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Friday, June 30, 2006
Over at The American Scene Ross posts about the conundrum that many couples face when having to discard their excess embryos in the context of in vitro fertilization. He states:
I have basically argued before that the axiomatic arguments made by both sides are a sham. I do not deny that pro-life individuals sincerley believe that life begins at conception, but, I do question why if abortion is a "genocide" equivalent to the "holocaust" they not take up arms in a just war against this murder? Yes, I know there are ways you can "reason" against such violence in the name of a good cause, but I find such reasoning as persuasive as "penumbras" which suggest a "right" to "privacy" in the American Constitution. Ross is correct to note that couples do not view embryos as a "clump of cells," but neither does this imply that such attachment is equivalent to that that they would feel toward a 3 year old child. I would argue that "pro-life" sentiment is roughly proportional to the degree of resemblence of the embryo/fetus to a conventional human physiognomy. And I do not believe that all such sentiment derives from socialization, much of it is hard-wired into us. Over the past generation cognitive science has suggested that there are powerful biases in our mental hardware which constrains and shapes how we perceive the world. For example, it seems clear that we have primed hardware geared toward facial recognition. And, this might have moral implications. I offer this research to illustrate the thrust of my point:
Two points:
My rough argument is that unconscious intuitional inputs shape how people "reason" about moral questions. I am certain that pro-life activists can give you rational, cogent and axiomatically precise1 reasons for why they stand and protest outside clinics which they consider dens of murder as opposed to entering and tearing the doctors away from their death devices, by force if necessary. But, I believe that mental subprocesses in regards to analyzing and categorizing inputs as "human" or "non-human" have a strong role to play underlying the persuasiveness of a chain of reasoning. This argument can be inverted, there are obvious reasons then why pro-choice people flinch and are offended when they see photographs of aborted fetuses. They may intellectually assert that they were just a cluster of cells, but clearly they are made uncomfortable by the resemeblence between the fetus and a nenonate. By logic alone I would hold that pro-life individuals should kill all those who deal in death in the name of a greater good (the lives of innocents), while those who argue that fetuses are just a "clump of cells" should have no hesitation in using such tissue for dog food and the like. Does this speak to Ross' implication that we need to look beyond intuition and rely on reason? I guess I would say that in this case the reasoning is rather specious, insofar as a plain reading of personhood beginning at conception would imply rather drastic action which only a few pro-life individuals are willing to commit. The rhetoric and averred positions are, I believe, far more distinct than what you would excavate from their moral guts. Addendum: It is well known that many pre-Christian European cultures practiced infanticide. This is a human universal, there is a tendency for genuine emotional attachment in cultures where infant mortality is high and infanticide not unknown to be delayed until a considerable time after birth and even into toddlerhood. Sometimes this is explicated in the idea that personhood only emerges at a fixed point after birth (e.g., at age 3). One might make an analogy to the common conventions of when individuals have free will and are responsible for their actions. In Mormonism that age is 7. Among many Muslims it is believed that small children are like angels and incapable of genuine sin because they know not what they do. But in any case, my point is that Christianity banished infanticide. Or did it? In the 18th century many poor families in France sent their children to "orphanages." The mortality rates at these "orphanages" by the age of 5 could be as high as 95% (source: Mother Nature). So clearly, the Catholic French, no longer pagans, and in fact subjects of the most Christian King, believed that their children had souls and that their lives were sacred, so they did not kill them when they could not support them. The simply sent them to the orphanage where they would almost certainly die of neglect. My point is that Christian ideals were enforced while the brutish realities of human "rationality" continued. Also, check out Ross debating Matthew Yglesias debating on abortion. Go 2/3 ahead, I liked that Yglesias didn't concoct a fake a priori chain of reasoning. Though I think he would look more seemly with a shorter buzz cut. 1 - Please note that I mean mostly Catholics here. By the time evangelicals "noticed" the abortion issue the Catholics had elucidated most of the reasoned arguments against abortion so there was no need for them to generate their own. Please note in the book Catholicism and American Freedom there is documentation of the fact that the evangelical flagship magazine, Christianity Today, an article was published in the late 1960s that was cautiously hopeful about the trend toward reproductive freedom in the United States. Remember, Ronald Reagan was the one who signed legislation which decriminalized abortion in California in the 1960s.
