Bacterial cells constantly need to monitor their environment and act accordingly.The trouble is, bacteria are very small and when you are so very small, all the effects of being quantized in terms of molecule numbers are becoming very strong: number of mRNA molecules for a certain gene is an integer value, and not a very high at that, events of receptor getting activated or RNA polymerase binding to the promoter are stochastic in nature, and since not too many of the individual events occur at a time, they are not averaged out due to the law of large numbers.All this results in bacteria gambling all the time: some react to stimulus, some don't, some produce more proteins in response to it, some less. This leads to so called phenotypic heterogeneity, when otherwise (genetically) identical bacteria become very different in terms of their responses.This could be a good thing and also could be a bad thing. Having a collection of different bugs instead of a clone army will provide certain versatility: some are ready for one conditions, and some are ready for others. For instance, some are ready to grow and divide right away and some are slower and more cautious. Both types of cells can be beneficial in different conditions: the active ones will drive the population growth, but will be sensitive to the antibiotic treatment, and the passive ones will wait until the treatment is over and then they will come to life. Sounds like a good strategy (and it has a name, this strategy - "bed hedging") and I guess it is exactly the reason why clone armies never caught on.On the other hand, this noise makes it really hard for bacteria to make an educated guess and respond to a stimulus in the best possible way - there is simply too much background to filter through!One of the widely used cellular response systems used by bacteria is so called stringent response. This one is mediated by a family of proteins called RSH (RelA SpoH Homologue, with RelA and SpoT being the first members to be discovered). These proteins sense different cues (aminoacid starvation, fatty acid starvation, heat shock and so on) and translate these input signals into modulation of the intracellular concentration of ppGpp - a modified G nucleotide which acts as a second messenger modulating numerous cellular processes, such as transcription, translation, replication and lots more.The RSH-mediated system in M. tuberculosis was shown to be vital for prolonged life in the host, linking it to the phenotypic heterogeneity. This bug has one RSH protein, Rel, which is capable of both producing and degrading ppGpp. The logical question is then - how is Rel activity and abundance regulated, and what is its distribution in the bacterial population?In the recent two papers (1 and 2) exactly that was done. Rel promotor was fused with a GFP ORF so that its activity can be monitored on the single cell level using flow cytometry. And indeed, they saw that cells are very strongly heterogeneous in respect to the GFP level, which reflects activity of the rel promoter. This heterogeneity turned out to be brought about by the positive feedback loop feeding Rel expression back to its promoter via activity of the MreAB and SigE proteins.Positive feed back loops are a common way of creating this sort of bistability in the biological systems and is a very common motif in the gene networks. What would be interesting is to see how common is this positive feedback among different bacteria, especially the ones that have different RSH system, such as the most commonly studied E. coli, which has two RSH proteins instead of one in M. tuberculosis: RelA, which is mostly producing ppGpp, and SpoT, which is mostly degrading it.Effects of noise in protein expression are also different in E. coli: here synthetic and hydrolytic components are split into two independently produced proteins, thus resulting in a system with more degrees of freedom. Sure enough, it is well documented that intrinsic noise in protein expression (that would be roughly variation in the protein expression between the two independent genes in one bacterial cell) is much less than extrinsic one (roughly - variation between different cells), but still - two genes is more than one!References:Potrykus K, & Cashel M (2008). (p)ppGpp: still magical? Annual review of microbiology, 62, 35-51 PMID: 18454629Mittenhuber G (2001). Comparative genomics and evolution of genes encoding bacterial (p)ppGpp synthetases/hydrolases (the Rel, RelA and SpoT proteins). Journal of molecular microbiology and biotechnology, 3 (4), 585-600 PMID: 11545276Dahl JL, Kraus CN, Boshoff HI, Doan B, Foley K, Avarbock D, Kaplan G, Mizrahi V, Rubin H, & Barry CE 3rd (2003). The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice. Proceedings of the National Academy of Sciences of the United States of America, 100 (17), 10026-31 PMID: 12897239... Read more »
Mittenhuber G. (2001) Comparative genomics and evolution of genes encoding bacterial (p)ppGpp synthetases/hydrolases (the Rel, RelA and SpoT proteins). Journal of molecular microbiology and biotechnology, 3(4), 585-600. PMID: 11545276
Dahl JL, Kraus CN, Boshoff HI, Doan B, Foley K, Avarbock D, Kaplan G, Mizrahi V, Rubin H, & Barry CE 3rd. (2003) The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice. Proceedings of the National Academy of Sciences of the United States of America, 100(17), 10026-31. PMID: 12897239
Sureka K, Ghosh B, Dasgupta A, Basu J, Kundu M, & Bose I. (2008) Positive feedback and noise activate the stringent response regulator rel in mycobacteria. PloS one, 3(3). PMID: 18335046
Ghosh S, Sureka K, Ghosh B, Bose I, Basu J, & Kundu M. (2011) Phenotypic heterogeneity in mycobacterial stringent response. BMC systems biology, 18. PMID: 21272295
Alon U. (2007) Network motifs: theory and experimental approaches. Nature reviews. Genetics, 8(6), 450-61. PMID: 17510665
Ingolia NT, & Murray AW. (2007) Positive-feedback loops as a flexible biological module. Current biology : CB, 17(8), 668-77. PMID: 17398098
Lidstrom ME, & Konopka MC. (2010) The role of physiological heterogeneity in microbial population behavior. Nature chemical biology, 6(10), 705-12. PMID: 20852608
Taniguchi Y, Choi PJ, Li GW, Chen H, Babu M, Hearn J, Emili A, & Xie XS. (2010) Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells. Science (New York, N.Y.), 329(5991), 533-8. PMID: 20671182
Part 1 of a 6-talk series on the history of life on Earth I held in Cyprus.
