Nominate him for a theater award for special effects, for having designed and built an inexpensive fog machine to use for the school's upcoming production of Grease.

    The kid is my kid and the school's response was D.  But imagine if my kid wasn't white and male.  If his name were Ahmed Mohamed or Kiera Wilmot?  There might have been handcuffs, felony charges, letters home to parents about "the incident".  If someone had called the police, would they have arrested him because he couldn't explain why he'd built one, when they could have rented a fog machine?  (The police thought it suspicious when Ahmed Mohamed couldn't tell them anything more than his device was a clock.) Why would you build a fog machine, or a clock?  He must have built it for a purpose, nefarious almost certainly.

    Perhaps the purpose was to understand how these machines work?  There is an amazing amount of joy in showing that you understand something well enough to build a working apparatus. To tweak and fix.

    As a parent, I want the school to exercise an abundance of caution.  But once you're sure it's just a clock — or a fog machine — perhaps it's time to slow down, and engage some common sense.  Is there anything else that suggests this kid would build anything danger?  Besides his name, or the color of her skin, or his religion.

    Scientists and engineers are not hatched full grown from eggs in labs.  As kids, they tinker and think and build and design, with Legos and parts from Radio Shack and Home Depot.  They are in theater and on robotics and Science Olympiad teams.  We need to get as excited about what they do as we are about how the football team is doing.

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    There Is No Theory of Everything by Simon Critchley at Opinionator:

    Over the years, I have had the good fortune to teach a lot of graduate students, mostly in philosophy, and have noticed a recurring fact. Behind every new graduate student stands an undergraduate teacher. This is someone who opened the student’s eyes and ears to the possibility of the life of the mind that they had perhaps imagined but scarcely believed was within their reach. Someone who, through the force of their example, animated a desire to read more, study more and know more. Someone in whom the student heard something fascinating or funny or just downright strange. Someone who heard something significant in what the student said in a way that gave them confidence and self-belief. Such teachers are the often unknown and usually unacknowledged (and underpaid) heroes of the world of higher education.....
    A Dying Young Woman’s Hope in Cryonics and a Future by AMY HARMON at The New York Times:
    In the moments just before Kim Suozzi died of cancer at age 23, it fell to her boyfriend, Josh Schisler, to follow through with the plan to freeze her brain. As her pulse monitor sounded its alarm and her breath grew ragged, he fumbled for his phone. Fighting the emotion that threatened to paralyze him, he alerted the cryonics team waiting nearby and called the hospice nurses to come pronounce her dead. Any delay would jeopardize the chance to maybe, someday, resurrect her mind......
    Antibiotic resistance: myths and misunderstandings by Tara C. Smith at Aetiology:
    Since the development of penicillin, we have been in an ongoing “war” with the bacteria that make us ill. Almost as quickly as antibiotics are used, bacteria are capable of developing or acquiring resistance to them. These resistance genes are often present on transmissible pieces of DNA–plasmids, transposons, phage–which allow them to move between bacterial cells, even those of completely different species, and spread that resistance. So, once it emerges, resistance is very difficult to keep under control. As such, much better to work to prevent this emergence, and to provide conditions where resistant bacteria don’t encounter selection pressures to maintain resistance genes.....
    Is natural sleep the only kind that counts? Or can we make that artificial, too? by Ben Locwin at Genetic Literacy Project:
    With all the money we as a society spend on sleep, from $7 billion on beds per year (in the U.S. alone) to nearly 9 million Americans on prescription sleep treatments, to over $1 billion on over-the-counter or alternative sleep therapies and activities, you’d sure think we were all well-rested. I’ve provided some neuroscientific lectures to sleep centers on some of the reasons we think people need to sleep – including the adenosine hypothesis, homeostasis, memory consolidation, parasympathetic restoration of the body, and so forth – but none of the experts in the field are at a consensus of why sleep actually needs to occur. I recently wrote an article on how losing out on sleep can potentially have epigenetic effects on one’s genome, which could be one factor of many as to why chronic sleep deficits are related to a litany of health problems and diseases.......

    When Is the Best Time to Give Birth? by Robert D. Martin Ph.D at How We Do It:
    Medical intervention in human birth has become so widespread that spontaneous delivery is an increasingly rare event. Yet convincing evidence reveals an underlying 24-hour biorhythm, reflecting a general pattern among mammals, including nonhuman primates. This is perhaps no more than a carryover from ancestors adapted for birth while inactive. But the basic rhythm may remain biologically important, such that we ignore it at our peril.......
    Blind cave fish evolved a shrunken brain to save energy by Mo Costandi at Neurophilosophy:
    At some point back in deep time, a group of fish were washed into a limestone cave somewhere in northeastern Mexico. With no way out and little more than bat droppings to eat, the fish began to adapt to their new troglodytic lifestyle. Unable to see other members of their group in the dark, they lost their colourful pigmentation. Then they lost their eyesight, their eyes gradually got smaller, and then disappeared altogether. This was accompanied by a dramatic reduction in the size of the brain’s visual system. Yet, the question of why the blind cave fish lost its eyes and a large part of its brain remains unresolved. Now, biologists in Sweden believe they have found the answer. In new research published today, they report that loss of the visual system saves the fish a substantial amount of energy, and was probably key to their stranded ancestors’ survival.......
    The Unexpected Science of Manipulating Neurons With Light by Sarah Zhang at Wired:
    The first time I learned that scientists could control neurons with light, I definitely did not keep my cool. My response was something like, “Holy shit, I had no idea you could do that!”—perhaps not the best thing to say when you’re trying to convince a neuroscience professor to hire you as an undergraduate researcher. I did not get hired. That was 2008, when the groundbreaking new technique of optogenetics was just bursting into neuroscience. Optogenetics is matter of putting light-sensitive proteins, called opsins, in specific neurons using genetic tools. (The name is quite logical.) The resulting possibilities still have a shade of science fiction: A flash of blue light to a certain bundle of neurons can turn an ordinary mouse into a seething ball of aggression. Or implant false memories. Or let deaf mice hear again. Hundreds, if not thousands, of labs now use this technique.....
    Do You Really Understand Why Water Boils? New Survey Says, Probably Not. by Nadia Drake at No Place Like Home:
    Good news, America: Roughly 75 percent of us know who developed the polio vaccine, that ocean tides are caused by the tugging of the moon’s gravity, and that astrology and astronomy are, in fact, different things. Phew. Great news! The vast majority of us (86 percent) know the Earth’s core is hotter than its surface, and that if you want to make nuclear weapons, you’re going to need some uranium (82 percent of you know that, which I guess could be somewhat concerning). The not-so-good news: Two-thirds of you don’t understand why water boils, and figuring out what makes sounds loud is hard.....
    What happens when you poke, prod and pinch black widow spiders? You might be surprised… by Catherine Scott at Expiscor:
    People seem to have a particular fear mixed with fascination when it comes to venomous animals, and whenever I talk about my work with black widows I am invariably asked questions like, “have you been bitten yet?” The answer is, of course, no. Spiders almost never bite people. I’m always quick to relate that in my experience black widows are not aggressive, even when I go around poking and prodding them with my bare hands. Replicated experimental results always carry more weight than anecdotes, however, so I am delighted to share this recent paper: Poke but don’t pinch: risk assessment and venom metering in the western black widow spider, Latrodectus hesperus. ....

    The life aquatic with flying reptiles by Mark Witton at Mark Witton blog:
    Whether or not pterosaurs could swim, or how well they could swim, is a recurrent discussion among those interested in flying reptiles. For the most part, palaeontologists have seemed happy to assume that pterosaurs were aquatically capable, at least long enough to permit their escape from water, because so many pterosaur fossils occur in coastal or marine sediments. Moreover, some long-known specimens show evidence of pterosaurs feeding on aquatic prey. Odds are that pteroaurs would end up in water some of the time, even if only by accident, so it makes sense that they could at least keep themselves afloat for a while. Plus, virtually all tetrapods can swim one way or another, including bats and bird species which, on first principles, seem ill-suited to aquatic locomotion. Pterosaurs might be a bit strange, but they'd have to be very strange not to be capable of at least limited aquatic locomotion.....
    Einstein’s Parable of Quantum Insanity by Frank Wilczek at Quanta Magazine:
    First of all, note that what Einstein describes as insanity is, according to quantum theory, the way the world actually works. In quantum mechanics you can do the same thing many times and get different results. Indeed, that is the premise underlying great high-energy particle colliders. In those colliders, physicists bash together the same particles in precisely the same way, trillions upon trillions of times. Are they all insane to do so? It would seem they are not, since they have garnered a stupendous variety of results......

    Homo naledi, a great story about a fantastic find in human evolution and anthropology:
    2 climbers crawled through a suffocatingly tiny cave and discovered a new human ancestor that could be 'one of the greatest fossil discoveries of the past half century' by Tanya Lewis at Business Insider:
    The recent discovery of bones from a previously unknown human ancestor in a cave in South Africa adds a tantalizing new piece to the puzzle of human evolution. A couple of cavers stumbled across the remains of at least 15 individuals in South Africa's Cave of Stars. The species, which is named Homo naledi ("naledi" means "star" in the South African language Sotho), had a small brain, yet remarkably humanlike features. And the bones appear to have been deposited in the cave intentionally, a sign that this human ancestor may have buried its dead..........

    Homo naledi: 1,500 Fossils Revolutionize Human Family Tree by Andrew Howley at Rising Star Expedition blog
    All about the fossilized bones of (maybe) Homo naledi by Tabitha M. Powledge at On Science Blogs
    Meet The Woman Who Helped Discover A New Species Of Human by Nina Wolpow at Refinery29
    Archaeology’s Disputed Genius by Bobby Bascomb at PBS Nova
    The View From a Caver/Scientist by Elen Feuerriegel at NatGeo Voices
    'Small spelunkers required': the ad that led to the discovery of Homo naledi by David Smith at Guardian
    This Face Changes the Human Story. But How? by Jamie Shreeve at National Geographic
    Rising Star posts by John Hawks at John Hawks' blog
    Human Ancestors In The ‘Chamber Of Stars': Did H. Naledi Perform Burial-Like Rituals? by Dawn Papple at Inquisitr
    12 Theories of How We Became Human, and Why They’re All Wrong by Mark Strauss at National Geographic
    The Ugly Nationalist Politics of Human Origins by Candida Moss at The Daily Beast
    Who are you calling Homo naledi? Professor Onthemoon's somewhat accurate timeline of the human race by First Dog on the Moon at Comment is free
    6 Tiny Cavers, 15 Odd Skeletons, and 1 Amazing New Species of Ancient Human by Ed Yong at Atlantic
    Homo naledi, the newly discovered species of ancient human, explained by Joseph Stromberg at Vox
    Mysterious New Human Species Emerges from Heap of Fossils by Kate Wong at Scientific American
    South African cave yields strange bones of early human-like species by Nell Greenfieldboyce at NPR
    A New Human Ancestor Arises From The Depths Of A South African Cave by Kristina Killgrove at Forbes
    Who Apes Whom? by By FRANS de WAAL at NYTimes
    Homo naledi: Scientific sensation or just a big show? by Johan von Mirbach at Deutsche Welle
    New Homo Species Found by Bobby Bascomb at The Scientist
    Did ‘rising star’ shine too bright? by Darren Curnoe at The Conversation
    Dawn of Humanity at NOVA
    Homo naledi: Handling a Scientific Rorschach Test by Aaron Jonas Stutz at The Biocultural Evolution Blog


    Ahmed Mohamed swept up, 'hoax bomb' charges swept away as Irving teen's story floods social media by AVI SELK at The Dallas Morning News
    The Ahmed Mohamed Story Shows How The U.S. Stifles Innovation by Judy Stone at Forbes
    Ahmed Mohamed is a victim of American schools' harmful obsession with security by Libby Nelson at Vox
    Why We Need More Ahmed Mohameds by Ramy Zabarah at Popular Mechanics
    How de Blasio Should Expand Computer Science Education. Hint: Don’t Arrest Ninth Graders Showing the Way by Zeynep Tufekci at The Message
    7 Kids Not Named Mohamed Who Brought Homemade Clocks to School And Didn't Get Arrested by Andy Cush at Gawker
    Here's how a Texas school explained arresting a 14-year-old Muslim boy for making a clock by Max Fisher at Vox
    The internet and Barack Obama are standing up for Ahmed Mohamed, the teenage clockmaker by Annalisa Merelli at Quartz
    Kids Bring Clocks To School To Support #IStandWithAhmed by Brian Patrick Byrne and Leigh Cuen at Vocativ
    In defense of information by, of, and for the people by Jacquelyn Gill at The Contemplative Mammoth
    9 Ways the World Is Supporting Ahmed Mohamed by Shaunacy Ferro at Mental Floss
    How to Make Your Own Homemade Clock That Isn’t a Bomb by Marcus Wohlsen at Wired
    Hey Liberals, #IStandwithAhmed Isn't Only About Racism. It's About School Zero Tolerance Insanity. by Robby Soave at Hit & Run blog
    Building scientists #istandwithahmed #kierawilmot by Michelle M. Francl at The Culture of Chemistry

    National Geographic Magazine was acquired by Fox last week, and the reactions were all over the spectrum:
    National Geographic: The Whole World Is Watching. Something. by Greg Laden at Greg Laden's Blog
    Rupert Murdoch just bought National Geographic. Here’s the problem everybody should be talking about. by Jack Mirkinson at Salon
    The best reactions to Murdoch buying National Geographic by Anthony Colangelo at The NewDaily
    National Geographic’s new Fox partnership is good for the magazine, and maybe the planet by Heather Timmons and Steve Mollman at Quartz
    Upcoming Cover Stories For National Geographic Now That Rupert Murdoch Owns It by Mallory Ortberg at The-Toast
    Fox Says It Won’t Interfere With National Geographic’s Editorial Content by Andrew Beaujon at Washingtonian

    And if that is not enough, more readings for later this weekend:

    Medieval Skeleton Found Dangling From the Roots of a Fallen Tree by George Dvorsky at io9
    Why you shouldn’t know too much about your own genes by Carolyn Johnson at Wonkblog
    Scientists want to rethink bans on tinkering with human embryo DNA by Olivia Goldhill at Quartz
    Anti-GMO activists are the ones practicing “tobacco science”. by Marc Brazeau at Food and Farm Discussion Lab
    Dealing with the rational fear about GMOs and global catastrophe by Nathanael Johnson at Grist
    Why Narrating the Future May Be Better Than Trying to Predict It by Adam Frank at Nautilus
    Jellyfish proteins: modern snake oil for brain health by Steven Salzberg at Genomics, Medicine, and Pseudoscience
    From the portals of hell to built-in fire protection: intumescents by Michelle M. Francl at The Culture of Chemistry