As of this morning the journal Intelligence has a positive review of Lynn's Race Differences in Intelligence, from behavior geneticist John Loehlin. One issue raised earlier was the reliability of the numbers Lynn reports. Loehlin writes:
Are the numbers accurate? I checked a sample of 40 of the 615 rows in the IQ tables against their sources. . . Result: 14 of the 40, about 1 in 3, showed discrepancies, although mostly minor ones. For example, there were 9 with discrepancies in Ns, such as using an overall N from the study instead of the actual N on which the particular IQ was based. In a similar number of cases, the ages or age ranges were a bit off. . . my [IQ score] estimates and the values in the tables were typically within a couple of IQ points. I only came across one large discrepancy - an IQ 14 points too high (in Table 12.1, row 20; due, according to an e-mail from Lynn, to a clerical error in adding instead of subtracting a Flynn correction). The citations and references were, on the whole, accurate. In short: Yes, the general trends in the tables are probably dependable, if the assumptions regarding Flynn effects, etc., are correct, but it is prudent (as always) to check with original sources before quoting particular results. Loehlin concludes in a manner similar to my review: Is this book the final word on race differences in intelligence? Of course not. But Richard Lynn is a major player, and it is good to have his extensive work on this topic together in one place. Future workers who address these matters under this or any other label will find that Lynn has done a lot of spadework for them. And they will also find that there is plenty to ponder over within these pages.
I have a post on my other weblog where I'm asking about why mathematical disciplines tend to more conservative in academia. I know there are many references in JSTOR but I'm strapped for time, so could people please dump references into the comment box? I am especially interested in the psychometric finding (I've seen it!) that shows high IQ individuals stronger in math than verbal skills tend to be more conservative while the inverse are more liberal. Thanks ahead.
When looking for genes or alleles involved in a phenotype, especially "complex" phenotypes where many genetic factors are involved, the most powerful approach is often an association study-- type a large number of variants in some cases and some controls (or just a bunch of people if you're talking about a quantitive trait) and see if a certain variant is present more often in the cases than the controls.
As it's currently impractical to sequence a large number of genomes (and thus genotype all the possible genetic variants in the genome), one has to pick and choose which sites to genotype. Nowadays, the markers that are used are Single Nucleotide Polymorphisms (SNPs). But even with chips that can now type 500,000 SNPs in parallel, there's no way to genotype them all (there are an estimated 10 million SNPs in the genome). Plus, there are deletions, duplication, inversions, etc-- there are plenty of ways that two genomes can differ. Luckily, some SNPs are correlated with others, so that the genotype at one gives you information about the genotype at the other. So by typing 500,000 SNPs in a person, you could theoretically have information about the genotypes at millions of sites. The HapMap Project is an attempt to identify all the common SNPs in the genome and map the correlations between them. But as I noted before, there are also stuctural polymorphisms in the genome. An important question is: are there correlations between SNPs and structural polymorphisms? If there aren't, then doing an association study using only SNPs might miss a lot of the potential variation in the genome. Previous studies have shown that common deletions and SNPs are correlated. This is encouraging. However, a new study takes a closer look at some areas where copy number polymorphisms (i.e. one person might have three copies of the region, another person only two) are common, and finds that the variation is not very closely correlated with SNPs. This is less encouraging, as it means that it would be possible to do a full-genome association scan without taking into account any copy number variation in the sample. The authors present some possible reason for this lack of correlation, and I'm inclined to be optimistic-- most of the copy number polymorphisms they identify are rare, while the SNPs in the HapMap (especially the first version, which they use) are generally common. The correlation coefficient being highly dependant on the frequencies of the variants, it's possible that the newest version of the HapMap, or directed sequencing, could find better correlated SNPs. That said, if it turns out that structural polymorphisms aren't well-correlated with SNPs, it will be important to keep in mind-- perhaps SNP-based studies could be supplemented with assays designed to detect structural polymorphism.
