This report is from today's London Independent. The source is the latest issue of Nature, so there will doubtless be other reports.

Update from Razib: Carl Zimmer and John Hawks have much more.

One point that is really confusing about the Hobbits is their small brain size. Consider the graph to the left. Human (hominids) brains keep getting larger, come rain or shine. The Hobbits, if they truly are what is claimed, radically reversed this trend. Convential explanations of island ecology seem a bit weak when set against this almost inevitable encephalization that seems to have characterized our lineage.

I was poking around looking for something else and found this ESI special topics website. It updates every other month and provides interviews with the authors of the most highly cited papers at the time. I really think the "fronts" are interesting and could be useful. They give you a map of journal articles that seem to be forming a cluster and generating excitement within a certain field. Here's one for hippocampal GABA(A) receptors.

I'm hoping they do a map for the RNA decapping and degradation since they have identified it as a Fast Moving Front. They have an interview with Roy Parker about P-bodies and RNA degradation here. I've done a little bit on the topic before. The hot topic in the social sciences is apparently "Democracy". So check it out. ESI special topics: from Decapping to Democracy.

Given that some of the readers here are actual, like, scientists, this article on the relationship between marriage and scientific success may be of interest. Actually, the only interesting part is the intro:

Several years ago, Satoshi Kanazawa, then a psychologist at the University of Canterbury in Christchurch, New Zealand, analyzed a biographical database of 280 great scientists--mathematicians, physicists, chemists, and biologists. When he calculated the age of each scientist at the peak of his career--the sample was predominantly male--Kanazawa noted an interesting trend. After a crest during the third decade of life, scientific productivity--as evidenced by major discoveries and publications--fell off dramatically with age. When he looked at the marital history of the sample, he found that the decline in productivity was less severe among men who had never been married. As a group, unmarried scientists continued to achieve well into their late 50s, and their rates of decline were slower.

"The productivity of male scientists tends to drop right after marriage," says Kanazawa in an e-mail interview from his current office at the London School of Economics and Political Science in the United Kingdom. "Scientists tend to 'desist' from scientific research upon marriage, just like criminals desist from crime upon marriage."

Kanazawa's perhaps controversial perspective is that of an evolutionary psychologist. "Men conduct scientific research (or do anything else) in order to attract women and get married (albeit unconsciously)," he says. "What’s the point of doing science (or anything else) if one is already married? Marriage (or, more accurately reproductive success, which men can usually attain only through marriage) is the goal; science or anything else men do is but a means. From my perspective, scientists are no different than anybody else; evolutionary psychology applies to all humans equally," he adds.

The rest is a bunch of quotes from dudes bitching about how they can't meet women; read at your own risk.

Related: Kanazawa on domestic violence and the sex ratio

Jeez, how long has it been since we had a good chat about comely girls? Via Dienekes, this article shows that in a sample of early 20-something girls at a Scottish university, daughters of happily married parents (HM) had more attractive and feminine faces than those whose parents either had separated pre-puberty (S) or had remained married but unhappily (UM). Color pictures in PDF here (L-to-R: S, UM, HM). As for body shape, the HM daughters had lower BMI (i.e., were slimmer) and lower waist-to-hip ratio (WHR, i.e., a more hourglass figure) than the other two groups. The authors make it clear that theirs is a correlational study that remains agnostic on the causal mechanisms, though Dienekes' post & comments discuss possibilities.

First, though, there's an interesting wrinkle: the authors and some of their references argue that the independent variable is presence of father (or parental cohesion), which yields the order S -> UM -> HM. The dependent variables are the markers of attractiveness, etc. However, the functions do not always turn out to be monotonic -- some curves decrease and switch to increasing like a U. Table 2 in the article summarizes the rank-ordering on the 3 facial markers. For "attractiveness," the order is UM -> S -> HM. For "health," it's UM -> S = HM. And for "masculinity," it's UM = S -> HM. Thus, if our graph has "parental cohesion" on the x-axis, the curve would be U-shaped for "attractiveness" and "health," though J-shaped for "masculinity." For body shape, Figure 2 shows that one variable, "impedence" (a measure of % body fat), wasn't significantly different among the groups. "Waist-to-chest ratio" (WCR) is a measure of the inverted-triangle shape of the upper body, something that men don't pay much attention to. The two important variables are BMI and WHR. On the latter, HM had significantly more hourglass figures than UM, though the S didn't differ significantly from either. On BMI, the HM were significantly slimmer than S, and apparently UM are in between.

