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More evidence for the GZK cosmic ray cut-off

Tuesday, July 29, 2008

Last December we had a rather detailed discussion of ultrahigh-energy cosmic rays (UHECRs). The occasion for this was an important announcement of cosmic ray observations from the Pierre Auger Observatory. Science magazine ranked this result as the third most important "breakthrough" of 2007. (See here.)

The results reported then actually included a variety of important tentative conclusions from the data. Two in particular stood out. One was a statistical analysis that indicated some likelihood that the UHECRs had originated in the nuclei of active galaxies. This conclusion is still controversial, as the statistics involved have been disputed.

A second conclusion seems to be more secure, and has since received additional confirming evidence. This is the conclusion that something known as the GZK cutoff has been verified.

This predicted phenomenon is rather easy to understand at a general level, because it rests on well-known assumptions of special relatively. We know that the universe is suffused with a cosmic microwave background of photons that have an equivalent "temperature" of about 2.725 K. These photons are in the microwave part of the spectrum, which means they have fairly low energy. The energy of these photons is as low as it is because their wavelength has been stretched by a factor of about 1000 since they were last scattered, about 380,000 years after the big bang. This stretching is a result of the expansion of the universe itself.

Now consider a particle moving through this background at a very high velocity – such as a UHECR. According to special relativity, a photon observed from the reference frame of the fast-moving particle will have the same velocity (299,792,458 m/s) regardless of the particle's velocity. However, the wavelength of the photon will appear to be shortened by a very large factor, depending on the particle velocity. This is equivalent to a "blue shift", as if the source of the photon were moving towards the particle at the same velocity.

The net result is that the energy carried by the photon – as perceived by a UHECR – will be extremely high. High enough to destroy the particle (or at least consume a substantial portion of its energy). Hence UHECRs with energies above a certain limit should be observed very infrequently. This limit is called the GZK cutoff. It is about 6×1019 eV.

(In fact, there is some low probability of UHECRs with higher energy being observed, if the UHECR happened to come from a source very close to us, so that it was unlikely to interact with a CMB photon. Credible events attributable to UHECRs having energies as high as 3×1020 eV have been reported.)

It is rather important that the GZK cutoff be verified, since it rests on the assumption that special relativity is valid. If the GZK cutoff were not observed, either our understanding of cosmic rays would be very flawed, or else special relativity itself would be threatened. The latter would require a massive rethinking of contemporary physics – something that wouldn't be attempted without extremely good reason.

Fortunately, evidence for the GZK cutoff continues to grow:

Do cosmic rays get bogged down in the cosmos? (7/8/08)
Physicists are closer to understanding how ultrahigh-energy cosmic rays make their way to Earth thanks to new measurements made at the Pierre Auger Observatory in Argentina. The study shows that the number of such cosmic rays reaching Earth drops off rapidly for rays with energies of more than about 4×1019 eV.

The observations are consistent with a 40-year-old theory that ultrahigh-energy cosmic rays cannot travel very far through the universe without losing energy as they scatter off the cosmic microwave background.

This is not the first confirmation of the GZK cutoff since last November. In March, a similar conclusion was reached based on observations from a completely different cosmic ray detection facility – the University of Utah’s High-Resolution Fly’s Eye cosmic ray observatory. See here, here.

Further reading:

Observation of the suppression of the flux of cosmic rays above 4x10^19eV – technical paper at the arXiv reporting the result discussed above

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Resveratrol and cancer

Monday, July 28, 2008

I suppose some readers here may be getting tired of the news flow on resveratrol. The substance may not actually live up to all the hype. But it surely does seem to have quite a variety of beneficial properties. (Most recent previous note is here.) The latest thing resveratrol seems to do is help reduce cancer risk – and a specific mechanism of action has been identified:

Cancer Preventive Properties Identified In Resveratrol, Found In Red Wine, Red Grapes (7/7/08)
Early laboratory research has shown that resveratrol, a common dietary supplement, suppresses the abnormal cell formation that leads to most types of breast cancer, suggesting a potential role for the agent in breast cancer prevention. Resveratrol is a natural substance found in red wine and red grapes. It is sold in extract form as a dietary supplement at most major drug stores.

"Resveratrol has the ability to prevent the first step that occurs when estrogen starts the process that leads to cancer by blocking the formation of the estrogen DNA adducts. We believe that this could stop the whole progression that leads to breast cancer down the road," said Eleanor G. Rogan, Ph.D., a professor in the Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center.

The reason that estrogen plays a role in breast cancer is that it has a tendency to bind to DNA. (That's what "DNA adduct" refers to.) This binding can damage the DNA, and plausibly may interfere with the expression of genes needed for protection against cancer. Resveratrol seems to interfere with adduct formation:
The formation of breast cancer is a multi-step process which differs depending on type of disease, a patient's genetic makeup and other factors. However, scientists know that many breast cancers are fueled by increased estrogen, which collects and reacts with DNA molecules to form adducts. Rogan and colleagues found that resveratrol was able to suppress the formation of these DNA adducts. ...

Rogan said resveratrol works by inducing an enzyme called quinone reductase, which reduces the estrogen metabolite back to inactive form. By making estrogen inactive, resveratrol decreases the associated risk.

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"Consumers" are well-programmed robots

Sunday, July 27, 2008

Brand Names Subconsciously Afftect People's Shopping Goals (7/17/08)
Even 60 milliseconds of exposure to a brand name such as Wal-Mart or Tiffany can alter consumers’ subconscious goals, according to new research.

Authors Tanya L. Chartrand, Joel Huber (both Duke University), Baba Shiv (Stanford University), and Robin J. Tanner (University of Wisconsin) examined goals that are triggered when consumers shop. “Results suggest that simple exposure to brand names has the potential to activate goals which then influence choices,” write the authors. “This data thus opens the door to an intriguing new way to think about the role and power of brands.”

The research suggests that goals can be triggered without consciousness. In other words, passing a discount store on the way to the sporting good store might affect an eventual purchase. ...