Thursday, June 29, 2006
Rikurzhen has pointed us to this paper in press at Intelligence by the Minnesota psychometrician Wendy Johnson and her colleagues. This is actually the latest in a series of technical papers analyzing the mental test scores of the twins, spouses, and siblings (biological and adoptive) who took part in the Minnesota Study of Twins Reared Apart (see here, here, here, and here).
I think the results of the first paper in the series are worth briefly highlighting. The Minnesota group administered three different IQ batteries to their sample. It turns out that the respective g factors extracted from all batteries are almost perfectly correlated. This is strong evidence that the g factor extracted from any large and diverse battery of mental tests is an estimate of a one true g. A continuing theme of these papers is an attack on the Cattell-Horn-Carroll model of the structure of mental abilities. Rejecting the prominent distinction in this model between fluid and crystallized g, they favor a model first put forth by Sir Cyril Burt and Philip Vernon which posits a verbal-educational and spatial-mechnanical split in the stratum below g. I will try to sidestep this issue in my selective summary of their most recent paper. I do not think the background of this minor controversy is necessary to understand the topic of this post, which is sex differences. Johnson and her colleagues extracted four dimensions of variation from their data: (1) a unipolar domain-general mental ability, that is, our old friend g; (2) a bipolar verbal-image rotation dimension; (3) a bipolar focus-diffusion dimension; and (4) a unipolar memory ability. By "bipolar" is meant a trade-off; for example, after controlling for g, individuals who tend to do well on verbal tests tend to do poorly on image rotation. "Focus-diffusion" refers to a trade-off between the ability to concentrate attention on a particular task and the ability to maintain holistic sensitivity to an overall gestalt. Males showed a small and insignificant advantage on g amounting to about 2 IQ points. Males tended toward the image rotation end of the second dimension, females toward the verbal end. Males tended toward the focus end of the third dimension, females toward the diffusion end. Females showed a significant advantage in memory. I admit that I'm having trouble seeing how this factor structure is consistent with their overall model. For this reason I think the results are best conveyed by the sex differences in residual test scores after controlling for g. The following are some representative standardized sex differences in the residuals of the regressions on age and first principal component scores (an estimate of g factor scores) with positive values indicating a male advantage: Spelling: -0.657 Arithmetic: 0.528 Information: 0.393 Word Fluency: -0.636 Associative Memory: -0.415 Coding: -0.826 Picture Completion: 0.807 Picture Arrangement: 0.396 Mechanical Ability: 1.431 (!) Block Design: 0.478 Cubes: 0.752 Mental Rotation: 1.039 The WAIS tests (Arithmetic, Information, Coding, Picture Completion, Picture Arrangement, Block Design) are described in an earlier post. The lower-order factors below g showed significant heritability. Effects of shared environment, on the other hand, were dropped without significant deterioriation of model fit. This is yet another item of evidence that the environmental causal agents distinguishing the sexes in mental abilities, if any, do not resemble those that are said to distinguish one family from another.
Possible Asian "small penis" gene identified in Japanese sample
posted by Darth Quixote @ 6/29/2006 09:27:00 AM 
 
Jason Malloy has alerted us to an interesting 2003 paper by Sazaki et al. 81 Japanese patients with penis sizes 2 SD below Japanese age norms were genotyped at SRD5A2, which encodes an enzyme that converts testosterone to DHT. Deficient activity of this enzyme results in "various degrees of male pseudohermaphroditism." Three cases showed unusual mutations. One of these, a missense mutation severely reducing enzyme activity, was found in heterozygous condition in 2 of the 100 controls. (One of the special cases was homozygous for the mutation; the other two were heterozyous for the mutation and for additional mutations of the same gene. The three cases also failed to respond to testosterone enanthate treatment for penile lengthening, while responding positively to 5-alpha-DHT so that their penis lengths ended up at "nearly the average of age-matched Japanese controls.") Previous studies have found this mutation homozygous in two Vietnamese brothers with extremely small penises and heterozygous in 5 Chinese males after examination of an ethnically diverse group of 543 males. In the words of the authors, "[t]hese findings imply that R227Q [the missense mutation] may be relatively frequent in Asian populations."
