Distant homology and being a little pregnant

ResearchBlogging.org

(Thanks to F.B.  for the inspiration).

Sigh… people don’t seem to learn. It’s been almost 22 years (yikes!) since a distinguished group of scientists published a letter in Cell calling for a responsible use of the word “homology”. If you were born when that letter was published, then in the US you can already drink legally. And you may very well want to, by the time you finish reading this post.

As of today there are one hundred and sixty seven articles listed  in PubMed with the phrases “distant homology” or “remote homology” in either the title or the abstract.

Please: make it stop.

Humpty1

Homology is a qualitative term.  It means having a common evolutionary origin. Two genes / proteins / organs are either homologous, or they are not. They cannot be “somewhat homologous” or “partially homologous” or (a favorite among molecular and structural biologists) “distantly / remotely homologous”.

Homology is inferred from similarity.  Similarity is quantitative. If organs are sufficiently similar, like mammalian forelimbs, then they are considered to be homologous. They maybe more similar (like the hands of humans and chimpanzees), or less similar (like human hand and a bat wing). Nevertheless, once they pass a certain similarity threshold, homology is inferred. The same applies to sequences of proteins and nucleic acids.  Similarity can be measured. Different degrees of similarities can be compared and scaled.

homology-limbs

If two protein sequences are aligned, and 40% of the amino acids in the alignment are identical, then the two sequences have a 40% identity. The do not have a 40% homology. They are  homologous, and the homology is inferred from the similarity.  We observe that the two sequences are similar, and then we conclude that they are homologous. We use the sequence similarity, as measured by percent identity, to trace a line of common descent for those proteins we deem homologous.

(As an aside I should say that the percentage of sequence identity, or %ID is not a very good measure for inferring homology, nor is it for measuring similarity. It is an easy one to use: but it is very coarse and prone to errors. There are many better measures out there, including statistical ones like e-values, p-values or information theoretic ones like bit scores. But I digress, and this is a matter for another post.)

But once we confuse observations with conclusions, things quickly become an impossible muddle.

Am I not not just picking nits here? I mean, surely when the term “distant homology” comes up in a paper or in conversation, we all know the meaning. Distant homology means having a common evolutionary origin,  but with a common ancestor that was around a long time ago. “Distant homology” is intuitive, brief yet understandable. it is less cumbersome than: “homologous, with a distant common ancestor, as concluded form a low yet statistically significant similarity” which is what we really should say if we properly separate observations from conclusions, as captain nitpick would have us do.

Allow me to answer with two examples.  First, I have read several papers discussing “structural homology”  in the context of protein structure. Those papers that discuss structural homology were actually using a verbal shortcut for  a homology inferred from structural similarity. That is, they inferred common descent from protein structural similarity. This kind of inference is highly contentious, and while not necessarily wrong, must be done with great care and proper caveats. However, once the researchers rolled up observations with conclusions by using the “structural homology” verbal shortcut, they absolved themselves from convincing the reader that structural similarity is indeed a good measure of homology, and jumped directly to the conclusion that there is indeed an homology here. The framework for inferring homology from sequence similarity is well worked out, but not so for structure, yet.   Therefore, even if we do use the verbal shortcut “distant homology”, we can only use it by virtue of having a certain measure of similarity well-established already, as in sequence based similarity. If it is not well established, and in using structural similarities, we fail to go through the proper scientific channels that consist of providing convincing observations prior to providing conclusions.

Second: even worse is the use of the term “functional homology”. This is a clear case of the word homology used as a drop-in synonym for similarity. The misnomer “functional homology”  is typically used in studies where proteins that are clearly not homologous perform similar functions. Why infer evolutionary descent when clearly that was not intended in the first place? Well, once you start confusing similarity with homology, observations with conclusions, and make them synonymous, this is what happens.

So don’t even start this confusion.  Separate observations from conclusions, and make the former support the latter. Homology is qualitative, similarity is quantitative.  Genes cannot be distantly homologous any more than a woman can be a little pregnant.

Now you can have that drink. Unless you are a little pregnant.


Gerald R. Reeck, Christoph de Haëna, David C. Teller, Russell F. Doolittle, Walter M. Fitch, Richard E. Dickerson, Pierre Chambon, Andrew D. McLachlan, Emanuel Margoliash, Thomas H. Jukes and Emile Zuckerkandl (1987). “Homology” in proteins and nucleic acids: A terminology muddle and a way out of it Cell, 50 (5) DOI: 10.1016/0092-8674(87)90322-9

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The workings of a cellular water pore, and something about obesity

ResearchBlogging.org

Maintaining a water balance is essential to life.  Cells must regulate their water content carefully and within a very narrow margin. Too much water intake, and the cell bursts like a water balloon; too much water outflow, and it shrivels like a raisin.

The cell itself is contained in a waterproof membrane. But there are gateways in that membrane, to import solutes and food, extract waste and also maintain a water and electrolyte balance. One way to maintain a water balance is the aquaporin: a protein complex running through the membrane that lets water flow into the cell, in a controlled fashion Aquaporins are essentially very narrow tubes, the width of the tube is the width of a single water molecule.

How is this water pore controlled?

Two groups at the University of Gothenburg in Sweden and at the Max Planck institute in Goettingen, Germany have solved the structure of yeast aquaporin 1 Aqy1 at a resolution of 1.15 Å (1.15×10-10m),  enabling them to resolve water molecules and positions of atoms in the protein at a very rare clarity. They reported their findings in June’s PLoS Biology.

Gerhard Fischer, Urszula Kosinska-Eriksson and their colleagues discovered that on  the side of the aquaporin that is in the cell there is a rather elaborate gating mechanism to control water influx. Just how elaborate is not exactly clear. The end of the protein chain  forms a complex termed “helical bundle” with a Tyrosine residue in the channel, which blocks the water flow.

A: General view of the view of the yeast aquaporin, wiht the single-molecule-wide water channel in the middle; B: a close up showing the constriction near the end of the channel, and the gating mechanism. doi:10.1371/journal.pbio.1000130.g002

A: General view of the view of the yeast aquaporin, with the single-molecule-wide water channel in the middle; B: a close up showing the constriction near the end of the channel, and the gating mechanism. Click to enlarge. doi:10.1371/journal.pbio.1000130.g002

Aqy1 is actually a tetramer — four protein pore molecules arranged together in the membrane, all facing the same direction. So it’s more like a sheaf of four tubes.