So, aside from perhaps BMI, the facial and bodily markers suggest that the underlying cause increases thusly: UM -> S -> HM. Call it "home harmony." The biological correlate of this in the literature the authors cite is response to stress (cortisol), so perhaps in the sample the daughters of UM parents experienced greater stress from the arguing, bickering, and so on, compared to the daughters of S parents, who at least weren't frequently fighting in the daughter's presence. Remember, the sample was of university students, so it likely didn't include those from the underclass or the lower end of the working class. That suggests that, above a certain threshold of SES, having antagonistic parents stay together produces more dissonance in the home than if they separated, at least from the daughter's p-o-v.

Now on to the possible causes. Well, the first is what I just mentioned: the prevailing view that differences among father absent or father present homes reflect differences in stress during childhood. Humans have evolved a common set of responses, and those who happen to grow up without fathers turn out a different way from those who grow up with fathers. This is an environment / chance explanation. But as mentioned at the lead author's webpage and in the comments at Dienekes' post, there is also a (not mutually exclusive) genetic explanation: fathers who are apt to easily leave their wife & children, or who are too unruly for the wife to bother staying with, could be this way in part due to genes (perhaps for response to testosterone) which they pass on to their daughters.

Moreover, since it's usually not impossible to read warning signs about who's less reliable & dependable than who else, we could also look at the mothers who mate with the more flight-prone males. Such females would likely show a greater propensity for risk-taking or thrill-seeking, presumably heritable, so assortative mating could be exacerbating the genetic influence of father. It would be interesting to take a large sample of males from S, UM, and HM parents and ask them who they were most attracted to among the S, UM, and HM female composite faces. That would settle whether there was an assortative mating effect. It would also be interesting to genotype those from S vs HM parents to see if the former were more likely than expectation to have the 7R allele at the DRD4 locus -- if so, that would suggest involvement of heritable personality traits like novelty-seeking, impulse control, and so on, in both the dissolution of the marriage as well as the suite of behavioral outcomes of the daughter. It might also suggest why the daughters of S parents were judged more attractive than those from UM parents -- presumably the S parents were more "wild child"-like than the UM parents who had to "wimp out" to some degree in suppressing their impulses to split up. Perhaps greater "wild child"-ness increases one's sexiness score (since "sexy" usually connotes something more exciting or thrilling than just "attractive" or "beautiful"). The prototype here would be Angelina Jolie, who looks more than a bit masculine, who's well known to be possessed of a thrill-seeking disposition, and whose parents divorced when she was a baby.

To close, why would a tinge (though not an excess) of masculinity and rebelliousness make a female sexier, when these usually serve to make males sexier? These traits mix a "danger" component with the "beauty" component, which creates the thrill. My hypothesis is that, assuming the "cheesecake theory" of aesthetic pleasure popularized in How the Mind Works -- that art, cuisine, etc. are human devices to directly stimulate our evolved pleasure centers -- we enjoy stimulating not just the "relaxation" (or parasympathetic) division of our nervous system, but occasionally the "danger" (or sympathetic) division as well. Things that highly stimulate these divisions are, respectively, the beautiful and the sublime in an older terminology. Those whose aesthetic preferences lead them to want more than others to stimulate their "danger" system would appreciate a greater dosage of dangerous, masculine traits in females. Rawrrr.

More obviously non-controversial research on cognition and sex differences, Differences in cue use and spatial memory in men and women:

Men and women differ in their ability to solve spatial problems. There are two possible proximate explanations for this: (i) men and women differ in the kind (and value) of information they use and/or (ii) their cognitive abilities differ with respect to spatial problems. Using a simple computerized task which could be solved either by choosing an object based on what it looked like, or by its location, we found that the women relied on the object's visual features to solve the task, while the men used both visual and location information. There were no differences between the sexes in memory for the visual features of the objects, but women were poorer than men at remembering the locations of objects.

Science is like a box of chocolates, you don't get to know the details until you start rooting through it. Major tables with p values below the fold.