It is perhaps worth pointing out that testosterone levels show a complex and as-yet poorly understood relationship to spatial ability (Pinker, 2002, ch. 18; see also the note here). The paper is available for free here.
Sex, Booze and Violence - Another tale from the Blank Slate
posted by dobeln @ 6/29/2006 07:06:00 AM
The Swedish government, a world leader in gender equity, decided last year to ban bars and restaurants from enforcing different ages of admittance for men and women. Up until then it was commonplace to allow women to enter at, say, age 20, while the men had to wait until they were 22 or so to get in.
Now, I know this will shock you all, but according to local police this exercise in equality has led to increased levels of violence in Stockholm. According to "Stockholm City": We noticed that violence went up last autumn, that's why we launched an inquiry. It shows that when bars have dropped age limits for guys, they admit these younger guys who can't handle alcohol very well, and then you have a fight on your hands, says Lars Lehman. Why, it's almost as if men and women were different or something!
Wednesday, June 28, 2006
I can't get enough Dinosaur Comics. This might be my favorite site on the internet.
T-Rex on: HeLa Cells, Thermodynamics, Genetics, Philosophy, Intelligent Design, and Science vs. Religion (prequel, 1, 2, and 3). OK, enough. Get back to work!
The March 2006 issue of Cytogenetic and Genome Research was entirely dedicated to genomic imprinting. I know some of y'all cats are into this business. There's one by Haig entitled Intragenomic Politics, and several on regulatory mechanisms which are more my speed, including one about small non-coding RNAs.
Of course, the articles aren't free, but perhaps arrangements could be made for the really important ones.
Tuesday, June 27, 2006
Every once in a while I realize something with my conscious mind that I've understood implicitly for a long time. Such a thing happened to me yesterday, while reading a post on Stalin, by Amritas. It is this: S = P + E Social Status equals Political Capital plus Economic Capital Now, if someone were to have just shown me that equation, I would probably have been unimpressed. It seems like a definition, a tautology, a pseudo-mathematical formulation of the expression "socioeconomic status". What I suddenly realized, though, is that this formula has tremendous explanatory power. So much so, that I want to call it the "Universal Law of Interpersonal Dynamics". Now, I am not a psychologist, sociologist, or anthropologist, and I am not familiar with the literature, so I don't claim that it's an original idea. I'm sure that such a thing must have be expounded upon by someone before me. But I'm a fairly well-educated person, and I've never encountered such a thing in any popular forum. Assuming that it more-or-less stands after it is posted, it deserves to be popularized. Here's an example of its explanatory power: If we assume that a major human drive is to maximize S, we can predict that people with high P will attempt to minimize the value of E (since S-maximization is a zero-sum game). And so we see. Throughout history there has been an attempt to ennoble P while stigmatizing E. Conversely, throughout history, people with high E use it to acquire P. Thus, in today's society we see that socially adept people, who have inborn P skills, tend to favor socialism or big government - where their skills are most valuable, while economically productive people are often frustrated by the fact that their concrete contribution to society is deplored. Now, you might ask yourself why the reverse isn't true, why people with high P don't use it to acquire E, while people with high E don't attempt to stigmatize P? Well, I think that is true. But, while the equation is mathematically symmetrical, the nature of P-talent and E-talent is not. P-talent can be used to acquire E from the E-adept, but the E-adept are no match for the P-adept in the attempt to stigmatize P. Furthermore, P is endogenous to the system, while E is exogenous. In other words, the P-adept have the ability to manipulate the system itself to make P-talent more valuable in acquiring E, while the E-adept have no ability to manipulate the external environment to make E-talent more valuable in acquiring P. Of course not all people fall neatly into one of these two categories. Some people are naturally both P-adept and E-adept, while others, unfortunately, are neither. This, too, is asymmetrical in its implications, since the both-adept have a choice of pursuing either P-strategies or E-strategies (indeed, there are many real-world applications which leverage both), but the neither-adept have no choice but to support a P-strategy, since cooperation of this kind is itself a P-strategy (libertarianism, by contrast, would get them neither P nor E). Put another way: Socialism is all about taking the "economic" out of "socioeconomic status", meaning that gaining social status becomes a purely political game. Which is why it appeals to both the socially adept and the economically inadept. They both hate status that is based on dirty economics. Those boors don't deserve it. Now, I don't think that this is a new phenomenon at all. Back in hunter-gatherer times, I have no doubt that there were already people who gained social status through P-strategies. But the social systems were so small, and the harsh economic realities to obvious, that it probably took a lot of political-talent units to equal one economic-talent unit. Now, however, societies are very large and complex, and the sources of economic productivity are not well-understood. The playing-field has tipped dramatically toward the socially adept, the merely economically adept now often, endearingly, termed "losers". I leave it as an exercise to the reader to show how the Universal Law of Interpersonal Dynamics predicts the following:
(Cross-posted on Rishon Rishon.)
