tag:blogger.com,1999:blog-9633767.post9177969587554306460..comments2024-03-18T06:11:04.848-07:00Comments on The Curious Wavefunction: Thinking about Alzheimer's Disease as HistoriansWavefunctionhttp://www.blogger.com/profile/14993805391653267639noreply@blogger.comBlogger10125tag:blogger.com,1999:blog-9633767.post-17409654482258793072008-10-07T05:54:00.000-07:002008-10-07T05:54:00.000-07:00On a related note, I completely share your sense o...On a related note, I completely share your sense of selfishness...Wavefunctionhttps://www.blogger.com/profile/14993805391653267639noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-3260373027012878082008-09-21T09:34:00.000-07:002008-09-21T09:34:00.000-07:00Retread, thanks for recounting the fascinating iro...Retread, thanks for recounting the fascinating iron wars. The affinity of sidereophores for iron is astronomical. It would be interesting if a similar scenario exists for copper. I also recall reading somewhere that our mucus membranes are rich in iron binding proteins; they work precisely to try to prevent bacteria from establishing a stronghold at these entry points.<BR/><BR/>TheChemist: It's pretty much whooshing around in my head too. Must...get...coffeeWavefunctionhttps://www.blogger.com/profile/14993805391653267639noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-76585861171275533952008-09-20T18:20:00.000-07:002008-09-20T18:20:00.000-07:00I admit my own reasons for wanting to see these di...I admit my own reasons for wanting to see these diseases go away are selfish in the extreme. I don't kno anyone who has died of a neurodegenerative disease (thankfully). Instead I worry more that I myself will succumb to one.<BR/><BR/>You obviously put a lot of thought into this, and I admit a lot of it just <I>whooshed</I> past me.The Chemisthttps://www.blogger.com/profile/15970398885870679916noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-46698304820099816292008-09-18T18:19:00.000-07:002008-09-18T18:19:00.000-07:00Your idea that a protein sopping up iron would be ...Your idea that a protein sopping up iron would be a defense against infection is quite correct, and a huge amount of work has been done on the thrust and parry over iron between man and bug. I think of what follows as the iron wars. <BR/><BR/> [ Cell vol. 116 pp. 15 - 24 '04 ] All microorganisms require an internal iron concentration in at least the microMolar range. However, iron is essentially insoluble (attoMolar). Bacteria secrete iron chelators with extremely high affinities (siderophores) to shuttle iron into themselves. The ability to acquire iron is a key determinant in establishing bacterial virulence in vivo. <BR/><BR/>Our innate immune system combats bacterial infection by iron depletion extracellularly. Components of the bacteriostatic system include lactoferrin and transferrin which sequester free iron. Other members release proteins that competitively bind siderophores (an antimissile defense if you wish).<BR/><BR/> [ Nature vol. 432 pp. 811 - 813 '04 ] The lipocalins are a large family of proteins. They vary in amino acid sequence but their 3 dimensional structures are similar. They are made of beta sheets forming a barrel or a cuplike structure to carry chemicals. Retinol binding protein is a lipocalin. Enterochelin, a major siderophore of bacteria, chelates iron with an incredibly high affinity (10^-49 ! ! ! ). Lipocalin2 binds to enterochelin with an affinity of 10^-10 molar. Lipocalin from human tears, binds to bacterial and fungal siderophores as well. Mice lacking the homolog of lipocalin 2 are very susceptible to bacterial infection. <BR/><BR/>Tomorrow -- why the amyloid better protect us outside the brain<BR/><BR/>RetreadAnonymousnoreply@blogger.comtag:blogger.com,1999:blog-9633767.post-38580730440810751662008-09-18T14:19:00.000-07:002008-09-18T14:19:00.000-07:00The CFTR and TB stories are both fascinating. Espe...The CFTR and TB stories are both fascinating. Especially CFTR with its six hundred mutations seems to be convoluted; I guess it's a little easier to unravel because of the 75% occurence with one mutations.