"Although the men tested tended to be older than the women (one-way ANOVA: F1,45=2.94, p=0.09) and the two experimenters tested subjects of significantly different ages (F1,45=9.24, p=0.004; experimenter A's subjects: mean, 22.44 years; range, 21-24; experimenter B's subjects: mean, 21.41 years; range, 20-24), age was not correlated with performance on either task (controlling for sex and experimenter; feature: F1,43=1.36, p=0.25; location: F1,43=0.45, p=0.50). Therefore, the observed differences in performance between the men and women on the location task is unlikely to have been due to differences in their ages."





"One-sample t-tests were used to determine whether the number of times that the men and women chose the new location on the probe trials differed from random (i.e. a score of three). The choices of the men did not differ from random (n=20, t=0.42, p=0.68), but those of the women did (n=20, t=-3.33, p=0.004). Women chose the new location significantly less often than would be expected if they were making choices at random."

I've signed up for Clustrmaps before, but this weblog gets too many hits so it maxed out. This time I upgraded to the premium service and we shouldn't overtax it, so it is now there, above frappr.

A little while back, I mentioned epigenetics, noting that arrays for the detection of methylated sites in the genome are starting to become available. Recently released from The American Journal of Human Genetics is a new article that uses just that type of array to detect epigenetic variation in human sperm. what do they find? Here's the first paragraph of the discussion:

In this study, we performed an in-depth analysis to address the question of epigenetic variability in the germline. The main conclusions are that (1) the male germline exhibits locus-, cell-, and age-dependent DNA methylation differences and that (2) DNA methylation variation is significant across unrelated individuals, at a level that, by far, exceeds DNA sequence variation.

That is, different people carry different epigenetic information in their germline. The next question is clear-- does this information get tranmitted to the next generation?

In general, I had been under the impression that methylation was "cleaned" off the DNA after fertilization, but that's nothing but a general rule, and exceptions abound. If epigenetic information can be efficiently transmitted from parents to their children, that would be a huge--for the study of disease, for the study of genetic conflict, and for genetics in general. The authors of the article mention that the age of your father is a risk factor for schizophenia, and transgenerational effects on other traits have been seen before. Could this be the mechanism?

This sort of phenomenon could also raise some hairy policy issues-- imagine that we know smoking causes specific epigenetic changes that, if transmitted to a child, increase their risk of some disease. Would we then be justified in banning smoking by anyone who is fertile? Or what if smoking decreases the risk of some disease in your offspring? Would the tobacco companies get back all the money they've paid out in settlements?

Of course, I'm getting way ahead of myself-- no one knows how widespread the transmission of epigenetic variation will be. But this is fascinating stuff, and well worth keeping in mind...

Excellent review of the latest findings on sex influences and brain anatomy/functioning by Larry Cahill over at Nature Reviews - Neuroscience [open access]. One comment from Cahill:

A third, also related, misconception holds that the differences within a sex are much more substantial than those between the sexes, the implication being that sex influences can therefore be dismissed as trivial.

Now, where have I heard this (sort of) argument before...?

I was pointed to this research (via David) that is just out about the correlation between variation on DRD4 and "sexual arousal." From the press release:

Interestingly, some forms of variants in this gene were shown to have a depressing effect on sexual desire, arousal and function, while other common variant had the opposite effect - an increase in the sexual desire score. The latter is believed to be a relatively new mutation, and it is estimated that it appears in Homo sapiens "only" 50,000 years ago at the time of humankind's great exodus from Africa. Approximately 30% of many populations carry the heightened arousal mutations, while around 60% carry the depressant mutation.

In short, it seems like a very sexual orientation is a derived trait, while the ancestral character tends to be more "repressed." My first thought was that someone should forward this to Geoffrey Miller, his theories relating to sexual selection and cognitive evolution are predicated on weak pair-bonding and operational polyandry as males and females form temporary relationships which dissolve within 5 years after sexual novelty has expired (you need lots of reproductive skew to really ramp up sexual selection, and polygyny is the normal way to go about that). In contrast, other theorists, like pervert-cum-anthropologist Desmond Morris, have posited the importance of pair bonding and monogamy in the natural history of our species. The relatively trivial sexual dimorphism among humans (around 10%) between the sexes in terms of overall size and canine ratio suggests a more monogamous past, while the sperm competition research implies a more "mixed" picture (one problem is that the words do not really map onto to the full distribution well). The short of it is that monogamous species tend to be less "sexy" in many ways because they don't need to be, whether that be in behavior, display or semen volume (much of this costs resources and so can detract from fitness). The spread of a sexy variant within the last 50,000 years is very interesting, because it is within the last 50,000 years that the cultural explosion has erupted that made us more than just "anatomically modern" humans, that is, behavorially modern. Honestly, I would have guessed that the sexy variant was ancestral, but this data will surely result in new stories being told over the next few years if future research confirms and elaborates on it, because sex + evolution = mucho $$$ in terms of book sales.

