How exactly do lineages diverge to the point that they can be considered separate species, and especially reach reproductive isolation, is still an ongoing question in evolutionary biology. Classical views of speciation hypothesize the existence of speciation genes, defined as … Continuer la lecture →... Read more »
Ellegren H, Smeds L, Burri R, Olason PI, Backström N, Kawakami T, Künstner A, Mäkinen H, Nadachowska-Brzyska K, Qvarnström A.... (2012) The genomic landscape of species divergence in Ficedula flycatchers. Nature, 491(7426), 756-60. PMID: 23103876
Q: When is an identical twin not an identical twin? A: Pretty much all the time (at least according to some people) as our increasing understanding of the complexity of genetics stretches and modifies long-held beliefs about the building blocks of life and their role in our health and wellbeing.DNA methylation differences? @ Wikipedia Today I'm talking about identical (monozygotic) twins - siblings derived from one fertilised egg - and how the science of epigenetics might have some interesting implications for autism research as per the study by Wong and colleagues* (open-access). I should perhaps also direct you to some other interesting research recently discussed in this area too (see here) which might be relevant.Regular readers will probably already know about my amateur interest in epigenetics (see here and here) and how the area of the epigenome - those chemical marks which have the ability to influence the expression of the genome - has started to yield some potentially important observations. At times I'll admit to being slightly too over-excited at the possibilities of epigenetics. Subsequently brought back down to earth by more sobering accounts (see here**) but not yet ready to poo-poo the whole science just yet***.I don't want to rehash the whole epigenetic story in this one post, so instead am going to concentrate on the particular area covered by Wong et al and their analysis of the methylome (yes, another -ome for you) which is concerned with the addition of methyl groups to various regions of the genome and how that subsequently alters the expression of genes. DNA methylation has been a sort of peripheral topic in relation to cases of autism for quite some time now; brought to the forefront by all that folic acid (see here) and MTHFR research (see here) and the availability of those lovely methyl groups. Suffice to say that we are still very much at the beginning when it comes to looking at the relationship between all these elements and very complicated conditions like autism.Anyhow, after that very long introduction (I am only an amateur science blogger after all), a few details from the Wong paper might be in order, bearing in mind it is open-access:Part of the UK TEDS initiative and partly sponsored by Autism Speaks who were involved in that recent environmental epigenetics symposium (see here), researchers looked at 50 monozygotic (MZ) twin pairs. It wasn't just a case of 25 twin pairs where one twin was diagnosed with an autism spectrum disorder (ASD) compared with 25 twin pairs where both were concordant for ASD. No, instead the authors looked at a variety of phenotypic combinations based on concordance/discordance for ASD and various core traits based on the Childhood Autism Symptom Test (CAST) schedule. Supplementary table 1 shows the combinations (see here).A genome-wide analysis of DNA methylation was undertaken on blood samples provided by participants. I can't pretend to intimately know all the techniques that were employed so won't profess to do so. What I can glean from the paper is that both DNA methylation differences between MZ twin pairs discordant for ASD and analyses between groups scoring high and low on the various core symptom areas were completed with "the aim of identifying real, biologically relevant within-twin and between group DNA methylation differences".Results: "ASD is not associated with systemic differences in global DNA methylation". In other words, within the twins, there is quite a high degree of similarity when it comes to patterns of DNA methylation. This might tie in with other work looking at methylation in cases of autism and other family members (see here). When looking at DNA methylation patterns between twin pairs discordant for ASD, specific sites of the genome however seemed to show some variability as a function of ASD diagnosis or not. The authors list the top 50 "differentially methylated CpG sites" (see here) showing gene and position, with a combination of hyper- and hypo-methylated regions identified. Top of the methylation differences pops was the NFYC promoter which was "consistently hypermethylated in affected individuals" (see here for some additional papers on this gene). Hypermethylation by the way, generally means gene silencing as per its function when it comes to transposons (think HERVs). Various other data are presented based on either syndrome or trait specific differences across the twins. I'm not going to go through all of these because, well