In this talk, what we know about the early Earth’s geology and atmosphere will be reviewed, using that knowledge as the base on which to discuss the two main hypotheses about how life originated.
This will lead on to a discussion of the earliest life forms on Earth and how they revolutionised atmospheric and oceanic chemistry and forever changed the course of evolution on Earth.... Read more »
Marshall, C., Emry, J., & Olcott Marshall, A. (2011) Haematite pseudomicrofossils present in the 3.5-billion-year-old Apex Chert. Nature Geoscience, 4(4), 240-243. DOI: 10.1038/ngeo1084
So, here's a thing:
Best URL for sharing: http://www.darwineatscake.com/?id=30
URL for hotlinking or embedding: http://www.darwineatscake.com/img/comic/30.jpg
This relates to a criticism that I made of evolutionary psychology, but which applies to many naive adaptationist arguments: it is easy to come up with a plausible-sounding adaptive explanation of just about anything. In most cases, it is equally easy to come up with an equally plausible-sounding explanation of the exact opposite phenomenon.
Barnett AG, Plonka K, Seow WK, Wilson LA, & Hansen C (2011). Increased traffic exposure and negative birth outcomes: a prospective cohort in Australia. Environmental health : a global access science source, 10 PMID: 21453550
... Read more »
Barnett AG, Plonka K, Seow WK, Wilson LA, & Hansen C. (2011) Increased traffic exposure and negative birth outcomes: a prospective cohort in Australia. Environmental health : a global access science source, 26. PMID: 21453550
Tuberculosis may be defeated through a new therapeutic approach, based on countering the microbial stress response and restoring normal metabolism.... Read more »
Baek, S., Li, A., & Sassetti, C. (2011) Metabolic Regulation of Mycobacterial Growth and Antibiotic Sensitivity. PLoS Biology, 9(5). DOI: 10.1371/journal.pbio.1001065
Three articles recently published in PLoS ONE are the harbinger of a RosettaCon 2010 PLoS one collection. How do you design a new enzyme from scratch? How do you model peptide binding with almost no prior information? And what puzzles CAN'T Rosetta solve?