A brief animation from the Protein Data Bank showing the four subunits together from different angles. (You need Java to see this, takes a bit of time to download and start).

Fischer and Kosinska-Eriksson also suggest the possibility of other control mechanisms. First, by phosphorylation: binding organic phosphate molecules to proteins is a common control mechanism in the cell, and a way to pass on signals. they found that when a certain well-located amino acid that can be phosphorylated is replaced by one that cannot be phosphorylated, the ability ot regulate water flow is hampered. Another suggestion they have is mechanosensitivity, or membrane movement,such as occurs during environmental stress. It is known that Aqy1 plays a role in cold shock: when the yeast is exposed to freezing temperature. There is definitely much more to learn about how aquaporins are controlled, triggered, and blocked.

Here is an animation of another aquaporin,  Escherichia coli‘s aquaglyceroporin GlpF, showing water molecules (red & white spheres) moving through the channel.  It was created by the Theoretical and Computational Biophysics Group at the University of Illinois Urbana-Champaign. Red is negative charge, blue is positive. Look for the yellow sphere about 1/3 form the top… (outside the cell) it eventually reaches the bottom (inside the cell), but that takes a while, due to Brownian motion. Electrostatic charges along the pore eventually force an overall one-way traffic into the cell.

The animation was created using VMD (they say that at the end credit, but that is a very short frame, and hard to catch).

You can read more about aquaporins on the aquaporin page of the Theoretical and Computational Biophysics Group. The page has great graphics, animations, and a high resolution version of the movie, and much more information about different types of aquaporins, and how they control the cell’s water content.

Aquaporins have also been implicated in obesity.  Mice that had the gene for aquaporin-7 knocked out have started to accumulate fat at the age of 12 weeks, and become heavier than their counterparts: a mouse form of adult onset obesity. The reason is that aquaporin-7 is expressed in fat cells and this particular aquaporin also transfers glycerol. Glycerol is a small three-carbon carbohydrate synthesized in fat cells from glucose as a building block for to fat molecules. Aquaporin-7 acts as a glycerol pressure valve, letting some of it back into the bloodstream. If the aquaporin-7 is missing, glycerol accumulates in the fat cells, forcing the cell to synthesize more fat form this basic fat building block. The fat cells become larger, and the animal bearing them –  fatter. This has been known for four years now, but I haven’t seen any recent progress on this aspect of obesity, at least not through an (admittedly cursory) scan of PubMed.

Fat cell metabolism. Glucose may end up as glycerol. If aquaporin-7 is not expressed, excess glycerol get stored as fat. FFA: free fatty acids. After Gema Frühbeck  Nature 438, 436-437 (24 November 2005)

Fat cell metabolism. Glucose may end up as glycerol. If aquaporin-7 is not expressed, excess glycerol get stored as fat. FFA: free fatty acids. After Gema Frühbeck Nature 438, 436-437 (24 November 2005)


Fischer, G., Kosinska-Eriksson, U., Aponte-Santamaría, C., Palmgren, M., Geijer, C., Hedfalk, K., Hohmann, S., de Groot, B., Neutze, R., & Lindkvist-Petersson, K. (2009). Crystal Structure of a Yeast Aquaporin at 1.15 Å Reveals a Novel Gating Mechanism PLoS Biology, 7 (6) DOI: 10.1371/journal.pbio.1000130

Tajkhorshid, E. (2002). Control of the Selectivity of the Aquaporin Water Channel Family by Global Orientational Tuning Science, 296 (5567), 525-530 DOI: 10.1126/science.1067778

Frühbeck, G. (2005). Obesity: Aquaporin enters the picture Nature, 438 (7067), 436-437 DOI: 10.1038/438436b

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Romantic redux: Yo-Yo Ma, Elgar’s Concerto for Cello in E minor

Since I touched upon the Romantic movement in the last post… few are as strongly associated with it as Edward Elgar.

Daniel Barenboim conducts the Chicago Symphony Orchestra. Recorded 1997 in Carnegie Hall.

First movement (Adagio – Moderato):

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A Romantic, Maybe too Romantic, Scientist

ResearchBlogging.org

In the Hatena story about symbiosis, I posted the following picture drawn by Ernst Haeckel:

Lichen, from "Art Forms of Nature" / E. Haeckl

Lichen, from "Art Forms of Nature" / E. Haeckl

Beautiful!  In this day and age of imaging, high resolution photography, and molecular graphics, we forget that scientific drawing was a skill as necessary to life scientists  as microscopic imaging, or molecular graphics is today.  Indeed, biology was very much a descriptive discipline in the 19th century, and being able to articulate your findings –in words as well as in art — was as valuable a skill as the ability to posit a hypothesis and then design an experiment to test it.  Possibly even more valuable in some circles. Scientists won medals and were awarded promotions based on their drawing skills. A naturalist’s drawings could not be inaccurate, nor could the images be occluded or embellished, they had to be very precise. But that does not mean that there was no room for artistic input.  Those could be found in the hues, the lighting, the composition, point of view angles and arrangement of the subjects drawn. Haeckel definitely had his distinctive style: part Romantic, with a Gothic undercurrent. In Art Forms of Nature he would take a series of subjects in the same genus, and arrange them in the contemporary style tessellated form, like this (all pictures are from Wikimedia Commons and are in the public domain):

no images were found

Darwin himself was so impressed by Haeckel’s drawings that he wrote they were “..the most magnificent works which I have ever seen, & I am proud to possess a copy from the author“. Haeckel himself was a staunch supporter of evolution by natural selection, and held Darwin in great esteem. It very brave stand taken by a young assistant professor in Jena in Germany  at a time when evolution itself was already quite accepted in many scientific circles, but Darwin’s theory of natural selection was still hotly debated. Haeckel served to popularize evolution, and his popular lecture series in Jena attracted hundreds of listeners. His beautiful drawings serve as a frontispiece to his scientific writings, serving not only to illustrate, but to attract his readers.