because that's called plagiarism. I will draw your attention to one particular finding which might be important as they identified "one MZ twin pair, concordant for a very severe autistic phenotype, that appear to represent epigenetic outliers at multiple CpG sites across the genome". I'm immediately drawn back to my autism or autisms post and that all-important phenotypic variability as potentially being relevant here too. That and the tie-up with more structural changes to the genome as per the mention of CNVs and hotspots.I know I've gone on a bit in the post but this is potentially a very important paper. Not only does it put the epigenome, or at least one part of the epigenome, firmly on the autism research map, but it offers something of a partial explanation for [some of] that 'missing heritability' which was talked about not so many years ago (see here).The fact also that methylation patterns might be variable both intra-twins and intra-ASD is also important; suggesting that as with more traditional genomic findings in relation to autism, there isn't going to be just one epigenomic factor affecting risk or presentation, but rather a plethora of sites which are hyper- or hypo-methylated, potentially also linked to (affecting?) more structural changes to the genome in cases of ASD.Don't get me wrong, the same questions remain as are seen in other areas of biological functioning with autism in mind: the heterogeneity, the reliance on diagnosis by observation and note-taking, the (elevated) risk of comorbidities, etc. All of which cloud the waters of association. Distinct however from the question of whether there is anything that can be done when s... Read more »
Wong, C., Meaburn, E., Ronald, A., Price, T., Jeffries, A., Schalkwyk, L., Plomin, R., & Mill, J. (2013) Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Molecular Psychiatry. DOI: 10.1038/mp.2013.41
I’m thankful that my body knows how to handle days when I feed it wonderful things, like a banana and a giant bowl of strawberries, then follow it up with a few gut-busting mini-doughnuts. Although worms and other organisms don’t have access to doughnuts like I do, their bodies still have protections in place to handle changes in their diet. Today’s image is from a paper describing how the germline is protected from a changing diet.Organisms consume a variety of food options, yet their bodies know how to regulate these changes to maintain homeostasis, all the way down to the cellular level. A recent paper shows how an organism’s germline stem cells (GSCs), the source of eggs and/or sperm, are protected from food intake. Gracida and Eckmann found that the nuclear receptor NHR-114 protects GSCs from dietary perturbations in worms, possibly through a detoxifying response to certain food intake. Without NHR-114, worms on certain bacterial diets become sterile due to germ cell division defects during development. The dietary sensitivity is based on intake of the amino acid tryptophan. In the images above, gonads of worms fed a certain bacterial diet are stained to see individual germ cells (cell cortex staining in green in merged; DNA is purple). Compared to wild-type worms (left), worms depleted of NHR-114 (right) have germ cell defects, notably cells with multiple nuclei (arrowhead).Gracida, X., & Eckmann, C. (2013). Fertility and Germline Stem Cell Maintenance under Different Diets Requires nhr-114/HNF4 in C. elegans Current Biology, 23 (7), 607-613 DOI: 10.1016/j.cub.2013.02.034 Copyright ©2013 Elsevier Ltd. All rights reserved. ... Read more »
Gracida, X., & Eckmann, C. (2013) Fertility and Germline Stem Cell Maintenance under Different Diets Requires nhr-114/HNF4 in C. elegans. Current Biology, 23(7), 607-613. DOI: 10.1016/j.cub.2013.02.034
An unemployed neighbor wins the lottery, a friend who regularly boasts about his good health becomes ill. We are highly sensitive to changing fortunes of others. We want to know who’s doing worse and who’s doing better than before, as these shifts in our social environment may have implications for our own well-being. In particular we are drawn to unexpected changes: underdogs that beat the odds and top dogs that fall from grace. Whether we witness the creation of a hero or the demise of a hero – we love it.... Read more »
Feather, N., & Sherman, R. (2002) Envy, Resentment, Schadenfreude, and Sympathy: Reactions to Deserved and Undeserved Achievement and Subsequent Failure. Personality and Social Psychology Bulletin, 28(7), 953-961. DOI: 10.1177/014616720202800708