    The Moral Argument for Doping in Sports by Steve Paulson at Facts So Romantic
    The most romantic creature in the animal kingdom? Well, it’s not the flatworm, that’s for sure by Nicola Davis at The Observer
    How to negotiate with publishers: an example of immediate self-archiving despite publisher’s embargo policy by Pandelis Perakakis at Pandelis Perakakis, PhD
    The future of food: from jellyfish salad to lab-grown meat by Nicola Davis, Rachel David, Zoë Corbyn, Kit Buchan, and Stefan Gates at Future of food
    Science Literacy by Loreall Pooler at Loréall’s Nerdy Mind
    Help! I’m interviewing a scientist, what do I ask? by Paige Brown Jarreau at From The Lab Bench
    Straws in the LHC wind: Lepton universality and an update on "that bump" by Jon Butterworth at Life and Physics

    A Wasp That Turns a Spider Into the Walking Dead by James Gorman at SCIENCETAKE
    The Great Quake and the Great Drowning by Ann Finkbeiner at Hakai Magazine
    Gender Bending in the ‘Burbs by Perrin Ireland at onEarth
    The genetic innovation that kept the world from starving (no, it’s not GMOs) by Andrew Porterfield at Genetic Literacy Project
    So what were apatosaurs doing with their crazy necks? by Mike Taylor at Sauropod Vertebra Picture of the Week
    Peter Thiel on biotechnology again: "Get rid of the randomness" by Ashutosh Jogalekar at The Curious Wavefunction
    High-Tech Lights to Help Baby Sleep, or Students Stay Alert by DIANE CARDWELL at The New York Times
    Two Seattle girls launched a balloon to the edge of space this weekend, and have the video to prove it by James Risley at Geekwire

    Cancer Research, Irreproducibility, and the Insidiousness of the “Julia Child Argument” by Dan Graur at Judge Starling
    The best way to stop a mosquito bite from itching is surprisingly simple by Rebecca Harrington at TechInsider
    Under the Hood: Why Scientists are a Great Fit for Science Communication by Ada Hagan at MiSciWriters
    Facebook: an effective platform for science communication? by Andrew Maynard at 2020 Science
    When Sleep and School Don't Mix by Alexandra Sifferlin at Time
    If at first you don’t succeed, tweet it by Chris Woolston at Nature
    New Study: Burn it All (Fossil Fuel), Lose it All (Antarctic Ice and Today’s Coasts) by ANDREW C. REVKIN at Dot Earth
    #MySciBlog Part 2 – A huge survey of science blog readers by Paige Brown Jarreau at From The Lab Bench

    Making the 9/11 Memorial Lights Bird-Safe by Jesse Greenspan at Audubon
    Bird deaths averted when 9-11 light show turned off for confused migrants by Rex Graham at Birdsnews
    Web reduction for rival obstruction! by Catherine Scott at spiderbytes
    Medieval Miracles and Occupational Health by Iona McCleery at Remedia
    Segestriidae: tube web spiders by Catherine Scott at spiderbytes
    Social Darwinism: Myth and Reality by Paul Crook at This View of Life
    Castianeira: ant-like spiders by Catherine Scott at spiderbytes
    The Chromeurytominae: Australo-Asian Mystery Wasps by Christopher Taylor at Catalogue of Organisms
    Why Americans are so obsessed with pumpkin spice everything – according to science by Jordan Gaines Lewis at The Conversation

    Ancient Dwarf Crocodile Relative Discovered On Scottish Isle by Shaena Montanari at Forbes
    Nessie dwarfed by new Scottish crocodile by Jon Tennant at Green Tea and Velociraptors
    Almost all our research on sex work is terrible by Topher Hallquist at topherhallquist
    Researcher as victim. Researcher as predator. by Cameron Neylon at Science in the Open
    Honey isn’t as healthy as we think by Peter Whoriskey at Wonkblog
    No, Alzheimer's is not contagious by Jen Christensen at CNN
    The Scientist Who Discovered Fish Smarts by Nathan Siegel at Ozy
    Your Lawn Is Giving Frogs a Sex Change by Tom Philpott at MOTHER JONES
    I’d rather be teaching non-majors by Stephen Heard at Scientist Sees Squirrel
    Here’s What I Saw in a California Town Without Running Water by Julia Lurie at Climate Desk
    Melatonin could help treat multiple sclerosis by Hanae Armitage at Science
    Genetics: Dawkins, redux by Nathaniel Comfort at Nature
    If our body clocks fit in with the normal working day when we turn 50, why do I feel so knackered? by Simmy Richman at The independent

    Study Concluded That Waking Up At 8am Leads to Sleep Deprivation by Joe Hennessey at TheMonitorDaily
    What's Wrong With This Sleep Guide That's Stirring Controversy? by Rachel Grumman Bender at Yahoo Parenting
    AIP award in Broadcast/New Media goes to Anna Rothschild, Greg Kestin for NOVA|PBS Video by American Institute of Physics at Eurekalert
    Hummingbirds Are Such Jerks by Ann Finkbeiner at The Last Word On Nothing
    Creative People Are... by Scott Barry Kaufman at Beautiful Minds
    Why you should start work at 10am (unless you're in your 50s) by Emine Saner at Shortcuts

    Genes illuminate how the brain ‘thinks’ by Ben Locwin at Genetic Literacy Project
    Why I'm sceptical about the idea of genetically inherited trauma by Ewan Birney at Notes & Theories
    Why do GMO science communication? by Anastasia Bodnar at Biology Fortified
    Stimulating Neurons with Sound by Kate Yandell at The Scientist
    The Sounds of Silence: Science-based tinnitus therapeutics are finally coming into their own. by Jenny Rood at The Scientist
    Phytochemical Helps Differentiate Workers from Queen Bees by Ashley P. Taylor at The Scientist
    When is the best time to give birth? by Greg Laden at Greg Laden's blog
    When the Soviets First Landed on Mars by Andrés Cala at Ozy

    Humans are hard-wired for laziness, study finds by Alex Hutchinson at The Globe and Mail
    If You Can’t Make Predictions, You’re Still In A Crisis by Scott Alexander at Slate Star Codex
    The 92 Nobel Prize nominations of Robert Burns Woodward by Ashutosh Jogalekar at The Curious Wavefunction
    Amphiascus: Can a Copepod be a Friend of Mine? by Christopher Taylor at Catalogue of Organisms
    What’s in a name? The blurred lines between reptiles, dinosaurs and birds by Katherine Ellen Foley at Scienceline
    The Tree Room at Understanding Evolution: your one-stop source for information on evolution
    How smartphone light affects your brain and body by Skye Gould and Kevin Loria at Tech Insider

    Previously in this series:

    FieldNotes: a view to spotted horses in the morning
    FieldNotes: The Word For World is Blue (or is it Gold?)
    FieldNotes: Golden Mean, polite middle-ground, and optimal numbers of legs.
    FieldNotes: speeding up and slowing down time
    FieldNotes: from Captain Ahab to Jeff Goldblum, chasing the giants
    FieldNotes: this is not your grandparents' neuroscience!
    FieldNotes: Brontosaurus in, Food Babe out.
    FieldNotes: Rogue Microwave Ovens Call Home
    FieldNotes: Let the sleeping apes lie
    FieldNotes: one thing leads to another leads to another
    FieldNotes: Seductive Allure of Seductive Allure of Neuroscience Explanations
    FieldNotes: do African horses do flehmen at the sight of Derby hats?
    FieldNotes: How The Bird Got Its Beak
    FieldNotes: When Snakes Had Legs...
    FieldNotes: Only before the bicameral mind evolved could people fall for Bohannon's cheap stunts
    FieldNotes: Water, fire, origin of life, origin of cooking.
    FieldNotes: Jurassic World, and other strange animals...
    FieldNotes: Honey Badger Don’t Care!
    FieldNotes: Hallucigenia is back on its head again.
    FieldNotes: Poisonous and grieving quail, reclusive rail, and giants!
    FieldNotes: When Snark was a Boojum
    FieldNotes: In a grip of the legs of a snake
    FieldNotes: Cecil and grief
    FieldNotes: Science Notes and high school start times
    FieldNotes: Earthly Octopus Genome, and Elephant Tracking
    FieldNotes: Amplituhedron and the dissection of cats
    FieldNotes: Oliver Sacks, and irreproducible psychology
    FieldNotes: Hand-drawn biology, wearing rubber gloves, and the invention of the submarine

    Homo naledi: Mark Thiessen/National Geographic.

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    Just as he did previously, Prof. Erland Stevens of Davidson College is teaching a comprehensive med chem edX class that would be useful for anyone wanting to dive into the field. The course attracted 25,000 students last year. Here's the syllabus and list of topics - it certainly looks like something I would enthusiastically check out if I were starting out in the field, or even if I had been in it for a while.

    Information on the course:

    • The course: D001x Medicinal Chemistry
    • Host platform: edX
    • Date: Starts 10/5/15, but enrollment is open until 12/11/15
    • Length: 8 weeks
    • Cost: free
    • Time: 6-8 h/wk for all content, 1 h/wk to peruse the video lectures
    • Pre-req: chem (organic functional groups, line-angle structures), biology (parts of cell), math (logarithms & exponents)
    • Topics (~1 wk per topic)
    • Drug Approval (early drugs, regulatory process, cost, IP concerns)
    • Enzymes & Receptors (inhibition, Ki, ligand types, Kd)
    • Pharmacokinetics (Vd, clearance, compartment models)
    • Metabolism (phase I & II reactions, CYP450 isoforms, prodrugs)
    • Molecular Diversity (binding, drug space, combi chem, libraries)
    • Lead Discovery (screening, filtering hits, drug metrics)
    • Lead Optimization (functional group replacements, isosteres, peptidomimetics)
    • Case Studies on Selected Drug Classes
    • Bonus features
    • Interviews with pharma professionals, including scientists from Novartis (a partner on the course)
    • Virtual labs involving online tools for predicting drug-relevant activity
    • Target audience: pre-med students, graduate students, recent pharma hires, research assistants

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    A new set of mathematical abstracs. We start with the hyperbolic Pascal trianlges:

    Fibonacci and Pell sequences in the hyperbolic Pascal triangle
    In this paper, we introduce a new generalization of Pascal's triangle. The new object is called the hyperbolic Pascal triangle since the mathematical background goes back to regular mosaics on the hyperbolic plane. We describe precisely the procedure of how to obtain a given type of hyperbolic Pascal triangle from a mosaic. Then we study certain quantitative properties such as the number, the sum, and the alternating sum of the elements of a row. Moreover, the pattern of the rows, and the appearence of some binary recurrences in a fixed hyperbolic triangle are investigated.
    Hacene Belbachir, László Németh & László Szalay (2015). Hyperbolic Pascal triangles, arXiv: 1503.02569v1
    A new representation for pythagorean triples:

    Geometric interpretation of $m$ and $n$
    In this paper we introduce a formula that parameterises the Pythagorean triples as elements of two series. With respect to the standard Euclidean formula, this parameterisation does not generate the Pythagorean triples where the elements of the triple are all divisible by 2. A necessary and sufficient condition is also proposed for a Pythagorean triple obtained from this formula to be primitive.
    \[a = −2n + 4nm + 4m^2 − 4m+1\] \[b = 2n^2 − 2n + 4nm\] \[c = 2n^2 − 2n + 4nm + 4m^2 − 4m + 1\].
    Anthony Overmars & Lorenzo Ntogramatzidis (2015). A new parameterisation of Pythagorean triples in terms of odd and even series, arXiv: 1504.03163v1
    And in conclusion a story about the lexicographic representation of numbers:
    It is proven that, contrarily to the common belief, the notion of zero is not necessary for having positional representations of numbers. Namely, for any positive integer $k$, a positional representation with the symbols for $1$, $2$, $\dots$, $k$ is given that retains all the essential properties of the usual positional representation of base $k$ (over symbols for $0$, $1$, $2$, $\dots$, $k−1$). Moreover, in this zero-free representation, a sequence of symbols identifies the number that corresponds to the order number that the sequence has in the ordering where shorter sequences precede the longer ones, and among sequences of the same length the usual lexicographic ordering of dictionaries is considered. The main properties of this lexicographic representation are proven and conversion algorithms between lexicographic and classical positional representations are given. Zero-free positional representations are relevantt in the perspective of the history of mathematics, as well as, in the perspective of emergent computation models, and of unconventional representations of genomes.
    Vincenzo Manca (2015). On the lexicographic representation of numbers, arXiv: 1505.00458v1

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    Donald Trump used the latest Republican debate as an opportunity to express wildly inaccurate anti-vaccine claims, embracing the thoroughly discredited position that vaccines cause autism. This claim has been exhaustively debunked, by countless scientific studies and by reports from the Institute of Medicine and the CDC. It started with a now-retracted 1998 study by one of the great villains in medicine, Andrew Wakefield, who continues to push his fraudulent views despite having lost his medical license.

    Trump's comments were nutty and dangerous, but Ben Carson's response was, in some ways, worse. Carson had the chance to set the record straight, and because of his medical credentials, he could have been effective. He failed.

    Trump has been an anti-vaxxer for years, so his comments were not surprising. Science blogger Orac posted a 2007 Trump quote that almost exactly mirrors what he said in the debate.

    What was much more surprising, and deeply disappointing, was the response of candidate Ben Carson, who until last year was a pediatric neurosurgeon at Johns Hopkins School of Medicine. (Note that although I too work at Hopkins Medicine, I've never met Dr. Carson.) Carson did point out vaccines don't cause autism, but then he made a series of false claims that come right out of the anti-vax playbook.

    When the moderator asked Carson to respond to Trump's anti-vaccine rant, Carson had a golden opportunity to do some real good: he could have corrected the record and pointed out the real harm that comes from anti-vaccination misinformation. Instead, he said things like this:
    “Vaccines are very important, certain ones, the ones that would prevent death or crippling. There are others, a multitude of vaccines that don’t fit in that category, and there should be some discretion in those cases.”
    Forbes bogger Tara Haelle has already explained the grievous error here: all our vaccines prevent death.  Carson's claim is simply false, and it's shocking that a highly trained physician would make this statement, on a national stage, without knowing the facts. What Carson should have said–but didn't–was this, from the Every Child By Two organization:
    "Each and every vaccine added to the list of recommended immunizations will save the lives and/or reduce the number of disabilities of children in the United States. With the introduction of every new vaccine, rates of both disease and deaths have fallen across the country."
    Carson then dug himself even deeper into the anti-vaccine camp with this claim:
    "But it is true that we are probably giving way too many in too short a period of time."
    This claim is right out of the anti-vaccine playbook: it was the basis of the "too many, too soon" campaign launched by Jenny McCarthy's Generation Rescue, the country's leading anti-vaccine activist group. In fact, the vaccine schedule is very safe, and misinformation like this trope leads to parents withholding vaccines from their children, which in turn can cause sickness, disability, and death.