His was a troubled soul. The love of his life, Anna Sethe Haeckel died of a sudden illness at a young age. He remarried, but never recovered from his broken heart, calling Anna the “only true love” of his life. While being a popular advocate of natural selection, he also attracted a lot of ire form his peers and the public. He was strongly opposed to any form of organized religion, even more so following his personal tragedy. His was the religion of Spinoza and Goethe — that of monism. Unlike Darwin, Haeckel zealously recruited Evolution to a cultural fight, and has caused a massive backlash from established religious circles that is lasting to this very day. He was  Romantic, in the sense that he was influenced by such as Goethe and Humboldt, seeking underlying unities in nature and in life, a quest which may have lead him to his greatest  — yet  false — achievement.

The central medusae is Desmonema annasethe. Haeckel named them after his wife Anna Sethe. The medusae tentacles reminded him of her "long flowing hair".

The central medusae are Desmonema annasethe. Haeckel named them after his late wife Anna Sethe. The medusae tentacles reminded him of her "long flowing hair".

Haeckel is best known for formulating the now-rejected Biogenetic Law which states that the embryonic development of an individual organism (its ontogeny) followed the same path as the evolutionary history of its species (its phylogeny). The Biogenetic Law, or Law of Recapitulation (ontogeny recapitulates phylogeny) was in the books until the late 20th century. Although it is pretty clear that the phases an embryo goes through do not match the species history, it is still an idea that is circulating in popular culture and pseudo-scientific circles. Haeckel was accused at his time and later of forging the famous embryo sketches, an accusation that, if it weren’t for the support of Darwin and other prominent scientists of his time, would probably have caused him to lose his job. The forgery vs. overzealous interpretation debate continues to this very day, and unfortunately serves  in very a warped interpretation as an argument against evolution. The creationist reasoning goes something like: “Haeckel lied –> the law of recapitulation is founded on a fraud –> all evolution is a fraud”.  Not a very smart argument, since recapitulation was never a pillar of natural selection.

In 1997 Michael Richardson and colleagues published an article titled:  “There is no highly conserved embryonic stage in the vertebrates: implications for current theories of evolution and development”.  In the article, they compared photographs of embryos to Haeckel’s illustrations, and found gross discrepancies, which they interpreted as probable fraud.The other side of the story is that Richardson et. al left the yolk sacs in, (Haeckel removed them) and compared their photos to a derivative work rather that Haeckel’s drawings where the embryos are actually quite different from each other.  In 2002 they published another paper, where they explored Haeckel’s ideas as well as his drawings, and concluded that although deeply flawed, it is hard to show fraud especially since Haeckel himself was not the strict recapitulationist that his later followers were.

Haeckel, E. 1874. Anthropogenie: Keimes- und Stammes-Geschichte des Menschen; From left to right: fish, salamander, turtle, chicken, pig, cow, rabbit, human. The uppermost row of illustrations represents a conserved stage across Vertebrata

Haeckel, E. 1874. Anthropogenie: Keimes- und Stammes-Geschichte des Menschen; From left to right: fish, salamander, turtle, chicken, pig, cow, rabbit, human. The uppermost row of illustrations represents a conserved stage across Vertebrata

I’m not getting into this discussion, really, which sometime seems like a 150 year old flame war on fark.com (Let’s see if this link gets my blog farked, hehe). My take is that an amazing artist and naturalist such as Haeckel was seeing from his own heart’s desire, but so were a lot of other embryologists, way down to  my biology teacher in high school. (I dropped the developmental biology course in college, something I regret now, so I don’t’ know what went on there). The seduction of an all-encompassing elegant theory explaining embryonic development has caused many to go, in some form or another, for the Biogenetic Law.

Man, but his drawings are amazing. I can’t wait for my mail order of  Art Forms of Nature to come in. and I wonder how Haeckel, if he had lived today, would have injected from his artistic talent into macromolecular drawings such as this:

Illustration of aquaporin, a membrane molecule that controls the flow of water to the cell. The central mesh in A and B shows the water flow. Mouse over for credits, click for original.

Illustration of aquaporin, a membrane molecule that controls the flow of water to the cell. The central mesh in A and B shows the water flow. ischer G, Kosinska-Eriksson U, Aponte-Santamaría C, Palmgren M, Geijer C, et al. 2009 Crystal Structure of a Yeast Aquaporin at 1.15 Å Reveals a Novel Gating Mechanism. PLoS Biol 7(6): e1000130. doi:10.1371/journal.pbio.1000130

Update: Art forms of Nature in PDF and HTML is available here.


Richardson, M., Hanken, J., Gooneratne, M., Pieau, C., Raynaud, A., Selwood, L., & Wright, G. (1997). There is no highly conserved embryonic stage in the vertebrates: implications for current theories of evolution and development Anatomy and Embryology, 196 (2), 91-106 DOI: 10.1007/s004290050082

RICHARDSON, M., & KEUCK, G. (2002). Haeckel’s ABC of evolution and development Biological Reviews of the Cambridge Philosophical Society, 77 (4), 495-528 DOI: 10.1017/S1464793102005948

Robert J. Richards (2008). The Tragic Sense of Life

Ernst Haeckl Kunstformen der Natur (in HTML and PDF format, German).

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From predator to plant in one gulp

ResearchBlogging.org

The story of a predator that, upon eating a certain food, suddenly becomes a peaceful plant. Sort of.

Free-living versus symbiotic

A working definition for symbiosis is two or more species that live and interact. Mutualism means that each derives a certain benefit from the other, or at most causing no harm to each other. Their relationship is that of “give and take”. For example cleaning fish serve other fish by cleaning off parasites and getting protection, food and rides in return. Sometimes the mutualistic symbionts have practically fused into a single functional organism. The Portuguese Man o’ War is a colony of four different organisms which form a composite jellyfish;  None of the individuals which can exist in a free-living form. Lichen is a colony of two: a photosynthetic partner providing sugars, and a fungus providing other nutrients as well as preventing the dehydration of the photosynthetic partner.

