The extended mind/cognition hypothesis is that objects in our environments can literally become part of our cognition. This has numerous implications for how we should be doing psychology and neuroscience, but the argument is currently most robust in the philosophy of mind literature. Two staunch critics are Adams & Aizawa, who claim the hypothesis is grounded in a fallacy.... Read more »
In the following I summarize the major points of the article "Responsive supply chain: A competitive strategy in a networked economy" by Gunasekaran, Lai and Cheng (2008).
Responsive Supply Chain (RSC)
The authors define a RSC to contain both aspects of Agile Manufacturing and Supply Chain Management. They argue, that both complement each other in the objective to improve organizational competitiveness.
The concept of SCM, Agile manufacturing and RSC can be compared as follows:
Comparison of Supply Chain Concepts (Source: Gunasekaran et al. 2008) Building Blocks
The framework consists of these major building blocks:Strategic PlanningFocus on Strategic Alliances, global sourcing and TechnologyVirtual EnterpriseThe framework is especially based on the concept of the Virtual Enterprise, where companies specialize their core competencies and focus on their network of supply and demand side partner companies. To achieve this the planning processes have to be intensively IT supported.Knowledge and IT managementAutomation and IT play a dominant role in the development of a physically distributed or virtual enterprise. The most important elements for IT support are: strategy formulation, tactical management, operations control and systems
According to the authors "The proposed framework can be employed as a competitive strategy in a networked economy in which customized products/services are produced with virtual organizations and exchanged using e-commerce."
Framework for a Responsive Supply Chain (Source: Gunasekaran et al. 2008)
I found one major drawback of this paper: The presentation is not what you should expect from an A-journal paper. Sometimes the content of the paragraphs does not match the caption (Caption: Strategic Planning, Content: the virtual enterprise), furthermore the literature review feels like a succession of short abstracts of papers, without obvious connection between each of them.
Gunasekaran, A., Lai, K., & Cheng, T. C. E. (2008). Responsive supply chain: A competitive strategy in a networked economy☆ Omega, 36 (4), 549-564 DOI: 10.1016/j.omega.2006.12.002
... Read more »
Gunasekaran, A., Lai, K., & Cheng, T. C. E. (2008) Responsive supply chain: A competitive strategy in a networked economy☆. Omega, 36(4), 549-564. DOI: 10.1016/j.omega.2006.12.002
Although ovarian clear cell carcinoma does not respondwell to conventional platinum–taxane chemotherapyfor ovarian carcinoma, this remainsthe adjuvant treatment of choice, because effectivealternatives have not been identified.This sentence is a depressing reminder of the status of medical treatment of far too many tumor types. Present in roughly 12% of U.S. ovarian cancer cases, ovarian clear cell carcinoma (OCCC) is a dreadful diagnosis.Two papers this week made a significant step forward in understanding the molecular basis -- and heterogeneity -- of this horror. Seemingly the finale of an old-fashioned race to publish, groups centered at the British Columbia Cancer Center (in New England Journal of Medicine) and Johns Hopkins University (in Science) published papers with the same headline finding: inactivating mutations in the chromatin regulating gene ARID1A (whose gene product is known as BAF250) are a key step in many -- but not all -- OCCC. I'll use the shorthand Vancouver and Baltimore to refer to the respective groups.Both papers got here by the largest applications of second generation sequencing to cancer so far published. The Vancouver work relied on transcriptome sequencing (RNA-Seq) of a discovery cohort of 18 patients; the Baltimore group used hybridization targeted exome sequencing on just 8 patients. Both used Illumina paired-end sequencing for the discovery phase; Vancouver also used the same platform for validation on a larger cohort.Whole genome sequencing is likely the future for cancer genomics. A non-cancer paper just published 20 genomes in one shot, underscoring how this is becoming routine with easy samples & a work which is apparently in press (I have no inside knowledge; it has been discussed at several public meetings) will have perhaps a dozen human genomes in it. But, there are still cost advantages to focusing on expressed genetic regions (and perhaps a bit more) and perhaps further information to be gleaned from actually looking a gene expression. These two papers give an opportunity, albeit a bit constrained, to compare the two approaches. One interesting note comes straight out of the Vancouver data. After finding ARID1A mutations in 6/18 discovery samples, they re-screened those samples plus 211 additional samples. In total this set included 1 OCCC cell line, 119 OCCC, 33 endometrioid carcinomas and 76 high-grade serous carcinomas. The validation screen was by long-range PCR (mean product size 2067 bp) products sheared and sequenced on the Illumina. One