    Let me show you what Carson could have done. Six years ago, Bill Maher–one of the most left-wing talk show hosts in the media, and an anti-vaxxer himself–was interviewing former Republican Senate majority leader Bill Frist, who is also an M.D. Here's what happened:

    Dr. Frist interrupted Maher and said "wait, this is important," and proceeded to school Maher on how vaccines save lives. I wasn't a big fan of Frist, but he did a fantastic job here. Carson, in contrast, just pandered to the audience, and to Trump.

    The moderator also asked Rand Paul, the other M.D. among the candidates, to respond to Trump's anti-vax claims. He too repeated the anti-vaccine trope that he "ought to have the right to spread my vaccines out a little bit." This is nonsense as well: Paul does have that right, and no one has ever proposed taking it away. It's bad medicine, though, and as doctor, Paul should know better. He failed as well.

    It's far more harmful to the public when a high-profile doctor makes anti-vaccine statements than when a blowhard like Trump makes them. Dr. Ben Carson and Dr. Rand Paul should both know better.

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    TPP is catching up, or trying to, on lots of things. Here's a link to some research summaries for the latest issue of the American Journal of Botany. The very first article is pretty interesting because fruits almost universally turn from green to a "fruity" color to signify ripeness advertising to seed disperses that a reward is available (often, but not always). But this particular tropical plant has reddish immature fruits and green mature fruits, a situation rather like the leaves of some tropical plants that flush red and then turn green, however a protective function for the red pigmentation could not be supported! So there you go! You can be pretty sure that one of the authors knew about fruit color changes and dispersal, and then noticed that this plant was not playing according to the "rules" so curiosity made them ask why and they devised a research project to test the various ideas involved. Thousands of such questions and studies exist if you just learn how to observe.  
    Other studies involved microlichens, fern gametophytes (haploid ferns), genetics of cellulose systhesis, and the origin of C4 photosynthesis. Pretty diverse stuff, but that is the nature of botany and this journal in particular. 

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    Oh, this is just too cool!  Loop wheels with built in springs would look just great on TPP's bicycle and at my age, and another year was just chalked up, anything that makes the ride smoother is looked upon with great favor!  Wonder if they have one that glows in the dark?  Can't tell you how many rims TPP has dinged up on nasty bumps over the years.  Here's a link to the article at Treehugger, but the link in their article to the wheel page did not work. Come on guys, we wants the link! 

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  • 09/22/15--03:21: Happy posts!
  • September is a nice time of year when you are not a student or faculty member for whom the month is quite hectic. Enjoying September is a great side benefit of retirement. And it includes TPP's birthday and his annual birthday celebration of cooking for his friends a once a year special dish. This tradition began with the idea of not doing birthdays any more, but just doing "fish soup", but now the number of fish soups has begun to add up too, so to continue the enjoyment of September TPP has been staying away from depressing blog topics which abound!
    Middle Eastern Conflicts/Refugee Crisis - Didn't any of these world leaders play Risk while growing up? Depressing.
    T-Rump, Fe-fi-forina, Sanctimonous, Chucklebee, and all the rest remaining. The GOP's view for America is deeply, profoundly depressing.  Cymbalta please with a side dish of Citalopram.
    Discrimination called religious freedom. While you are free to believe as you wish, you may not impose those beliefs on others especially if you have a government job or run hospitals like St. Whatever's. Sad and depressing.
    Garden fatalities - It was a tough year for a lot of plants especially because they got either too much water or not enough. A long-time garden resident, a bristle cone pine looks to be in a fatal decline, as do a couple of small Japanese maples.  The golden chain tree suddenly died early this summer, and after looking great last year a small cluster of Oregon grape bushes (Mahonia) crashed. Some replacements have been purchased and now must be planted. Nothing like yanking out dead trees and digging big holes to brighten your day. Did get a nice bottle of wine from the local nursery and a keep up the good work card.
    Apples. Local source of Northern Spys had a crop failure for that variety, but the Jonathons are superb this year. Eh, that's farming.
    However on the bright side and to keep from ruining the good September mood, the Chi-town Cubs are still winning more than losing and usually by mid- September they would have been in the sub-basement of the league for at least a month. TPP doesn't really follow them, but so many friends do that the Cub's success is brightening the moods of many friends and colleagues.
    Bernie Sanders' candidacy. Don't know it he would be a good president or not, but he makes TPP smile. Just going to Liberty University was a political tour de force. He's like a T-Rump antibody.

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  • 09/22/15--08:46: Just doing it
  • My inverse PCR reaction using the Q5 High Fidelity polymerase (creates blunt ends) worked on the first try!  I now have the antitoxin-deletion fragment I can ligate to a SpecR cassette to create the antitoxin knockout plasmid. Running 1/10 of the reaction in a gel gave a reasonable band, so I think I have enough DNA for the next steps.

    I was initially planning to cut the SpecR cassette out of a plasmid the Honours student made, but we didn't have any of the blunt-cutter (BstZ1) this would need.  Since money is tight, I decided to instead do what the Honours student had done, using her primers to amplify the fragment with the Q5 High Fidelity polymerase, adding 5' phosphates with T4 polynucleotide kinase and ATP, and then blunt-end ligating this with the inverse PCR fragment.

    The SpecR PCR didn't work the first time, using the Honours student's plasmid as template.  The plasmid DNA didn't look very good in a gel, so after consulting with the Honours student by email I tried using some chromosomal DNA she had made from another knockout mutant.  This worked very well.  My only concern is that in a gel the SpecR fragment had a short smear of what looked like shorter DNA below it (sorry, forgot to save photo image).

    Next step will be to clean up both PCR products.  The Honours student did this by gel purification, using a kit favoured by the sabbatical visitor, but I think I'll just use our usual spin columns.  The grad student warns me that the recovery won't be great, but I think I have DNA to spare.

    Next step will be to phosphorylate the 5' ends of the SpecR fragment.  This procedure looks very straightforward.  I could also treat the inverse PCR fragment, but this would allow that fragment to ligate to itself, creating many side reactions that I don't want.

    Then maybe another spin-column step, because I think I should remove the kinase so it doesn't phosphorylate the other fragment. But I could instead just heat-inactivate the kinase (20 mi at 65°C, says NEB), since the kinase and ligase enzymes have nearly identical reaction buffers, and both use ATP.  After heat-inactivation I'd just need to add the other fragment, the ligase, and maybe a bit more ATP.

    Then transform into competent E. coli (IDH5-alpha? I'm pretty sure I have lots in the freezer) and plate on spectinomycin.  The plasmid I want should give resistance to ampicillin too.

    What about controls?  (I'll only do the easy ones this time.  If the transformation fails I'll do more controls.)
    • Negative control: Mix of fragments before addition of ligase.  
    • Negative control for transformation: No DNA.  
    • Positive control for ligation:  I'd need to digest a plasmid.
    • Positive control for kinase:  Do the ligation reaction with non-phosphorylated DNA
    • Positive control for transformation: One of the Honours student's successful plasmids.

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    Here's a valuable and comprehensive review on one of the most glaring pieces of evidence for why drug discovery is so hard - the fact that very small structural changes in molecules can lead to drastic changes in their biological activity.

    I particularly like this review because it's absolutely chock-full of examples of small structural changes which not only impact the magnitude of binding of a small molecule to a receptor protein but invert it - that is, change an agonist into an antagonist. And the receptor family in this case is GPCRs, so it's not like we're talking about a minor rash of examples in a scientifically insignificant and financially paltry domain.

    Here's one of my favorite examples from the dozens showcased in the piece; in this case a set of small molecules targeting the nociceptin receptor which is being studied as a potential target in treating heart failure and depression.

    At first sight it's compelling how such similar groups as a cyclooctyl, a cyclooctyl-methyl and a phenyl can lead to complete inversion of activity, from 200 nM agonism to 1.5 nM antagonism. Thinking in 3D however makes the observation a bit more comprehensible. The N-cyclooctyl on the right is going to have a very well-defined conformational preference - pointing pretty much straight in one direction. The cyclooctyl-methyl on the other hand is going to have much more conformational freedom. It's also going to occupy much more space than the phenyl group on the right.

    Now this kind of retrospective analysis may well be the explanation, but very few medicinal chemists would have been able to predictive this complete inversion in activity at the outset (as a medicinal chemist recently quipped at a Gordon Conference, "We medicinal chemists are very good at predicting the past.")

    Here's a more diabolical example that would have been even harder to predict. In this case the target concerns two suptypes of the mGlu (metabotropic glutamate) receptor which is involved among other things in Parkinson's and anxiety.

    In this case, not only does that 'magic' methyl group and its precise stereochemistry change an antagonist into an agonist but it even changes the agonism/antagonism mix at two separate receptors. Try explaining that, even in retrospect.

    These kinds of well-known activity cliffs reinforce the essentially non-linear nature of medicinal chemistry, a quality that is essentially emergent since it arises from the interaction of small molecules with a highly non-linear biological system. Neither experimental chemistry nor computational modeling would allow us to predict activity cliffs like these because of the lack of sensitivity in such techniques.

    It's things like these which I always think really need to be communicated to laymen to impress the staggering difficulty of drug design to them - most of the times we are simply ignorant when it comes to designing molecules like the ones above with any kind of predictive power and we can only find out about their fickle properties in retrospect. Perhaps then we will get less heat from the public for why we sometimes have to spend (and charge) so much money for our products.

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  • 09/23/15--09:18: Perils of lawn mowing
  • Our lawns need mowing in spite of the dry conditions interspersed with a couple of deluges. It's been nearly 3 weeks since they were last mowed, but the last thing a lawn needs in lolly-coddling. Crab grass is growing exceptionally well this year, and mowing will help prevent the production of a major crop of seeds. Mowing our lawn requires a lot of dodging and weaving in and around all the trees, bushes, and garden beds, and it's really icky out there right now because the garden spiders, many of whom are nearing the size of Shelob, have webs spanning up to 8 feet across walk ways. The problem is that your attention when mowing is directed downward so you walk into the webs head high. Now TPP doesn't have a major problem with spider, but the webs are icky nonetheless. The dry conditions have caused a lot of leaves to fall prematurely, and it is harvest season here abouts, and the lawn mower just kicks up clouds of dust and spores, something that sets off TPP's mucus production and irritates the sinuses. So adding to the tedium of lawn mowing is the misery of allergies and the ickiness of spider webs such that the enjoyment of the activity is largely lost. At least the lawn season is coming to an end.

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    It's been quite awhile since the last FFF. This plant may have been featured before, but so what?  TPP knew the second he entered the greenhouse that this plant was in flower because of its fragrance, a very perfumed, somewhat heavy fragrance, but quite lovely and one of the best smelling flowers in our collection.  The butterfly ginger (Hedychium coronarium) stands about 1.5 m tall so you don't have to stoop over to look at or smell the flowers. Wish we could introduce the scratch your monitor screen and smell technology. Students in economic botany extract the fragrance by harvesting the new flowers each morning, slicing them lengthwise, and placing them cut side down on a layer of highly purified vegetable fat (i.e., Crisco) in a shallow covered dish (i.e. Petri). After several days the fat becomes impregnated with the fragrance because like many fragrance molecules they are lipid soluble so they dissolve into the fat to be released upon mild heating like rubbing between you fingers or on your skin behind your ear. You can do this with any fragrant flower as a nice kid/garden activity. The process is called enfleurage, a really old perfume technique.

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    The very essence of #mathematics is its freedom. (Georg #Cantor)
    The way we deal with today's numbers in schools is essentially the same manner used by our ancestors Pythagoreans, who saw the numbers as concrete objects, of course, but in a way that prevented them from conceiving the infinity. The only ancient mathematician who approached the infinity was Archimedes, but in the history of mathematics can be considered a fairly unique case of lack of development mainly due to the isolation of the mathematicians at that time and of noticeable difference in quality between the Sicilian and colleagues. In order to return to touch the wall of infinity and use them in a profitable way the Earth had to wait the arrival of Georg Cantor.
    The German mathematician actually faced numbers, revolutionizing mathematics, using essentially sets and logic, two tools that enabled him not only to approach, but even manipulate the infinite thanks to the transfinite numbers. Leading his steps was probably the following conviction:
    The very essence of mathematics is its freedom.
    According to Daniel Bonevac, this veritable mantra, written in 1883, is emblematic of the Cantor's libertarian approach to mathematics. With this milestone, Bonevac try to write a theory of mathematical truth, in order to explain some facts more or less established:
    1) that the mathematical statements are either necessarily true or necessarily false;
    2) that mathematical truth is derived primarily from logical truth;
    3) that the existence in mathematics involves a kind of modality, which requires only the consistency or the constructability.
    The construction of the theory builds on the mathematical language $L$ of Zermelo-Fraenkel set theory, which is appropriately extended in a new language, said $L'$, containing a set of constants metalinguistic statements (but not necessarily finite). Given this extension, then any predicate in $L$ will be a predicate in $L'$ not with constants.
    The last step is the definition of a parametric model $M$, defined as a pair of applications: the first associates to each atomic predicate of $L$ a truth value; the second is in turn a set of applications that can be called rules of the game, showing explicitly, if it were needed, that the modern game theory is simply a some kind of logical application.
    The idea of ​​the approach is quite simple. Take first the phrase "There is a pebble in my shoe". Its degree of truth depends by the inclusion of the word pebble in our vocabulary, and so you need to extend the language to include the word, or in other words it is possible, under the circumstances, the restriction in situations in which it is true that "There is a pebble in my shoe".
    On the other hand "Some flying horse is named Pegasus" is true in the case of a mythological game, false in the case of a biological game.
    In particular the latter situation suggests Bonevac to adopt an approach that is as inclusive as possible, or that it does not exclude any of the possible games: in this way you get what Bonevac calls the semantics of open models.
    The mathematics that emerges from this semantic discussion contains within it the Godel's incompleteness theorems, showing that they are inseparable from mathematics itself, but also show themselves to be more natural than amazing. Bonevac shows also how the concept of truth is necessary to mathematics, which becomes explicitly dependent from logic. On the other hand within this semantic not only the continuum hypothesis of Cantor is unprovable, but, together with the axiom of choice, it is false.
    We can only assume that, as with many cantorian logicians, the initial goal of Bonevac was to build an axiomatic system in which the continuum hypothesis were true, but even if this goal was not achieved, in my view he has instead proofed something that we usually take to established (and the denial of which sometimes becomes a way to challenge our stakeholders mathematicians), or that the math does not lie.
    Bonevac D. (1983). Freedom and truth in mathematics, Erkenntnis, 20 (1) 93-102. DOI: (pdf)

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  • 09/26/15--10:10: Troubleshooting
  • Yesterday I kinased my SpecR PCR fragment, ligated it to the inverse-PCR fragment and transformed this into E. coli DH5alpha.   But my transformations gave only the same tiny colonies as the negative controls (no-DNA and no-ligation).  One of the positive controls (another AmpR SpecR plasmid made by the undergrad) gave thousands of AmpR and SpecR transformants, so I know that the competent cells (RbCl2-competent, frozen many years ago) and the antibiotic plates are fine.