Lichen, from "Art Forms of Nature" / E. Haeckl

Lichen, from "Art Forms of Nature" / E. Haeckel

The Endosymbiotic Hypothesis

The endosymbiotic hypothesis maintains that eukaryotes evolved from  symbiotic interactions between bacteria. There is plenty of evidence for that in  chloroplasts and mitochondria: they have their own DNA; their membranes, their DNA,  their ribosomes all resemble those of bacteria. The relationship between a eukaryotic cell and its mitochondria is heavily mutualistic: the cell gets ATP, the mitochondria / chloroplasts (M/C) get.. well, to live and reproduce, which they cannot do outside a living cell. Over time, M/C have have lost most of their genomic material to the host: many of the proteins needed to construct an M/C are not encoded in the M/C but in the host’s nucleus, and transported to the M/C.  This is probably as intimately connected as two organisms can get, before you cannot tell that they were two separate organisms before they fused into an organism and an organelle. Indeed, the threshold set for distinguishing between an endosymbiont and an organelle lies in protein import. According to this working definition, once an endosymbiont starts importing proteins, it is no longer considered an endosymbiont and becomes an organelle.  As with any working definition, if you scratch the surface a bit you will find cases where this rule does not apply well. Viruses are a case in point, acquiring host proteins and actually acting as a vector transferring them between hosts.

Vegging out

Two researchers have shown a striking example of   endosymbiosis forming  now:  in 2005 Noriko Okamoto an  Isao Inouye reported on a unicellular organism called Hatena. Hatena (“enigma” in Japanese) leads a curious life cycle. Hatena is a single-cell organism, swimming around in the water, using a little feeding apparatus to eat cells and organic material smaller than itself.  At some point, it would feed on another unicellular algae, the Nephroselmis. Once Hatena swallows Nephroselmis, it does not digest it. Rather, Nephrosolmis makes itself comfortable home inside Hatena. The alga starts growing inside Hatena: it grows to about 10 times its original size, filling up most of Hatena. The alga also seems to lose most of its own organelles, except for the chloroplast. The chloroplast actually grows bigger.

Hatena changes too as a result. Before ingesting the alga, it has a rather complex “mouth”, or feeding apparatus. After ingesting the algae, this mouth disappears only to be replaced by an eyespot from the algae. The eyespot is a light sensing organelle, a very primitive eye, that guides algae to light sources. In this case, it also guides the host, Hatena, to light. Hatena has obviously stopped feeding, and least through its mouth. It is now swimming to the light, letting the alga photosynthesize its food for both of them.

I get the plant, you get the steakhouse coupons

Hatena reproduces by binary fission. So once it splits itself,  what happens to the symbiotic alga? Well, one daughter cell gets the alga, and the other gets to be a predator… at least until it eats another alga. So here we are, looking at a fascinating evolutionary snapshot: two creatures, they can live apart or together. One is a predator,but is ready to be a plant under the right circumstances; the other is not quite an organelle of the first yet, but definitely on its way.

Right: Hatena with chloroplast, and without. Left: the red bit on the top of the cell marks the eyespot.

Right: Hatena with chloroplast, and without. Left: the red bit on the top of the cell marks the eyespot.

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Okamoto, N. (2005). A Secondary Symbiosis in Progress? Science, 310 (5746), 287-287 DOI: 10.1126/science.1116125

OKAMOTO, N., & INOUYE, I. (2006). Hatena arenicola gen. et sp. nov., a Katablepharid Undergoing Probable Plastid Acquisition Protist, 157 (4), 401-419 DOI: 10.1016/j.protis.2006.05.011

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Boogie Balagan: Lamentation Walloo

Thanks to Michael Shapira for introducing me to this insane group combining blues-rock with Rai, Arab and Israeli music.

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The Incredible Shrinking Genome

ResearchBlogging.org

Mass Extinctions and Genomics

The geological signs for mass extinctions are very distinct: the photo shows the boundary of the Cretaceous-Tertiary KT extinction that happened ~65 million years ago (Mya), and killed some 70% of the species on Earth, most famously the dinosaurs. This was the last mass extinction, and its effects on Earth’s life is very clear and dramatic. Mammals have evolved and spread (radiated is the term used in evolutionary biology) to occupy many of the ecological niches dinosaurs have left vacant. The dinosaurs that remained are now birds (yes, superficial explanation, I know, but basically true), while one mammalian group, primates, have evolved an intelligence which ultimately lead to smartphones and blogging. Plant life has changed as well, with many more flowering plant species, and fewer ferns and conifers. The marks of the KT extinction are therefore found everywhere: in fossils, in geological records and in extant life.

Badlands near Drumheller, Alberta where erosion has exposed the KT boundary. From Wikimedia Commons

Badlands near Drumheller, Alberta where erosion has exposed the KT boundary. From Wikimedia Commons

Everywhere? Can we also find marks of the KT extinction in genomes? A study that has been published recently claims so. The study was published in the first issue of a new open access journal, Genome Biology and Evolution by a group in Indiana University, Bloomington. To understand what they discovered, some background information is needed.

Mobile DNA Gain and Loss

Organisms can acquire DNA from other organisms by inserting bits of foreign DNA, known as mobile DNA, into the genome. One way this is done is by viral infections. Some viruses integrate genomic material of their own, and sometimes of other host organisms into the hosts they infect. If those viruses happen to also infect germ cells – sperm or ova – those insertions or retrotransposons would be passed on to subsequent generations. It is quite easy to identify these viral insertions: they are flanked by characteristic DNA stretches called Long Terminal Repeats or LTRs. During the infection and insertion process, LTRs serve as “insertion hooks” if you will, allowing the the virus to insert its genome, and whatever other genomic elements from former hosts that happened to hitch a ride with the virus. Once the LTRs are in place in the host’s genome, they serve no purpose. Over generations, the left-side LTR and the right-side LTR acquire mutations and drift away from their original sequences. For evolutionary biologists, paired LTRs thus serve as a molecular clock. Since the LTRs were identical at the time of insertion, the amount of dissimilarity between the paired LTRs can tell us how long ago they were inserted. Also, we can look at the total number of LTRs in a species and see how many are newly acquired LTRs, how many older. So we get a picture of LTR acquisition into the lineage leading to that species species over millions of years. Of course, after a very long time, the paired LTRs will not be recognizable as such, since they have diverged too far away from each other to be recognizable as a paired element. But we can recognize LTRs up to a divergence of 50%: a pretty high divergence rate.