While I'm recommending weblogs, I thought I'd point readers to Clark Gobles' Mormon Philosophy & Theology. Now, I know that most readers here aren't religious, and there is probably a mildly anti-philosophical bias as well, but, if you want to sample an "Intermontane" flavor of Derrida discourse, Clark is your man. Think of him as the Napoleon Dynamite of philosophy and cognitive psychology.
If you're at all interested in long-term potentiation (LTP) and long-term depression (LTD), you're going to want to read this review/opinion by Govindarajan, Kelleher, and Tonegawa in July's Nature Reviews Neuroscience. This team has previously written one of the best comprehensive reviews of neuronal translation control mechanisms. They do a brief reprise on that business, broadly suggesting which signaling molecules are involved and emphasizing that protein synthesis happens local to the stimulated synapses. Then they turn their attention to synaptic tagging/capture experiments for the bulk of the paper.
As some here must be sick of hearing by now, memories are likely to be stored as changes in synaptic weights. LTP and LTD are increases and decreases respectively in synaptic weight. The long-lasting (late) phases of LTP and LTD require protein synthesis. Govindarajan et al make the case that this is achieved by increased efficiency in general translation machinery. Synaptic tagging and cross-tagging experiments have shown that the proteins generated by a given L-LTP or L-LTD inducing stimulus can be captured by synapses that have only received E(early)-LTP or E-LTD inducing stimuli, thus producing late phase plasticity. Govindarajan et al note that transport speeds are known for important plasticity-related proteins, like AMPA receptor subunits, and that it would take them about an hour to move the length of your average dendritic branch. In tagging experiments, if L-LTP and E-LTP stimuli are separated by around this length of time, the capture of plasticity proteins does not occur. So they are suggesting that plasticity proteins are probably only shared within a dendritic branch, producing 'clusters' of synapses that have undergone long-term change. I'm not sure the transport speed issue is central to their theory or if you could simply argue that the generated proteins are degraded in that hour, but one prediction they didn't make that I think follows is that in cell populations with shorter dendritic branches you should see greater spread of these induced proteins or maybe a longer time window for capture, and vice versa. The clustered plasticity model carries advantages over a dispersed model where synapses are changed at more random sites across the neuron in part because stimulated synapses in the same dendritic branch sum supralinearly. The whole of the stimulation is greater than the sum of its parts. To get cells to fire in the dispersed model would take a lot more network activation than that in the clustered model. The authors argue that this has implications for ease of memory recall. I have an interest in trying to understand the relationship between broad-scale network activities like theta oscillations and sharp-wave ripples and the small scale on which plasticity is studied. There is a little bit about that in this review. ...assuming that connectivity between the set of presynaptic neurons and postsynaptic neurons is random, clustered plasticity would be advantageous compared with dispersed plasticity only if the density of active inputs is high enough to enable the setting of potentiation and depression tags at multiple synapses within at least one dendritic branch in the postsynaptic neuron. In support of this, 30-50% of hippocampal cells are active in a given environment, hippocampal activity resembles theta-burst stimulation, which has been used as a robust inducer of plasticity, and 45-75% of synapses are capable of undergoing plasticity. Therefore, in an episode (a sequence of related events; the hippocampus is important for acquiring memory of such sequences), it is probable that there is sufficient activation so as to result in many dendritic branches in the hippocampus containing multiple tagged synapses. The probability of this being the case is even higher when sharp waves are considered. In rats, it has recently been shown that sharp wave activity during exploration carries information about the