“To the best of our knowledge, this provides the first evidence that such brands can automatically activate purchase goals in individuals and that these goals can influence consumers’ product preferences without their awareness or conscious intent,” the authors conclude.

Even though we like to think we’re in control of our choices, this research indicates that our response to some brands is deeply rooted in our subconscious.

Emphasis added.

Too bad humans can't be programmed to think rationally. But that would be counterproductive to society's real goals.

BDNF transcription puzzles

There's more news out about BDNF, a neural growth factor that plays a large role in the development of the brain, and in the operation of various brain processes, such as learning. (Previous discussion here.)

To begin with, there is the curious fact that the gene for BDNF can be transcribed into (at least) two different messenger RNA sequences – yet exactly the same protein is produced from each. In this case there are two alternative 3’ untranslated regions in the two transcripts. Since the regions are untranslated, why bother with the different transcripts?

Learning Suffers If Brain Transcript Isn't Transported Far Out To End Of Neurons (7/10/08)
Neuroscientists at Georgetown University Medical Center have solved a mystery that lies at the heart of human learning, and they say the solution may help explain some forms of mental retardation as well as provide clues to overall brain functioning.

Researchers have long puzzled over why a gene known as brain-derived neurotrophic factor (BDNF), which is crucial to the ability of neurons in the hippocampus to grow and connect to each other -- forming the basis of memory and learning -- produces two different transcripts, which then each fabricate identical proteins.

In the July 11 issue of Cell, the scientists report the answer, and it has to do with transportation. They found that the longer of the two transcripts (messenger RNAs, or mRNAs) include extra sequences that "motor" molecules attach to, in order to move the information far away from the nucleus of the cell and toward the long, tree-like branches of the nerve cell known as dendrites. There, protein-synthesizing machines use that mRNA to produce protein that helps small protrusions (called dendritic spines) on these dendrites grow.

The shorter of the mRNAs are also moved from the nucleus into the cytoplasm of the neuron, but they do not need to be transported to dendrites. These transcripts produce an identical protein, but in this case, investigators believe they help the axon, the long cable-like body of a neuron, grow.

The dendritic spines are where synapses form with the axons of other neurons, and it is the building of synapses that enables learning. Our earlier discussion noted how important BDNF is for growth of the dendritic spines.

But this research also answers a more general question about the not infrequent existence of different RNA transcripts that produce the same protein:
"The fascinating thing is that many genes produce multiple transcripts for the same protein -- and no one has known why," [lead investigator Baoji Xu] says. "So what we found here is likely very applicable to other genes. It reveals a mechanism for differential regulation of subcellular functions of proteins."

Another account of this research amplifies a few details:

If the Splice Is Right—BDNF to Dendrites, APP to Endosomes (7/11/08)
In the BDNF work, first authors Juan Ji An, Kusumika Gharami, and Guey-Ying Liao led the effort to determine whether the 3’ alternative splicing of BDNF, which has no effect on the protein coding region, was instead a way to target the message to soma versus dendrite. To do this, they first looked at localization of the splice forms and found the long form was preferentially located in dendrites in cultured rat cortical neurons. The long 3’ sequence was sufficient to target a green fluorescent protein reporter mRNA to dendrites, and that the message was translated there. ...

While the study strongly implicates dendritically targeted BDNF in the normal formation and function of spines, the data beg the question of how BDNF acts. In their discussion, the authors favor an autocrine mechanism involving activation of the TrkB receptor. In addition, they point out that the strategy of using alternative 3’UTRs to target the same protein to different subcellular localization may not be unique to BDNF.

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Hydrogen economy?

Here's a little more discussion of the prospects for a "hydrogen economy". I'd welcome it if it were practical, but I'm still skeptical. (Some previous discussion of hydrogen here).

Hydrogen economy sustainable in 15 years (7/17/08)
Hydrogen would be most efficient when used in fuel cells, which extract energy via a chemical reaction rather than by combustion. But fuel cells are still very expensive and distributing hydrogen to consumers would require new infrastructure. Consequently, a large-scale transition to hydrogen will require help from the federal government.

More on this report: Hydrogen Vehicles Coming Soon? Two Million Could Be On Roads By 2020 (7/17/08), Fuel cell cars still 15 years away at best: study (7/17/08)

Looking at Hydrogen to Replace Gasoline in Our Cars (7/3/08)
The jury is still out on whether hydrogen will ultimately be our environmental savior, replacing the fossil fuels responsible for global warming and various nagging forms of pollution. Two main hurdles stand in the way of mass production and widespread consumer adoption of hydrogen “fuel cell” vehicles: the still high cost of producing fuel cells, and the lack of a hydrogen refueling network.

Reining in manufacturing costs of fuel cell vehicles is the first major issue the automakers are addressing. While several have fuel cell prototype vehicles on the road—Toyota and Honda are even leasing them to the public in Japan and California—they are spending upwards of $1 million to produce each one due to the advanced technology involved and low production runs. ...

Another problem is the lack of hydrogen refueling stations. Major oil companies have been loathe to set up hydrogen tanks at existing gas stations for many reasons ranging from safety to cost to lack of demand. But obviously the oil companies are also trying to keep customers interested in their highly profitable bread-and-butter, gasoline.

Choanoflagellates II

Saturday, July 26, 2008

No sooner than we do an article on a topic that may seem esoteric to some – namely tyrosine kinase signaling in choanoflagellates – than new information comes along to add to the picture.

The previous discussion was about how remarkable it is that a complete set of sophisticated intercellular signaling proteins exists in a single-celled organism. The new research partially echoes the previous findings:

Primitive Single-Celled Microbe Expert In Cellular Communication Networks (7/7/08)
When it comes to cellular communication networks, a primitive single-celled microbe that answers to the name of Monosiga brevicollis has a leg up on animals composed of billions of cells. It commands a signaling network more elaborate and diverse than found in any multicellular organism higher up on the evolutionary tree, researchers at the Salk Institute for Biological Studies have discovered.

Their study, which will be published during the week of July 7-11 in the online edition of the Proceedings of the National Academy of Science, unearthed the remarkable count of 128 tyrosine kinase genes, 38 more than found in humans.