The paper to published in Molecular Psychiatry is Polymorphisms in the dopamine D4 receptor gene (DRD4) contribute to individual differences in human sexual behavior: desire, arousal and sexual function. Click through and you will see why Jews are relevant, the study was done in Israel on university students, and found that particular DRD4 variants correlated with questionnaire responses. Is this generalizable to other populations?

Well, DRD4 has shown up elsewhere. For example, DRD4 promoter SNPs and gender effects on Extraversion in African Americans. And of course, there is the Harpending and Cochran review in PNAS, In our genes, which argues that the variation in the allele frequencies between populations is suggestive of their respective evolutionary histories.

I had some issues with figuring out their notation for the mutation, and the fact that I don't have full access to the journal article in question doesn't help, but here is a map from Alfred which shows regional variation at the promoter C/T mutation. On visual inspection I really don't have anything much to say in regards to the map and the allele frequencies (I assume that the C variant is associated with sexiness since it is in the minority). If any readers have access to the article I would suggest you might clear up of the extra-Israeli distributions of these variants as I wouldn't be surprised if it is mentioned in the discussion.

Addendum: Perhaps sexiness evolved to "spice" up the monogamous pair bond?

The American Journal of Human Genetics has a paper in its pre-print section titled "A geographically explicit genetic model of worldwide human settlement history." I quickly skimmed it (and uploaded it into the GNXP forum). I have serious issues some of the inferences made in regards to the "obvious" fit of such coalescence data with a particular demographic history. I am convinced that meta-population dynamics tend to be ignored (in part because they are just another complication) even though they can also explain the data. Nevertheless, this jumped out at me:

We further neglected key events such as spatial and temporal environmental variation. Our results thus suggest that various environmental factors tend to be spatially relatively homogenous for human migration patterns, when considered over a large geographic distance.

As I stated above, meta-population dynamics, local extinctions and recolonizations, are issues that the authors seem to ignore when it comes to ignore their there results, especially given that environmental parameters are likely to be very relevant to marginal groups. They even allude to what seems like an abortive extra-African colonization in the Levant by anatomically modern H. sapiens sapiens which ended in local population extinction. But, the idea that humans are relatively buffered from environmental variation is roughly correct, and I'm talking about "humans" in a very broad sense. Our genus, Homo, broke out of the African continent almost immediately after its genesis. Dmanisi shows that beyond a shadow of a doubt.

Thought this might be of interest: Brandon Berg, one of my co-conspirators at Catallarchy, wrote a post a while ago sketching out a possible way in which the decline in fertility rates might be overstated in the statistics that are commonly bandied about. The basic idea is that if the mean age of motherhood is increasing each year, the stats are likely to be skewed because of the way they're calculated (simple summing of the fertility rates for each age group). Now he's written a short follow-up demonstrating how sensitive the fertility numbers are to this effect. He suggests that the European fertility rates could realistically be understated by about 0.1-0.3, which is not huge but still significant.

Update: Related: Population Fallacies Part 2

A new study tracks the effects of alcohol drinking during each trimester of pregnancy for 636 mother-child pairs.

Light to moderate drinking during the second trimester led to the most pronounced cognitive deficits at age 10. The catch is the effect was found only for the African-Americans in the study and not for the white children, suggesting that race differences may make alcohol drinking more harmful for the babies of African-American mothers:

No such association was found for Caucasian children in the study. "This racial difference could not be explained by the amount or pattern of drinking during pregnancy or socioeconomic factors," [study chief Dr. Jennifer A.] Willford told Reuters Health. This suggests that genetics play a role in these racial differences, the investigators add.

Also:

"Our study also showed that prenatal alcohol exposure was associated with lower IQ for African-American but not Caucasian children, said Willford. "Importantly, we know that this racial difference was not due to differences in the amount or pattern of alcohol use during pregnancy or by differences in socioeconomic status. We cannot say why the racial difference exists, but laboratory animal and human studies show that it may be partly explained by genetic factors."