environment explored by the animal. Furthermore, sharp wave-type activity would lead to high enough activity to enable activation of multiple synapses in a dendritic branch. I don't think this quite does it, but at least folks are starting to turn their attention to it. It's weird to try to make actual predictions about memory based on this hour timeframe of integration. Would a given dendritic branch represent events in about a two-hour window with a peak in the very middle? When a salient or unexpected event occurs that might drive neuromodulation and increase protein synthesis occurs, do events an hour on either side of that event benefit from the upregulation? How much time worth of events is integrated in a single sharp-wave ripple or compressed in a single theta oscillation? All I know now is about distances that are integrated and it seems like it is not an hour's of exploration.
Via Free Association comes a profile of Craig Venter, the so-called "maverick biologist".
1. Apparently Venter is going to be publishing his own genome sequence shortly and making it publicly available, which is pretty cool. If technically trivial, would you do the same? I'll go ahead and say I would--Venter makes the good point that we don't know what most of it does anyways, so GATTACA-like scenarios are far from being reality. And data is hard enough to come by as it is; I'd be happy to let other people play around with my genome sequence and see what they find. 2. The article makes some mention of the "race" to sequence the genome, and how it ended in a tie. I've explained before why that's BS: Venter and Celera published eventually published an independent genome sequence, but they didn't do it until 2004.
When I'm writin' I'm trapped in between the lines. I escape when I finish the rhyme. - Rakim
I wanted to go a little deeper into one of the new papers in the recent Cell. It is a set of findings in miRNA research that can be tangentially related to synaptic plasticity. For the field of miRNA research, this paper is important because it is one of the clearest examples of miRNA derepression. To date, in most examples of miRNA-mediated gene silencing the target RNA is moved to P bodies where it is eventually degraded. Why make all this RNA just to destroy it? Not to mention that the system would be a lot more flexible if new RNAs didn't have to be transcribed each time new proteins were needed. A couple papers have come out recently that show RNAs being released from repression in response to environmental signals, but this one proposes a distinct mechanism and examines the relationship with P bodies. Interestingly, the other two papers were both concerned with synaptic plasticity. The authors were able to find modular elements in the 3' UTR (untranslated region, a common area for regulatory elements in mRNA) of the cationic amino acid transporter 1 (CAT-1) mRNA that confer susceptibility to repression by a specific miRNA (miR-122) and derepression by interaction with a protein called HuR. These elements can act independently of the rest of the CAT-1 message. For instance, certain chunks of the 3' UTR can be attached to a glowy protein stolen from fireflies (luciferase) to make it a target for miR-122. They do a decent job mimicking the behavior of CAT-1 in a human hepatoma cell line in ideal growth conditions. Under less than ideal growth conditions, such as amino acid starvation, CAT-1 protein is upregulated within an hour while CAT-1 mRNA comes up in a range around 4 hours. So CAT-1 protein is regulated independently of the mRNA levels. The luciferase reporter constructs that only contain miR-122 binding sites are not affected in the starvation condition. Translation remains low. A further 1-kb of the CAT-1 3' UTR is needed for a protein increase in response to cellular stress. This chunk of UTR contains three adenine (A) and uracil (U) rich regions. These, like other AU-rich elements (AREs), interact with an RNA-binding protein called HuR. People have generally thought that Hu binding to AREs stabilized the RNA by blocking exonucleolytic degradation. The authors carried out binding assays and also measured the effect of each of these AREs independent of the others. They found that the strength of HuR binding to a particular ARE predicts the amount of stress-inducibility of a reporter with that ARE. Thus, the story so far is that