The retina is a beautiful and wondrous structure, and it has some really weird cells. Retina by Cajal (source)Retinal Ganglion Cells (RGC) have all sorts of differentiating characteristics. Some are directly sensitive to brightness (like rods and cones), while some are sensitive to the specific direction that a bar is traveling. I am discussing really amazing new techniques to see inside cells this month, and have already posted about the magic that is Array Tomography. Today we'll look at another amazing new technique that (like array tomography) combines nano-scale detail with a scale large enough to see many neurons at once. This technique is called Serial Block-face Electron Microscopy (SBEM), and was recently used to investigate how starburst amacrine cells control the direction-sensitivity of retinal ganglion cells.Serial Block-face EM (source)SBEM images are acquired by embedding a piece of tissue (like a retina) in some firm substance and slicing it superthin (like 10s of nanometers thick) with a diamond blade. The whole slicing apparatus is set up directly under a scanning electron microscope, so as soon as the blade cuts, an image is taken of the surface remaining. Then another thin slice is shaved off and the next image is taken, and so on.Using this technique, Briggman et al. (2011) are able to trace individual neurons and their connections for a (relatively) large section of retina. What is so great about this paper is that before they sliced up the retina, they moved bars around in front of it and measured the directional selectivity of a bunch of neurons. Then, using blood vessels and landmarks to orient themselves, they were able to find the exact same cells in the SBEM data and trace them.Briggman et al. (2011) Fig1C: Landmark blood vesselsThe colored circles above represent the cell bodies and the black 'tree' shape are the blood vessel landmarks. Once they found the cell bodies, the could trace the cells through the stacks of SBEM data. What is really neat is that you can try your hand at this yourself. This exact data set has been turned into a game called EYEWIRE by the Seung lab at MIT. Reconstructing the cells, they could not only tell which cells connected to which other cells, but they could also see exactly where on the dendrites the cells connected. This is the really amazing part. They found that specific dendritic areas made synapses with specific cells.Briggman et al. (2011) Fig4: dendrites as the computational unitThis starburst amacrine cell overlaps with many retinal ganglion cells (dotted lines represent the dendritic spread of individual RGCs)...BUT its specific dendrites (left, right, up down etc) synapse selectively onto RGCs sensitive to a particular direction. Each color represents synapses onto a specific direction-sensitivity. e.g. yellow dots are synapses from the amacrine cell onto RGCs which are sensitive to downward motion.This suggests that each individual dendritic area of these starburst amacrine cells inhibits (probably) a specific type of RGC, and that these dendrites act relatively independently of one another. "The specificity of each SAC dendritic branch for selecting a postsynaptic target goes well beyond the notion that neuron A selectively wires to neuron B, which is all that electrophysiological measurements can test. Instead the dendrite angle has an additional, perhaps dominant, role, which is consistent with SAC dendrites acting as independent computational units." -Briggman et al (2011)(discussion)These cells are weird for so many reasons, but the ability of the dendrites to act so independently of one another is a new and exciting development that I hope to see more research on soon. © TheCellularScaleBriggman KL, Helmstaedter M, & Denk W (2011). Wiring specificity in the direction-selectivity circuit of the retina. Nature, 471 (7337), 183-8 PMID: 21390125... Read more »
Briggman KL, Helmstaedter M, & Denk W. (2011) Wiring specificity in the direction-selectivity circuit of the retina. Nature, 471(7337), 183-8. PMID: 21390125
Study says laser light can turn cocaine addiction on and off in rats.
Francis Collins, the director of the National Institutes of Health (NIH), had one word for it: “Wow.”
Writing in the director’s blog at the online NIH site, Collins said that a team of researchers from NIH and UC San Francisco had succeeded in delivering “harmless pulses of laser light to the brains of cocaine-addicted rats, blocking their desire for the narcotic.”
Wow, indeed. It didn’t take long for the science fiction technology of optogenetics to make itself felt in addiction studies. The idea of using targeted laser light to strengthen or weaken signals along neural pathways has proven surprisingly robust. The study by the NIH and the University of California at San Francisco, published in Nature, showed that lab rats engineered to carry light-activated neurons in the prefrontal cortex could be deterred from seeking cocaine. Conversely, laser light used in a way that reduced signaling in this part of the brain led previously sober rats to develop a taste for the drug. As Collins described the work:
The researchers studied rats that were chronically addicted to cocaine. Their need for the drug was so strong that they would ignore electric shocks in order to get a hit. But when those same rats received the laser light pulses, the light activated the prelimbic cortex, causing electrical activity in that brain region to surge. Remarkably, the rat’s fear of the foot shock reappeared, and assisted in deterring cocaine seeking.