But it also points out that M. brevicollis actually has a more extensive tyrosine kinase system than metazoa do:
"We were absolutely stunned," says Manning. "Based on past work, we had expected maybe a handful of these kinases but instead discovered that this primitive organism has a record number of them. Two other essential parts of the tyrosine kinase network - PTP and SH2 genes - are also more numerous than in any other genome, showing that it is the whole network that is elaborated here." ...

The Monosiga kinases are more divergent than anything previously seen in animals, which may help scientists understand the fundamentals of how all tyrosine kinase signaling works. Despite their extreme diversity, Monosiga kinases time and again arrive at the same solution to a problem, as do animal kinases, but using a distinct method for instance to create a sensor structure that emerges from the cell, or to target a kinase to a specific part of the cell. "This convergent evolution suggests that there are only a limited number of ways build a functional network from these components," says Manning.

And as was pointed out before, this discovery merely suggests new questions that need to be answered:
With all this new information, one obvious question remains unanswered: what is a single-celled organism doing with all this communications gear? "We don't have a clue!" says Manning, "but this discovery is the first step in finding out."

A possible answer, though one for which no evidence exists, as far as I know, is that M. brevicollis actually developed from the type of cell it strongly resembles ("collar cells") found in sponges. Perhaps the tyrosine kinase signaling system actually evolved in sponges, but then some of the constituent cells decided to go it alone. It would still need to be explained why the kinases didn't disappear in subsequent evolution. Since they are still present, they must serve some useful purpose.

Further reading:

The protist, Monosiga brevicollis, has a tyrosine kinase signaling network more elaborate and diverse than found in any known metazoan – research article from PNAS that reports the research discussed (open access)

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High-temperature superconductivity

Monday, July 21, 2008

"Normal" superconductivity is a phenomenon that has been known to physicists since 1911, when it was discovered by Heike Kamerlingh Onnes. The phenomenon involves the essentially total loss of electrical resistance in certain materials – mostly metals and metallic alloys – at temperatures very close to absolute zero (0° K, which is -273.15° C). Most metallic elements, except for ferromagnetic metals and some noble metals like silver and gold, become superconducting at sufficiently low temperatures.

The low temperatures needed for normal superconductivity are now easily maintainable in the laboratory, for instance by immersion in liquid helium, which has a boiling point of 4.22° K. Although such temperatures are routinely achievable, it's not easy or cheap to do so. Nevertheless, even some very large devices, such as the Large Hadron Collider, depend on superconductivity in their operation.

It is quite easy to measure experimentally when superconductivity is occurring, because Ohm's Law states that V=I×R, where V is voltage, I is current, and R is resistance. Consequently, resistance is given by R=V/I. So if there is a current flowing between two points in a material even though the voltage difference is zero, the resistance must be zero.

In most materials, resistance decreases as the temperature decreases. In superconductors, by definition, there is a temperature, called the critical temperature (TC), at which resistance abruptly becomes essentially 0. By that we mean the resistance is too low to measure, and an electric current flowing in a superconducting material does not dissipate any measurable heat. So the current (I) can flow for an indefinitely long period of time, without any loss.

Clearly, superconductivity is an extremely useful property to have in a material. It could, for example, allow transmission of electricity over wires without any loss at all, as opposed to the loss that normally occurs due to generation of heat. Unfortunately, the highest critical temperature known in a "normal" superconducting material is about 39° K. That record was established in 2001 with magnesium diboride (MgB2). Liquid helium isn't needed to keep such a material in a superconducting state. Liquid nitrogen, which is commonly used commercially and has a boiling point of 77.36°K (-195.79° C) suffices, even though it has to be kept cooled to well below its boiling point.

So it was with high hopes that the discovery in 1986 of "high-temperature" superconductors was greeted. One measure of the perceived importance of the discovery is the fact that the discoverers (Karl Müller and Johannes Bednorz) were awarded a Nobel Prize the very next year.

There were strong hopes at the time that eventually materials would be discovered that exhibited high-temperature superconductivity even at room temperatures. This would make possible the economical production of useful things like maglev trains. Although maglev trains have in fact been built that use high-temperature superconductors, the requirement for liquid nitrogen still makes them very expensive to build and maintain.

High-temperature superconductivity was first observed in ceramics based on copper oxide (CuO2). The material also incorporated the elements lanthanum and barium, and had a transition temperature of about 35°K. Just two days ago it was announced that a rather more exotic cuprate material, incorporating tin, lead, indium, barium, and thulium, had the highest TC found so far, about 195° K (-78° C) – that's the sublimation temperature of CO2. (See here.)

Although 195° K is a huge improvement over 35°K, it is still far below "room temperature". This still makes the routine use of high-temperature superconductors in most applications uneconomical, or at best difficult. There's an additional problem in that most high-TC materials are ceramics, so they lack the ductility of metallic materials, which is often required in practical applications like wires and cables. Furthermore, such materials are generally tricky to manufacture at all, and require exotic elements like thulium.

For all the reasons mentioned, more than 20 years after the discovery of high-TC materials, there is a great deal of disappointment and frustration that progress hasn't lived up to the initial high hopes.

One of the main obstacles to progress has been the surprising fact that we do not even have an adequate theory of how high-temperature superconductivity works. We do have a good theory of how "normal" superconductivity works, but that theory, even with tweaks, does not appear to be applicable at temperatures more than about 40° K. Before 1986, the highest TC known was 23° K. So at first it might seem as though 35° K was not that big an advance.

However, in 1986 it was thought that the existing theory did not apply at temperatures more than about 30° K. The fact that in 1986 both theory and experiment did not anticipate a TC of 35°K is what made the discovery so unexpected. The fact we still don't have an adequate theory for most high-TC materials means it isn't possible to figure out theoretically what sorts of materials might have TC exceeding the currently known upper limit.

So let's quickly review the theory of "normal" superconductivity. It's surprisingly simple (which is also why it doesn't extend beyond 40°K). The theory is known as BCS theory, for its developers, John Bardeen, Leon Cooper, and John Schrieffer.