    (The other positive control was her pGEM-Spec construct; this gave no transformants for either Amp or Spec.  Since this prep didn't work as a PCR template either I should now throw it out.)

    I wasn't totally surprised, because I already suspected that there was something wrong with the PCR amplification of the spec cassette.  The PCR product looked right when I ran an aliquot of the PCR reaction in a gel, with a sharp band just smaller than 2 kb.  But there was also a faint smear of smaller DNAs below this band, and after I had used a spin column to clean up the pCR reaction (should remove primers, enzyme and salts) the sharp band was smaller and blurry, and the DNA smear had become as second blurry band. The column cleanup of the inverse-PCR fragment gave a nice sharp band of the right size, so I don't think the problem was with the column treatment.

    This was cause for concern, so I repeated the spec PCR, thinking that maybe I had screwed up (why would a cleaner band be smaller and blurrier?).  But I got the same result.  I again used the student's primers and template chromosomal DNA, but I lowered the annealing temperature for the first two cycles because the 5' 12 bp of each primer are not complementary to the template DNA. Before cleanup the amplification product looked the same as before (red arrow in left gel) - a sharp band with a faint smear below it (the smear doesn't show up in the photo).  After cleanup it again turned into a slightly smaller blurry band with a second blurry band below it (two red arrows in the right gel).  The larger sharp band indicated by the white arrow is the inverse-PCR fragment after identical cleanup.

    I have no idea what could cause the SpecR PCR fragment to behave like this.  Before I dig into it I should check that the cloning failure was not instead caused by a failure of the kinase or ligation reactions.

    Test for kinase and ligation:  I'm taking the inverse-PCR fragment, and kinasing and ligating it.   This should produce a simple plasmid with the antitoxin gene deleted.  I'll transform this into DH5alpha, selecting for AmpR. (Again no-DNA control and p∆AT:spec control.)  If I get lots of transformants then the problem is the Spec PCR fragment.  If I get none then the problem is the kinase or ligase reaction.  I was hoping to use singly-cut p∆AT:spec as a ligation control, but neither SacII nor HincII appear to cut where they should, so I'm doing without this control.

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    In late September there isn't much to do with your kitchen garden except clean up and recap. On the whole it was an OK year, considering all the garden neglect, but why the zucchini stopped producing while still healthy is a mystery. Tomatoes are just about shot although those magnificently indeterminate grape tomatoes will keep making a few fruit. Looks like a few late eggplant and peppers will be produced as well because they recovered somewhat from the blighty conditions. Late pole beans are just about ready to pick and maybe a few snap peas will make it too. The big surprise were the cucumbers which are still making some fruit. Usually the bacterial wilt nails them in August. No idea how these escaped, maybe it was a bad year for the beetle vectors. The wet spring and early summer may have aided the milky spore fungus that attacks beetle larvae because the Japanese beetles were not all that bad and June bugs were uncommon. 
    Some fall lettuce will be ready soon, but the bloody squirrels dug up all the spinach, a downside of container gardening. This time of year the squirrels dig up everything. And now, as announced excitedly by the kitty-girls, they have partners in crime, a pair of chipmunks, which are rather unusual around here especially in town. So far no problems have arisen from their residency, and they are plenty cute.  Guess the gardens are wildlife friendly so long as the kitty-girls remain inside or on a leash, a binary choice.
    Unfortunately a lot of lawn remains to be mowed and it has to be done before going to a dinner party later. Yesterday was spent digging holes, planting trees & shrubs, and watering those and other newish plantings before a dinner club wine and goodies party. The weather is quite beautiful in terms of temperature, but it's dry, dry enough to create a lot of early leaf fall, and so mowing will kick up a lot of dust and spores so TPP's sinuses and eyes will suffer. Apparently margaritas are an remedy.

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    White wine with fish is a no brainer, but the assembled dinner party was largely drinking red wine in honor, no doubt, of the evenings' entertainment, the appearance of a "blood moon".  The party took place in a sufficiently rural area with minimal light pollution for optimal naked eye viewing, and perhaps you don't realize how much even a small city produces until you see it glowing from a distance. The cloud cover most conveniently removed itself just as the eclipse started. And yes, it was a quite spectacular moon as the many images posted around the internet showed, further demonstrating that there are certain subjects for which phone cameras are just not adequate, and most amusingly so. The dinner was most excellent, and the post-dinner discussion and drinking topic that was most entertaining was what wine do you drink while waiting for the apocalypse, the harbinger of which was this reddish, eclipsed full moon? The conclusion was that this was a simple matter; drink the best stuff you have because it won't have a chance to get any better what with the apocalypse and all. No use hoarding a special bottle for an occasion that will now never happen, so pass that super Tuscan. While an amusing enough discussion, it remains deeply depressing that NASA, the Church of the Latter Day Saints, and others felt the need to issue statements trying to convince certain people that no apocalypse was actually going to happen. How can people be so gullible, and ignorant, in this day and age?  But if remain unconvinced, then give us your wine, but only the good stuff please. Clinking empty wine bottles together will scare away the blood dragon and restore our moon's color.

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  • 09/29/15--05:40: Water on Mars
  • "Our quest on Mars has been to 'follow the water', in our search for life in the universe, and now we have convincing science that validates what we've long suspected. This is a significant development, as it appears to confirm that water -- albeit briny -- is flowing today on the surface of Mars."
    John Grunsfeld from the press release. The abstract of the paper follows:
    Determining whether liquid water exists on the Martian surface is central to understanding the hydrologic cycle and potential for extant life on Mars. Recurring slope lineae, narrow streaks of low reflectance compared to the surrounding terrain, appear and grow incrementally in the downslope direction during warm seasons when temperatures reach about 250–300 K, a pattern consistent with the transient flow of a volatile species. Brine flows (or seeps) have been proposed to explain the formation of recurring slope lineae, yet no direct evidence for either liquid water or hydrated salts has been found4. Here we analyse spectral data from the Compact Reconnaissance Imaging Spectrometer for Mars instrument onboard the Mars Reconnaissance Orbiter from four different locations where recurring slope lineae are present. We find evidence for hydrated salts at all four locations in the seasons when recurring slope lineae are most extensive, which suggests that the source of hydration is recurring slope lineae activity. The hydrated salts most consistent with the spectral absorption features we detect are magnesium perchlorate, magnesium chlorate and sodium perchlorate. Our findings strongly support the hypothesis that recurring slope lineae form as a result of contemporary water activity on Mars.

    Ojha, L., Wilhelm, M., Murchie, S., McEwen, A., Wray, J., Hanley, J., Massé, M., & Chojnacki, M. (2015). Spectral evidence for hydrated salts in recurring slope lineae on Mars Nature Geoscience DOI: 10.1038/ngeo2546

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  • 09/29/15--05:14: Fearful things!
  • Fear is a powerful motivator and so its use in political rhetoric is so common, but unfortunately people can come to fear the wrong or even imaginary things.  Tom Tomorrow explains what fears keep right-wingers up at night. It explains a lot.

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    I am honored and frankly a bit stunned to hear that my post on the "fundamental philosophical dilemma" of chemistry was awarded first place in the annual 3 Quarks Daily science writing prize contest. I am deeply thankful to the editors of the site, to those who nominated the post and to Prof. Nick Lane who judged the final nine entries.

    I am especially gratified that my entry was selected by Prof. Lane, biochemist and science writer extraordinaire, whose latest book "The Vital Question" proposes a novel theory of the origins of life based on the genesis and evolution of the energy generating apparatus in cells. And I am stunned because my entry was included in a roster of entries that included some very fine writing indeed by writers whose work I have admired for a long time, so I didn't expect my own entry to win. Congratulations especially to my fellow prizewinners, Aatish Bhatia and Nadia Drake, for their incisive and highly readable pieces. The list of finalists is also very much worth taking a look at.

    Here's what Nick Lane had to say about the post and about his own views on writing:

    When I read a blog, I'm not really looking for a beautiful piece of writing, or stunning visuals, or links to amazing videos, even though these things make a great post. I'm looking for a personal point of view, usually from someone with a particular vantage point, whether scientific or journalistic. I'm looking for something that I couldn't find so easily in the mainstream media, grounded in personal experience, and more idiosyncratic than most magazines would allow you to get away with. (That's one of the things I like about writing books too.)

    I don't really know where to draw the line between a blog and a news story, or a feature article, or even a short story. Some of the finalists here did not really write blog posts at all, in my view, but achieved a higher calling, works of art in their own right. So with all that in mind, here goes:

    The winner is Ashutosh (Ash) Jogalekar. I loved this post. It is personal and authoritative, and grows from what starts out as a quirky irritation in the day job into a profound commentary on the limits of the controlled experiment in chemistry, stemming from fundamental physics. Ash begins with the different interactions between atoms in molecules – electrical charges, hydrophobic interactions and the rest – and shows them to be different aspects of the same fundamental electrochemical force, making it impossible to achieve any independent changes in a molecule. He finishes with a lovely twist, justifying the thrill of experiment as the only way to explore design in chemistry, making the subject endlessly fascinating. 

    Ash's writing style is crisp and clean, admirably precise without being patronising, even in the use of italics, which can easily feel preachy. Not here. I followed the links for genuine interest, and there was a great discussion in the comments pointing out an equivalent problem in biology, in the use of knockout models. In an age when science is being pushed towards supposedly managed outcomes, this is a refreshing reminder of why it can't be planned.

    Many thanks to Prof. Lane for his very thoughtful appraisal and appreciation of the piece. I am especially thrilled to see writing about fundamental chemistry - a topic that doesn't usually get much billing in the popular science literature - being recognized. The limits of performing controlled experiments in science is a topic close to my heart, and I'm glad to see that others have thoroughly appreciated the problem too. 

    Occasionally we'll hear drumbeats about the "end of science" which proclaim the complete ascendancy of knowledge in one field or another. While this kind of proclamation ignores the simple fact that progress in different fields is not all created equal (as a commenter on a blog recently mentioned, "we can land a probe on a comet at 17,000 miles/hr but we still don't know if butter's bad for you") I think it's also important to realize more fundamental, epistemological limits to knowledge that arise from the kinds of limits on measuring basic atomic and molecular interactions that I was talking about in my post. 

    But crucially, while some may see such limits as heralding "the end", I see them as heralding endless opportunities and fascinating discoveries which will forever remain open-ended. If that's not the opposite of "the end" I don't know what is.

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  • 09/29/15--08:40: 2015 Nobel Prize predictions

  • The nice thing about Nobel Prizes is that it gets easier to predict them every year, simply because most of the people you nominate don't win and automatically become candidates for the next year (note however that I said "easier to predict", not "easier to correctly predict").

    Having said that, there is a Bayesian quality to the predictions since the previous year's prize does compel you to tweak your priors, even if ever so slightly. Last year's award was for a biophysical instrumental technique so that probably rules out similar awards this year. 

    This year I have decided to separate the prizes into lifetime achievement awards and specific discoveries. There have been fewer of the former in Nobel history and I have only three in mind myself, although the ones that do stand out are no lightweights - for instance R B Woodward, E J Corey, Linus Pauling and Martin Karplus were all lifetime achievement awardees. If you had to place a bet though, then statistically speaking you would bet on specific discoveries since there have been many more of these. So here goes:

    Lifetime achievement awards

    Harry Gray and Steve Lippard: For their pioneering and foundational work in the field of bioinorganic chemistry; work which has illuminated the workings of untold number of enzymatic and biological processes including electron transfer.

    Stuart Schreiber and Peter Schultz: For their founding of the field of modern chemical genetics and their impact on the various ramifications of this field in chemistry, biology and medicine.

    Robert Langer for his extensive contributions to drug delivery: Much of what Langer does is actually chemistry, but his practical impact has been on medicine so a prize for him would lie more squarely in medicine. It's clear though that he deserves some kind of lifetime recognition.

    Specific awards

    John Goodenough and Stanley Whittingham for lithium-ion batteries: This has been on my list for a long time. Very few science-based innovations have revolutionized our basic standard of living the way lithium-ion batteries have. However, prizes for devices have been few, with the charged-coupled device (CCD) and the integrated circuit being exceptions. More importantly, a device prize was given out just last year in physics (for blue light-emitting diodes) so based on that Bayesian argument stated above, it might make it a bit unlikely for another device-based invention to win this year.

    Franz-Ulrich Hartl and Arthur Harwich for their discovery of chaperones: This is clearly a discovery which has had a huge impact on our understanding of both basic biological processes as well as their therapeutic relevance. I worked a bit on nuclear receptors myself during a postdoc and appreciate the amazing complexity and importance of their signaling roles. However, as often happens with the chemistry prize, this one could also go to medicine.

    Alexander Pines for solid-state NMR: Another technique that has clearly come of age. Using our Bayesian ruler again though, last year's chemistry prize went to an instrumental technique (super-resolution electron microscopy) so it seems implausible to have the same type of prize given out this year.

    Krzysztof Matyjaszewski for atom-transfer radical polymerization, Barry Sharpless for click chemistry, Chi-Huey Wong for oligosaccharide synthesis and Marvin Caruthers for DNA synthesis: It's highly unlikely that these three gentlemen will receive any prize together, but I am grouping them under the general title of "organic and polymer synthesis" for convenience.

    Matyjaszewski's name has been tossed around for a while, and while I am no expert in the field it seems that his ATRP method has had enough of a practical and commonplace impact to be a serious contender; plus an award for polymer chemistry has been long due. Click chemistry has also been extensively applied, although I am less certain of its industrial use compared to say, the undoubted applications of palladium-catalyzed chemical reactions.

    In the world of biopolymers, oligosaccharide synthesis has always been an important field which in my opinion has received the short end of the stick (compared to the glamorous world of proteins and nucleic acids, lipids and carbohydrates have always been the black sheep) so recognizing Wong might be a kind of redemption. On the other hand, recognizing Caruthers for DNA synthesis (perhaps along with Leroy Hood who automated the process) seems to be an obvious honor in the Age of Genomics.

    The medicine prize

    As is traditionally the case, several of the above discoveries and inventions can be contenders for the medicine prize. However we have left out what is potentially the biggest contender of all until now.

    Jennifer Doudna, Emmanuelle Charpentier and Feng Zhang for CRISP-Cas9: I don't think there is a reasonable soul who thinks CRISPR-Cas9 does not deserve a Nobel Prize. In terms of revolutionary impact and ubiquitous use it almost certainly belongs in the same shelf that houses PCR and Sanger sequencing. 