exon proved troublesome and required further PCR and sequencing by Sanger. In any case, the key bit here is in the discovery cohort this approach found ARID1A mutations which had been missed by the original RNA-Seq. As the authors state, a likely culprit is nonsense mediated decay (NMD). It would be interesting to go into their dataset to see if these samples had a markedly lower expression of ARID1A, though I don't have easy access to it (it has been deposited, but with protections that should be the subject of a future post).One interesting contrast between the two studies is the haul of genes. The Vancouver group found ARID1A as a recurrently mutated gene; the Hopkins group not only bagged ARID1A but also KRAS, PIK3CA and PPP2R1A. KRAS and PIK3CA are well-known oncogenes in multiple tumor types and had previously been implicated in OCCC, but PP2R1A is a novel find. The Vancouver group did specifically search for KRAS and PIK3CA mutants in their cohorts by PCR assays and found one patient sample and one cell line with KRAS mutations. Again, it would be interesting to review the RNA-Seq data to generate hypotheses as to why these were not found in the Vancouver set. On the other hand, the RNA-Seq data did identify one case of a rearranged ARID1A. While it is possible to use hybridization capture to identify gene fusions, this cannot be practically done in a hypothesis-free manner. In other words, without advance interest in ARID1A that approach would not work. In addition, CTTNB1 (beta catenin) mutations had been found previously in OCCC and were specifically checked (and found) by the Vancouver group, but none were reported by the Baltimore group. One final small discrepancy: both groups looked at cell line TOV21G for their mutations of interest and both found the same activating KRAS and PIK3CA alleles. However, Vancouver found one ARID1A allele but Baltimore found that one and a second one (actually, the two mutations I am calling the same [1645insC and 1650dupC] aren't described precisely the same, though I'm guessing it is a difference in an ambiguous alignment).One other surprise is that TP53 (p53) and PTEN mutants had apparently been reported either for OCCC or endometriosis-associated tumors, yet neither group reported any. An analysis that is not explicitly found in either paper but I feel is valuable is to look at the co-occurrence of these mutations. If we look only at patient samples, then the big take-home is that neither group saw co-occurrence of KRAS and ARID1A (the TOV21G cell line is at odds with this conclusion). Mutually-exclusive mutations have been seen in many tumors. For example, KRAS mutations are generally mutually-exclusive with other mutations in the RTK-RAS-RAF-MAPK pathway. In contrast, ARID1A mutations are found in conjunction with mutations in CTTNB1, PIK3CA and PPP2R1A -- one patient sample in the Baltimore data was even triple mutant for ARID1A, PIK3CA and PPP2R1A. About 30-40% of sample are mutated for none of these genes as far as this data can tell; the hunt for further causes will continue. Will they be epigenetic? Mutations in regulatory elements?Another interesting comparison is simply the number of mutations per sample. The Hopkins exome data typically has very small numbers of mutations (after filtering out germ line variants); as few as 13 in a sample and as many as 125 -- and the high number was from a tumor which had previously been treated with DNA-damaging agents (all of the other tumors in the Hopkins study were treatment naive). In contrast, the Vancouver data often found more than 1000 non-synonymous variants per tumor. Unfortunately, no clinical history information is available for the Vancouver cohort, so we don't know if this is from DNA-damaging therapeutics or differences in the sequencing or variant filtering. In an ideal world, we could filter each data set with the other group's filtering scheme to see how much of an effect that would have.The Vancouver group went beyond sequencing to examine samples by immunohistochemistry (IHC) for expression of the ARID1A gene product, BAF250. There is a strong, but imperfect, negative correlation between mutations and BAF250 expression. Some mutated but BAF250-expressing samples may be explained by the target of the antibody; the truncated forms may still express the correct epitope. Alternatively, ovarian cells may be very sensitive to the dosage of this gene product (in some samples both wt and mutant alleles were clearly found in the RNA-Seq data). Also of interest will be samples lacking expression but unmutated; these may be the places to identify further mechanisms for tumors to eliminate BAF250 expression. The Vancouver study illustrates one additional bonus from RNA-Seq data: a list (in the supplemental data) of genes differentially expressed between ARID1A mutant and ARID1A wild-type cells.Another interesting bit from the Vancouver paper is looking at two cases in which the tumor was adjacent to endometrial tissue. In one of these, the same truncating mutation was found in the adjacent lesion and tumor -- but not in a distant endrometriosis. Hence, the mutation was not driving the endometriosis but occurred afterwards.I'm sure I'm