Electrical conductivity at ordinary temperatures is based, of course, on the largely free movement of electrons in a metallic or semi-metallic material. Resistance is simply the result of interactions that transfer energy from the electrons to atoms of the material. Eventually all the energy carried by the electrons is dissipated as heat, and the current (I) goes to 0, unless energy is supplied (say, from a battery).

According to BCS theory, at sufficiently low temperatures two electrons having opposite spins pair up with each other to form "Cooper pairs". Electrons normally repel each other due to the Coulomb force resulting from their electrical charge. But each electron also, because of Coulomb force, distorts the lattice of positively charged ions of the material. This distortion is called a "phonon". In fact, the distortion itself has a vibrational, wavelike nature – like the quantum wavelike behavior of an electron or any other subatomic particle.

A phonon has a net positive charge of nearly the same magnitude as the negative charge of an electron, so this pairing mostly cancels out the electrical charge of the electron-phonon pair. But the cancellation is only approximate, so that each electron-phonon pair has a small net charge, which may be positive or negative. Consequently, electron-phonon pairs can attract other pairs having opposite charge. The Cooper pair is this pairing between electron-phonon pairs.

Cooper pairs form only when the electrons involved have opposite spins. Consequently, a Cooper pair has zero net spin, making it a boson. This is important in BCS theory, since bosons aren't subject to the Pauli exclusion principle. The result is that many Cooper pairs can be simultaneously in the same quantum state.

At a sufficiently low temperature it becomes impossible for Cooper pairs to interact with the lattice of the material. This is because, due to the Heisenberg uncertainty principle, there is a lower limit on the amount of energy (ΔE) that can be exchanged between a Cooper pair and the lattice. If the binding energy within the Cooper pair is less than ΔE, no interaction that disrupts the pair is possible, so the pair represents a stable bound state. It can therefore move completely freely within the lattice, with no resistance at all.

The net result is that the electrons which are paired up within Cooper pairs can move completely freely within the lattice. And since electrons themselves still have a net charge, the effective result is an electrical current that flows with zero resistance. Another way of thinking about this is that a pair of electrons moves through the lattice accompanied by distortions of the lattice, but in such a way that no energy is transferred to the lattice.

If all this legerdemain seems a little suspicious, remember that it's a quantum effect that is possible only at very low temperatures, and that's why the BCS theory does not apply, even with any variations that physicists have been able to conceive, above approximately 40° K.

Materials capable of high-temperature superconductivity are more complex than typical "normal" superconducting materials. The latter include many metallic elements, such as mercury or lead. But the former are ceramics, which are often, but not always, based on copper oxide. In the so-called cuprate superconductors, atoms of additional elements are included between planes consisting of copper oxide. This process is referred to as "doping". It has the effect of inserting either a surplus or a deficit of electrons (called "holes" in the latter case), and it is these electrons and holes that are available for carrying electric charge in the material.

It is thought that these electrons and holes are able to pair up in some way that is analogous to Cooper pairs, and that the resulting pairs are the necessary bosonic charge carriers. But one basic problem in this field is that it has not even been possible to determine experimentally exactly what the hypothetical pairs consist of.

There is a vast theoretical and experimental literature, estimated as upwards of 100,000 published papers, dealing with the field of high-temperature superconductivity. Nevertheless, the development of an adequate theory to explain the effect is still considered to be one of the most important unsolved problems in condensed matter phyaics.

Now there is additional experimental work that claims to have made significant progress:

Room Temperature Superconductivity: One Step Closer To Holy Grail Of Physics (7/9/08)
The researchers have discovered where the charge 'hole' carriers that play a significant role in the superconductivity originate within the electronic structure of copper-oxide superconductors. These findings are particularly important for the next step of deciphering the glue that binds the holes together and determining what enables them to superconduct.

Dr Suchitra E. Sebastian, lead author of the study, commented, "An experimental difficulty in the past has been accessing the underlying microscopics of the system once it begins to superconduct. Superconductivity throws a manner of 'veil' over the system, hiding its inner workings from experimental probes. A major advance has been our use of high magnetic fields, which punch holes through the superconducting shroud, known as vortices - regions where superconductivity is destroyed, through which the underlying electronic structure can be probed.

"We have successfully unearthed for the first time in a high temperature superconductor the location in the electronic structure where 'pockets' of doped hole carriers aggregate. Our experiments have thus made an important advance toward understanding how superconducting pairs form out of these hole pockets."

By determining exactly where the doped holes aggregate in the electronic structure of these superconductors, the researchers have been able to advance understanding in two vital areas:

(1) A direct probe revealing the location and size of pockets of holes is an essential step to determining how these particles stick together to superconduct.

(2) Their experiments have successfully accessed the region betwixt magnetism and superconductivity: when the superconducting veil is partially lifted, their experiments suggest the existence of underlying magnetism which shapes the hole pockets. Interplay between magnetism and superconductivity is therefore indicated - leading to the next question to be addressed.

Do these forms of order compete, with magnetism appearing in the vortex regions where superconductivity is killed, as they suggest? Or do they complement each other by some more intricate mechanism? One possibility they suggest for the coexistence of two very different physical phenomena is that the non-superconducting vortex cores may behave in concert, exhibiting collective magnetism while the rest of the material superconducts.

Further reading:

A multi-component Fermi surface in the vortex state of an underdoped high-Tc superconductor – original research paper (sub. rqd.)

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Resveratrol is getting rather confusing

Monday, July 14, 2008

Here, have another glass of this great Cabernet...

But hold on about jumping to conclusions. The resveratrol story keeps getting more complicated, according to the most recent research. This is in addition to what we just discussed here.

To begin with, there is additional confirmation that resveratrol does confer health benefits – at least in mice. However – and this is a major qualification – the research did not indicate there was a general extension of longevity in the mice.