    There are two sets of questions I have about it though: Firstly, whether an award for it would still be rather premature. While there is no doubt as to the broad applicability of CRISPR, it also seems to me that it's rather hard right now to apply it with complete confidence to a wide variety of systems. I haven't seen numbers describing the percentage of times that CRISPR works reliably, and one would think that kind of statistics would be important for anyone wanting to reach an informed decision on the matter (I would be happy to have someone point me to such numbers). While that infamous Chinese embryo study that made the headlines recently was quite flawed, it also exposed the problems with efficacy and specificity that still bedevil CRISPR (these are problems similar to the two major problems for drugs). My personal take on it is that we might have to wait for just a few more years before the technique becomes robust and reliable enough to thoroughly enter the realm of reality from one of possibility.

    The second question I have about it is the whole patent controversy. Generally speaking Nobel Prizes try to stay clear of controversy, and one would think that the Nobel committee would be especially averse to sullying their hands with a commercial one. The lack of clear assignment of priority that is being played out in the courts right now not only tarnishes the intellectual purity of the discovery, but on a more practical level it also makes the decision to award the prize to all three major contenders (Doudna, Charpentier and Zhang) difficult. Hopefully, as would be fitting for a good novel, the allure of a Nobel Prize would make the three protagonists reach an agreement to settle their differences over a few beers. But that could still take some time.

    The bottom line in my mind: CRISPR definitely deserves a prize, and its past results and tremendous future potential may very well tip the balance this year, but it could also happen that the lack of robust, public vindication of the method and the patent controversy could make the recognition seem premature and delay the actual award.

    Craig Venter, Francis Collins, Eric Lander and others for genomics and sequencing: The split here may be pretty hard here and they might have to rope in a few consortiums, but as incomplete and even misleading as the sequencing of the human genome might have been, there is little doubt that it was a signal scientific achievement deserving of a Nobel Prize.

    Alec Jeffreys for DNA fingerprinting and assorted applications: Alec Jeffreys is another perpetual favorite on the list and one whose invention has had a huge societal impact.

    Karl Deisseroth, Ed Boyden and others for optogenetics:Optogenetics is another invention that will almost certainly get a prize; its methodology is fascinating and its potential applications for neuroscience are amazing. But its validation seems even more incomplete to me than CRISPR's so it would be rather stunning if they get the prize this year. (On a side note: I am probably among the minority who think that awarding the prize for RNA interference in the 1990s was also too early and quite premature).

    Ronald Evans for nuclear receptors: It would be odd if a major class of proteins and therapeutic drug targets went unrecognized.

    Bert Vogelstein, Robert Weinberg and others for cancer genes: This again seems like a no-brainer to me. Several medicine prizes have been awarded to cancer genetics so this certainly wouldn't be a novel idea, and it's also clear that Vogelstein and Weinberg have done more than almost anyone else in identifying rogue cancer genes and their key roles in health and disease.

    A brief note on the physics prize: There is no doubt in my mind that the Nobel committee needs to give the prize this year to the ATLAS-CMS collaboration at the LHC which discovered the Higgs boson. A prize for them would emphasize several things: it would put experiment at the center of this important scientific discovery (there would have been no 2013 Nobel Prize without the LHC) and it would herald a new and necessary tradition of awarding the prize to teams rather than individuals, reflecting the reality of contemporary science.

    So that's it from my side. Let the games commence!

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    The Congo River catfish Chrysichthys brevibarbis, copyright John P. Sullivan.

    With their long barbels around the mouth and lack of scales, the catfish of the Siluriformes are one of most instantly recognisable groups of fishes. They are also one of the more diverse, with close to 3000 species and including a third of the world's freshwater fishes (Diogo & Peng 2010). Within the catfish, the Claroteidae are a distinctly African group of thirteen genera divided between two subfamilies, the Claroteinae and Auchenoglanididae. They are characterised by a moderately elongate body with a distinct adipose fin, and strong spines in the dorsal and pectoral fins (Geerinckx et al. 2003). Distinctive features of the Claroteinae include the presence of a toothplate on the palate. The Auchenoglanidinae have a rounded caudal fin and the anterior nostrils moved to the anteroventral side of the upper lip (Geerinckx et al. 2004). For a long time, the claroteids were included in the catfish family Bagridae before being raised to the level of their own family in 1991. A molecular phylogenetic analysis of the Siluriformes by Sullivan et al. (2006) placed the claroteids within a clade of African catfish that they somewhat whimsically labelled as 'Big Africa'. The Bagridae, meanwhile, were placed within 'Big Asia' (though one true bagrid genus, Bagrus, does occur in Africa). Sullivan et al. (2006) questioned claroteid monophyly, finding Auchenoglanidinae to be sister to a clade grouping the Claroteinae with the family Schilbidae, but other morphological studies have found claroteids as a monophyletic unit (Diogo & Peng 2010).

    Lake Tanganyika catfish Lophiobagrus brevispinis, from

    The Claroteinae are notable for having undergone something of an adaptive radiation in one of African Great Lakes, Tanganyika. Though not as dramatic as the famous radiation of cichlids in the same lake, the Tanganyikan claroteines comprise over a dozen species divided between four genera (Bailey & Stewart 1984; Hardman 2008). Seven of these are placed in the genus Chrysichthys which has a wide distribution around Africa; the other three genera are unique to the lake. Molecular phylogeny indicates that the majority of Tanganyikan claroteines represent a single colonisation of the lake; only Chrysichthys brachynema has colonised Lake Tanganyika independently (Peart et al 2014). This indicates that the genus Chrysichthys as currently defined is non-monophyletic (something that had previously been suggested on morphological grounds) but any consequent reclassification is yet to occur. The species of Chrysichthys are mostly larger than the endemic Tanganyikan genera, ranging from 19 to 77 cm within Tanganyika (species elsewhere in Africa may reach up to 1.5 m). Of the endemic genera, the monotypic Bathybagrus tetranema is about 15 cm in length but the other two genera Phyllonemus and Lophiobagrus are even smaller, less than 10 cm in length. Bathybagrus and Lophiobagrus also both have reduced subcutaneous eyes. In Bathybagrus, this possibly reflects their occurrence at greater depths than other Tanganyika fish, occurring down to 80 m (nowhere near the depths reached by Lake Baikal sculpins but still impressive enough in the low-oxygen depths of a tropical lake). Lophiobagrus species are specialised to live in the gaps between rocky rubble on the lake bottom. The species of this genus have also been observed secreting a toxic mucus that can be fatal to other fish; this mucus is believed to be secreted from enlarged glands behind the pectoral fins.

    Subcutaneous eyes are also found in two claroteines outside Tanganyika: the species Amarginops platus and Rheoglanis dendrophorus, both found in the Upper Congo (Hardman 2008). These two species are specialised for life in river rapids.


    Bailey, R. M., & D. J. Stewart. 1984. Bagrid catfishes from Lake Tanganyika, with a key and descriptions of new taxa. Miscellaneous Publication, Museum of Zoology, University of Michigan 168: 1–41.

    Diogo, R., & Z. Peng. 2009. State of the art of siluriform higher-level phylogeny. In: Grande, T., F. Poyato-Ariza & R. Diogo (eds) Gonorynchiformes and Ostariophysan Relationships: A Comprehensive Review pp. 465–515. Science Publishers.

    Geerinckx, T., D. Adriaens, G. G. Teugels & W. Verraes. 2003. Taxonomic evaluation and redescription of Anaspidoglanis akiri (Risch, 1987) (Siluriformes: Claroteidae). Cybium 27 (1): 17–25.

    Geerinckx, T., D. Adriaens, G. G. Teugels & W. Verraes. 2004. A systematic revision of the African catfish genus Parauchenoglanis (Siluriformes: Claroteidae). Journal of Natural History 38: 775–803.

    Hardman, M. 2008. New species of catfish genus Chrysichthys from Lake Tanganyika (Siluriformes: Claroteidae). Copeia 2008 (1): 43–56.

    Peart, C. R., R. Bills, M. Wilkinson & J. J. Day. 2014. Nocturnal claroteine catfishes reveal dual colonisation but a single radiation in Lake Tanganyika. Molecular Phylogenetics and Evolution 73: 119–128.

    Sullivan, J. P., J. G. Lundberg & M. Hardman. 2006. A phylogenetic analysis of the major groups of catfishes (Teleostei: Siluriformes) using rag1 and rag2 nuclear gene sequences. Molecular Phylogenetics and Evolution 41: 636–662.

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  • 09/30/15--11:23: Fall fell, so autumn
  • Today really felt like the first real autumn day, cool, crisp, dry (too dry!), and cool enough over night to require a light blanket with the optional two black kitty-girl warmer, but only for Mrs. Phactor. TPP is not complaining. He picked a handful of grape tomatoes and enough small eggplant for a pasta dinner. This also means it will soon be time to harvest prairie biomass for another master's degree project, but that will probably be done next week. Time to go looking for some prairie gentians; although vividly blue they hide deep within the grassy canopy and so are seldom seen by most people. A bottle gentian grew in our gardens for a few years, but it did not sustain itself. It's a strange plant whose flowers never actually open requiring fairly substantial bees to force their way in. Now TPP is on the prowl for a couple of big, winter squashes, they type with hard, dark orange flesh.  They are around but right now shops want "Halloween" prices for them, not squash prices, so perhaps some will wait for a post October sale. Of course there may also be enough squash remaining in the freezer from last year. Inventory control is so hard, and it's a form of spelunking to find out what frozen items lurk in the depths of the freezer. Mrs. Phactor already pointed out that at least 5 packages of Andouille sausage await the urge to make some gumbo.  And cool fall weather is perfect for a pot of gumbo!  See how things just sort of work out especially as the transition continues from margarita season to NY cocktail season. 

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    TPP loves botanical art, and this is just freaking amazing! An artist plants a 1.2 acre plot to recreate a Van Gogh painting. This is simply wonderful!  Mrs. Phactor adds a "Wow! Van Gogh would be proud." Too bad it has to be seen from the air.

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    Tracking the Ocean’s Circadian Rhythm by Christina Reed at Simons Foundation:

    To a distant observer on the Pacific waters north of the island of Oahu, Hawai’i, two ships seemed to be engaged in an odd dance. One would remain stationary while the other cruised ahead — but to nowhere in particular. Instead, it casually chased two buoys drifting several meters below the surface. After a time, the second ship would adjust its bow thruster, kick in its diesel engines and race to catch up with the leading ship. But there was sound science behind the maritime jockeying. For nearly two weeks this summer, the 46 scientists onboard were investigating the ‘days in the life’ of the smallest ocean creatures in an effort to fully understand the microbial ecology that underpins the marine food chain. It was the first expedition of the Simons Collaboration on Ocean Processes and Ecology (SCOPE), and preliminary results suggest that the wealth of data obtained will answer many questions about ocean microbiology.....
    How the Body’s Trillions of Clocks Keep Time by Veronique Greenwood at Quanta Magazine:
    Carrie Partch was at the tail end of her postdoc when she made the first discovery. The structural biologist was looking at a database of human proteins, noting those that shared a piece with the ones she’d been studying. “I was just sort of flipping through it thinking, ‘I should know all of these,’” she recalls. “Then this one came up, and it had a different domain architecture than I’d ever seen.” She looked further into the protein, called PASD1, whose function was unknown. She found that among the few proteins it resembled was one called CLOCK. And that made her sit up straighter — because CLOCK is at the heart of a very large, mysterious process......
    Coffee Time: How caffeine shifts our circadian clocks. by Rachel E. Gross at Slate:
    Caffeine is America’s favorite (legal) white powder. You may know intimately the contours of its high: the jump in your step, the buzz in your brain, that jolt that renders you oh so gloriously and involuntarily alert. In a new study, researchers have quantified the effect of this potent stimulant on your circadian rhythm and explained how it works not just on your brain but also on the cells in your body. Caffeine was already known to alter the circadian clock in red bread mold, green algae, fruit flies, and sea snails. But humans were liable to be a little different. For the first half of the study, published Wednesday in Science Translational Medicine, researchers at the University of Colorado–Boulder measured how caffeine influenced the circadian rhythms of five human caffeine consumers over 49 days.....