Levitt and Fryer type sophism using motor development scales aside, cognitive differences between African American and white children show up very early, and persist in a number of transracial adoption studies (I'm collecting this research into an Ebook that I'll release here on gnxp when it can be finished). So studies like this are at least getting warmer than "acting white" type mythologies.

The majority of cells in the nervous system are not neurons. They are glia. There are several subtypes of glia, one of which is astrocytes. Glia means glue. In general, people think of glia in their support role in the nervous system. Holding it together, disposing of waste and other menial tasks.

This little commentary here (pdf) in the current Cell describes a change in thinking that is occuring with regard to glia. They are stepping into a more active role. In this case, they modulate the ability of hypothalamic synapses to undergo plasticity. Compared to lactating rats, virgin rats have closer astrocyte encasement of synapses. The astrocytes release a chemical called D-serine into synapses that binds to a co-agonist site on NMDA receptors. NMDA receptor activation is considered the first checkpoint for increases in synaptic strength. More D-serine = more effective NMDA receptor activation.

In the study described, virgin rats have a lower threshold for LTP induction than do lactating rats. This is nicely illustrated below the fold.


So better glia encapsulation of synapses = more D-serine in synapses = more NMDAR activation = easier to undergo synaptic enhancement. This is in the hypothalamus mind you, not usually a major locus for memory studies. I'd like to see what's going on during these states in the hippocampus. For those of you interested in intelligence and Ashkenazis and all that business, you might note that the major abnormality of Einstein's brain was an greater glia to neuron ratio. I don't know what that means either.

Today's London Sunday Times has a good opinion piece by Simon Jenkins on global warming, here. My attitude is that we should leave our descendants to deal with their own problems, as they will be richer and better-informed than we are. Let us take decisions according to our own needs and priorities. But then I'm biased, as I've always disliked the 'doom-and-gloom' brigade, many of whom have a not-very-hidden anti-capitalist agenda.

This weeks Nature has a news article called "What is a gene?". Here's what they have to say:

In classical genetics, a gene was an abstract concept - a unit of inheritance that ferried a characteristic from parent to child. As biochemistry came into its own, those characteristics were associated with enzymes or proteins, one for each gene. And with the advent of molecular biology, genes became real, physical things - sequences of DNA which when converted into strands of so-called messenger RNA could be used as the basis for building their associated protein piece by piece. The great coiled DNA molecules of the chromosomes were seen as long strings on which gene sequences sat like discrete beads. This picture is still the working model for many scientists. But those at the forefront of genetic research see it as increasingly old-fashioned - a crude approximation that, at best, hides fascinating new complexities and, at worst, blinds its users to useful new paths of enquiry.

...

The one gene, one protein idea is coming under particular assault from researchers who are comprehensively extracting and analysing the RNA messages, or transcripts, manufactured by genomes, including the human and mouse genome. Researchers led by Thomas Gingeras at the company Affymetrix in Santa Clara, California, for example, recently studied all the transcripts from ten chromosomes across eight human cell lines and worked out precisely where on the chromosomes each of the transcripts came from. The picture these studies paint is one of mind-boggling complexity. Instead of discrete genes dutifully mass- producing identical RNA transcripts, a teeming mass of transcription converts many segments of the genome into multiple RNA ribbons of differing lengths. These ribbons can be generated from both strands of DNA, rather than from just one as was conventionally thought. Some of these transcripts come from regions of DNA previously identified as holding protein-coding genes. But many do not. "It's somewhat revolutionary," says Gingeras's colleague Phillip Kapranov. "We've come to the realization that the genome is full of overlapping transcripts."

...

Many scientists are now starting to think that the descriptions of proteins encoded in DNA know no borders — that each sequence reaches into the next and beyond. This idea will be one of the central points to emerge from the ENCODE project when its results are published later this year.

Remember, when this blows up, you heard it here first!