... Read more »
Raveh, B., London, N., Zimmerman, L., & Schueler-Furman, O. (2011) Rosetta FlexPepDock ab-initio: Simultaneous Folding, Docking and Refinement of Peptides onto Their Receptors. PLoS ONE, 6(4). DOI: 10.1371/journal.pone.0018934
The beauty of social media is that sometimes someone shares something monumental before you even pick it up yourself in a journal you’re subscribed to. I love that – it’s a great way to see how others find things with … Continue reading →
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Atwal, J., Chen, Y., Chiu, C., Mortensen, D., Meilandt, W., Liu, Y., Heise, C., Hoyte, K., Luk, W., Lu, Y.... (2011) A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid- Production in Vivo. Science Translational Medicine, 3(84), 84-84. DOI: 10.1126/scitranslmed.3002254
“Bring out yer dead!” Thankfully, epithelial sheets have a much more efficient and beautiful way of clearing out dying cells than the famous Monty Python scene. Today’s stunning images are from a paper describing the signaling epithelial cells use to push out dying cells. It’s no wonder that the authors’ image made the cover of Journal of Cell Biology!The function and health of an organ strongly depends on the integrity of the epithelial sheet protecting it. In order to preserve the epithelial barrier, dying cells are pushed out of the epithelial sheet in a precise and finely-tuned process called apoptotic cell extrusion. In this event, cells surrounding the dying, apoptotic cell form an actin and myosin ring that contracts to push the dying cell out of the sheet. A recent paper describes the signaling that takes place to initiate cell extrusion. The dying cell produces a signal called bioactive lipid sphingosine-1-phosphate (S1P), which activates actin-myosin contraction via its receptor (S1P2) in neighboring cells. The images above show epithelial sheets in normal and S1P2 mutant zebrafish larvae. In the mutant, the apoptotic cell (green) stays in the epithelial sheet and lacks the actin ring (red) seen in the wild-type tissue. Gu, Y., Forostyan, T., Sabbadini, R., & Rosenblatt, J. (2011). Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway originally published in The Journal of Cell Biology, 193 (4), 667-676 DOI: 10.1083/jcb.201010075... Read more »
Gu, Y., Forostyan, T., Sabbadini, R., & Rosenblatt, J. (2011) Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway. originally published in The Journal of Cell Biology, 193(4), 667-676. DOI: 10.1083/jcb.201010075
The post title is a bit tongue in cheek after I suffered a case of foot in mouth yesterday. I had the pleasure of presenting to some behavioural ecologists at the University of Zurich and was advocating for more “evolutionary biology imperialism” in economics. In the way that economists charge out of their field and [...]... Read more »
ALFORD, J., FUNK, C., & HIBBING, J. (2005) Are Political Orientations Genetically Transmitted?. American Political Science Review, 99(02). DOI: 10.1017/S0003055405051579
Hypothesis: A close look at a common North American songbird, the white-throated sparrow, reveals that it may be evolving a second pair of sex chromosomes! ... Read more »
Huynh, L., Maney, D., & Thomas, J. (2010) Chromosome-wide linkage disequilibrium caused by an inversion polymorphism in the white-throated sparrow (Zonotrichia albicollis). Heredity, 106(4), 537-546. DOI: 10.1038/hdy.2010.85
Joron, M., & Whibley, A. (2010) Stripes, sex and sparrows: what processes underlie heteromorphic chromosome evolution?. Heredity, 106(4), 531-532. DOI: 10.1038/hdy.2010.106
Moore, R. (2008) Sex chromosome evolution: A ‘missing link’ in the evolution of sex chromosomes. Heredity, 102(3), 211-212. DOI: 10.1038/hdy.2008.115
Tuttle, E. (2003) Alternative reproductive strategies in the white-throated sparrow: behavioral and genetic evidence. Behavioral Ecology, 14(3), 425-432. DOI: 10.1093/beheco/14.3.425
Thorneycroft, H. (1966) Chromosomal Polymorphism in the White-Throated Sparrow, Zonotrichia albicollis (Gmelin). Science, 154(3756), 1571-1572. DOI: 10.1126/science.154.3756.1571
by Vincent Racaniello in virology blog
Contemporary human viruses most likely originated by cross-species transmission from non-human animals. Examples include HIV-1, which crossed from chimpanzees to humans, and SARS coronavirus, which originated in bats. Since the 1989 discovery of hepatitis C virus (classified as a hepacivirus in the family Flaviviridae) the origin of the virus been obscure. During the characterization of [...]... Read more »
A. Kapoor, P. Simmonds, G. Gerold, N. Qaisar, K. Jain, J.A. Henriquez, C. Firth, D.L. Hirschberg, C. Rice, S. Shields.... (2011) Characterization of a canine homolog of hepatitis C virus. Proc. Natl. Acad. Sci. USA. info:/
New research by UNC Chapel Hill scientists suggests that hip bones grow with age.... Read more »
Berger AA, May R, Renner JB, Viradia N, & Dahners LE. (2011) Surprising evidence of pelvic growth (widening) after skeletal maturity. Journal of orthopaedic research : official publication of the Orthopaedic Research Society. PMID: 21608025