    Myth of the ‘Missing Link’ in evolution does science no favors by Sean Nee at The Conversation:
    This spring, the world learned of a newly discovered missing link between microbes and humans called Lokiarchaeota. The actual story is that the microbe Lokiarchaeota, discovered on the deep sea floor by a hydrothermal vent called Loki’s Castle, shares features with both bacteria and us. The spin is that this makes it a missing link between the two. Microbiologists have been discreetly quiet about this narrative fiction; although the microbe is fascinating, and so deserves the spotlight, it is no more a missing link than the platypus is a missing link between ducks and humans. This missing link imagery, based on the idea that evolution is a methodical process with logical, continuous connections to be discovered and mapped, might set up a good story. But it’s wrong – and can detrimentally influence our understanding of immediately threatening processes like the rapid evolution of flu.......
    Should Apes Be Saved From Ebola? by Caleb Hellerman at The Atlantic:
    Flat on her back on a gurney, the chimpanzee is an unsettling sight: Around 130 pounds, the animal is limp, with drool pouring from corner of her mouth, a common side effect of sedation. She looks helpless, like a patient laid out on a hospital bed. But this chimp isn’t hurt; she’s been anesthetized, knocked out so a veterinarian can give her an experimental vaccine against Ebola—a disease that’s been quietly devastating Africa’s primate population since long before last year’s outbreak began. The most recent Ebola epidemic is the largest in history, but smaller outbreaks have been erupting at least since the 1970s. Ebola is a zoonosis, a disease that can be transmitted from animals to people, and by some measures its impact on animal populations has been even more dramatic than its effect on the people of west Africa. Hard numbers are hard to come by, but some conservationists estimate that Ebola has wiped out around a third of the world’s wild chimpanzees and gorillas over the past few decades.....
    Domestication Seems to Have Made Dogs a Bit Dim by Rachel Nuwer at Smithsonian:
    Dogs are considered some of the most intelligent animals on the planet. Thanks to a relationship with humans that dates back tens of thousands of years, dogs can respond to emotions, recognize numerous words and be trained to follow commands. Notably, these seemingly smart accomplishments all hinge on the partnership between our two species. Now, however, tests of canine problem-solving skills indicate that dogs rely on humans so much that we actually seem to be dumbing them down........
    New Evidence The Nazis Didn't Come Close To The Bomb by Carmen Drahl at Forbes:
    With World War II raging, a team of scientists in the U.S. got a top-secret mission: harness nuclear energy. They succeeded, as we now know, and they ushered in the Atomic Age with the mushroom clouds that devastated Hiroshima and Nagasaki. But before that point, as the researchers toiled day and night, one question haunted them: How close were the Nazis to a nuclear weapon of their own? The answer is they weren’t very close at all. According to an investigation published this month in the journal Angewandte Chemie, 1940s uranium samples from Germany don’t show evidence of a self-sustained nuclear chain reaction— the chemical underpinnings of an atomic bomb. The study adds scientific support to historical accounts that the Germans didn’t succeed in their wartime nuclear aspirations. An international team carried out the investigation, led by Maria Wallenius, a radiochemist who coordinates nuclear forensics analysis at the Institute for Transuranium Elements, part of the European Commission’s in-house science service........
    Is Homo naledi just a primitive version of Homo erectus? by John Hawks at john hawks weblog:
    We’ve gotten lots of feedback on the new species Homo naledi. Most has been enormously positive, a little bit has been critical. In particular, a few scientists have come forward with criticism of the idea that H. naledi is really a new species. Fortunately I can address those criticisms easily by pointing to some easy-to-find answers.....
    Why Do We Admire Mobsters? by Maria Konnikova at The New Yorker:
    In 1947, when Elaine Slott was sixteen, she travelled with her mother and sister to visit her aunt and uncle in Florida. The day after they arrived, however, Elaine and her aunt boarded another plane by themselves. Elaine soon found herself speeding to Cuba, where the family had business interests. Elaine remembers that night well. After they landed, she and her aunt left Havana and drove for several hours into areas that seemed increasingly remote. It was very late and very dark when they finally arrived at a stately house. Along with a few guests, a number of family members, including Elaine’s uncle, had gathered there for a dinner party. Their host, who had been cooking pasta, emerged from the kitchen wearing a white apron. He introduced himself to Elaine as Charlie......
    How NASA Is Solving the Space Food Problem by Elizabeth Preston at Eater:
    When admiral George Anson reached the shore of England in 1744, four years after setting sail, he brought fewer than half the 2,000 men he'd left with. Most of his crew had died of scurvy, and eventually, even the survivors were too weak to throw the bodies overboard. But according to NASA nutritionist Scott Smith, Anson had it easy. Like other ill-fated expeditions, Anson's was ravaged by a single missing nutrient: vitamin C. Yet he was at least traveling where some food existed. Astronauts on the long-distance voyages of the future will have to bring all their own food, and it will have to contain the right quantities of every vitamin and mineral they need. Scurvy's just the start of what could go wrong. "There's not one nutrient that you could run out of, on a three-year mission, that's not going to end badly," Smith says. Running out of nutrients is only one of the food challenges that Smith and his colleagues at NASA's Johnson Space Center in Houston are facing. If they succeed, they can help humankind make our next giant leap — onto Mars.....
    Giraffes Hum to Each Other Throughout the Night, And Zookeepers Never Noticed by Allison Eck at PBS Nova:
    Until now, giraffe caretakers had reason to believe that their long-necked vegetarian friends were strictly silent beings. A 13-foot-long trachea isn’t exactly conducive to easy vocalization. Scientists assumed that, if anything, giraffes—like elephants—might produce infrasonic (ultra-low) sounds below the range of human hearing. But without the data to back it up, researchers couldn’t guarantee that giraffes weren’t simply producing audible noises out of human earshot. So a team at the University of Vienna painstakingly gathered 947 hours of giraffe noises over an eight-year period at three European zoos and measured their spectral characteristics, with the goal of finding out once-and-for-all whether giraffes’ socially-structured society lends itself to vocal communication.....
    Also see: Giraffes spend their evenings humming to each other by Karl Gruber at New Scientist. But this is not new - this was discovered way back in 1998, see: Infrasound From the Giraffe by Elizabeth von Muggenthaler at Fauna Communications and Tall Blondes, Silent Sentinels? at PBS Nature and Giraffes can talk, after all by Associated Press at The Augusta Chronicle and Do giraffes make any vocalizations? at Yahoo Answers, for examples...

    And if that is not enough, more readings for later this weekend:

    Researchers have discovered a better way to wait in line, and you’re going to hate it by Ana Swanson at Wonkblog
    Interview: Rachel Armstrong, Innovative Scientist Who Wants to Grow Architecture by Alessia Andreotti at Next Nature
    A Deep Dive into What Exxon Knew About Global Warming and When (1978) it Knew It by ANDREW C. REVKIN at Dot Earth
    California's Mountains Are At A 500-Year Snow Low by William Herkewitz at Popular Mechanics
    Scientists have revived a 30,000 year-old prehistoric virus by Jennifer Welsh and Guia Marie Del Prado at Tech Insider
    Dinosaur skeletons aren’t decor – they shouldn’t be sold to the highest bidder by Brian Switek at Comment is free
    The world’s 3 trillion trees, mapped by Chris Mooney at Washington Post
    Hydropower: Does NC's Original Renewable Have A Place In Its Future? by Dave DeWitt at WUNC
    Photograph 51: how do you bring science to the stage? by Stephen Curry at Occam's corner
    Happier People Are Raised By Parents Who Do These Two Things by Dr Jeremy Dean at PsyBlog
    How I Became a Crowd-Sourced Zoologist by Zach St. George at Nautilus
    Cool clock, Ahmed. Want to bring it to the White House? We should inspire more kids like you to like science. It's what makes America great. by @POTUS at Twitter
    The Book No One Read: Why Stanislaw Lem’s futurism deserves attention. by Lee Billings at Nautilus
    Get Buried in an Egg and Turn Into a Tree by Zara Stone at Ozy

    Bats save corn farmers $1 billion per year by Russell McLendon at MNN
    Using Melatonin To Help Children Fall Asleep by Wendy Sue Swanson, MD, MBE at Seattle Mama Doc
    A Pregnancy Souvenir: Cells That Are Not Your Own by Carl Zimmer at NYTimes
    Alphabet Hires Director Of National Institute Of Mental Health by Alexandra Ossola at Popular Science
    Paleo People Were Making Flour 32,000 Years Ago by Jeremy Cherfas at The Salt
    So Funny, It Doesn't Hurt: Can improv be a form of therapy? Some psychologists think so. by Kathleen Toohill at The Atlantic
    Obama Seeks Psychological Help with Climate Change by Evan Lehmann at ClimateWire
    Liberals swear more on Twitter than rightwingers, says study by Ian Sample at Guardian
    Philosophy and reality by Larry Moran at Sandwalk
    Caffeine at night is an even worse idea than we thought by Blair Shiff at 9News
    Why storing solar energy and using it at night is closer than you think by Chris Mooney at Washington Post
    What Comes After Heirloom Seeds? by Michael Tortorello at The New Yorker
    Citizen science community responds to Nature editorial at Citizen Science Association
    Handmade boats bring citizen science to the Mystic River by Elizabeth Preston at BetaBoston by Brad Plumer at Vox
    For Entertainment! For School! For News! For Fact-Checking! Why do people read science blogs? by Paige Brown Jarreau at FromTheLabBench
    The Mystery of the Appalachian Bend by Dan Lewis at Now I Know
    A time to remember by Jessa Gamble at The Last Word On Nothing
    Aquarium Corals of Anchorage Poison 10 1/2 Humans, Two Dogs, and One Cat by Jennifer Frazer at The Artful Amoeba
    'Invisibility cloak' could turn beer bellies into six-packs by Ian Sample at Guardian
    2015 Ig Nobel prizes: dinosaur-like chickens and bee-stings to the penis by Alan Yuhas at Guardian
    Hyperbolic Pascal triangles and other stories by Gianluigi Filippelli at Doc Madhattan
    Humps, lumps and fatty tissues in dinosaurs, starring Camarasaurus by Mark Witton at Mark Witton's blog
    Sex robots are actually going to be good for humanity by Kate Devlin at Quartz
    A Brief History of Toilet-Based Animal Attacks by Forrest Wickman at Slate
    Not Up for Debate: The Science Behind Vaccination by Aaron E. Carroll at The Upshot
    Want To Take the Best US Road Trip? According to a Scientific Algorithm, Here’s Your Map! by Randy Olson at Conscious Life News
    Your City's New 4-Legged Lawn Mower by Farah Halime at Ozy
    20 Cognitive Biases That Affect Your Decisions by Jennifer M Wood at Mental Floss

    Can DNA Evidence Solve a 30-Year-Old Crime? by James Vlahos at The Atlantic
    Pushing the Limits: Merging the power of multiple brains at CBS News
    Marine life needs protection from noise pollution by Emma Brown at Nature
    Wasps Have Genetically Modified Butterflies, Using Viruses by Douglas Main at Newsweek
    Solving the Mystery of an Ancient Epidemic by Simon Davis at The Atlantic
    Patent for first method to create human sperm, but does it work? by Andy Coghlan at New Scientist
    The Evolution of Everything by Matt Ridley review – the rightwing libertarian gets it wrong by John Gray at Guardian
    Parent planning – we shouldn’t be allowed to choose our children’s sex by Tamara Kayali Browne at The Ethics Centre Blog
    Read/write access to your genomes? Using the past to jump to the future by Razib Khan at Genes to Genomes
    Missing the Soil for the Seeds in Cancer Research by Claudia Fischbach at SA Guest Blog
    5 Important New Insights About Why We Get Angry by Todd B Kashdan Ph.D. at The Creativity Post
    Caffeine In Coffee May Throw Off Circadian Rhythm, And All It Takes Is One Double Espresso by Samantha Olson at Medical Daily
    Climate Change Is the Moonshot of Our Times by Martin Rees at Facts So Romantic
    An archaeobotanical exploration of poo by Karen Stewart at Mola
    Healthy as a Horse? by Doctor Ramey at David Ramey, DVM
    or Entertainment! For School! For News! For Fact-Checking! Why do people read science blogs? by Paige Brown Jarreau at From The Lab Bench

    It's Time To Get Serious About Reducing Food Waste, Feds Say by Allison Aubrey at The Salt
    Google's NIH health hire: Smartphones can detect mental health breakdowns by Kayt Sukel at Fortune
    The Problematic Obsession With ‘Curing’ Autism by Jesse Singal at Science Of Us
    Finding Your Way Home by Peter Godfrey-Smith at Boston Review
    The "Black Piranha" of Ascension Island by Steven Bedard at Expeditions
    How to Restart an Ecosystem by Greg Carr at Nautilus
    Fighting apatosaur art #1: Brian Engh and Fighting apatosaur art #2: Brian Engh again by Mike Taylor at Sauropod Vertebra Picture of the Week
    “We’re still dealing with autism like it’s this wacky historical aberration”: Steve Silberman on the truth about autism by Michael Schulson at Salon
    Carl Safina On Wild Wolves And Bottle-Fed Squirrels by Barbara J. King at NHPR
    7 scientific studies too weird to believe by Kelly Dickerson at Tech Insider
    Why do we read blogs, anyway? by Paige Brown at Medium
    Why every school should bring dogs into the classroom by Chris Weller at Tech Insider
    Does genome size affect fitness in seed beetles? by Larry Moran at Sandwalk
    When Alice, Wittgenstein, and Russell met at the Mad Hatters Tea Party by Eric Gerlach at The Philosopher
    How To Print Your Own 3D Replicas Of Homo Naledi And Other Hominin Fossils by Kristina Killgrove at Forbes

    Why we need predators by Sarah Zielinski at Wild Things
    Preserving Tattoos Of The Dead Is A Little Macabre But Not New by Kristina Killgrove at Forbes
    It Is Incredibly Difficult to Obtain an Evolution Education by Glenn Geher Ph.D. at Darwin's Subterranean World
    A Parent's Nightmare by Kristin Foss at The Winnower
    Weekend Diversion: Mockery Gets You Nowhere by Ethan Siegel at Starts With A Bang!
    Captive Snake With No Male Companion Gives Birth, Again by Jim Salter at Time
    ‘Tree of Life’ for 2.3 Million Species Released by Robin A. Smith at Duke Today
    A Peek Inside the Pluto Public Relations Machine by Kirk Englehardt at The Leap
    Do Wild Dogs Sleep as Much as Your Pets? by C. CLAIBORNE RAY at NYTimes
    What We'll Need To Have A Successful Human Colony On Mars by Ethan Siegel at Forbes
    9 Years of Muck, Mud and Debate in Java by RACHEL NUWER at NYTimes
    Scott Aaronson on "The theorem that proves rationalists can't disagree" by Julia Galef at Rationally Speaking
    Why is the scientific revolution still controversial? by Ian Sample at Science Weekly
    Introducing the All-Female Team of Scientists Who Discovered Homo Naledi by Maddy Myers at Mary Sue
    Fish Fate by Dorit Eliyahu at The Drawer's Drawer
    Meet the Gemini Radar Evaluation Pod by Amy Shira Teitel at Vintage Space

    Previously in this series:

    FieldNotes: a view to spotted horses in the morning
    FieldNotes: The Word For World is Blue (or is it Gold?)
    FieldNotes: Golden Mean, polite middle-ground, and optimal numbers of legs.
    FieldNotes: speeding up and slowing down time
    FieldNotes: from Captain Ahab to Jeff Goldblum, chasing the giants
    FieldNotes: this is not your grandparents' neuroscience!
    FieldNotes: Brontosaurus in, Food Babe out.
    FieldNotes: Rogue Microwave Ovens Call Home
    FieldNotes: Let the sleeping apes lie
    FieldNotes: one thing leads to another leads to another
    FieldNotes: Seductive Allure of Seductive Allure of Neuroscience Explanations
    FieldNotes: do African horses do flehmen at the sight of Derby hats?
    FieldNotes: How The Bird Got Its Beak
    FieldNotes: When Snakes Had Legs...
    FieldNotes: Only before the bicameral mind evolved could people fall for Bohannon's cheap stunts
    FieldNotes: Water, fire, origin of life, origin of cooking.
    FieldNotes: Jurassic World, and other strange animals...
    FieldNotes: Honey Badger Don’t Care!
    FieldNotes: Hallucigenia is back on its head again.
    FieldNotes: Poisonous and grieving quail, reclusive rail, and giants!
    FieldNotes: When Snark was a Boojum
    FieldNotes: In a grip of the legs of a snake
    FieldNotes: Cecil and grief
    FieldNotes: Science Notes and high school start times
    FieldNotes: Earthly Octopus Genome, and Elephant Tracking
    FieldNotes: Amplituhedron and the dissection of cats
    FieldNotes: Oliver Sacks, and irreproducible psychology
    FieldNotes: Hand-drawn biology, wearing rubber gloves, and the invention of the submarine
    FieldNotes: Homo naledi, #‎IStandWithAhmed‬ and NatGeo Fox

    Laguna Design/Science Source

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    The Economic Ornithology of Sunflower Seeds by Ben Young Landis at See. Food. Write.:

    Under the yellow pallor of a smoke-filled sky, I walked along the edge of an underworld of sunflowers. I was visiting a sunflower farm in Woodland, California, but a major wildfire was ablaze many miles to the east, casting a ghastly gloom over counties upon counties across the the state’s Central Valley. Some people mistook the gray skies for an overcast day, but the reality was far more grim. In total, the Butte Fire of September 2015 burned more than 70,000 acres (280 square kilometers) — more than twice the area of Paris, France — and destroyed at least 475 residences and claiming two human lives. Filtered through this airborne layer of ash and soot, sunlight takes on an otherworldly, yellowish-orange tint — making this sweeping vista of dying sunflowers appear all the more apocalyptic. Mention sunflowers, and our immediate mental image is one of golden-faced blossoms perched upon proud, green stems. But this field of desiccated stalks looked more like an enormous zombie army, marching in unison with some unholy purpose, heads drooped, a husk of their former, vibrant selves.......
    ‘Tree of Life’ for 2.3 Million Species Released by Robin A. Smith at Duke Today:
    A first draft of the “tree of life” for the roughly 2.3 million named species of animals, plants, fungi and microbes -- from platypuses to puffballs -- has been released. A collaborative effort among eleven institutions, the tree depicts the relationships among living things as they diverged from one another over time, tracing back to the beginning of life on Earth more than 3.5 billion years ago.....
    Your Tooth Enamel Might Have Started As Fish Scales by Mary Beth Griggs at Popular Science:
    Your pearly-white smile has a fishy origin story. And no, we're not referring to your overuse of tooth whitening products. Actual fish were involved, millions of years ago. Tooth enamel is the hardest substance in the human body, protecting your teeth from damage. Enamel is only found on vertebrate teeth, but how it came to armor our mouths remained a bit of a mystery. Now, scientists think they might have found an answer in 400 million-year-old fish scales. In a paper published today in Nature, researchers found that a shiny substance in fish scales called ganoine is related to enamel. .....
    As Sea Ice Melts, Antarctic Seafloor Life Flourishes by Douglas Main at Newsweek:
    One of the more alarming prospects of climate change is that it threatens to create so-called “positive feedbacks” that are likely to make warming worse. As vast chunks of sea ice melt, for example, they leave swathes of open water that are less reflective than the ice, and therefore absorb more heat. This leads to more warming......