Upon insertion:     CCCAAAGGG——————-CCCAAAGGG

Generations later: CCGAATGGG——————-CCCAGAGAG

Therefore, looking at a complete genome, we can see old LTRs, young LTRs, and many in-between. It is like looking an old house, which every new owner has decided to do something when they occupied it: this one added a patio, that one carved out a window, and a third has installed a porch swing. We can tell the window is fairly old because of its design, while the porch swing is new because the brand name did not exist five years ago.

LTRs are also lost, not just gained. There are many mechanisms for LTRs to be removed from a lineage: it may be lost by “fading out” through an accumulation of mutations, or by being excised from the genome through some loss of a section. An LTR may also have a deleterious effect, such as increasing the possibility of cancer, or decreasing he viability of the immune system. After all, an LTR is an uninvited guest in the genome, and we all know that uninvited guests are not the most desirable ones… therefore, those LTRs will be selected against in a Darwinian fashion, as they reduce their host’s fitness. Using the house analogy, the owners may change the house to revert to its original design in some places, fill up the pool the previous owner has dug, or the porch swing may simply have been sold.

LTR loss rate vs. gain rate can be modeled statistically, and from that model the expected distribution of LTRs of different ages in the genome can be inferred. Basically the model states that we will see a distribution of many LTRs that have been gained fairly recently in the genome, and fewer and fewer older LTRs. This is because the probability of any single LTR being lost from the genome increases exponentially over time. Indeed, the authors looked at a fly (Drosophila), plant (Arabidopsis) and fish (Fugu) genomes. They found that the distribution of LTRs fit the expected statistical model quite well.

Loss of LTRs in Mammals

But when they looked at mammalian genomes, including those of primates, things became strange. Instead of seeing a predominantly young LTR population, they saw a middle-age population. Young LTRs were few, while there was and unexpectedly high number of old LTRs. Was it because mammalian genomes have been gaining less LTRs lately? Or was it because old LTRs were being lost at an excessive rate? A combination of both? Something else? And why is this only in mammals? And not even all mammals at that, because we do not see this anomaly in rodent lineages, for example.

When they looked closely at how long ago the LTR population has peaked, they discovered another weirdness: almost without exception, the peak (and subsequent decline) occurred just after the KT extinction. Of course, “just after” in evolutionary terms can mean one to five million years, but the association with the KT boundary was too clear to ignore. We know why there is an iridium-rich line in the hills of south Texas, with many dinosaur fossils below it but none above it: the iridium-rich meteor that devastated Earth left an indelible mark. But a sudden peaking and subsequent decline in this mobile DNA element in mammals was puzzling.

i-am-getting-smaller

To check whether this phenomenon was due primarily to an increased rate of LTR loss or to a decreased gain the scientists looked at another type of mobile DNA element. An element that, unlike LTRs, does not fade and is rarely excised. This nuclear-mitochondrial gene or numt stems from is the slow migration of genes from mitochondrial genomes to nuclear genomes. Mitochondria are organelles existing in all animal and plant life that have their own, much reduced genomes: most of the genes encoding the proteins that are active in mitochondria were lost from the mitochondria and gained in the cell nucleus. But unlike most LTRs, these genes are essential; therefore mitochondrial gene loss from the nuclear genome is rare. Examining the mitochondrial gene insertion serves as a control: if there are more old mitochondrial elements than young ones, compared to non-mammals then that means that general acquisition rate of of mobile DNA elements in the genome is declining, and not because elements are being removed faster. They found that with mammalian numts, the rate of migration from the mitochondria to the nucleus has indeed slowed down.

shrinking

So it seems that mammalian genomes have been purging themselves from mobile DNA elements just around the KT boundary, give or take a couple of million years. (Or rather: not taking in new elements). Why is that? One hypothesis is the selective advantage: mobile DNA elements can disrupt the genome, decreasing a host’s fitness. But mammals have existed for millions of years before the KT extinction. According to the fossil records they were small carnivores: dinosaurs took up the large (and XXL) herbivore niches, and the large carnivore niches. Once they were gone, mammals started to radiate, fill those niches, and a whole new level of competition arose. The selective advantage of not having a genome encumbered by potentially damaging mobile DNA elements has probably become critical at this “be ye fruitful and multiply; bring forth abundantly in the earth, and multiply therein” stage. In effect, the genomes of mammals has been shrinking by removing mobile DNA elements, just after the KT boundary. And according to the model presented in this study, this process is still ongoing: mammalian genomes are not at an equilibrium size. Unlike flies, mammals are still cleaning up.

Mammals Rule: Time to Clean House Genome?

Many questions are left unanswered: why would this genome cleaning take place as a result of a sudden reshuffling of the evolutionary deck, and the opportunity that was given to mammals? (If indeed the shrinking genome is a consequence of the KT extinction). Why would mobile DNA elements become a detriment then, more than before the KT extinction when mammals lived in the shade of the dinosaurs? If this genome house cleaning and shrinking is a result of rapid speciation that followed the KT extinction, wouldn’t we expect to see it in other  groups besides mammals? To the authors’ credit, the paper is written very cautiously, and the authors are very careful to present all caveats and controls they could muster. This makes it something of a long read, but a fascinating one at that.

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Rho, M., Zhou, M., Gao, X., Kim, S., Tang, H., & Lynch, M. (2009). Independent Mammalian Genome Contractions Following the KT Boundary Genome Biology and Evolution, 2009, 2-12 DOI: 10.1093/gbe/evp007

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(Not Only) Microblogging ISMB 2009

Intelligent Systems in Molecular Biology (ISMB) is a large international gathering of  computational biologists, mostly from the bioinformatics side: genomics, structural bioinformatics, computational genomics, etc. This year there is a friendfeed room for microblogging ISMB 2009. So if you are not in Stockholm, or also if you are, look it up. Most of the microbloggers also have their own blogs, and recap posts on those will be forthcoming (I hope).

My take on microblogging is that it is a nice public note taking mechancism, but going back to recap and provide a deeper analysis of the session one has attended is probably more useful in the long run. Now that I said it, I would probably have to do it. Watch this space.