short-shrifting further details from the paper; there's a lot of data packed in these two reports. But, what will it all mean for ovarian cancer patients? Alas, none of the genes save PIK3CA are obvious druggable targets. PIK3CA encodes the alpha isoform of PI3 kinase, a target many companies are working on. But that wasn't novel to these papers. PP2R1A is a regulatory subunit of a protein phosphatase and the mutations are concentrated on a single amino acid, suggesting these are activating mutations (as seen in ARID1A, inactivating mutations can sprawl all over a gene). Phosphatases have not been a productive source of drugs in the past, but perhaps that can be changed in the future. Chromatin regulation is a hot topic, but ARID1A is deficient here, not active. Given that tumors can apparently live with two mutated copies, the idea of further inactivating complexes with ARID1A mutations is probably not a profitable one. But, perhaps there is a ying-yang relationship with another chromatin regulator which can be leveraged. In other words, perhaps inhibiting an opposing complex could restore balance to the cell's chromatin regulation and inhibit the tumor. That's the sort of work which can build off of the foundation these two cancer genomics papers have provided. ... Read more »
Kimberly C. Wiegand, Sohrab P. Shah, Osama M. Al-Agha, Yongjun Zhao, Kane Tse, Thomas Zeng, Janine Senz, Melissa K. McConechy, Michael S. Anglesio, Steve E. Kalloger, Winnie Yang, Alireza Heravi-Moussavi, Ryan Giuliany,Christine Chow, John Fee, Abdalnas. (2010) ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas. New England Journal of Medicine. info:/10.1056/NEJMoa1008433
Jones S, Wang TL, Shih IM, Mao TL, Nakayama K, Roden R, Glas R, Slamon D, Diaz LA Jr, Vogelstein B.... (2010) Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma. Science (New York, N.Y.). PMID: 20826764
by Kimie Takahashi 高橋君江 in Language on the Move
The latest issue of Cross-Cultural Studies (published by the Center for Cross Cultural Studies, Hyung Hee University, Korea) includes an article about the dark side of TESOL authored by Ingrid Piller, Kimie Takahashi, and Yukinori Watanabe. Based on case studies from … Continue reading →... Read more »
Ingrid Piller, Kimie Takahashi, & Yukinori Watanabe. (2010) The Dark Side of TESOL: The Hidden Costs of the Consumption of English. Cross-Cultural Studies, 183-201. info:/
David Goldstein (Duke University, United States) and coworkers report steps towards unraveling the extent of human genetic variation, useful for directing medical effort towards genes critical to life. This news feature was written on September 12, 2010.... Read more »
Pelak, K., Shianna, K. V., Ge, D., Maia, J. M., Zhu, M., Smith, J. P., Cirulli, E. T., Fellay, J., Dickson, S. P., Gumbs, C. E.... (2010) The Characterization of Twenty Sequenced Human Genomes. PLoS Genetics, 6(9). DOI: 10.1371/journal.pgen.1001111
Original image here. Sea slugs are far more interesting than their name might imply. Aside from being beautiful, they have some unusual ways of making a living. In the case of a few unrelated species, they steal for a living. A handful of sea slugs have found away to make the most of the algae [...]... Read more »
Rumpho ME, Worful JM, Lee J, Kannan K, Tyler MS, Bhattacharya D, Moustafa A, & Manhart JR. (2008) Horizontal gene transfer of the algal nuclear gene psbO to the photosynthetic sea slug Elysia chlorotica. Proceedings of the National Academy of Sciences of the United States of America, 105(46), 17867-71. PMID: 19004808
Wagele, H., Deusch, O., Handeler, K., Martin, R., Schmitt, V., Christa, G., Pinzger, B., Gould, S., Dagan, T., Klussmann-Kolb, A.... (2010) Transcriptomic evidence that longevity of acquired plastids in the photosynthetic slugs Elysia timida and Plakobrachus ocellatus does not entail lateral transfer of algal nuclear genes. Molecular Biology and Evolution. DOI: 10.1093/molbev/msq239
The SGM autumn conference is now over - thanks to everyone who tweeted it so people like me could catch up on events without actually going. I've just got two more topics of my own little personal blog-conference to go, and this one is going to be on bacterial vesicles rather than secondary metabolism because it suddenly struck me that I don't actually know much about outer membrane vesicles, and this might be a good opportunity to explore them.So this is the penultimate post in my SGM topic series: Bacterial vesicles.The first thing to note about them is that they only form in Gram negative bacteria, which have an outer membrane covering a small glycopeptide layer (Gram positive bacteria have no outer membrane and a very large glycopeptide layer). The top layer simple peels off into a little vesicle, taking periplasmic proteins with it, as shown below:The mechanism for vesicle formation is largely unknown, but it is found in both pathogenic and non-pathogenic strains of bacteria, and used for several different purposes. In pathogenic bacteria the vesicles often contain virulence factors, which can destroy or damage host cells. in the wild, they may also bind to or destroy other bacteria. In less-virulent strains they have been shown to act as a method of removing