Furthermore, the way that the research was announced introduced further confusion. In one press release (from the publisher, Cell Press, of Cell Metabolism) we have:

Red wine ingredient wards off effects of age on heart, bones, eyes and muscle (7/3/08)
Large doses of a red wine ingredient can ward off many of the vagaries of aging in mice who begin taking it at midlife, according to a new report published online on July 3rd in Cell Metabolism, a Cell Press publication. Those health improvements of the chemical known as resveratrol—including cardiovascular benefits, greater motor coordination, reduced cataracts and better bone density—come without necessarily extending the animals' lifespan.

Sinclair and de Cabo's team further show evidence that resveratrol mimics the beneficial effects of eating fewer calories. In mice, they found that resveratrol induces gene activity patterns in multiple tissues that parallel those induced by dietary restriction and every-other-day feeding.

But in another press release, from NIH's National Institute on Aging, we find:

Resveratrol found to improve health, but not longevity in aging mice on standard diet (7/3/08)
Scientists have found that the compound resveratrol slows age-related deterioration and functional decline of mice on a standard diet, but does not increase longevity when started at middle age. This study, conducted and supported in part by the National Institute on Aging (NIA), part of the National Institutes of Health, is a follow-up to 2006 findings that resveratrol improves health and longevity of overweight, aged mice. The report confirms previous results suggesting the compound, found naturally in foods like grapes and nuts, may mimic, in mice, some of the effects of dietary or calorie restriction, the most effective and reproducible way found to date to alleviate age-associated disease in mammals.

The findings, published July 3, 2008, in Cell Metabolism, may increase interest in resveratrol as a possible intervention for age-related declines, said NIA scientists. The authors emphasized, however, that their findings are based on research in mice, not in humans, and have no immediate and direct application to people, whose health is influenced by a variety of factors beyond those which may be represented in the animal models.

Keep in mind, this is all about the same research. Clearly, there are some differences of spin being offered here. The second announcement seems to be closer to what was actually found, as can be seen from the abstract of the actual journal article:

Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span
A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

(Aside: in discussions like this you will often see the terms "longevity" and "lifespan" used almost interchangably. Properly speaking, "longevity" is usually the better term, as it refers to average length of life, a statistical property, while "lifespan" refers to maximum potential length of life. For the most part, the distinction can be glossed over, though it isn't entirely unimportant.)

Confused yet? Let me try to boil this down a little. This is just my interpretation, but the conclusions I see are these:

  1. Resveratrol fed to middle-aged mice can have health benefits, such as cardiovascular benefits, greater motor coordination, reduced cataracts and better bone density.
  2. The health benefits and gene transcriptional changes resulting from resveratrol in the diet are similar to, though not quite the same as, those resulting from calorie restriction alone.
  3. Resveratrol in the diet did not increase longevity of mice on normal diets, even though calorie restriction by itself has been shown to increase longevity (in mice), while resveratrol does increase longevity of mice on high-calorie diets.
  4. In mice on high-calorie diets where resveratrol increased both health factors and longevity, the improvement occurred without decreasing actual body weight.
  5. This research on mice may not be predictive of the effects that might be seen in similar experiments (which have not yet been done) on humans.

Putting this even more succinctly, in mice adding resveratrol to the diet slows down some undesirable side-effects of aging, but does not appear to actually increase longevity, whereas calorie restriction does slow aging and increase longevity somewhat. All bets are still off as to what effects resveratrol may have in humans.

How could it be that resveratrol had all these health benefits, but didn't increase longevity? The logical conclusion would be that resveratrol has little effect on conditions that usually cause mice to die. In particular, mice usually die of cancer, and resveratrol doesn't have much benefit in that regard, though calorie restriction does.

There might actually be good news for humans in this – if resveratrol did benefit cardiovascular health in humans, that would be great, since cardiovascular disease is the largest cause of human mortality. (Cancer's a big cause too, just not as big.)

In spite of the ambiguities, this is a very significant piece of research, in part because of the large team of experienced scientists – such as David Sinclair – who participated. Here are some additional news reports on the research:

But wait. We're not done yet. There are additional complications, as some of these other reports point out. For one thing, it isn't at all clear how resveratrol is beneficial at a molecular level. (And it's just as unclear why calorie restriction is beneficial – which might be different in some ways from the reasons applicable to resveratrol.) It is known that resveratrol has antioxidant and anti-inflammatory properties. Both of those are positives.

However, resveratrol also seems to activate the sirtuin protein Sirt1. There's quite a bit of research – in model organisms like nematodes, yeast, fruit flies, and rodents – that shows sirtuins have beneficial properties of their own. In particular, sirtuins do increase longevity, as does calorie restriction, in the model organisms, even if the molecular mechanisms aren't quite the same. (This is more evidence that the beneficial effects of resveratrol are not largely due to sirtuin activation.)

Regarding Sirt1 specifically, there have been at least two other recent research results published. The results are mixed. In some ways Sirt1 is shown to be beneficial, while in at least one way, it may be harmful. To the extent that resveratrol does serve to activate Sirt1, is may have the same helpful or harmful properties.

Here's the bad news, first:

Life-extending Protein Can Also Have Damaging Effects On Brain Cells (7/1/08)
Proteins widely believed to protect against aging can actually cause oxidative damage in mammalian brain cells, according to a new report in the July Cell Metabolism, a publication of Cell Press. The findings suggest that the proteins can have both proaging and protective functions, depending on the circumstances, the researchers said.

"Sirtuins are very important proteins," said Valter Longo of the University of Southern California, Los Angeles. "Overexpression can protect in some cases, and in other cases, it may do the opposite. It has to do with the fact that they do so many things." ...

SirT1, the mammalian version of yeast Sir2, controls numerous physiological processes including glucose metabolism, DNA repair, and cell death, the researchers added. In mammalian cells, SirT1 also controls several stress-response factors.

Now, the researchers show that cultured rat neurons treated with a SirT1 inhibitor more often survived treatment with oxidative stress-inducing chemicals. They further show evidence to explain the mechanism responsible for that effect.

They also found lower oxidative stress levels in the brains of mice without SirT1. However, those SirT1 knockout mice didn't live as long as normal mice do on either a normal or a calorie-restricted diet.