All this light zapping took place in a brain region known as the prelimbic cortex. In their paper, Billy T. Chen and coworkers said that they “targeted deep-layer pyramidal prelimbic cortex neurons because they project to brain structures implicated in drug-seeking behavior, including the nucleus accumbens, dorsal striatum and amygdala.” These three subcortical regions are rich in dopamine receptors. In rats that had been challenged with foot shocks before being offered cocaine, “optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking, whereas optogenetic prelimbic cortex inhibition significantly increased compulsive cocaine seeking.”
What this demonstrates is that similar regions in the human prefrontal cortex, known to regulate such actions as decision-making and inhibitory response control, may be “compromised” in addicted people. This abnormally diminished excitability in turn “impairs inhibitory control over compulsive drug seeking…. We speculate that crossing a critical threshold of prelimbic cortex hypoactivity promotes compulsive behaviors”
This all sounds vaguely unsettling; sort of a cross between phrenology and lobotomy. But it is no such thing, and the study authors believe that stimulation of the prelimbic cortex “might be clinically efficacious against compulsive seeking, with few side effects on non-compulsive reward-related behaviors in addicts.” For now, the researchers confess that they don’t know whether the reduction in cocaine seeking is caused by altered emotional conditioning, or pure cognitive processing.
Actually, nobody expects optogenetics to be used in this way with humans. The thinking is that transcranial magnetic stimulation, the controversial technique that employs noninvasive electromagnetic stimulation at various points on the scalp to alter brain behavior, would be used in place of invasive zaps with lasers. Expect to hear about clinical trials to test this theory in the near future. David Shurtleff, acting deputy director at the National Institute on Drug Abuse (NIDA), said in a prepared statement that the research “advances our understanding of how the recruitment, activation and the interaction among brain circuits can either restrain or increase motivation to take drugs.”
Chen B.T., Yau H.J., Hatch C., Kusumoto-Yoshida I., Cho S.L., Hopf F.W. & Bonci A. (2013). Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking, Nature, 496 (7445) 359-362. DOI: 10.1038/nature12024
Photo credit: Billy Chen and Antonello Bonci
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Chen Billy T., Yau Hau-Jie, Hatch Christina, Kusumoto-Yoshida Ikue, Cho Saemi L., Hopf F. Woodward, & Bonci Antonello. (2013) Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature, 496(7445), 359-362. DOI: 10.1038/nature12024
Even though I consider that I am across the literature at the boundary of economics and evolutionary biology, now and then an article pops up that I somehow missed. The latest article of this type is a 2009 article by Douglas Kenrick and colleagues, titled (as is this post) Deep Rationality: The Evolutionary Economics of Decision Making. [...]The post Deep Rationality: The Evolutionary Economics of Decision Making appeared first on Evolving Economics.... Read more »
Kenrick, D., Griskevicius, V., Sundie, J., Li, N., Li, Y., & Neuberg, S. (2009) Deep Rationality: The Evolutionary Economics of Decision Making. Social Cognition, 27(5), 764-785. DOI: 10.1521/soco.2009.27.5.764
Pop Quiz: which if the two orange circles is larger? If you think that the circle on the right (the one surrounded by the smaller blue circles) is larger, then you are either a human or a dolphin, but not a pigeon. As it turns out, both [...]... Read more »
Murayama, T., Usui, A., Takeda, E., Kato, K., & Maejima, K. (2012) Relative Size Discrimination and Perception of the Ebbinghaus Illusion in a Bottlenose Dolphin (Tursiops truncatus). Aquatic Mammals, 38(4), 333-342. DOI: 10.1578/AM.38.4.2012.333
Last week Science published a study (a follow-up of Salimpoor et al., 2011) in which Canadian researchers showed that music can arouse feelings of euphoria and craving, similar to tangible rewards that involve the striatal dopaminergic system. ... Read more »
Salimpoor, V., van den Bosch, I., Kovacevic, N., McIntosh, A., Dagher, A., & Zatorre, R. (2013) Interactions Between the Nucleus Accumbens and Auditory Cortices Predict Music Reward Value. Science, 340(6129), 216-219. DOI: 10.1126/science.1231059
Salimpoor, V., Benovoy, M., Larcher, K., Dagher, A., & Zatorre, R. (2011) Anatomically distinct dopamine release during anticipation and experience of peak emotion to music. Nature Neuroscience. DOI: 10.1038/nn.2726