misformed or unwanted proteins from the periplasmic space (the space between the two membranes). They can also play a part in antibiotic resistance, it's not yet certain how but my guess is that they pump the antibiotic into the periplasmic space then vesicle it off to stop it just diffusing back in again.When first discovered, the vesicles were thought to be a by-product of bacterial death, after all, why else would little bits of membrane with bacterial proteins inside be found floating around a large colony? However work done on pathogenic bacteria (which get more funding) and biopsies of infected tissues showed the vesicles playing an important part in infection. They are produced during the stationary phase of growth, the same period when bacteria start to produce most of their virulence factors and secondary metabolites. In an infected organism, this phase is after the bacteria has set off an inflammation reaction, and once it has multiplied in the site of infection. Factors that affect the formation of vesicles include oxygen stress, the availability of iron (finding a regular iron source inside human bodies is a regular problem for bacteria) and the composition of the outer membrane (suggesting that at least some of the mechanism is mechanical). It is a ubiquitous process carried out across a range of Gram negative species.As well as being used offensively, some vesicles were also shown to carry DNA between bacteria, although it's not at all clear how, or how the DNA gets into the periplasm in the first place. P. aeruginosa are also capible of transferring antibiotic resistant enzmyes between bacterial cell using the vesicles. This is not totally an act of complete altruism, as P. aeruginosa carries out much of it's infectious cycle as a biofilm, which requires lots of cells to form.As I said, the actually mechanism for the formation of the vesicles is not yet established, so there's probably quite a lot of work to do with imaging their formation, genetics to find out any genes involved, and a mixture of genetics and protein work to discover more about what goes inside the vesicles. It looks like an interesting area of research, with the potential for some quite amazing imagery-work, and I look forward to reading more about it.---Kuehn MJ, & Kesty NC (2005). Bacterial outer membrane vesicles and the host-pathogen interaction. Genes & development, 19 (22), 2645-55 PMID: 16291643... Read more »
Kuehn MJ, & Kesty NC. (2005) Bacterial outer membrane vesicles and the host-pathogen interaction. Genes , 19(22), 2645-55. PMID: 16291643
How mature are you? Have you ever wanted to find out, with a 5 minute brain scan? Of course you have. And now you can, thanks to a new Science paper, Prediction of Individual Brain Maturity Using fMRI.This is another clever application of the support vector machine (SVM) method, which I've written about previously, most recently regarding "the brain scan to diagnose autism". An SVM is a machine learning algorithm: give it a bunch of data, and it'll find patterns in it.In this case, the input data was brain scans from children, teenagers and adults, and the corresponding ages of each brain. The pattern the SVM was asked to find was the relationship between age and some complex set of parameters about the brain.The scan was resting state functional connectivity fMRI. This measures the degree to which different areas of the brain tend to activate or deactivate together while you're just lying there (hence "resting"). A high connectivity between two regions means that they're probably "talking to each other", although not necessarily directly.It worked fairly well:Out of 238 people aged 7 to 30, the SVM was able to "predict" age pretty nicely on the basis of the resting state scan. This graph shows chronological age against predicted brain age (or "fcMI" as they call it). The correlation is strong: r2=0.55.The authors then tested it on two other large datasets: one was resting state, but conducted on a less powerful scanner (1.5T vs 3.0T) (n=195), and the other was not designed as a resting state scan at all, but did happen to include some resting state-like data (n=186). Despite the fact that these data were, therefore, very different to the original dataset, the SVM was able to predict age with r2 over 0.5 as well.*What use would this be? Well, good question. It would be all too easy to, say, find a scan of your colleague's brain, run it through the Mature-O-Meter, and announce with glee that they have a neurological age of 12, which explains a lot. For example.However, while this would be funny, it wouldn't necessarily tell you anything about them. We already know everyone's neurological age. It's... their age. Your brain is an old as you are. These data raise the interesting possibility that people with a higher Maturity Index, for their age, are actually more "mature" people, whatever that means. But that might not be true at all. We'll have to wait and see.How does this help us to understand the brain? An SVM is an incredibly powerful mathematical tool for detecting non-linear correlations in complex data. But just running an SVM on some data doesn't mean we've learned anything: only the SVM has. It's