In brief: lowering Sirt1 levels helps cells withstand oxidative stress, while higher levels make cells more vulnerable to oxidative stress. Nevertheless, mice without Sirt1 at all live shorter lives. Confusing, no?

This research, which was published in the same issue of Cell Metabolism as the de Cabo-Sinclair study, went on to investigate in more detail what Sirt1 inhibition was doing. Here's the research abstract to explain:

SirT1 Inhibition Reduces IGF-I/IRS-2/Ras/ERK1/2 Signaling and Protects Neurons
Sirtuins are known to protect cells and extend life span, but our previous studies indicated that S. cerevisiae Sir2 can also increase stress sensitivity and limit life-span extension. Here we provide evidence for a role of the mammalian Sir2 ortholog SirT1 in the sensitization of neurons to oxidative damage. SirT1 inhibition increased acetylation and decreased phosphorylation of IRS-2; it also reduced activation of the Ras/ERK1/2 pathway, suggesting that SirT1 may enhance IGF-I signaling in part by deacetylating IRS-2. Either the inhibition of SirT1 or of Ras/ERK1/2 was associated with resistance to oxidative damage. Markers of oxidized proteins and lipids were reduced in the brain of old SirT1-deficient mice, but the life span of the homozygote knockout mice was reduced under both normal and calorie-restricted conditions. These results are consistent with findings in S. cerevisiae and other model systems, suggesting that mammalian sirtuins can play both protective and proaging roles.

(Technical aside: Note, in particular, the conjectured effect of Sirt1 on IGF-1 signaling. Sirt1 promotes phosphorylation of IRS2, the "Insulin receptor substrate 2", which enhances IGF-1 signaling, and this makes cells more vulnerable to oxidative stress. Conversely, inhibition of Sirt1 reduces cell vulnerability. (We discussed many properties of IGF-1, including relations to calorie restriction and longevity, here.))

As you recall, Sirt1 is what's called a histone deacetylase (HDAC) enzyme. (Some discussion here.) As such, one of the main properties of Sirt1 is that it can silence a bunch of genes at the same time, by removing acetyl groups from the histones to which the genes are normally bound. Clearly, that is why Sirt1 affects many diverse processes, and why it can be risky to mess with.

That's the cautionary news on Sirt1. But again on the positive side of the ledger for Sirt1 (and hence perhaps resveratrol also), there is one more study that did not receive as much media attention. The study, was published July 3 in the Proceedings of the National Academy of Sciences. Its authors included Matthias Tschöp and Paul Pfluger.

Here's the abstract (via BioInfoBank):

Sirt1 protects against high-fat diet-induced metabolic damage
Here, we report that mice with moderate overexpression of Sirt1 under the control of its natural promoter exhibit fat mass gain similar to wild-type controls when exposed to a high-fat diet. Higher energy expenditure appears to be compensated by a parallel increase in food intake. Interestingly, transgenic Sirt1 mice under a high-fat diet show lower lipid-induced inflammation along with better glucose tolerance, and are almost entirely protected from hepatic steatosis. We present data indicating that such beneficial effects of Sirt1 are due to at least two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via stimulation of PGC1-α, and lower activation of proinflammatory cytokines, such as TNF-α and IL-6, via down-modulation of NF-κB activity. Together, these results provide direct proof of the protective potential of Sirt1 against the metabolic consequences of chronic exposure to a high-fat diet.

From this news story already mentioned, here's a little more explanation:
Increasing levels of the mouse sirtuin, SirT1, prevents mice from developing heart problems and fatty livers even when they are fed high-fat diets, researchers at the University of Cincinnati College of Medicine and the Spanish National Cancer Research Center in Madrid reported June 30 in Proceedings of the National Academy of Sciences. These mice with higher levels of SirT1 eat more but also burn more calories than do mice with normal levels of the enzyme.

If you haven't had enough punishment yet, here's a more detailed report on all the research already discussed, and a bit more:

SIRT1, Resveratrol and More: Moving Closer to Anti-aging Elixir? (7/8/08)

One of the additional bits is this:
Working independently and publishing 4 June in PLoS ONE, researchers led by Tomas Prolla at the University of Wisconsin, Madison, report similar results in their microarray analysis comparing transcription profiles induced by CR and resveratrol. First author Jamie Barger and colleagues fed mice from middle age (14 months) to old age (30 months) a control diet, CR diet, or resveratrol-supplemented control diet. The researchers report a “striking transcriptional overlap” of CR and resveratrol (99.7 percent of gene expression changes correlating by direction) in heart, skeletal muscle, and brain (neocortex), and show that both regimens prevent age-related cardiac problems.

And here's the journal article, in full, being referred to:

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice (6/4/08) - also here
Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg−1 day−1), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.

If that sounds a bit familiar, it's because not only does it parallel the research reported by Sinclair and de Cabo discussed above, but in fact we're already written about it here, as it was described in this press release.

To summarize this whole thing, resveratrol has benefits for both general health and longevity. The benefits are similar to, but not quite the same as, those of either sirtuins or calorie restriction. Further, sirtuins, and hence resveratrol, may also have detrimental side effects. A lot more research, which must eventually include human studies, is needed.

There have also been a couple of other recent reports on completely different possible mechanisms to explain the benefits of calorie restriction, but we'll save those for another time.

Additional reading:

The Ongoing Saga of Sirtuins and Aging – overview in Cell Metabolism of the research by Li, et al (sub rqd)

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Sunday, July 13, 2008

Choanoflagellates are single-celled eukaryotic organisms – like amoebae, yeasts, or slime molds, as opposed to prokaryotic organisms like bacteria. Eukaryotic cells are different from prokaryotic ones in having a variety of internal and external structures, including a cell nucleus that contains the organism's genome.

One distinctive feature of a choanoflagellate is its flagellum, a whiplike structure made up of microtubules, which a choanoflagellate uses to propel itself in water. A choanoflagellate rather resembles an animal sperm cell.