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Yeah, yeah, the flu virus

ResearchBlogging.org

Since the Swine Influenza Media and Blogging Pandemic has died for now, I think I can finally write about ‘flu myself.  A quick aside: until I was about 15, I thought that the word Influenza came from the Arabic “Inf-Il-enza” meaning “goat’s nose”, which it is a bit runny, like a dog’s, or like someone with the flu. My father told me that, and as was usual with him, I could never tell whether he was joking or serious. The true etymology is actually Italian: “Influence” (of the stars).  Apparently stars caused the ‘flu until viruses were invented by the CIA and Big Pharma in the aftermath of The Bay of Pigs. (Hence, swine ‘flu).

bop

Let’s be serious now.

An interesting bioinformatic analysis on the influenza virus was published recently in BMC Microbiology. Jonathan Allen and colleagues looked for pandemic markers in the proteomes of different H1N1 pandemic strains. The first thing they looked for was human host specificity.  They found sixteen positions in the influenza proteome that were associated with human hosts. By doing that, they  have established a framework for recognizing which influenza strains are likely to carry over from birds to humans. But not every cross-species transmission is necessarily lethal to humans.  So they set up another SVM (Support Vector Machine: a statistical learning algorithm) to discover high lethality markers, using genomes from the 1918, 1957 and 1968 lethal H5N1 pandemic outbreaks, and the 1976 H1N1 New Jersey infection.  Human lethality markers were mostly in Neuraminidase and Hemagglutinin proteins, the two viral proteins most associated with its virulence. The  markers seem to be most prevalent in bird ‘flu strains, suggesting that birds were the primary reservoir for infection in those epidemics.

What Allen and colleagues have shown is that swine  H1N1 requires the least number of steps to get to be a human pandemic, using the  human pandemic conserved genomic markers. BUT — some strains might lead to H5N1 subtypes whose lethality is high.

This is a very interesting and well written paper, worth reading not only for its current relevance, but also because it is a thorough and careful study of animal to human influenza virus transfer, and of the ensuing pandemic risk.

Influenza virus cutout. Credit: Wikimedia commons.

Influenza virus cutout. Credit: wikimedia commons.


Allen, J., Gardner, S., Vitalis, E., & Slezak, T. (2009). Conserved amino acid markers from past influenza pandemic strains BMC Microbiology, 9 (1) DOI: 10.1186/1471-2180-9-77

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Hamburgers are pathological

ResearchBlogging.org

From Annals of Diagnostic Pathology. This is what happens when you bring a pathologist to a fast food joint. Hat tip to Laura for pointing this out.

Here were my initial thoughts about these findings. “Bleaaachhhh!” (I’m very verbal when reading scientific papers).

Eight fast food hamburger brands were subjected to a pathology examination. Here are the results, click to enlarge.

Eight fast food hamburger brands were subjected to a pathology examination. Here are the results, click to enlarge.

Well, it looks bad.. but. But. Cooked ground beef can have up to 60% water by USDA standards.  I would be more worried about the dry taste from the patty with 37% water. Many hamburgers have plant fillers (gluten, flour, breadcrumbs) to puff up their patties. You can only hope the places that serve them disclose that information, but probably not.  The parasites are disconcerting, but… if your burger is cooked well, you need not worry. Not that that’s any excuse for having them in the first place. Finally, unlike ground beef, the standards for burger are more lenient, and some amount of offal is accepted. Having said all that, the amount of real meat (skeletal muscle tissue) is low.. especially H7 with 2.1% (!) What are they putting in there?

OK, it is bad. Cook your own flippin’ burgers.


PRAYSON, B., MCMAHON, J., & PRAYSON, R. (2008). Fast food hamburgers: what are we really eating? Annals of Diagnostic Pathology, 12 (6), 406-409 DOI: 10.1016/j.anndiagpath.2008.06.002

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eMusic customer survey poll and results

eMusic, a subscription-based indie music estore has hiked its prices and concurrently signed a deal with Sony BMG to sell their back catalog. What’s wrong with this? Well, a lot. Read my previous post for details. It seems like the reaction on the intertubes has been less than joyful, with phrases like “corporate sellout” and “breach of contract” dominating.

I created an informal poll for eMusic customers, it is ongoing until June 15. The results are below. Yes, I know the many statistic caveats to an Internet-based poll. But if you take the results of this survey together with the bulk of the reactions on eMusic’s message boards, various blogs, and chatter on social networks, it seems that eMusic have a serious problem to fix. If you are an eMusic customer, please take the short poll.

Title: eMusic Customer Survey Results
Description: Ongoing poll

Click here and refresh the resulting page to get the most recent numbers.

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The day eMusic died?

eMusic is by far my favorite music store. A huge collection of indie, jazz, blues, classical, world, ambient… anything but mainstream. They keep the music DRM free,which means you are free to make as many copies as you please, and play on whatever device you like. For this reason, eMusic has little to offer from the Big Four labels (EMI, Universal, Sony and  Warner). In the name of copyright, these labels make various different attempts to limit your listening experience, limiting you to certain platforms, operating systems or music players including placing rootkit software on your computer to lock you out of your music or (as experienced by some customers of Sony) lock you out of your computer completely. Thanks, I do not need that.  As I am mainly a jazz, blues and classical music fan, with the occasional sprinkled indies, I get most of my listening needs from eMusic. I download the occasional album from Amazon MP3 store if I really feel the need for something not on eMusic.

I have a $15.99/30 days account which lets me download 50 tracks every 30 days: that’s just under $0.30 / track, a fantastic value considering that Amazon MP3 and iTunes charge upwards of $.90 per track. Also, I don’t support the big four’s DRM shenanigans, lawsuit frenzy and profit margins and I do support independent artists that would never have a chance of signing up with any of the Big Four.

Until now, that is.