a machine learning algorithm, that's what it does. There's a risk that we'll get "science without understanding" as I've written a while back.In fact the authors did make a start on this and the results were pretty neat. They found that as the brain matures, long-range functional connections within the brain become stronger, but short-range interactions between neighbours get weaker and this local disconnection with age is the most reliable change.You can see this on the pic above: long connections get stronger (orange) while short ones get weaker (green), in general. This is true all across the brain.It's like how when you're a kid, you play with the kids next door, but when you grow up you spend all your time on the internet talking to people thousands of miles away, and never speak to your neighbours. Kind of.Link: Also blogged about here.Dosenbach NU, Nardos B, Cohen AL, Fair DA, Power JD, Church JA, Nelson SM, Wig GS, Vogel AC, Lessov-Schlaggar CN, Barnes KA, Dubis JW, Feczko E, Coalson RS, Pruett JR Jr, Barch DM, Petersen SE, & Schlaggar BL (2010). Prediction of individual brain maturity using fMRI. Science (New York, N.Y.), 329 (5997), 1358-61 PMID: 20829489... Read more »
Dosenbach NU, Nardos B, Cohen AL, Fair DA, Power JD, Church JA, Nelson SM, Wig GS, Vogel AC, Lessov-Schlaggar CN.... (2010) Prediction of individual brain maturity using fMRI. Science (New York, N.Y.), 329(5997), 1358-61. PMID: 20829489
The burden of type 2 diabetes is staggering. Close to 20 million people in the United States are diagnosed with type 2 diabetes, and total costs related to diabetes are creeping toward $200 billion annually. Programs to prevent and treat diabetes are numerous, but the effectiveness of various types of programs and modes of education [...]... Read more »
Davies MJ, Heller S, Skinner TC, Campbell MJ, Carey ME, Cradock S, Dallosso HM, Daly H, Doherty Y, Eaton S.... (2008) Effectiveness of the diabetes education and self management for ongoing and newly diagnosed (DESMOND) programme for people with newly diagnosed type 2 diabetes: cluster randomised controlled trial. BMJ (Clinical research ed.), 336(7642), 491-5. PMID: 18276664
Deakin T, McShane CE, Cade JE, & Williams RD. (2005) Group based training for self-management strategies in people with type 2 diabetes mellitus. Cochrane database of systematic reviews (Online). PMID: 15846663
Deakin TA, Cade JE, Williams R, & Greenwood DC. (2006) Structured patient education: the diabetes X-PERT Programme makes a difference. Diabetic medicine : a journal of the British Diabetic Association, 23(9), 944-54. PMID: 16922700
Duke SA, Colagiuri S, & Colagiuri R. (2009) Individual patient education for people with type 2 diabetes mellitus. Cochrane database of systematic reviews (Online). PMID: 19160249
Farmer AJ, Wade AN, French DP, Simon J, Yudkin P, Gray A, Craven A, Goyder L, Holman RR, Mant D.... (2009) Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial. Health technology assessment (Winchester, England), 13(15). PMID: 19254484
Gillett M, Dallosso HM, Dixon S, Brennan A, Carey ME, Campbell MJ, Heller S, Khunti K, Skinner TC, & Davies MJ. (2010) Delivering the diabetes education and self management for ongoing and newly diagnosed (DESMOND) programme for people with newly diagnosed type 2 diabetes: cost effectiveness analysis. BMJ (Clinical research ed.). PMID: 20729270
Loveman E, Cave C, Green C, Royle P, Dunn N, & Waugh N. (2003) The clinical and cost-effectiveness of patient education models for diabetes: a systematic review and economic evaluation. Health technology assessment (Winchester, England), 7(22). PMID: 13678547
O'Kane MJ, Bunting B, Copeland M, Coates VE, & ESMON study group. (2008) Efficacy of self monitoring of blood glucose in patients with newly diagnosed type 2 diabetes (ESMON study): randomised controlled trial. BMJ (Clinical research ed.), 336(7654), 1174-7. PMID: 18420662
Skinner TC, Carey ME, Cradock S, Dallosso HM, Daly H, Davies MJ, Doherty Y, Heller S, Khunti K, Oliver L.... (2008) 'Educator talk' and patient change: some insights from the DESMOND (Diabetes Education and Self Management for Ongoing and Newly Diagnosed) randomized controlled trial. Diabetic medicine : a journal of the British Diabetic Association, 25(9), 1117-20. PMID: 19183318
Female Gouldian finches don't always stand by their man. Given the opportunity, they'll indulge in a promiscuous tryst with another male. But this infidelity is not merely cold-hearted cheating. It's an evolutionary ploy that enables the female finches to bolster their offsprings' odds of survival.
The benefits of promiscuity in monogamous animals such as the Gouldian finch are straightforward for males but less clear for females. Promiscuity offers male finches a way to increase the number of offspring they father. If a brief romantic encounter enables a male to have more offspring than its mate could provide, then the act is an evolutionary success. But with females, the benefits of promiscuity are more complicated. There are only so many eggs a female can lay in one breeding season and having an affair doesn't increase the number of offspring that will come from those eggs. So why would a female finch take on a lover?