Every Sunday, I'd like to post a review of an interesting peer-reviewed science article. To kick things off I'm picking an old favorite, originally posted in 1964! It is certainly well cited, Google Scholar lists the citation count at 452! Indeed this paper was a "Citation Classic" in Current Contents in 1981. At the time the lead author Robert Bolles, was still living and stated:"I have always believed in the idea that experimenters should look at their animals...the human eyeball is the instrument of choice if you want to observe a new phenomenon, and particularly if you want to gain a new understanding of it."Sprague-Dawley RatIn fact this article describes qualitatively the behaviors of infant rats from birth to about 24 days (rats are weened at day 21). In the first experiment, Bolles and Woods observed 13 litters with an average of 9 pups (117 pups) in their "natural" laboratory environment (cages). The animals were of the Sprague-Dawley line, which is still used today. They did use several different methods of observation and schedules of observation to arrive at a comprehensive guide to the ontogeny of lab rats.They begin with postural observations, describing three postures that develop over time: lying, sitting and standing. Lying being the default resting position of the rat, often using other bodies for support. Sitting began on day 4 when subjects first began to lift their heads, and was fully developed by day 17 when subjects could sit and perform activities such as grooming. Also beginning on day 4 are the first attempts to support weight on the legs, and by day 10 the animals can support themselves. By day 13 they can run, by day 15 they can stand on three legs and scratch with the fourth. They can rear up on two legs with support for the front legs on day 16 and can rear independent of support (for the purpose of play-fighting with siblings) by day 18.In similiar fashion reflexes are described. Without relating the specific timeline the reflexes are: twitiching, head waving, stretching and yawning, body flexion, righting reaction, freezing, sniffing, auditory orientation, and visual orientation. When describing startle response int he auditory orientation section there is a great footnote on the word "click:"*The sound used was relatively well-controlled and constant, but, unfortunately rather poorly defined; it was the sound of a Parker T-Ball Jotter pen being retracted at a distance of approximately 1 foot.Psychologists are hilarious. Also found it interesting that the animals did not freeze in fear until day 26 and they froze for approximately 15 seconds. I've never seen any rats hold still for that long unless they were sleeping. Following this functional activities are described. Here is the list: sleeping, consumatory behavior, locomotor activity, climbing, grooming, exploration manipulation, digging, and defecation Here the theme of development was similar as above, with rudimentary non-functional behaviors appearing first (such as scratching motion without making contact with the skin), that later developed into full-fledged adult-like behavior.Ultimately we get a description of the social behaviors in the observed rats. Social behavior in young rats is evidenced by chasing and fighting. Bolles, and Woods observed rats begin this social play-fighting on day 14 when their eyes began to open.The activity peaks between day 20 and 30 when the whole litter engages in a high level of activity.Table 1In a second experiment Bolles and Woods attempt to quantify the behaviors they observed in the first experiment. Using experimental methods the authors observed 12 rats (2 each from 6 litters) and summarized their behaviors as percentages. To the right is table 1 from the paper. There are many more graphs showing the time course of the development of behaviors and it really is a fascinating reference, but I won't reproduce all of that here.The first point of discussion and perhaps the most salient is that from these findings we can view rats as a far more social animal than might otherwise be considered. Early social interactions are to wrangle for nursing or comfort, and later become play fighting and chasing. As the authors noted this social behavior likely leads to long lasting changes in the adult organism and "offers interesting possibilities for research in this area." (See the next 50 years of rat studies for more on these possibilities)Bolles, R., & Woods, P. (1964). The ontogeny of behaviour in the albino rat Animal Behaviour, 12 (4), 427-441 DOI: 10.1016/0003-3472(64)90062-4... Read more »
Minocycline, the tetracycline antibiotic, is probably not something that most people would traditionally link with autism or conditions presenting with autism-like behaviours. Indeed, the suggestion that antibiotics or antimicrobials if you prefer, may be able to modify either the behaviour or linked biochemistry of the autism spectrum disorders (ASDs) or even influence the onset and expression of ASD is quite frankly a little bit unusual.Minocycline (for chemists) @ Wikipedia But unusual is what often crops up on this blog. And how if one assumes that autism, sorry the autisms, are not just conditions solely pertaining to the grey-pinkish matter floating inside our skull, one starts to see how behaviour and physiology might provide some interesting perspectives. Say for example, when one starts to look at the gut microbiome...On today's post I'm considering a few reports which recently cropped