reposted from: Cancer Research UK comments: http://scienceblog.cancerresearchuk.org/2010/05/12/potential-cancer-drug-dca-tested-in-early-trials/crabsallover highlights, key points, comments / links.I read about DCA in Cancer Research UK newsfeed on 16th May 2011. It was also mentioned by Guy http://www.meetup.com/HASSNERS/messages/boards/thread/11130311/20#42889221 on 25th May 2011.Update, 16th May 2011: Several websites are reporting that last week ‘cancer was cured without anyone reporting on it’. This is not true and seems, we think, to have arisen from a misreading of the date on the most recent paper on DCA (which was published on May 12th 2010 – i.e. this time last year).Everything we wrote in the post and comments below stands – DCA is still only a ‘potential’ cancer treatment, and more research is needed to find out whether it’s safer or more effective than existing therapies.- HenryDCA has been tested in a small trialThe controversial drug DCA (dichloroacetate) is in the headlines again, after researchers in Canada carried out a small-scale clinical trial of the drug in five patients with advanced brain tumours.Over the past year or two there have been several articles in the news and on the internet about DCA, which was claimed to be cheap, safe and “kill most cancers”.Understandably this caused a great deal of interest, especially as DCA is an off-patent drug and appears to be non-toxic to humans (although it can cause significant side effects, as we’ll see later).But before we jump to conclusions and hail DCA as a ‘wonder drug’, we need to look at the science behind the headlines.What is DCA and how does it work?Mitochondria are the 'power stations' in our cellsAll our cells need energy to grow and function, including cancer cells. Simply put, our cells usually generate energy by breaking down sugar (glucose). To do this, they use a process known as the Krebs cycle, which takes place in tiny structures within the cell called mitochondria (the ‘power stations’ of the cell).But cancer cells bypass this cycle and produce energy using a simpler process, known as glycolysis, which takes place outside the mitochondria in the cell’s cytoplasm (the main part of the cell).Mitochondria play a crucial role in cells. As well as generating energy for the cell, they can also trigger the cell to di... Read more »
Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D.... (2010) Metabolic modulation of glioblastoma with dichloroacetate. Science translational medicine, 2(31). PMID: 20463368
P. Kaufmann, K. Engelstad, Y. Wei, S. Jhung, M. C. Sano, D. C. Shungu, W. S. Millar, X. Hong, C. L. Gooch, X. Mao.... (2006) Dichloroacetate causes toxic neuropathy in MELAS . Neurology, 324-330. DOI: http://www.neurology.org/cgi/content/abstract/66/3/324
S BONNET, S ARCHER, J ALLALUNISTURNER, A HAROMY, C BEAULIEU, R THOMPSON, C LEE, G LOPASCHUK, L PUTTAGUNTA, & S BONNET. (2007) A Mitochondria-K Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth. Cancer Cell, 11(1), 37-51. DOI: 10.1016/j.ccr.2006.10.020
A review over why the sun is better than the tanning bed. ... Read more »
Anne Bagg Britt. (1995) Repair of DNA Damage Induced by Ultraviolet Radiation . Plant Physiologyq, 891-896. info:/
Steve Sweetman and I have just published a paper on a new maniraptoran theropod dinosaur from the Lower Cretaceous Wealden Supergroup of East Sussex, England (Naish & Sweetman 2011).
As you might know if you're a regular reader, much of my technical work has been devoted to Wealden theropods and I publish papers on them fairly regularly (recent articles: Benson et al. (2009), Naish (2010); see links below). I still have yet to publish one of my most significant contributions - the monographic description of the tyrannosauroid Eotyrannus lengi (the follow-up to the rushed and preliminary Hutt et al. (2001) paper) - but let's not talk about that. A large, state-of-the-art revision of Wealden theropods was submitted earlier this year and has been through review and accepted for publication.
I make no secret of the fact that many of the fossils I publish on are extremely fragmentary, in many cases being single bones. Identifications made on the basis of single bones can very occasionally be horribly, horribly wrong (one personal example: a cervical vertebra that I identified as oviraptorosaurian (Naish & Martill 2002) now seems to be from an abelisauroid), but they can often be made with confidence if the material is good enough, and if it preserves the required informative bits of anatomy. Read the rest of this post... | Read the comments on this post...... Read more »
Naish, D., & Sweetman, S. C. (2011) A tiny maniraptoran dinosaur in the Lower Cretaceous Hastings Group: evidence from a new vertebrate-bearing locality in south-east England. Cretaceous Research, 464-471. info:/10.1016/j.cretres.2011.03.001
An accounting of the fauna of the island of Palawan (Philippines) 14,000 to 5,000 years before present.... Read more »
Blogging has been swamped lately by that miracle called life but I could not help but be drawn to a paper in this week's Science which describes a most unholy and unexpected stabilizing alliance in a protein's innards.Proteins are known to form cross-links such as disulfide bonds to stabilize interactions with ligands and substrates. Any reasonable chemist would expect these kinds of interactions to be mediated between polar residues. But nature usurps us low-lifes once again. In this week's Science, a group led by Andrew Karplus reveals a surprising stabilizing covalent cross-link between two otherwise blissfully aloof protein parts- a valine and a phenylalanine. Who could have imagined these otherwise stable partners suddenly deciding to...bond?As chemists know however, there is only one kind of chemical entity that can