Read Full PostFemale Finches Reap the Benefits of Being Unfaithful originally appeared on About.com Animals / Wildlife on Sunday, September 12th, 2010 at 10:52:57.Permalink | Comment | Email this... Read more »
Pryke, S., Rollins, L., & Griffith, S. (2010) Females Use Multiple Mating and Genetically Loaded Sperm Competition to Target Compatible Genes. Science, 329(5994), 964-967. DOI: 10.1126/science.1192407
The winter of 2009/2010 was unusually cold across most of the Northern Hemisphere, leading to deaths and traffic chaos. Newspapers told lurid tales of planes sliding off icy runways, home-going revellers found frozen to death, and heavy snow and icy roads trapping motorists in their cars all night – and that was just in Britain. Needless [...]... Read more »
Cohen, J., Foster, J., Barlow, M., Saito, K., & Jones, J. (2010) Winter 2009–2010: A case study of an extreme Arctic Oscillation event. Geophysical Research Letters, 37(17). DOI: 10.1029/2010GL044256
Recent moves in Australia to more accurately record the number of actual suicide deaths does not automatically guarantee enhanced understanding of suicide causation.... Read more »
De Leo, D. (2010) Australia Revises its Mortality Data on Suicide. Crisis (The Journal of Crisis Intervention and Suicide Prevention). info:/
The brain is a metabolically expensive organ that uses quite a bit of energy. It's no surprise that it also generates a decent amount of heat during this energy usage process. A new paper has come out that poses and answers the question as to whether there is a thermodynamic limit to brain size (evolutionary wise). The author is basically asking how big can a brain get before it becomes too hot to function properly? What sort of constraints does evolution have in constructing a bigger brain, given the laws of our universe? The answer he gives, in short, is that there is plenty of room thermodynamically to evolve a larger brain.The paper first discusses the main cause of the generation of heat in the brain. The Na+/K+ pump helps to maintain the cell membrane potential of every neuron. The pump allows a neuron to have a high concentration of K+ ions and a low concentration of Na+ ions inside of it. The protein molecule pump hydrolyzes an ATP molecule, using that energy to move 3 Na+ ions out of the neuron and 2 K+ ions into the neuron. These ions are integral to the electrochemical signaling of a brain cell and their concentrations change in response to the propagation of an action potential down a neural axon. So the pump is necessary to restore ion balance to a neuron after it fires.The whole paper is a bit mathematically intense. The author's intent is to figure out how much energy an aggregate number of neurons use, mostly focusing on the Na+K+ pump and neglecting brain glucose utilization. The author goes on to discuss how the brain regulates the heat generated from all of this work that occurs and the specific constraints on neural processes. Some heat radiates from the scalp. Cerebral blood flow (cbf) is another method that the brain uses to cool itself. Up the evolutionary mammalian line, cbf essentially scales with brain volume. So I think that means the amount of blood vessels are basically proportional in creatures that have varying brain sizes. Due to this scaling up, there is apparently a small decrease in the rate of blood flow as you go from simpler to more complex organisms (mouse to human for example), because of more surface area coverage.Increasing cbf in a specific deep brain region can cause a resultant decrease in brain temperature there. According to the author mammal's brains can sustain a temperature upwards of 42 Celsius without becoming damaged. Though, the optimum temperature may be much lower than that. Certain drugs have the ability to increase the brain's temperature in part by vasoconstriction. Cerebral blood flow only acts as a coolant inside deeper brain regions where the blood is cooler than the surrounding brain tissue. So it's really not a coolant in the same manner as that in a heat engine. The cbf actually heats up more superficial brain regions that are closer to the skull so the mechanism is not uniform. The main purpose of cerebral blood flow is to bring glucose to neurons for their basic energy need. So the cooling ability is sort of a secondary aspect of blood flow and is probably not ideally suited for that purpose. Evolution has basically co-opted one process for a different purpose entirely. The blood flow's ability to cool is more important for larger brained mammals and less relevant for smaller brained ones where heat can dissipate from the head easier.The author of the paper notes some of the constraints of the brain taking into consideration excess heat production. He suggests that thinner axons/dendrites result in excess heat. However, he estimates that the axon's diameters are at a magnitude higher (averaging 12-1500 times) than the lower bound diameter that would be problematic. He also talks about the heat bounds relating to the propagation of neural signals and density of axonal packing. The author concludes that deep brain temperature is only weakly correlated with brain volume. So the brain could easily be scaled above the 5 kg limit of current land mammals. However, that is assuming that no other methods are utilized by evolution to "overclock" specific brain regions.I think that evolution finds whatever way it can to increase the brain's computational capacity. I've mentioned previously about some of the possible ways. Evolution exploits any pathway easily available. The firing speed of neurons is an aspect of overall computational capacity. However there are limits to this facet of brain functioning. Neurons can only fire continuously so many times before the sodium concentration in the cell becomes too high. This is especially true if neuronal axons were to become too thin. Those Na+/K+ pumps can only pump sodium ions out of the neuron so fast in certain cases. Evolution can