up on the research radar including the results of placebo-controlled trial of minocycline for Fragile X syndrome (FXS) published by Mary Jacena Leigh and colleagues* (open-access), a small open-trial of minocycline reported by Carlos Pardo and colleagues** (open-access) and although not autism-related, the results of a study by Parvin Ataie-Kachoie and colleagues*** (open-access) on what happened to an ovarian cancer cell line when minocycline was added, specifically with the cytokine IL-6 in mind. A bit of a mixed bag of studies by all accounts but with some potential common threads.The Leigh study has already been covered by some media (see here) so no grand description needed from me. Suffice to say that there is a suggestion from this MIND Institute study, that minocycline might have some modest positive impact on various aspects of behaviour in paediatric cases of FXS with the requirement for further research. As per some previous chatter on this blog, this is not necessarily new news for FXS as per studies like the one by Paribello and colleagues**** (open-access). Interestingly, the Paribello results also mention something called matrix metalloproteinase-9 (MMP-9) as a particular target of minocycline which has also been discussed on this blog (see here). So, potentially (potentially!) there may be some merit in looking at minocycline for cases of FXS; although as per my blog caveat, I'm not recommending anything.Moving on. The Pardo study (see here for the trial record), whilst small in participant numbers, looked more directly at the use of minocycline - and vitamin B6 - with ten children diagnosed with an ASD. The focus was on autism with a regressive aetiology linked to presentation, and alongside various behavioural measures, there was also analyses of various biological fluids for "markers of neuroinflammation". The study was open and unblinded so not exactly the same calibre as the Leigh trial.The main result of the trial, er... no clinical improvements following minocycline use, even after six months of use. Indeed not only were no significant changes to behaviour reported but a variety of respiratory and gastrointestinal (GI) side-effects correlated with minocycline use. The efficacy and safety profile was not particularly great based on these study results allowing for the lack of any control group and the dosage used.There were however, a few reported changes to some of the biochemistry under investigation, specifically with brain derived neurotrophic factor (BDNF) and hepatocyte growth factor (HGF) in mind but not in the more classically related parameters such as that MMP-9 connection. This lack of effect of minocycline on MMP-9 is slightly unusual but potentially revealing. Certainly the review by Siller & Broadie***** (open-access) hints that MMP inhibition might be a key part of the effects of minocycline in FXS. It's possible a few scenarios might pertain with regards to the biological/genetic differences between autism and FXS. One might even speculate that there is some involvement for the TIMPs (tissue inhibitors of metalloproteinases) in that non MMP inhibitory effect noted from minocycline in autism, but much more work is perhaps needed.Indeed the authors very overtly noted that "minocycline exerted biological effects that were not translated into behavioral or neurological changes" which certainly questions the link between some of the biochemistry that was seemingly affected and presented symptoms assuming there wasn't more subtle behavioural changes.Finally, there is the Ataie-Kachoie study on minocycline application to ovarian cancer cell lines. I'll freely admit that I know even less about cancer cell lines than I do about autism so please excuse any widely inaccurate statements that I might make. The long-and-short of it was that in the lab, minocycline seems to have an interesting effect on "the IL-6 signaling pathway" at least in ovarian cancer cells such that minocycline might reduce IL-6 or at least prevent increases after certain events. As part of my learning jounrney through this paper I did not know that IL-6 was for example being linked to cancer metastasis as discussed by Tawara and colleagues****** for example. Seemingly this metastasis might correlate with those MMPs (particularly MMP-2 and MMP-9).I know I'm moving further and further away from my autism and FXS purpose with the Ataie-Kachoie data, but there may be some lessons to be learned. That for example minocycline might affect cases of FXS by means of impacting on MMP-9 is already under discussion. The added suggestion that minocycline might also be working on cytokines like IL-6 in an anti-inflammatory fashion is certainly another source of discussion. Indeed, I note from the Pardo autism study, that in Table 3 showing the pre- and post-treatment effects on biochemistry, the value reduction for serum IL-6 just managed to escape that magical significance point coming in at p=0.08. The change in another interesting cytokine, TNF-alpha, was even closer (p=0.074).This has been a post comparing apples and pears to a large extent and reiterating my earlier caveat, I am by no means advocating minocycline for anything other than it's intended use with appropriate medical physician support and supervision. Outside of the discussions already included, what this post does serve to show is that (a) the actions of medicines are not necessarily restricted to what's printed on the patient information leaflet, an... Read more »