miR-122 represses CAT-1 constitutively, but in response to certain environmental conditions, HuR becomes active and binds to elements downstream from the miRNA sites and derepresses CAT-1. Now, often when a miRNA binds its target they will both localize to cytoplasmic processing bodies (PBs). This is the case for CAT-1 and miR-122. Under normal conditions CAT-1 is found in PBs, but in response to starvation CAT-1 moves out of PBs and associates with polysomes (protein synthesis machinery). HuR binding to the AREs is necessary for this relocalization. The authors mention a preliminary finding that Ago2 (of Slicer fame) remains associated with CAT-1 when it relocalizes, but they show data that miR-122 abundance in PBs doesn't change. I find it a little difficult to square these two, as one would expect that the interaction of Ago2 and CAT-1 RNA would be mediated by the miRNA, but perhaps miR-122 is just so abundant that some of it can wander off with CAT-1 without making a dent. So HuR is little like a molecular Lee Marvin rescuing CAT from certain destruction (yes, I went there). The ability of HuR to do this even when the AREs are on a different RNA being repressed by a different miRNA makes the mechanism seem more general. HuR is part of a family of proteins called ELAV-like RNA-binding or Hu proteins, some of which (HuB, HuC, and HuD) are neuron-specific. Research into regulation of neuronal proteins by these Hu proteins goes back several years now and has focused on regulation of a protein called GAP-43. GAP-43 is associated with axonal growth during development and is phosphorylated by protein kinase C (PKC) in response to LTP induction. It is not entirely clear what GAP-43 does at a mechanistic level yet, but the vague impression is that when GAP-43 is involved axons are growing and establishing new connections. I find it interesting that PKC may be regulating GAP-43 at more than one level. PKC can directly phosphorylate GAP-43 which leads to a number of changes in intracellular and membrane signaling. PKC activation also leads to upregulation of all three neuron-specific Hu family proteins. These proteins in turn stabilize GAP-43 mRNA and lead to GAP-43 protein increase. Hu proteins and GAP-43 are regulated in response to hippocampus-dependent learning tasks too. Abstract: Increase of the RNA-binding protein HuD and posttranscriptional up-regulation of the GAP-43 gene during spatial memory The Morris water maze is one of the most common behavioral tasks used to assess hippocampal function in rodents. It is assumed that the animals are learning to navigate in a two-dimensional space using distal cues to create a cognitive map. All of this should make synaptic changes in the hippocampus. Others have shown directly using zinc staining that over-training on the water maze task can actually lead to axonal growth into new layers of the hippocampus, which is a major structural change that may well contribute to permanent memory storage. I guess what I'm saying is that GAP-43 is probably a good candidate for a memory-related molecule that is regulated by miRNAs. If I had the bioinformatics know-how I would go look up the potential miRNA binding sites in GAP-43's 3' UTR. Then I would look to see if they had similar distance from the AREs in GAP-43's 3' UTR as they do in CAT-1. Then I would stretch and see if other proteins that have similar function to GAP-43 and share conserved sequences such as MARCKS and Neurogranin also have these sorts of motifs. These guys are also regulated in response to synaptic plasticity, and I think it would be really cool if they were regulated in coordination by Hu proteins derepressing the same miRNA. MARCKS has a CU-rich element that is recognized by HuD and HuR. I'm really thinking that miRNAs, since they don't have to be specific, could regulate protein modules, so GAP-43 and MARCKS could share the same miRNA. Here are a couple other interesting things that I haven't really integrated. Recently, a SNP in a human neuron-specific Hu protein (ELAVL4) was associated with age-at-onset of Parkinson's disease. Also, HuD and HuR appear to regulate acetylcholinesterase through an ARE in its 3' UTR. 1 in 20 human genes have AU-rich elements, so just tying things together with AREs isn't going to be enough, but if things had AREs and similar miRNA-binding sites I could see room for coordination.