    When It Comes To Science In Movies, Attitude Is As Important As Accuracy by Chad Orzel at Forbes:
    ....I’m fine with books and movies bending known science a bit for the sake of a good story. I would add one element to this, though, which is the attitude that the movie and the characters in it bring to the science. I think in many ways, that attitude is as important as the actual science portrayed on-screen. I obviously haven’t seen The Martian yet– though if any studio types are reading this and would like to send me to a preview screening, shoot me an email, we’ll talk– but I’ve recently read Andy Weir’s book, and have high hopes for the movie on the attitude front......
    A New Diagnosis by Cynthia L. Mills at Dog-Ma’s:
    Recently there has been talk of requiring veterinarians to report suspected animal abuse, just as doctors and nurses are required to report possible child abuse. I see this as appropriate, but I also see this as a conundrum, especially in the case of animal hoarding. Animal hoarders, for the most part, would not dream of harming their pets. They describe themselves and are described by others as animal lovers and rescuers. They despise abuse. Yet they, in so many cases, practice it......
    Rite to Die: Sallekhanā and End of Life by Layla Eplett at Food Matters:
    The Jain belief that nearly everything--even plants--has a soul and their adherence to nonviolence factors into their taking the vow of Sallekhanā, explains Dr. Whitny Braun, a bioethicist at Claremont Lincoln University. She has spent nine years researching Jainism and a book based off her dissertation on the subject is anticipated to be published in 2016. According to Braun, “Philosophically and logistically in life, the only way to be completely nonviolent is to stop taking other lifeforms and the only way to completely stop taking life forms is to not consume them. So for Jains, the ultimate way to exit this life is to stop eating, to stop taking those lifeforms.”.................
    The Window Operation: Hope through Surgery by Jaipreet Virdi-Dhesi at REMEDIA:
    ...........A 44 year-old female patient, nearly stone-deaf for half her life, laid upon the operating table. Two dental drills covered with sterile linen sleeves hung over the table, prepared and ready. The surgeon, a wispy, small man with a bushy pompadour underneath his surgeon’s cap, signaled to the anesthetist that the procedure was about to begin. Turning on his headlamp, the surgeon focused a powerful, pencil-thin stream of illumination on the patient’s right ear. Then he began the first incision on her outer ear, creating an opening the size of a small coin. Taking one of the drills, the surgeon devoured the tough mastoid bone, slowly proceeding for half an hour until he was able to expose the bony labyrinth of the inner ear. This was to be the new window that would, hopefully, restore sound vibrations and enable the patient to hear............

    There is flowing water on Mars!
    NASA confirms that liquid water flows on Mars by Loren Grush at The Verge
    Mars has flowing rivers of briny water, NASA satellite reveals by Nsikan Akpan at PBS NewsHour
    The Long and Arduous Quest to Find Flowing Water on Mars May Be Over by Alfred S. McEwen at Scientific American
    NASA Finds “Strong” Evidence For Water On Mars by Kelly Oakes at BuzzFeed
    Water on Mars: Astrobiology Implications Must be Taken with a Grain of Salt by David Warmflash at Visionlearning
    If there is liquid water on Mars, no one—not even NASA—can get anywhere near it by Akshat Rathi at Quartz
    Water Flows on Mars Today, NASA Announces by Clara Moskowitz at Scientific American
    Why NASA Didn't Just Send Over A Rover To Look For Water On Mars by Joe Palca at The Two-Way

    And if that is not enough, more readings for later this weekend:

    The Dark Side of Empathy by Paul Bloom at The Atlantic
    by Jamil Zaki at The New Yorker
    Interview with Corvid Cognition Researcher Claudia Wascher at Animal Cognition
    Five Sea Creatures to Really Freak Out the Boston Fish Bros by Elizabeth Preston at Inkfish
    Science on a shoestring: how to get results despite massive budget cuts by Dean Burnett at Brain flapping
    The extraordinary case of the Guevedoces by Michael Mosley at BBC
    Yet another survey suggests the climate change ‘debate’ is settled among scientists by Chelsea Harvey at Washington Post
    Melatonin Linked to Seasonal Relapses of Multiple Sclerosis by Diana Kwon at Scientific American
    Blood test can prevent suicide? How to prevent “biomarker porn” by Andrew Porterfield at Genetic Literacy Project
    Time to Rethink the Reconsolidation Theory of Memory? by Neuroskeptic at Neuroskeptic
    Where In Our Solar System Are We Most Likely To Find Life? by Ethan Siegel at Forbes
    Precision Medicine: Much More Than Just Genetics by Ricki Lewis, PhD at DNA Science Blog
    Giant Megaphones Built In Estonian Forest Amplify the Sounds of Nature by Olivia Harrison at Mental Floss
    Here's how much of the world would need to be covered in solar panels to power Earth by Rebecca Harrington at Tech Insider

    Freedom and truth in mathematics by Gianluigi Filippelli at Doc Madhattan
    Throwback Thursday: Logic Is No Match For Science by Ethan Siegel at Starts With A Bang!
    The one thing I teach that nobody ever forgets by Stephen Heard at Scientist Sees Squirrel
    Coffeeshop Science by Ann Finkbeiner at The Last Word On Nothing
    The Hunt for Mona Lisa's Bones Is A Publicity Stunt, Not Science by Kristina Killgrove at Forbes
    Genetic Secrets of the Last Truly Wild Horses by Douglas Main at Newsweek
    Academics: leave your ivory towers and pitch your work to the media by Kristal Brent Zook at Impact of research

    It’s Twins! Two Embryos in One Anolis sagrei Egg by Ambika Kamath at Anole Annals
    Most doctors are not scientists, Ben Carson paper bag edition by Orac at Respectful Insolence
    Visions of Future Physics by Natalie Wolchover at Quanta Magazine
    What's the best time to make love? An Oxford University sleep expert shares some tips by Rozina Sabur at Telegraph
    The Role Of Organic Pesticides In California by Steven Savage at Forbes
    What Cuba Can Teach Us About Food and Climate Change by Raj Patel at Slate (see also: Alternative Agriculture in Cuba by Sara Oppenheim at AMERICAN ENTOMOLOGIST)

    Here’s the Evolution-Questioning ‘Sticker’ Alabama Puts on Its Biology Textbooks by Zoë Schlanger at Newsweek
    Population structure and recombination by Charles Goodnight at Evolution in Structured Populations
    Volkswagen and the Era of Cheating Software by Zeynep Tufekci at NYTimes
    How Different Cultures Understand Time by Richard Lewis at Business Insider
    Healing Spas and Ugly Clubs: How Victorians Taught Us to Treat People With Disabilities by Lisa Hix at Collectors Weekly
    How the enamel that coats your teeth evolved by Sid Perkins at Science
    Here’s what Ridley Scott has to say about the science in The Martian by Meghna Sachdev at Science
    Activists blame scientists, GMOs for dying iconic Italian olive trees, block GM solution by Andrew Porterfield at Genetic Literacy Project
    Starting work before 10am isn’t just soul crushing, this scientist says it’s equivalent to torture by TYLER FYFE at The Plaid Zebra
    Why bison put their females in charge by Virginia Morell at Science
    Communication, Literacy, Policy: Thoughts on SciComm in a Democracy by Rick Borchelt at Keyed In Blog
    Are science blogs echo chambers? by Paige Brown Jarreau at From The Lab Bench
    Climate Got Your Tongue? by Perrin Ireland at onEarth
    Why Is the Man Who Predicted Climate Change Forgotten? by Simon Worrall at National Geographic

    How the Body’s Trillions of Clocks Keep Time by Veronique Greenwood at Wired
    Statins: Heart disease drug speeds up ageing process, warns new research by Lucy Johnston at
    These animals are male on one side and female on the other by David Robson at BBC
    Fighting apatosaur art #4: #MikeTaylorAwesomeDinoArt by Mike Taylor at Sauropod Vertebra Picture of the Week
    Anoles’ Namesake Salamander Rediscovered After 30 Years by Jonathan Losos at Anole Annals
    Archimedes’ legendary sphere brought to life by Jo Marchant at Nature
    Michael Faraday on Mental Discipline and How to Cure Our Propensity for Self-Deception by Maria Popova at Brain Pickings
    3-D Printing’s Next Act: Nerve Regeneration by Mike Orcutt at MIT Technology Review

    Camera Traps: Setup for Success by On Assignment at Nat Geo Travel
    The AP will no longer use “skeptics” to describe people who don’t believe in climate change by Olivia Goldhill at Quartz
    Introduction to Molecular and Genome Evolution by Dan Graur at Judge Starling
    Causation vs Correlation by Rebecca Goldin at STATS blog
    Shaky science: 9 Retracted Studies That Left a Big Mark by Mihai Andrei at ZME Science

    Data “Overflow” Compromising Science? by Bob Grant at The Scientist
    Publish or perish culture encourages scientists to cut corners by Virginia Barbour at The Conversation
    Interdisciplinary research by the numbers by Richard Van Noorden at Nature
    Archaeologists Discover 7-Pound Calcified Uterus in British Cemetery by Megan Gannon at Mental Floss
    My Son Has the Kind of Autism No One Talks About by Bonnie Zampino at HuffPo Parents
    Sumatran rhinos likely to become extinct, conservationists warn by Adam Vaughan at Guardian
    Declining Student Resilience: A Serious Problem for Colleges by Peter Gray at Freedom to Learn
    Let’s Talk X-rays by Doctor Ramey at David Ramey, DVM
    More Doubts Over The Oxytocin And Trust Theory by Neuroskeptic at Neuroskeptic
    Ancient hominid ears were tuned to high frequencies by Bruce Bower at Science News
    Homo naledi: determining the age of fossils is not an exact science by John Hawks at The Conversation
    Using Science to Make Government Work Better by Sam McNerney, Jon M. Jachimowicz and Dave Nussbaum at MIND Guest Blog
    Ignoring science isn't just a Republican problem. It's an American problem. by Dan Rather at Mashable
    A Beetle Utopia on an Artist's Conk Fungus by Jennifer Frazer at The Artful Amoeba

    It’s alive!! Study adds to evidence that viruses are alive by Dr. Jekyll at Lunatic Laboratories
    Harry Potter Magic Comes to Life by Victoria Barker at ScicommLSU
    Hearing Loss Costs Far More Than Ability to Hear by JANE E. BRODY at Well
    Homo naledi fossil discovery a triumph for open access and education by John Hawks at The Conversation
    Can Vitamin B Cure Deafness? by Jaipreet Virdi-Dhesi at From the Hands of Quacks
    What Archaeologists Really Think About Ancient Aliens, Lost Colonies, And Fingerprints Of The Gods by Kristina Killgrove at Forbes
    Are science blogs echo chambers? by Paige Brown Jarreau at From The Lab Bench
    Vaccinating boys against cervical cancer? by Susanne Dambeck at Lindau Blog
    Dan Rather emerges as an ally for science by Ulli Hain at Science Extracted
    Sex not as simple as X and Y by Andrew Porterfield at Genetic Literacy Project

    The Winners of the 3QD Science Prize 2015 by Nick Lane at 3 Quarks Daily
    Fighting apatosaur art #5: Mark Witton by Mike Taylor at Sauropod Vertebra Picture of the Week
    Zoltan Takacs’s venomous vision by Peter Hess at Scienceline
    Queer in STEM by Jeremy Yoder at Genes to Genomes
    Editor’s Selection: “The Martian” is a Transcendent Sci-Fi Opus by Jovana Grbic at ScriptPhD
    Lizard Playground Dedicated to Anole Happiness and Fitness by Jonathan Losos at Anole Annals
    National Science Foundation Grant Enables Arizona State University to Develop SciStarter 2.0 to Advance Citizen Science by Dr. Caren Cooper, Ira Bennett and Steve Gano at Citizen Science Salon

    AP News Caves to Right-Wing: Will No Longer Use Term ‘Climate Change Denier’: Will Use ‘Climate Change Doubter’ by K.J. McElrath at Ring of Fire
    Open Science and Innovation: Of the People, By the People, For the People by Jenn Gustetic, Kristen Honey, and Lea Shanley at The White House blog
    Writing Young: Crafting Science Stories for Kids by Elizabeth Preston at The Open Notebook
    What is the “science of science communication”? by Dan Kahan at JCOM
    Values Argument: GMOs a Concern Since Farming is Remote by Hank Campbell at ACSH
    Ears of early humans could hear frequencies used in speech by Sam Wong at New Scientist
    These fish would rather walk by Susan Milius at Science News

    Why Do Narcissists Lose Popularity Over Time? by Scott Barry Kaufman at Beautiful Minds
    Fighting apatosaur art #6: the ones that got away by Mike Taylor at Sauropod Vertebra Picture of the Week
    Citizen Science at the White House by Caren Cooper at Citizen Science Salon
    Curiously Feathered Dinosaurs by Glendon Mellow at Symbiartic
    A Day without Cars Draws Attention to Urban Environments and Health by Melissa C. Lott at Plugged In
    Science of the People, by the People and for the People by Caren Cooper at SA Guest Blog
    What we can learn from a PLOS Medicine study of antidepressants and violent crime by James Coyne PhD at Mind the Brain
    Love thy enemy's enemy: why hummingbirds nest near hawks by GrrlScientist at GrrlScientist
    Has Science Realized This 350-Year-Old Alchemist Wish List? by Joanna Klein at Nautilus
    Media and organic created myth: UN endorses small-scale organic farming over biotech by Iida Ruishalme at Genetic Literacy Project
    Gene-edited 'micropigs' to be sold as pets at Chinese institute by David Cyranoski at Nature
    Jerry Coyne retires by Larry Moran at Sandwalk
    E.O. Wilson explains why parks and nature are really good for your brain by Chris Mooney at The Washington Post
    Exclusive Video: First "Glowing" Sea Turtle Found by Jane J. Lee at National Geographic

    Brawny Bones Reveal Medieval Hungarian Warriors Were Accomplished Archers by at Forbes
    Jurassic Pork: What Could a Jewish Time Traveler Eat? by Roy E. Plotnick, Jessica M. Theodor and Thomas R. Holtz at Evolution: Education and Outreach
    New Dinosaur Species Probably Endured Snow and Darkness for Months on End by Allison Eck at NOVAnext
    Marvels of illusion: illusion and perception in the art of Salvador Dali by Susana Martinez-Conde, Dave Conley, Hank Hine, Joan Kropf, Peter Tush, Andrea Ayala and Stephen L. Macknik at Front. Hum. Neurosci.