create such havoc with stable functional groups- a metal. It turns out that the protein is a four-helix bundle diiron protein with two Fe atoms bound in proximity to the Val and Phe. The two irons apparently create their own cofactor by neatly supplying electrons to bond the Val and Phe to each other and moulding a cosy bed for themselves. The resolution is 1.2 A so the electron density is unambiguous. Intriguingly, the real function of the protein remains unknown.Organometallic chemists who are keeping the midnight oil burning trying to use metals to functionalize unreactive C-H bonds would not be too surprised that a metal is mediating such strange interactions. But the observation demonstrates something that chemists are all too familiar with by now- Nature has been there, and it's done that.Cooley, R., Rhoads, T., Arp, D., & Karplus, P. (2011). A Diiron Protein Autogenerates a Valine-Phenylalanine Cross-Link Science, 332 (6032), 929-929 DOI: 10.1126/science.1205687... Read more »
Blogging has been swamped lately by that miracle called life but I could not help but be drawn to a paper in this week's Science which describes a most unholy and unexpected stabilizing alliance in a protein's innards.Proteins are known to form cross-links such as disulfide bonds to stabilize interactions with ligands and substrates. Any reasonable chemist would expect these kinds of interactions to be mediated between polar residues. But nature usurps us low-lifes once again. In this week's Science, a group led by Andrew Karplus reveals a stabilizing covalent cross-link between, hold your breath, a valine and a phenylalanine. Who could have imagined these two otherwise blissfully aloof and stable partners suddenly deciding to...bond?As chemists know however, there is only one kind of chemical entity that can create such havoc with stable functional groups- a metal. It turns out that the protein is a four-helix bundle diiron protein with two Fe atoms bound in proximity to the Val and Phe. The two irons apparently create their own cofactor by neatly supplying electrons to bond the Val and Phe to each other and molding a cosy bed for themselves. The resolution is 1.2 A so the electron density is unambiguous. The function of the unusual cross-link seems to provide a barrier to protect the iron from potential iron chelators; experiments indicate that the iron is rapidly mopped up by chelators in mutants lacking the cross-link. Intriguingly, the real function of the protein itself remains unknown.Organometallic chemists who are keeping the midnight oil burning trying to use metals to functionalize unreactive C-H bonds would not be too surprised that a metal is mediating such strange interactions. But the observation demonstrates something that chemists are all too familiar with by now- Nature has been there, and it's done that.Cooley, R., Rhoads, T., Arp, D., & Karplus, P. (2011). A Diiron Protein Autogenerates a Valine-Phenylalanine Cross-Link Science, 332 (6032), 929-929 DOI: 10.1126/science.1205687... Read more »
As the developed world gobbles up natural resources and wipes out species after species of plants and animals, the issue of biodiversity–the variation of life forms within an ecosystem–becomes increasingly important to the survival of our planet. The more diverse the life forms, the healthier the ecosystem, meaning that the more species we eliminate, the [...]... Read more »
Fire, A., Xu, S., Montgomery, M., Kostas, S., Driver, S., & Mello, C. (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature, 391(6669), 806-811. DOI: 10.1038/35888
When the dinosaurs were ruling the land, other giant reptiles dominated the oceans. They included the ichthyosaurs, a group of reptiles that bore a strong resemblance to dolphins. They cut through the prehistoric oceans with streamlined bodies, flat flippers and powerful fluked tails. They gave birth to live young in the water. They snapped at fish and squid with pointed snouts, full of conical teeth.
But one of them was different. Shastasurus is a very different type of ichthyosaur. It has a very small head, a short snout and, most importantly, no teeth at all.
Martin Sander from the University of Bonn thinks that it was the black sheep of the family. It couldn’t have bitten its prey like other ichthyosaurs or modern dolphins. Instead, Sander thinks that it was a suction feeder. By quickly opening its mouth and pulling back its tongue, it created a sudden influx of water that swept its prey into its open jaws. Many whales, including sperm whales and beaked whales, hunt with a similar technique today and they too have greatly reduced teeth.
The part ...... Read more »
Sander, P., Chen, X., Cheng, L., & Wang, X. (2011) Short-Snouted Toothless Ichthyosaur from China Suggests Late Triassic Diversification of Suction Feeding Ichthyosaurs. PLoS ONE, 6(5). DOI: 10.1371/journal.pone.0019480
One of the great puzzles of cellular signaling is that often the molecules responding to an external signal are the same, yet the outcome is different. Take the MAP kinase pathway, for example: it’s activated by growth factors, cytokines and G protein coupled receptors, and in response to its activation the cell might differentiate, grow, [...]... Read more »
Batchelor E, Loewer A, Mock C, & Lahav G. (2011) Stimulus-dependent dynamics of p53 in single cells. Molecular systems biology, 488. PMID: 21556066
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