Today I logged into eMusic to prepare some music into my basket, as my 30 day account refills around the 14th every month. I am flying on June 14th, and I would like a quick download of new tracks on my MP3 player for the plane once my quota kicks in.  I discovered that on May 31 eMusic announced that they are expanding their music and that they are hiking their prices. So come July  my $15.99 can now buy me 37 tracks instead of 50, which means I will be paying $0.41 / track.  That’s a 41% price increase! Although it is cheaper than what is out there, it does not allow for the fun of cheap experimenting with new music: instead of thinking twice before I download a new track, and then saying “what the hell” it’s only $0.29 and downloading it anyway,  I’ll probably download less, and go for the “sure things”.  The experience of discovering the musical diamonds in the rough has suddenly become somewhat pricey.  I used to allocate 5-10 tracks to experimenting, usually relegating them to the “listened once- – did not like” list. But I occasionally discovered wonderful things. That left me with 40 well thought out downloads per month, and 10 frivolous ones. Now, I will probably have to cut back on the frivolity, as would many other  eMusic customers. In the long run,that is probably not good for the discovery of interesting new and different music that is out there — what eMusic was all about. Also, you have to be a subscriber to buy from eMusic: you cannot buy occasionally like you do from Amazon MP3. This means that prices should be somewhat cheaper, due to the guaranteed customer loyalty in their business model.

OK, but $0.41/track is  still cheaper than Amazon or iTunes, so why am I making such a big fuss? Also, times are tough, and they are running a business, not a fuzz-and-wawa charity.  Well, the other problem is  that eMusic justifies the hike due to a deal with Sony, getting  Sony’s back catalog that expands eMusic’s repertoire by some 200,000 tracks.  But the reason I and many others are eMusic customers in the first place, is that we do not really care to listen — at least not for a bulk of our listening time — to the Dixie Chicks, or Leonard Cohen, or Bruce Springsteen. So eMusic have hiked their prices to subsidize a deal with the kind of label most eMusic customers would not go to anyway! Not only because of the music, but also because of the above-mentioned business practices. Also because Sony would never have given a starting chance to the likes of  Department of Eagles,  Bon Iver, Shearwater or Vic Ruggiero. (Look them up)

Finally, eMusic announced this event as a done deal, completely surprising its customers. Danny Stein, eMusic’s CEO published a letter on May 31.  There are now 1200 customer replies to Mr. Stein’s letter, and it seems like many, if not most are terribly unhappy about the whole affair.

I could [sic] care less if the selection is broadened when my plan is cut in half. If eMusic didn’t already have what I wanted, then I wouldn’t have subscribed, much less bumped up the subscription plan. Thanks for nothing. Now, where is that exit door

Getting 90 downloads a month for $191.90 a year probably was too cheap. I only wish that its rectification wasn’t such a thinly veiled jump in the sack with big business.

There were other responses too, those that understood the need for a price hike, although they were still grumbling about expanding with a Big Four label, instead of with more indies.

I set up a three question survey, which I also publicized on eMusic’s blog.  I know these surveys are crap as far as  sampling goes, but I did it anyway, just to get a feel for things. Also, it may help, if I get a few hundred respondents, to send the results to Mr. Stein. If you are an eMusic customer, please take a minute to fill the survey.


Here is a piece on how eMusic manhandled the whole situation
by a poor, mismanaged response to their customers. I mentioned that inherent customer loyalty is a vital part of eMusic’s business structure. Well, it seems that eMusic has taken that loyalty for granted. Not a smart business move, as is obvious from the waves of ire on eMusic’s blog, other blogs and the various social networks.

What will  I do? See how this new situation plays out.  eMusic was insanely cheap, and a price hike was due at some point. I am just not happy about the way they raised their prices, and who they did it for.

Finally, here is a great video to a great song from Department of Eagles; one of the bands I discovered in my frivolous downloads.  I always imagined “No One Does it Like You” to be a mellow, tender, morning-after love song.  This video turned it into a rather disturbing and haunting battle of the sexes. Beautiful though, in its own way.

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Da Vinci, F0-F1 ATPase: a copyright-driven Update

Harvard University has removed from YouTube the video I embedded  in my Leonardo Da Vinci and the F0-F1 ATPase post, due to copyright concerns. It is a pity. I believe the main sufferer from this step is the lab that actually created this video, and now has one outlet less to publicize its work. One would think that after a projected loss of 30% of their endowment, Harvard would come up with more creative ideas for freely publicizing their researchers’ fine work, not less. (Yeah, I know no one reads my blog, but everyone goes to YouTube, including people who don’t normally read Nature).

Whatever. I hope that the IP admins at the  MRC in Cambridge (UK) have a more advanced view on these matters than their concurrents in Cambridge (US), and will keep the following videos up. Here are two F0-F1 ATPase videos from Dr. John E. Walker’s lab. Incidentally, John E. Walker received the 1997 Nobel prize for physiology or medicine for his work on the ATPase enzymatic mechanism. You may find some of these movies on his web page.

The first is a general overview of the F0-F1 in action:

The second shows views from above and then below the F1 domain around the rotating gamma subunit (that’s the blue eccentric stator in the middle):


The third is a group of what appear to be Japanese grad students /postdocs demonstrating the ATPase dance. I have no idea where this came from. I give them a “C-” in dancing, but an “A” in structural biology (to get an A+ they should have tossed tennis balls to represent synthesized ATP):

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Blood, sweat and spit

ResearchBlogging.org

A short follow up to the previous post on latherin. A quick reminder: latherin is a protein that exists in the horse’s sweat and saliva. In the sweat, latherin acts like a detergent, wetting the horse’s coat to allow for better water evaporation and hence better cooling. In the saliva, it helps wet the horse’s dry feed, aiding digestion. It’s an interesting example of a protein performing different physiological functions in different contexts.

Widdowquinn made an interesting observation about our tendency to color a protein with a function of our liking. Quoting the comment:  “Is the ‘function’ of latherin to aid heat transfer, or digestion, or both? Or does it make no sense to imbue the protein with any such ‘function’ – only to note that it is able to act in both these ways (potentially among others)“.