possibly add more pumps, but then that requires more energy which potentially generates more heat. The pumps work relatively slow, so even a maximum amount of them might not overcome a certain limit. Eventually you might run up into an insurmountable wall with this attribute of brain function. So evolution may have to do something else, like increase the overall amount of neurons.Sometimes the path that evolution follows is unexpected. Average neuronal firing rates in larger brains are actually less frequent than that of neurons in smaller brains. So there may be some limitation to increasing neuronal firing rate over the course of evolution as you scale upwards in size. You would also think that evolution would first do something like maximizing the amount of proteins in the synapse before it went on to increase overall neuron count. However evolution tends to fill in some of these finer details later on, instead of in a logical linear fashion. Scientists will probably increasingly figure out why occurs as time goes on. The author of the paper does his part to elucidate a few of these possible constraints on how the brain is arranged.With increasing brain complexity there is the potential for more pathways to open up that can be exploited to further increase overall computational capacity. With more complexity, however, there is also the possibility for evolution to have a harder time navigating a proper way forward. There may be too many entangled systems whereby changing the variable of one thing could have a negative effect on something else. When cerebral blood flow is too high, for instance, it can damage the brain. So evolution may not be able to just take obvious routes (like increasing brain blood flow speed) to decrease brain heat. Not to mention how blood flow is mainly involved with delivering energy to cells. So any change in cbf could potentially negatively affect that process as well. Short of developing a whole secondary cooling system, evolution is stuck co-opting cbf as a coolant system. Also more blood flow in the brain may mean less room for computational purposes. Of course, this paper indicates that increased cooling might not be necessary. It may tend to get difficult as evolution moves forward to undo things or reach a path that is radically different from what previously evolved. Evolution has to essentially make due with whatever it has.In the past, scientists from Japan have constructed a "heat pipe" that can be implanted directly into discrete brain regions. This device can essentially be used to cool brain areas by diverting heat to an outside heat sink. The researchers developed this implant specifically for the purposes of reducing epileptic seizures. Over-excited neurons in an epileptic seizure are more active, use more energy and thus generate more heat. This excess heat that is generated can cause a feedback loop exciting more neurons to fire thus potentially prolonging the seizure. So cooling the brain could be a way of reducing problems associated with this condition. It is possible that this could be used to better regulate the temperature of future engineered brains.I think the fact that our universe allows brains to evolve to the size they do may be an example of the anthropic principle. First, there is the rare earth perspective of life. Our planet is situated in a near perfect distance ... Read more »
Karbowski, J. (2009) Thermodynamic constraints on neural dimensions, firing rates, brain temperature and size. Journal of Computational Neuroscience. DOI: 10.1007/s10827-009-0153-7
Here’s an interesting thought question: How much would global temperature warm if we used only the existing energy infrastructure (i.e., power plants, furnaces, motor vehicles) until these machines reached the end of their useful lives? Once they died, they would be replaced by devices that did not emit CO2.
Steven Davis and colleagues addressed this question [...]... Read more »
Davis, S., Caldeira, K., & Matthews, H. (2010) Future CO2 Emissions and Climate Change from Existing Energy Infrastructure. Science, 329(5997), 1330-1333. DOI: 10.1126/science.1188566
As said by Futurama’s mad scientist at large, Professor Farnsworth, quantum mechanics mean that anything can happen for any reason or without one. Of course this was really a swipe at how so many of us tend to see the complex physics of quantum objects, and it’s a very valid one since there’s a seemingly [...]... Read more »
Jin, X., Ren, J., Yang, B., Yi, Z., Zhou, F., Xu, X., Wang, S., Yang, D., Hu, Y., Jiang, S.... (2010) Experimental free-space quantum teleportation. Nature Photonics, 4(6), 376-381. DOI: 10.1038/nphoton.2010.87
Lydersen, L., Wiechers, C., Wittmann, C., Elser, D., Skaar, J., & Makarov, V. (2010) Hacking commercial quantum cryptography systems by tailored bright illumination. Nature Photonics. DOI: 10.1038/nphoton.2010.214
Well, it's hard for several reasons which I have discussed in previous posts, but here's one reason demonstrated by a recent paper. In this paper they crystallized the ß2 adrenergic receptor with an antagonist. Previously, in the landmark publication of the ß2 structure in 2007, the protein had been crystallized with an inverse agonist. Recall that an inverse agonist inhibits the basal activity of the GPCR whereas an antagonist stabilizes both active and inactive states but does not affect the basal activity. In this case they crystallized the ß2 with an antagonist and compared the resulting structure to that of the agonist-GPCR complex. And they saw...nothing in particular. The protein backbone and side-chain locations are very similar for the antagonist (compound 3) and inverse agonist (compound 2) shown in the figure below. As we can see in the figure, about the only side-chain that shows any movement is the tyrosine on the left (Y316). No wonder that cross-docking the two ligands (that is, docking one ligand into the other ligand's protein conformation) gave very accurate ligand orientations; this