<BR/>However I do think we shouldn't read too much into such coincidences. I am reminded of Stephen Jay Gould's excellent essay where he warns that what may look like adaptations to stimuli might just be "side-products" (his famous spandrels analogy)<BR/>http://ethomas.web.wesleyan.edu/wescourses/2004s/ees227/01/spandrels.html<BR/>It's very hard to predict what amount of evolutionary pressure might result in what adaptation. But it can be a useful way of thinking.<BR/>I need to think more about this. Keep up the information flow, thanksWavefunctionhttps://www.blogger.com/profile/14993805391653267639noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-88341236062148481362008-09-17T18:27:00.000-07:002008-09-17T18:27:00.000-07:00Great post -- lots of ideasDisease as defense agai...Great post -- lots of ideas<BR/><BR/>Disease as defense against infection -- the classic example is sickle cell anemia -- people with one copy of the sickle gene are protected against malaria, those with two get sickle cell anemia. However, the evolutionary defense against malaria has produced the more obscure disease of Thalassemia which also renders the red cell more resistant to the parasite -- and unlike sickle cell anemia there are many different forms of Thalassemia. <BR/><BR/>These are the best examples -- here are a few of the more controversial<BR/><BR/> [ Nature vol. 329 pp. 289 - 290 '97 ] The increased frequency of lysosomal storage diseases (Tay Sachs, Neimann Pick and Gaucher's) in Jews is thought to be enhanced resistance of the heterozygote to tuberculosis. The highest frequencies of the genes are found in Jews from areas with the highest rates of tuberculosis (Austria Hungary)<BR/> Two letters on this paper [ Nature vol. 331 p 666 '88 ] attacking and defending this idea. Death rates from tuberculosis were 1/254 from grandparents who were Tay Sachs heterozygotes, which is significantly lower than in those who were not carriers (10/356)<BR/><BR/>The most common hereditary disease of Caucasians is cystic fibrosis. [ Nature vol. 383 pp. 79 - 82 '98 ] An explanation of why mutations in CFTR should be so common (and why so many different mutations have arisen) -- Salmonella typhi uses the gene product to enter intestinal cells. Unlike sickle cell anemia in which one mutation is responsible Science vol. 301 p. 573 '03 -- over six HUNDRED different mutations in CFTR (the gene defective in cystic fibrosis) are known ! . This certainly looks like selective pressure to me. Nonetheless, just one mutation accounts for 75% of cases (a deletion of a codon (#508) for phenylalnine) -- interestingly this mutation prevents CFTR from reaching the cell surface (where bacteria can bind to it.<BR/><BR/>That's enough for now -- tomorrow -- the iron wars between humans and bacteria<BR/><BR/>RetreadAnonymousnoreply@blogger.comtag:blogger.com,1999:blog-9633767.post-76544130832687915272008-09-17T10:34:00.000-07:002008-09-17T10:34:00.000-07:00Hmm..I wonder if this could be of any help:doi:10....Hmm..I wonder if this could be of any help:<BR/>doi:10.1016/j.jphotochem.2006.05.004Wavefunctionhttps://www.blogger.com/profile/14993805391653267639noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-45883966859139553912008-09-16T13:09:00.000-07:002008-09-16T13:09:00.000-07:00Actually, it happened long before I was born.The a...Actually, it happened long before I was born.<BR/>The absorption spectrum for Congo Red looks fairly impressive. I wonder how well the sulfonic acid group would adhere to titania?Ψ*Ψhttps://www.blogger.com/profile/15089754859676425655noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-29051328860328394382008-09-16T12:08:00.000-07:002008-09-16T12:08:00.000-07:00Oh...I am sorry to hear that; it must have been ha...Oh...I am sorry to hear that; it must have been hard...<BR/><BR/>Actually some of the molecules that disrupt amyloid might interest you; they are flat, pretty and dead :) (like Congo Red)Wavefunctionhttps://www.blogger.com/profile/14993805391653267639noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-41674550882779519412008-09-16T10:20:00.000-07:002008-09-16T10:20:00.000-07:00I don't know enough about biology to shoot it down...I don't know enough about biology to shoot it down, but you have some really fascinating ideas here. (I have to hold a little interest in neurodegenerative diseases--my grandmother died of Pick's.)Ψ*Ψhttps://www.blogger.com/profile/15089754859676425655noreply@blogger.com