No sweat. Credit: ishkamina from Flickr

No sweat. Credit: ishkamina from Flickr

This observation is very true and is  interesting especially with latherin. Latherin is part of a large group of evolutionarily related proteins containing a domain known as Bactericidal permeability-increasing protein (BPI) / Lipopolysaccharide-binding protein (LBP) / Cholesteryl ester transfer protein (CETP). The observed common function of all proteins that have this domain is that they bind fatty molecules (lipids) that constitute the cell membrane.  The differences lie in the context of which lipids they bind and what happens as a consequence. For example, BPI proteins serve as potent antibacterial agent, binding lipopolysaccharide (LPS), a bacterial toxin expressed on the outer layer of the bacterial membrane. LPS causes a severe inflammatory response when in the blood stream, but BPI, secreted by our immune system, dampens down the response, and also kills the bacteria it binds.  LBP also binds LPS, but acts as an alarm system, increasing the inflammatory response. Another family similar proteins is found on the lung surface, and are also a line of defense against bacteria, by similar mechanism. This is the Palate, Lung, and Nasal epithelium Carcinoma associated protein (PLUNC).  The names is scary, but it was given in the context of their discovery, cancer research. PLUNC family proteins are used as cancer markers, but cancer has nothing to do with their primary function. BASE is another interesting and puzzling homolog, which may be a “dying gene”: expressed in a small quantity, but does not seem to be producing a viable well-folded protein product. It is expressed in mammary glands, and in saliva. Sounds familiar?  Remember that mammary glands are evolutionarily modified sweat glands: BASE is also used clinically as a marker for breast cancer.

CETP has nothing to do with bacterial membranes; rather, it transports a precursor of cholesterol, which is a building block for animal membranes.

So we see here an interesting case of functional radiation: while the different proteins in the family maintain very similar sequences, their functions differ in physiological  context, and also in  organisms which express them (even bacteria use an LPS against other bacteria!), and the tissues that express them.

BPI and relatives on human chromosme 20

BPI and relatives on human chromosme 20. Click to enlarge.

Moreover, with the exception of CETP, the genes coding for those proteins are clustered together in the same region in chromosome 20. This indicates that they are not only homologs (i.e. arose form a common ancestor) but paralogs: homologs that have arisen due to gene duplication. Gene duplication is a potent evolutionary mechanism for acquiring new functions: while the ancestral gene continues to do its work, the duplicate, which is redundant, has less selective pressure on it, can may adopt other functions. We also see a duplication in the same chromosomal neighborhood of the latherin gene in the horse, but only two, or possibly three neighboring paralogs.

Latherin and a neighboring homolog in horse chromosme 21. If you like playing around with the UCSC genome browser, try finding the third.

Latherin and a neighboring homolog in horse chromosme 21. Click to enlarge. If you like playing around with the UCSC genome browser, try finding the third.

So we went from horse sweat, to bacterial defense, to a dying gene in human which is very much alive and lathering in horses. Ah, the zigzagging wonders of protein evolution! Was latherin initially a bacteria-killing  protein that just happened to work well as a sweat enhancer? Possibly, seeing that even bacteria have a BPI domain.  It might even still serve in a capacity as an immune defense protein, both in the sweat glands and in the salivary glands. Yes, we do color genes with the brush we happen to hold in our hand at the moment, but it seems like nature uses many different brushes, and it’s fun to try and find them all. (Does this metaphor even make sense?)

Disclaimer: genomic map pictures were generated using the fantastic UCSC Genome Browser. No horses or unicorns were harmed during the making of this post.


Bingle, C., & Craven, C. (2004). Meet the relatives: a family of BPI- and LBP-related proteins Trends in Immunology, 25 (2), 53-55 DOI: 10.1016/j.it.2003.11.007

Bingle, C. (2004). Phylogenetic and evolutionary analysis of the PLUNC gene family Protein Science, 13 (2), 422-430 DOI: 10.1110/ps.03332704

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Glowing like a horse

ResearchBlogging.org

Dennis Mitchell: "Margaret, you are all sweaty"
Margaret Wade: "Dennis, girls don't sweat. Horses sweat,
boys perspire and girls glow"
Dennis Mitchell: "Margaret, you are glowing like a horse".
                              -- Dennis the Menace / Hank Ketcham

Horse sculpture, Louisville Kentucky. Credit: Atelier teee, Flickr.

Horse sculpture, Louisville Kentucky. Credit: Atelier teee, Flickr.

Horses and humans sweat but most other mammals do not. Sweating lowers the body’s surface temperature by evaporating off the surface of the skin. The heat drawn by evaporation is removed from the surface, thereby cooling it.  But as anyone who has been skiing in a poorly-ventilated jacket can tell you, this does not work well if the sweat is not allowed to evaporate. Indeed, most mammals have fur, which would trap the sweat not allowing it to evaporate quickly. They use alternative cooling mechanisms, like evaporative cooling from the respiratory tract, or panting. The horse’s solution is to mix in its sweat a protein called latherin which acts as a surfactant. This means it lowers the surface tension of the water in the sweat, allowing the water to  it wet the horse’s coat hairs better and allowing for faster evaporation. Latherin acts like it’s name suggests: it is basically a kind of naturally produced soap, and racehorses are known to lather up during a race.

Wild Horse Monument, Washington. Credit: ankeyd, Flickr

Wild Horse Monument, Washington. Credit: ankeyd, Flickr

Horses are also known to foam at the bit. In an article published today in PLoS ONE, Rhona McDonald and her colleagues at the Universities of Glasgow and Manchester show that lathering up and foaming at the bit are two facets of the same phenomenon as latherin is also produced by the horse’s salivary glands. Horses’ food is unusually dry, and latherin in the salivary glands serves to make it nice and mushy, turning oats into oatmeal. Here is an interesting case of adaptation of the same protein to different functions: helping initial digestion, and helping the cooling mechanism, through the same biophysical principle of a surfactant agent.

Horse sculpture, fountain hills Arizona. Credit: Dan Shouse, Flickr

Horse sculpture, fountain hills Arizona. Credit: Dan Shouse, Flickr

We use artificial surfactants, such as soap to clean ourselves. That includes toothpaste, which is mostly detergent, explaining the foam that we generate while brushing our teeth. It may also be that the latherin acts as a tooth cleaning agent for the horse: a third use. But that possibility is  is not mentioned in the paper. Maybe the authors did not want to look a gift horse in the mouth.

Update: this post has been selected as Blog Pick of the Month for June 2009 by EveryOne, PLoS-ONE’s community blog.



McDonald, R., Fleming, R., Beeley, J., Bovell, D., Lu, J., Zhao, X., Cooper, A., & Kennedy, M. (2009). Latherin: A Surfactant Protein of Horse Sweat and Saliva PLoS ONE, 4 (5) DOI: 10.1371/journal.pone.0005726

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