was essentially a softball problem for a docking program since the antagonist was being docked into a protein conformation that was virtually identical to its own. But of course, we know that antagonists and agonists affect GPCR function quite differently. As this study shows, clearly the action is not taking place in the ligand-binding pocket where things aren't really moving. So where is the real action? It's naturally taking place on the intracellular side, where the GPCR interacts with a medley of other proteins. And as the paper accurately notes, the difference between antagonist and inverse agonist binding is probably also reflected in the protein dynamics corresponding to the two ligands. Good luck modeling that. That's the whole deal with modeling GPCRs. Simply modeling the ligand-binding pocket is not going to help us understand the differences between the binding of various ligands; one has to model multiprotein interactions and subtle effects on dynamics that are relayed through the helices. The program Desmond which I described in a earlier post is a powerful MD program, but even MD is going to really turn heads when it can take account of multiprotein interactions, and such interactions happen on a time-scale much longer than what even Desmond can access. We have a long way to go before we can do all this. But please, don't stop.Wacker, D., Fenalti, G., Brown, M., Katritch, V., Abagyan, R., Cherezov, V., & Stevens, R. (2010). Conserved Binding Mode of Human β-2 Adrenergic Receptor Inverse Agonists and Antagonist Revealed by X-ray Crystallography Journal of the American Chemical Society, 132 (33), 11443-11445 DOI: 10.1021/ja105108q... Read more »
Wacker, D., Fenalti, G., Brown, M., Katritch, V., Abagyan, R., Cherezov, V., & Stevens, R. (2010) Conserved Binding Mode of Human β Adrenergic Receptor Inverse Agonists and Antagonist Revealed by X-ray Crystallography . Journal of the American Chemical Society, 132(33), 11443-11445. DOI: 10.1021/ja105108q
When writing a thesis, a chore that always takes more time than predicted is building the bibliography. Even with good software to manage your citations and references (EndNote, RefWorks, JabRef etc.), peppering your text with references and engaging in discussion with your sources takes time. (I often wonder how it was even possible to do [...]... Read more »
PORRINOJR, J., TAN, V., & DALUISKI, A. (2008) Misquotation of a Commonly Referenced Hand Surgery Study. The Journal of Hand Surgery, 33(1), 20-2000000000. DOI: 10.1016/j.jhsa.2007.10.007
Hol, J., de Jongste, J., & Nieuwenhuis, E. (2009) Quoting a landmark paper on the beneficial effects of probiotics. Journal of Allergy and Clinical Immunology, 124(6), 1354-2147483647. DOI: 10.1016/j.jaci.2009.07.047
PARADIS, M. (2006) More belles infidèles—or why do so many bilingual studies speak with forked tongue?☆. Journal of Neurolinguistics, 19(3), 195-208. DOI: 10.1016/j.jneuroling.2005.11.002
Hegemonic masculinity takes a heavy toll on men in the general community but as Green et al. (2010) discover, an even heavier toll on men in the military. The prohibitions against such men speaking up and seeking help for their heightened emotional distress are many, and severe. Tis preferable, it would seem, for male soldiers to suffer in silence than dare to name their psychic torpor. Is this further evidence for the necessity of peace? I say yes, for sure.... Read more »
Green G, Emslie C, O'Neill D, Hunt K, & Walker S. (2010) Exploring the ambiguities of masculinity in accounts of emotional distress in the military among young ex-servicemen. Social science . PMID: 20739109
As the tools of genetic analysis improve by leaps and bounds, the cost falling with each advance, more and more research is taking place into genetic influences on human longevity. This is an enormously complex area of study, and has little to no relevance to any repair-based methodology for lengthening human life. Outside the field of regenerative medicine, most aging researchers do not work on repair strategies such as SENS, however. Meanwhile there is plenty of funding for genetic studies of all sorts - compared with comparatively little available for initiatives to repair the biochemical damage of aging. This is a sad state of affairs, but it is what it is: one of the numerous things we must help to change in the years ahead if we are to see significant progress towards engineered longevity in our lifetimes. In any case, here is a good (and open access) example of the sort of genetic longevity studies presently taking place: detailed associations and commonalities are being uncovered in the genomes of long-lived people, and there is a lively debate over just how important any individual longevity-associated genetic variants are likely to be. Centenarians often reach old age with delayed onset or...... Read more »
Boyden, S., & Kunkel, L. (2010) High-Density Genomewide Linkage Analysis of Exceptional Human Longevity Identifies Multiple Novel Loci. PLoS ONE, 5(8). DOI: 10.1371/journal.pone.0012432
The goal of every vaccine is to induce lifelong protection for the patient from the specific nasty of interest. But in order to understand how one would receive ‘lifelong protection’ following the injection of a dead or weakened nasty, or even just the bits of one, we need to go backwards a bit and have a look at how we develop an immune response.... Read more »
Lefrançois L, & Obar JJ. (2010) Once a killer, always a killer: from cytotoxic T cell to memory cell. Immunological reviews, 235(1), 206-18. PMID: 20536565
Do you write about peer-reviewed research in your blog? Use ResearchBlogging.org to make it easy for your readers — and others from around the world — to find your serious posts about academic research.
If you don't have a blog, you can still use our site to learn about fascinating developments in cutting-edge research from around the world.
Research Blogging is powered by SMG Technology.
To learn more, visit seedmediagroup.com.