Willing to Do the Math: An Interview with David Botstein on PLoS Genetics

To interrupt your regular science programming, check out the back story on Miss "Poland." Turns out she is a washed-up Miss Venezuela, and that the reputed powerhouse of beauty contests has done some exporting before. Here is a gallery of the contestants for Miss Poland this year (not Kingdom of Saudi Arabia work safe, but since "work" in the KSA means letting some brown dude from brownland do everything I guess that's a dumb caveat). Hey, at least they didn't have to import from Japan to fill their babe quota because of a depauperate local environment :) (hat tip to Jaakkeli for the last link, who is associated with gnxp on the 6 out of the top 10 hits on google for his name)

Deadsmith dropped me another gem about a transcriptional profiling study in yeast getting a little more sugar. I will continue to share these with you until somebody tells me to stop. As before, any ire or accolades should be directed to him, as much as you can direct either one at a floating handle in cyberspace:

I really like the idea of studying things like cancer and Alzheimer's in things like yeast. Yeast are just so easy to do genetics on. I like things that are reliable and easy to work on (I also like 20 year old Toyotas).

Okay, just file the following away... I may not even come back to it today:

Despite the canonized pathways of metabolism in eukaryotes, notably yeast, there is still quite a bit about metabolism that is unknown. Metabolism is important for lots of things in biology, since biological organisms have energy requirements, but one particularly interesting aspect of metabolism for humans is how it changes in cancerous tissue. One of the hallmarks of tumor cells is the excessive metabolism of glucose, often the result of mutations that have left the glycolysis machinery running unattended.

There. Now onto another topic: transcriptional response to environmental changes in yeast.

Organisms, even unicellular ones, have to respond to their environment. They can do this in the short term by leveraging the proteins that comprise the cell against the problem (think heat shock proteins refolding proteins, for example). But if the stimulus is long-lasting, then the cell too needs a long-lasting response, and we generally start thinking about transcription of genes to make new RNA to, in turn, make new proteins to come to the aid of the cell in its hour(s) of need.

But the details of these responses have not been particularly well-studied, so today I review an attempt to perturb yeast cultures while monitoring their transcriptional and metabolic responses (pdf) that was published by the Botstein lab at Princeton University's Lewis-Sigler Institute for Integrative Genomics in collaboration with Michal Ronen, a graduate student-turned post-doc at Stanford. Botstein has long been tangled in the development of microarray technology and interpretation, so it's no surprise that this study teams the microarray with an old microbiology tool, the chemostat, to profile the transcriptional response of yeast to small doses of glucose.

The chemostat, for those unfamiliar, is a device that allows the steady-state growth of a microbial culture by continually adding nutrients and removing excess culture and byproduct. On a side note, the chemostat was invented by nuclear physicist Leo Szilard, Einstein's coauthor of the letter that kicked off the Manhattan Project (man, those guys all had night jobs!).

Anyway, the idea here is to grow yeast in a chemostat, and then give them a tiny little glob of glucose to metabolize, and see how they respond transcriptionally and metabolically. The transcriptional measurement was done by microarray, and the metabolic assay was as simple as looking at how long it took for the glucose to "go away" and the ethanol to show up. I say "go away" because there are two obvious ways for it to do so: 1) glucose could be dissipating through the chemostat, or 2) it could be metabolized by the yeast. Since it "goes away" much faster if there are yeast in the chemostat, and since ethanol shows up on the chemostat if yeast are there, it's safe to assume that the yeast are metabolizing the glucose to ethanol, as yeast are wont to do.

The interesting data, of course, is in the transcriptional response. The glucose doses came in one of two sizes: really small, and small. Both doses were too small to allow the cells to change in number (division) or size (growth without division), yet over the course of the next 3 hours (about one yeast cell cycle), 25% of genes changed expression at least 2 fold. Within minutes, there were dramatic expression differences, exhibiting the transcriptional response to the new carbon source, and over the remainder of the 3 hours measured, the RNA levels returned to their initial state in different modes.

Most of the genes behaved in a "burst response," meaning that their transcripts dropped dramatically, then climbed back to initial state levels. These included the galactose metabolism genes, TCA cycle genes, and interestingly, ribosomal genes.

The glucose metabolism genes, including both glycolysis and gluconeogenesis, both showed a "lasting response," though in opposite directions (glycolysis goes up and falls off slowly, gluconeogeneis goes down and comes up slowly).

A couple of genes, including the hexokinase genes, exhibited a bidirectional response, first dipping quickly, and then peaking well above baseline. These guys are known to work in a cross-regulatory circuit with MIG1 and RGT1. MIG1 is responsible for repressing the expression of gluconeogenesis and galactose genes, and is upregulated by glucose presence in the cell (all this is outlined in the diagram I’ve taken from pg. 391 of the article and posted below). RGT1, meanwhile, represses the hexokinase transporter, which is responsible for importing glucose into the cell. The point is, these genes are in a repression-oscillator circuit, and thus have a bidirectional response that generates a smooth combined effect for regulating the switch from glucose to alternative carbon sources.