Monday, June 26, 2006
Well, pretty soon Craig Newmark's cherubic visage is going to be on Time. Craig's List is expanding and taking over the world.
So, the numbers of "personals" posted in Sweden's Craig's List: 131. Finland? 34. As for the debate about which is the "gay capital of Europe" between partisans of Stockholm & Helsinki: Men seeking men in Stockholm: 13 Men seeking men in Helsinki: 1 (and I think this is a bisexual individual?) Are Finns even terrified of the internet? It seems that they are proto-Solarians. (note, Finland's total fertility rate is a bit higher than Sweden's).
If you're a pseudo-intellectual such as myself who gets tired of reading all the time but still wants to be able to pretend to be familiar with the great thinkers and major political figures of our time, you may be interested to find that many episodes of Charlie Rose are available for free on Google Video right now.
I have thus far been entertained and educated watching Milton Friedman, Bashar Al-Assad (President of Syria), Salman Rushdie and Deepa Mehta, and Shirin Neshat.
Half Sigma has piqued my interest of late. He makes really bold claims, above and beyond what a cautious reading of data might imply, but, at least he consults the data. That's more than can be said for most political blogging, which seems to draw from the bullshit of the heart. Inductivist is worth a go too (seem's that he's Half Sigma's GSS dealer that started him on the habit). Some of the sample sizes are way too small for my taste, but at least they deal in samples which have an N you can criticize. Read them like you'd read Peter Gammons (I never liked Gammons actually, I was always a Dick Schaap Sport's Reporters kind of guy, but Schaap is dead and I don't have a TV).
Before you read this, check out Razib's excellent 10 questions with Jim Crow, which I am unfortunately knocking off the top of the blog.
So a little while back, I wrote about a paper describing the evolution of a bacteria over the course of an infection (Aetiology also had a post--a better one, truth be told-- on the same paper). I speculated that different individuals might present different environments for the bacteria, thus presenting slightly different selective pressures. Moving up one level, one could imagine two populations being different genetically, so a pathogen could in theory adapt differently to life being passed around in the two. But does this happen? A new paper suggests that the answer is yes. The authors analyse HIV sequences from a couple genes isolated from individuals in two different African populations. From the sequences, they determine which codons are under selection in the different populations, and come up with seven amino acid sites under differential selection. They link this to the different genetics (especially genetics of the immune response) of the two groups. I certainly find that plausible, but I think there's certainly another possibility here: essentially, there's more than one way to skin a cat. We're talking about differential selection at the level of a single codon and assuming that the differential selection reflects differential selective pressures in the populations. But maybe the different virus populations just came across different, yet equivalent, ways to adapt to the same selective pressures. That is, maybe we're just seeing an example of the stochasticity of evolution.
James F. Crow is Professor Emeritus of Genetics at the University of Wisconsin. A collaborator with Motoo Kimura on Neutral Theory, he remains an active member of the evolutionary genetics community. 1) In 2002 in "Perspective: Here's to Fisher, additive genetic variance, and the fundamental theorem of natural selection," you conclude, "is there any other quantity that captures so much evolutionary meaning in such a simple way?" in reference to additive genetic variance. And yet, what about other factors like statistical epistasis? Do gene-gene interactions pack enough of an evolutionary punch to be anything more than a footnote in God's Book? Have you seen Loren Rieseberg's work at Indiana which points to the importance of loci of large effect? The remarkable thing about additive genetic variance is that it predicts the effect of selection, even in the presence of dominance and epistasis. Nature seems to follow least-squares principles. The result is that the additive component of variance pulls out of dominance and epistatic variance those components associated with allele frequency change under selection. Of course the theory is not exact, but it is a very good first approximation. Fisher did not ignore epistasis, as some have said; rather he showed how selection can utilize epistatic (and dominance) components of variance. On a more technical level, Kimura showed that under selection with loose linkage the population rather soon attains a state in which the linkage-disequilibrium variance approximately cancels the epistatic variance. Thus, under this circumstance the effects of selection are better predicted by ignoring additive by additive epistatic variance than by including it. See my book with Kimura ( |