But the type of animal cell that a choanoflagellate most strongly resembles is called a choanocyte (meaning "collared cell") and is found in sponges. Modern sponges were, until quite recently, considered to be lineal descendants of the earliest type of multicellular animal (metazoan). (As discussed here and here, comb jellies may be descended from an even earlier metazoan.)

A metazoan is more than simply a collection of cells living together in a cohesive colony, such as slime molds and some choanoflagellates. The cells of a metazoan are of different types, and they communicate among themselves in order to effect whatever behavior the organism has evolved to sustain itself.

With that in mind, it is quite interesting that the genome of choanoflagellates contains genes for three proteins that are used ubiquitously in metazoa for intercellular communication:

New Evidence That Ancient Choanoflagellates' Form Evolutionary Link Between Single-celled And Multi-celled Organisms (7/1/08)
What do humans and single-celled choanoflagellates have in common? More than you'd think. New research into the choanoflagellate genome shows these ancient organisms have similar levels of proteins that cells in more complex organisms, including humans, use to communicate with each other.

According to a paper published in the Proceedings of the National Academies of Science, these findings help confirm choanoflagellates' role as an evolutionary link between single-celled and multi-celled organisms. They also contend that these insights into the organism's genome may mean that the proteins used to help cells communicate may have other roles as well. ...

Choanoflagellates, or at least their ancestors, have long been suspected as being the bridge between microorganisms with only one cell and metazoan, or multi-cellular organisms. There are many clues that lead to this conclusion, including the fact that choanoflagellates are similar to the individual cells in ocean sponges and unlike most other flagellates, they use their flagellate, or tail, to push themselves through water, rather than being pulled by it.

By analyzing the recently-sequenced choanoflagellate genome, the researchers discovered another similarity between choanoflagellates and most metazoans--their genetic code carries the markers of three types of molecules that cells use to achieve phospho-tyrosine signaling proteins.

The type of signaling in question here utilizes phosphorylation – the addition of a phosphate (PO4) group to a protein at one or more of its constituent amino acids. It is tyrosine phosphorylation when the the phosphate is attached to a tyrosine unit. (Tyrosine is one of the 20 kinds of amino acids that make up proteins.)

This process is much like reading, writing, and erasing a single bit of information in a computer memory. It is the proteins that perform these operations that are found to be shared by choanoflagellates and most metazoa.
Animals depend on tyrosine phosphorylation to conduct a number of important communications between their cells, including immune system responses, hormone system stimulation and other crucial functions. These phospho-tyrosine signaling pathways utilize a three-part system of molecular components to make these communications possible.

Tyrosine kinases (TyrK) 'write' messages between cells by adding phospho-tyrosine modifications, protein tyrosine phosphatases (PTP) are molecules that modify or 'erase' these modifications, and Src Homology 2 (SH2) molecules 'read' these modifications so the recipient cell gets the message.

What is intriguing is that all three of these signaling proteins are found in choanoflagellates in significant amounts. Although the proteins exist in other single-celled organisms, they aren't found together or in the same amounts as they are in choanoflagellates. This is the sort of thing that makes a researcher think, "Hmmm, that's strange. Wonder what's up with that?"
The researchers conclude that the presence of the full three-component signaling system may have played a role in the development of metazoan organisms whose cells could communicate with each other in complex ways.

It would be interesting to find out whether choanoflagellates actually use the proteins to communicate among themselves, and if so, for what purposes. But those are questions that remain to be answered.

Further reading:

The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans – an earlier (2/08) journal article on the choanoflagellate genome, and possible links to metazoa (sub. rqd. for full access)

The Premetazoan Ancestry of Cadherins – companion research article to the preceding, from Science, 2/15/08 (sub. rqd. for full access)

Genome Of Marine Organism Tells Of Humans' Unicellular Ancestors (2/14/08) – press release that describes the preceding research

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Altruism and economics

Sunday, July 6, 2008

Another shocker: even economists may have to take into account that altruistic behavior, not just selfish behavior, can be rational, while selfishness can be suboptimal. Gordon Gekko, the Republican Party, and the Chicago School of Economics may not agree, but:

The Economics Of Nice Folks (6/19/08)
A basic tenet of economics is that people always behave selfishly, or as the 18th century philosopher economist David Hume put it, "every man ought to be supposed to be a knave."
You may recall that David Hume was recently mentioned here, concerning a related aspect of ethical theory.
But what if some people aren't always knaves?

Sam Bowles argues in Science June 20 that economics will get it wrong then, sometimes badly so. He points to new experimental evidence that people do often act against their own personal self-interest in favor of the common good, and they do so in predictable, understandable ways. Poorly-designed economic institutions fail to take advantage of intrinsic moral behavior and often undermine it. ...

These examples show that economists ignore human altruism at their peril. Standard economic theory assumes that incentives that appeal to self-interest won't affect any natural altruism that may exist, but that assumption is clearly wrong. Bowles discusses the research to date that helps to explain when and why that assumption breaks down.

The thesis here may be more clearly expressed in the abstract of the research review in question:

Policies Designed for Self-Interested Citizens May Undermine "The Moral Sentiments": Evidence from Economic Experiments (6/20/08)
High-performance organizations and economies work on the basis not only of material interests but also of Adam Smith's "moral sentiments." Well-designed laws and public policies can harness self-interest for the common good. However, incentives that appeal to self-interest may fail when they undermine the moral values that lead people to act altruistically or in other public-spirited ways. Behavioral experiments reviewed here suggest that economic incentives may be counterproductive when they signal that selfishness is an appropriate response; constitute a learning environment through which over time people come to adopt more self-interested motivations; compromise the individual's sense of self-determination and thereby degrade intrinsic motivations; or convey a message of distrust, disrespect, and unfair intent. Many of these unintended effects of incentives occur because people act not only to acquire economic goods and services but also to constitute themselves as dignified, autonomous, and moral individuals.

You may also recall that Sam Bowles showed up in this, from last November, concerning a more distantly related aspect of evolutionary ethical theory.

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Selfish genes

News flash: "selfish" genes actually exist. They aren't simply a metaphor.