    Previously in this series:

    FieldNotes: a view to spotted horses in the morning
    FieldNotes: The Word For World is Blue (or is it Gold?)
    FieldNotes: Golden Mean, polite middle-ground, and optimal numbers of legs.
    FieldNotes: speeding up and slowing down time
    FieldNotes: from Captain Ahab to Jeff Goldblum, chasing the giants
    FieldNotes: this is not your grandparents' neuroscience!
    FieldNotes: Brontosaurus in, Food Babe out.
    FieldNotes: Rogue Microwave Ovens Call Home
    FieldNotes: Let the sleeping apes lie
    FieldNotes: one thing leads to another leads to another
    FieldNotes: Seductive Allure of Seductive Allure of Neuroscience Explanations
    FieldNotes: do African horses do flehmen at the sight of Derby hats?
    FieldNotes: How The Bird Got Its Beak
    FieldNotes: When Snakes Had Legs...
    FieldNotes: Only before the bicameral mind evolved could people fall for Bohannon's cheap stunts
    FieldNotes: Water, fire, origin of life, origin of cooking.
    FieldNotes: Jurassic World, and other strange animals...
    FieldNotes: Honey Badger Don’t Care!
    FieldNotes: Hallucigenia is back on its head again.
    FieldNotes: Poisonous and grieving quail, reclusive rail, and giants!
    FieldNotes: When Snark was a Boojum
    FieldNotes: In a grip of the legs of a snake
    FieldNotes: Cecil and grief
    FieldNotes: Science Notes and high school start times
    FieldNotes: Earthly Octopus Genome, and Elephant Tracking
    FieldNotes: Amplituhedron and the dissection of cats
    FieldNotes: Oliver Sacks, and irreproducible psychology
    FieldNotes: Hand-drawn biology, wearing rubber gloves, and the invention of the submarine
    FieldNotes: Homo naledi, #‎IStandWithAhmed‬ and NatGeo Fox
    FieldNotes: Circadian Rhythms in the brain, body and sea

    Open Tree of Life, Duke.

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    Some things decompose readily; some things decompose slowly; some thing essentially decompose so slowly that they essentially don't decompose; a very few things are forever. Waxes decompose very slowly, which is why cuticles of fossil leaves persist so well for millions of years. Sporopollenin is the stuff that land plant spore and pollen walls are made of and it doesn't decompose at all. No organism has an enzyme that breaks these molecules down. Wonder if they've tried feeding pollen to meal worms? TPP asks this because humans have invented a few nasty things that do not decompose either, so they hang around and accumulate. Styrafoam and other polystyrenes being some of the more common ones. But say what? Mealworms can eat styrafoam and subsist on it? That's just amazing! A colleague of mine used to keep a colony going and hand out the mealworms (beetle larvae really) to visiting school kids as a snack because they are edible. The real funny part came when he'd turn to their teacher and say, "Your teacher will show you how to try new foods." Ha! They were worse than the kids.  So now you can raise mealworms on styrafoam, one of the nastiest kinds of plastic pollutants, and then use the mealworms as a stir-fry ingredient, or chicken or fish food, or energy bars, or something. Where is my Man Eating Bugs cookbook?  This is such a handy discovery.

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    I did the test experiment described in the previous post, and then spent the past few days figuring out why my positive control transformation didn't work any more.

    The test experiment was to kinase, ligate and transform into DH%alpha the product of the inverse-PCR reaction.  If the T4 polynucleotide kinase reaction worked, its blunt ends would acquire 5' phosphates that would allow it to be circularized by T4 DNA ligase, and to then transform DH5alpha to ampicillin resistance.  The negative control was no DNA and the positive control was the same p∆TA:spec plasmid that had given thousands of AmpR and SpecR transformants in the previous experiment.

    Sounds great, but this time the positive control didn't give any transformants at all!  Background small colonies were frequent, possibly because the plates were a bit old and the ampicillin had lost its potency, so I didn't trust the few larger colonies on the inverse-PCR reactions plates.  I streaked a few of the large colonies to check if they were genuinely AmpR - one was.

    I repeated the control transformation and negative control with new Amp plates; the no-DNA control plates were clean but so were the p∆TA:spec plates.

    I thought the problem might be the plasmid, but I wasn't sure I have another reliable positive control. So I did a miniprep from the one genuine AmpR colony I had streaked and transformed the cells with that DNA.  I also had the usual no-DNA control, the undergrad's p∆TA:spec, another plasmid made by the undergrad (used successfully by me as the inverse-PCR template, and some pUC18 left by a sabbatical visitor.

    Success all around.  The miniprep DNA, the other undergrad plasmid and the pUC18 all gave lots of transformants (the photo shows part of a pUC18 plate), and the undergrad's p∆TA:spec and the no-DNA control gave none.  I don't know why the p∆TA:spec plasmid worked well in my first experiment - maybe I had grabbed a 'wrong' (i.e. good DNA)tube.

    Next step, repeating my original experiment (the one in the previous post), this time with better controls.

    1. DNA clean-up: I did a new inverse-PCR reaction because the old one got used up in the tests.  I need to start by doing a spin-column cleanup of it.
    2. Two kinase reactions: (i) the 'blurry' spec PCR product and (ii) the not-blurry inverse-PCR product.  Heat-inactivate the kinase before step 2 (65°C 20 min).  This time I'll use a newer stock of ATP, and the official kinase buffer
    3. Four ligase reactions: A. the kinased spec fragment plus not-kinased inverse-PCR fragment. B.  (kinase control) The kinased inverse-PCR fragment. C. (negative control) The not-kinased spec fragment plus the not-kinased inverse-PCR fragment . D. (positive control) pUC18 cut with EcoRI and heat-inactivated (65°C 20 min).
    4. Six transformations: Ligations A, B, C and D, plus 1 µl pUC18 as positive control and no DNA as negative control.
    Preparations:  EWe have enough kinase I've just sent the grad student to buy more ligase.  Luckily I have lots of frozen competent cells for the transformations.  I'll need to digest the pUC18 and check it in a gel, and pour lots of Amp plates and some Spec plates.

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    A couple of abstracts about the geomtery of space:

    Historically, there have been many attempts to produce the appropriate mathematical formalism for modeling the nature of physical space, such as Euclid's geometry, Descartes' system of Cartesian coordinates, the Argand plane, Hamilton's quaternions, Gibbs' vector system using the dot and cross products. We illustrate however, that Clifford's geometric algebra (GA) provides the most elegant description of physical space. Supporting this conclusion, we firstly show how geometric algebra subsumes the key elements of the competing formalisms and secondly we show how it provides an intuitive representation and manipulation of the basic concepts of points, lines, areas and volumes. We also provide two examples where GA has been found to provide an improved description of two key physical phenomena, electromagnetism and quantum theory, without using tensors or complex vector spaces. This paper also provides pedagogical tutorial-style coverage of the various basic applications of geometric algebra in physics.
    James M. Chappell, Azhar Iqbal & Derek Abbott (2011). Geometric Algebra: A natural representation of three-space, arXiv: 1101.3619v3
    We indicate that Heron's formula (which relates the square of the area of a triangle to a quartic function of its edge lengths) can be interpreted as a scissors congruence in 4-dimensional space. In the process of demonstrating this, we examine a number of decompositions of hypercubes, hyper-parallelograms, and other elementary 4-dimensional solids.
    J. Scott Carter & David A. Mullens (2015). Some Elementary Aspects of 4-dimensional Geometry, arXiv: 1504.01727v1
    There's also a minimalistic introduction to euclidean planes.

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    Recognition of aromatic rings by two very different
    mechanisms but through similar binding energies
    Over the years chemists have come up with many different ways to talk about the structure and energetics of molecules and especially to compare these parameters between various compounds. Doing this comparison is not just an academic exercise; for example, knowing which drug molecules are ‘similar’ or ‘different’ can be the deciding factor in picking one drug over another. It is also crucial for knowing the kinds of side effects that drugs can induce by interacting with off-target proteins.

    Unfortunately the application of these simple descriptions to matters of molecular description is a very good example of what happens when language collides with fuzzy, ill-defined facts in nature. ‘Similarity’ is a classic example. When you are talking about two drugs being similar for instance, are you talking about their similarity purely in terms of molecular structure (which itself can be defined in many different ways), or their similarity in terms of their effects on cancer cells, or their similarity to engage a common protein target in the body, or through similar side effects? Clearly there are many different ways to define similarity and all these ways are subjective to a large extent.

    But there is a problem with applying language to chemical concepts even at a very limited and basic level. A great example of this conundrum is hinted at by a paper from Brian Shoichet’s group at UCSF that just came out in the journal ACS Chemical Biology. The paper asks a very fundamental question: Do identical small molecules or ligands bind to very different proteins? The question in fact goes deeper: How do you define similarity and differences between various proteins to begin with?

    To investigate this question, the authors consider 59 ligands bound to 119 different proteins in the PDB. Many bind with high affinity, ranging from low nanomolar to mid micromolar. What the study does is to classify these protein-ligand pairs into three groups. The first group consists of pairs in which the same atoms in identical ligands bind to similar or identical residues in different proteins. The second group consists of the same ligand atoms in identical ligands binding to similar kinds of residues (hydrophobic, positively charged etc.). The third group in a sense is the most interesting since it involves identical ligands binding to completely different proteins; in these cases the binding involves neither similar ligand atoms nor similar protein environments.

    The authors find that a good two thirds of the set of protein-ligand pairs involve identical ligands binding to proteins with dissimilar residues. In addition, half of these involve ligands binding to proteins with completely different environments. There is thus no ‘pattern-matching code’ for the same ligand binding to different proteins.

    Why do identical ligands bind in very different protein environments? The simple reason is because chemical binding is to a large extent a non-specific process, and there are many ways to skin the protein-ligand cat. Hydrophobic groups bump into hydrophobic groups, positively charged groups interact with negative charged ones and polar atoms snuggle up against other polar atoms. As the authors say:
    "A reason why there is no simple code for ligand recognition among binding sites is that proteins have found multiple, at least superficially unrelated ways to recognize most common ligand groups. Thus, cationic amines can be recognized both by anionic residues such as aspartate or glutamate, but they can also be recognized by cation-Pi interactions. Nucleotide phosphates can be recognized by cationic residues such as arginines, but recognition by main chain amide nitrogens in a P-loop is also common. Ligand aromatic groups can stack with tyrosines, phenylalanines and tryptophans, but they can also form cation-Pi interactions many other variations might be mentioned."
    But sometimes hydrophobic groups can also snuggle up against polar atoms or poke out into solvent and polar groups can nestle into hydrophobic pockets to various extents, simply because the other atoms in the ligand compensate for such uneasy alliances by forming favorable interactions. This can lead to the same ligands binding to very different protein atoms. As I mentioned in a previous post, atoms end up somewhere simply because they can. The differential placement of atoms in protein pockets is reflected in the different binding affinities that the authors see in their set.

    From an evolutionary viewpoint this observation is very interesting. Protein-small molecule binding was constrained during evolution by the basic chemistry and physics of binding on one hand and by the damage incurred by too much non-specific binding on the other (as an extreme case, if every small molecule bound to every protein, there would be way too much noise and biological signaling networks would be effectively impossible). Thus there had to be a balance between promiscuity and specificity. Nature achieved this balance by tuning the affinity of small molecules for proteins over a wide range and by making sure that even weak affinity could translate to significant biological effects.

    Unfortunately these are precisely the affinities that we ourselves want to finely tune in a drug discovery program and as the paper shows, this is always going to be an uphill battle because of the multitude of interactions and the lack of correlation between ligand and binding pocket structure (one conclusion from the paper is that you cannot always predict new targets for known ligands simply by computationally comparing binding sites).

    But on another level I think this problem also speaks to the paucity of the language that we have for describing binding affinity and molecular interactions in general. Our metric for similarity in this case is the presence of similar ligand atoms binding to similar protein atoms. But nature can use another very simple measure of similarity – similarity in binding energy. It is not unreasonable to say that a ligand binds similarly to two proteins if it exhibits a similar binding affinity to both of them. And this binding affinity need not even be very different since even a few kcal/mol difference in binding energy can translate to a thousand fold difference in actual affinity (say from micromolar to nanomolar). Thus, what we call dissimilar binding may actually be judged as quite similar by nature. Consider the picture at the top of the post for instance: an aromatic ring can interact with a protein through either a stacking interaction with an aromatic amino acid or through a cation-pi interaction with a positively charged amino acid. The two interactions look very different, and yet they involve the same binding affinity. 

    All this goes back to something we mentioned before: Similarity is in the eye of the beholder, and what our eye sees as squiggly lines of ligands and protein residues on a computer screen, nature sees simply as thermodynamics, kinetics and quantum mechanics, and all of it lying on a continuum. We might be dismayed to know that the same ligand is binding to very different proteins, but this is because nature may not be regarding them as very different to begin with. To figure out protein-ligand binding then, we may have to see things from the point of view of nature rather than that of our impoverished language.