They also quantified the iron chelators, but I don't really see the significance, and the signal was much shakier, so I'll say only that about them.

It's interesting to think about the transcript levels that fell quickly, as I went into this paper thinking that it was going to be about transcription, not degradation. The authors mention in the discussion that the half-life of a glycolysis RNA 3 times longer in a glucose-rich culture, and that begs for more investigation (since we also don't know jack about RNA degradation)[Coffee Mug note: we know a little about RNA degradation].

Using all this data on the levels of the RNA rise and fall of each group of genes, and knowing a bit about how each gene in the system regulates the system, the authors then construct a couple of basic differential equations to model the transcription factor activity (TFA) of some of the genes. It's important to realize that TFA is hard to measure directly, so if you can construct a good model of how you think it's working from the expression data, then you can create predictive groups of TFA by functionality. They did such grouping by functional annotations from the Gene Ontology database, and thus the end result was a set of mathematical classifiers for the types of transcription factor activity.

As with all things yeast, this looks like a model study for something bigger. There are tons of other ways to perturb yeast, but it might be possible to look at these basic sugar metabolism circuits and their regulatory profiles (and predictive transcription factor activity models) and look at other cell lines. Maybe human cell lines? Maybe human cell lines with abnormal TFA profiles? Gee, what kinda human cells have abnormal transcription factor activity? Any with abnormal TFA that involve glucose metabolism that we care about?

Hrmmm... It turns out that Botstein is interested in human disease, and I doubt this has escaped his attention, since I've seen him lecture on other ideas that involve studying cancer in yeast.

Peep the structure of a whole empire. - Malik B

I have a couple of nice papers here looking at the inter-relation between LTP, actin polymerization, and dendritic spine structure. They are both pretty dense, so I'll do a single post on this Fukazawa et al. paper (pdf) and then, with the conceptual junk already on board, its should be easy to present the information form this later study by Okamoto et al. The majority of excitatory synaptic transmission in the hippocampus occurs at dendritic spines. There appear to be specialized structural components on both the sending (pre-synaptic active zone) and receiving (spine, post-synaptic density) sides of a synapse that mediate efficient transmission. Modification of this structure provides a highly plausible mechanism for enhancing or diminishing the connection between two neurons in a lasting way.

There is an intimate relationship between the structure of the spine and actin polymerization within the spine. Actin is a cytoskeletal protein with the ability to form long filaments to which other proteins can bind and interact in complexes. It is really remarkable that actin forms in integral part of synaptic protein complexes and helps to determine structure considering that the actual subunits that make up an actin filament turnover really quickly. According to Fukazawa et al., over 80 percent of actin in dendritic spines turns over in less than a minute. This makes one have to shift perspective a little bit and deal with actin as a dynamic process. All of the things actin does when it forms filaments must be regulated by altering the rate of polymerization or depolymerization rather than by a single polymerization event that is maintained once organized.

Fukazawa et al. suggest a number of ways in which LTP might be realized through actin structure modification:

1. Change in spine morphology. Production of new spines or growth of spines in a manner that produces more synaptic contact.
2. Actin-regulation of endo- and exocytosis of AMPA receptors (the major receptor subtype in excitatory neurotransmission). Actin plays a direct role in the physical process of exocytosis, so changes in polymerization could affect how many receptors are in the synapses. It is fairly well accepted that increased synaptic AMPA receptor content is a key mechanism for LTP.
3. The actin cytoskeleton could serve as something like a railroad on which post-synaptic density proteins are trafficked up to the synapse. I suppose these proteins could also be AMPA receptors, but this is about getting them from the dendrite to the synapse rather that from the intracellular space to the cell membrane.
4. Since post-synaptic protein complexes often center around actin, the function of proteins that need to be in close proximity in those complexes to activate each other might depend heavily on the integrity of actin filaments. So turning polymerization up or down could affect activity levels of post-synaptic signaling molecules.
   

So the obvious questions are: How does actin change after LTP induction? And are these changes in actin necessary for LTP?