New Discovery Proves 'Selfish Gene' Exists (6/20/08)
A new discovery by a scientist from The University of Western Ontario provides conclusive evidence which supports decades-old evolutionary doctrines long accepted as fact.

Since renowned British biologist Richard Dawkins ("The God Delusion") introduced the concept of the 'selfish gene' in 1976, scientists the world over have hailed the theory as a natural extension to the work of Charles Darwin.

Although I think that the idea of the "selfish gene" was a nice way to conceptualize the situation, the above remarks seem to be a little hyperbolic. It's not clear that this theoretical insight was that Earth-shattering. And the adjective wasn't meant to be taken literally:
In studying genomes, the word 'selfish' does not refer to the human-describing adjective of self-centered behavior but rather to the blind tendency of genes wanting to continue their existence into the next generation. Ironically, this 'selfish' tendency can appear anything but selfish when the gene does move ahead for selfless and even self-sacrificing reasons.

Nobody seriously thinks that genes have psychological "wants" or "needs". It's just that the effect of a gene may resemble what might be conscious advantage-seeking behavior in a human.

Or then again, specific human behavior may have adaptive evolutionary value even if it's not consciously undertaken for personal advantage or evolutionary success. Indeed, many human motivators that might seem to be "wants" or "needs" may have beneficial evolutionary consequences that are different from the apparent immediate objective of the specific motivator. (Sex itself is the best example of this. Even though a few species succeed without sex.)

And on the other hand, behavior that outwardly appears altruistic can be undertaken for genuinely "selfish" reasons, such as the personal satisfaction that can be enjoyed, or perhaps even public and social acclaim. If such social reward reliably does ensue, the behavior may well have adaptive value for an individual and a social group. The literature is replete with discussions of such issues.

However all that may be, the research in focus here gives actual evidence of the existence of a gene in honey bees behaving selfishly. The gene (which still remains to be explicitly identfied) disadvantages ordinary worker bees by making them sterile, but at the same time contributes to the success of the colony by promoting reproductive success of the queen bee. The gene can be called "selfish" because it condemns most bees to a lifetime of drudgery, in order to promote its own survival through the success of the colony and its most elite member(s).
Because the 'selfish' gene controlling worker sterility has never been isolated by scientists, the understanding of how reproductive altruism can evolve has been entirely theoretical -- until now.

Working with Peter Oxley of the University of Sydney in Australia, Western biology professor Graham Thompson has, for the first time-ever, isolated a region on the honey bee genome that houses this 'selfish' gene in female workers bees.

This means that the 'selfish' gene does exist, not just in theory but in reality. "We don't know exactly which gene it is, but we're getting close."

Who ever suspected that Republican political philosophy existed among honey bees?

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Mirror neurons control erection response to porn

Does anyone find this surprising? Isn't it exactly the effect one would expect mirror neurons to have? (Past discussion here.) However, it is welcome to note basic research that has practical applications...

Mirror neurons control erection response to porn (6/16/08)
You don't have to be a scientist to observe that pornographic images lead to erections in men. But you would have to be one to show those images to volunteers while meticulously measuring the volume of response in the brain and penis.

Harold Mouras, at University of Picardie Jules Verne in Amiens, France, and his colleagues wanted to understand the cerebral underpinnings of visually-induced erections.

They suspected there might be a role for mirror neurons, a special class of brain cell that fires both when people perform an action and when they observe it being performed.

Not a terribly difficult guess to make. So what did they find?
While the volunteers watched the movies, the researchers watched their brains using functional magnetic resonance imaging (fMRI).

They also kept tabs on the tumescence of the other target organ, using a hand-crafted "penile plethysmograph" – essentially an airtight tube in which the enlarging penis causes measurable pressure changes.

As expected, all the subjects got erections and many parts of the brain lit up.

Interestingly, the volume of the erections correlated with the strength of activation in a part of the brain called the pars opercularis, which is known to display mirror neuron activity. Even more intriguing, the brain activation, say the researchers, precedes the penile response.


Comb jellies, again

Comb jellies were in the news back in April, and I discussed that here. They're a lot like jellyfish, only different. In particular, they are now thought to be the closest living relatives of the earliest animals on this planet.

The most recent news is that, although the bodies of these animals appear primitive, their genetic machinery has interesting resemblances to that of more modern animals, including humans.

Genes key to the development of modern animals' body plans show up in primitive-looking comb jellies (6/6/08)
No one suspected that the primitive comb jellies — watery, rotund and nearly invisible sea creatures — would rely on an intricate interplay of genes to design their rudimentary bodies. Yet researchers got a surprise when they looked at the comb jelly’s genes. Scientists found pattern-making genes that, in most animals, plot out the position of the head, brain, limbs and rear ends during development. These “homeobox” genes turned on in a specific pattern in the comb jellies, even though these ancient sea creatures are headless, brainless, limbless and rear end–less, scientists show in the June Development Genes and Evolution.

Homeobox genes are genes that have specific genetic code sequences. The sequences code for portions of proteins (called homeodomains) that are in turn able to bind to DNA, so that the proteins act as transcription factors. These transcription factors are especially important in the process of embryonic development, as they determine the overall body plan of the organism. Homeobox genes aren't unique to animals. They're also found in plants and fungi.

However, although comb jelly homeobox genes are similar to those of other animals, and they have functions in comb jellies that are vaguely similar to their functions in other animals, there are important differences too:
Certain genes expressed in the mouths of comb jellies and in the heads of other animals could indicate that the comb jellies’ mouths correspond to the front-end of all animals (except for amorphous sponges), Martindale says. And it implies that the mouth region of an ancestral headless animal is in the same area where the first head eventually arose. Although comb jellies are using the same basic toolkit as other animals, they might be doing so in an entirely different way, Martindale says. Genes involved with limb formation in other animals were expressed at seemingly random points along the comb jellies’ throat-like pharynx, for example.

“Mice, flies and even cnidarians [jellyfish and sea anenomes, mainly] seem to be built on the same basic plan, but the sponges and comb jellies don’t fall into that mold,” Martindale says.

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