If this were a journal club talk I would be enjoined to get to the data already, but I have a couple more things you have to understand to get the paper, and I think it is interesting so you have to bear with me. In this Fukazawa et al. paper the LTP they are studying is actually done in a live animal. Most of the experiments involve inducing LTP via a specific pathway, and then staining the hippocampus to determine the state of actin. Actin can is found in two forms, globular (G-actin) and filamentous (F-actin). Death cap mushrooms make a poison called phallotoxin or phalloidin that binds to F-actin and not G-actin. The authors have phalloidin conjugated to a fluorescent molecule, so they can stain hippocampi and look for F-actin, indicating an increase in polymerization.

The other cool thing is the specificity of the pathways they are stimulating. LTP was induced either by stimulation of the medial (MPP) or lateral perforant path (LPP) which project from the medial (MEC) and lateral entorhinal cortices (LEC) respectively. Others have shown that the MEC is specialized for representing spatial information while the LEC is more responsible for the non-spatial input into the hippocampus. The potentials generated in the hippocampus by these inputs generate different types of traces. LPP potentials tend to take longer to peak and last longer. The LPP and MPP both synapse in the same subregion of the hippocampus, the dentate gyrus, but they synapse on different parts of the dendrites of dentate gyrus cells (the outer molecular layer (OML) and middle molecular layer (MML) respectively, shown below. The LPP input synapses on dendrites further away from the cell body than does the MPP input. I find this intriguing because I also recently read that spines far away from the soma have thinner necks and are less able to diffuse calcium that comes in through NMDA receptors. As we all know, calcium starts doing interesting things if it hangs out in a dendritic spine very long. On the other hand, where does the calcium that diffuses through a stubby-necked spine go…into the dendrite where it could influence protein synthesis? This generates all sorts of interesting ideas about how modulation of spatial input could influence plasticity at non-spatial synapses. Would spatial information be remembered in a longer-lasting but fuzzier manner than non-spatial information? Or would calcium influx due to spatial representation modulate the ability of dendritic potentials further away from the soma to induce action potentials?

Back to the paper. The initial set of experiments involved inducing LTP just through the MPP to alter the synapses in the middle molecular layer (MML) of the dentate gyrus on one side of the brain and looking at what happens to actin and spine structure. Here is just one picture of a hippocampus labeled with fluorescent phalloidin:

Note that things are much brighter particularly in the MML. The level of F-actin has increased in the input layer has increased 45 minutes after LTP induction. They go on to show that this increase is happening in dendritic spines. In parallel, the average length of synaptic apposition (basically how much contact between axon and spine) increases in the stimulated side of the hippocampus. One thing to note is that, at least at this early timepoint, the number of spines does not appear to change. Rather it is the structure of existing spines that is altered by LTP induction.

LTP can be induced to varying degrees with more or less high-frequency stimulation (HFS). In vivo LTP can last several weeks if induced with enough juice to begin with. Fukazawa et al. have short (HFS 90) and long-term (HFS 500) plasticity inducing protocols similar to E-LTP vs. L-LTP or LTP 1 vs. LTP 2 etc etc.. HFS 90 produces LTP that lasts around a day. The F-actin increase is observed 45 minutes after HFS 90, but not 1 week later. HFS 500 produces LTP and an F-actin increase that are still going strong a week later. Actually the F-actin increase is still there five weeks later, which is a substantial portion of a rat lifespan. The initial increase in F-actin is NMDA receptor dependent.

For long-lasting changes in synaptic strength, actin must be allowed to continually polymerize at a higher rate (or depolymerize at a slower rate). This change in polymerization rate is in part mediated by synthesis of new proteins since cycloheximide (a protein synthesis inhibitor) and latrunculin A (an actin polymerization inhibitor) have the same effect of allowing LTP that lasts up to 8 hours but blocking any longer-lasting changes.

The understanding of this process goes even deeper in this paper. The authors identify a particular promoter of actin depolymerization named ADF-cofilin that is negatively regulated by phosphorylation by a kinase called LIMK-1. That is, more LIMK-1 activity equals more actin polymerization (through a double-negative of regulation steps). The authors show that ADF-cofilin phosphorylation is higher in the stimulated side, and blocking this phosphorylation shortens the length of LTP.

I find this last little bit especially interesting because it allows me to integrate some information from the first paper showing microRNA regulation of neuronal processes in mammals. MicroRNAs are recently discovered short bits of non-coding RNA that specifically inhibit the translation (either through degradation or se