Leigh, M., Nguyen, D., Mu, Y., Winarni, T., Schneider, A., Chechi, T., Polussa, J., Doucet, P., Tassone, F., Rivera, S.... (2013) A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome. Journal of Developmental , 34(3), 147-155. DOI: 10.1097/DBP.0b013e318287cd17
Multiple sclerosis (MS) is an immune-mediated inflammatory disease characterized by demyelination in the central nervous system, which leads to a variety of neurological symptoms. Although there is currently no cure for MS, several drugs are available to try and modify … Continue reading →... Read more »
D'haeseleer M, Beelen R, Fierens Y, Cambron M, Vanbinst AM, Verborgh C, Demey J, & De Keyser J. (2013) Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1. Proceedings of the National Academy of Sciences of the United States of America, 110(14), 5654-8. PMID: 23509249
I have had “Thrift Shop” stuck in my head for what seems like days.Yes, it is always on the radio, and yes, I usually listen to it when it is playing. Don't judge me. But why (*Stella scream* wwhhhhyyyyy!) has it established a permanent residence in my brain? I’m going to use a few studies to make the case that it isn’t my fault; I’m led around by my biochemistry. Basically, I’m blaming it on my neurons.Hmmm…where to start. Let’s try to figure out why we like a song (or music in general) in the first place. A study by Valorie Salimpoor et al. in 2011 suggests that it comes down to the biochemistry of pleasure. We, as humans, as animals, find many things in our lives to be pleasurable. Why is this? Well, our brain tells us so. Pleasure is, in essence, a reward for a good stimulus. In the brain, it is largely mediated by dopamine, which also works to reinforce and motivate these behaviors. Now, most people will agree that music is a pleasurable stimulus, but as an abstract stimulus (one not directly related to survival) is it regulated by the same dopamine pathways? In this 2011 study, subjects were asked to select their own “highly pleasurable music” to play for these tests (since musical preferences are so individualized). Then the researchers used PET scanning to estimate dopamine release. Since there are physiological changes that occur during moments of extreme pleasure, they also used the “chills” or “musical frission” response, an objective phychophysiological measurement of clear and discrete patterns of autonomic nervous system arousal. To tease out the response to the music versus the anticipation of the music, they combined the temporal specificity of functional MRI (through the temporal profile of blood oxygenation level - BOLD) with the neurochemical specificity of the PET scan.Salimpoor's group found that the pleasure experienced when listening to music is associated with dopamine activity, that there was a positive correlation between the intensity of “chills” and dopamine release, and an increased BOLD response. In fact, dopamine levels surge during key passages of favorite music and just in anticipation of it. This release is pivotal for establishing and maintaining the behavior, making listening to music a valued experience.Ok, biochemistry…check. Let’s go bigger: What parts of your brain light up when you hear music you like? Salimpoor et al. has published a new study in the April 2013 edition of Science that looks at neural processes active when this pleasurable musical event is happening. Specifically, they look at the reward value the first time a song is heard. We now know that dopamine is involved in familiar music, so what about previously unheard music? To test this, the researchers recruited people, asked them to share their musical tastes (“indie” and “electronic” were the most popular), and used music excerpts selected from a music-recommendation software to pick a unheard song within that preference. To assess reward value, to see if participants liked a song enough that they wanted to hear it again, they were given the option purchase the music with their own money (I know if I have to use my own money then I make sure I love it). Then the participants underwent fMRI scans while listening to musical excerpts and were asked to provide bids of how much they were willing to spend for each song.The researchers found that the reward value (amount of the bid) was directly related to the region of the brain associated with positive prediction error (the NAcc for you brain folks), or pleasant surprises. Increased functional connectivity with this region was made with the auditory cortices, the region known to play a role in the retrieval of previously stored sound information (STG), and the areas implicated in beat processing (caudate and premotor areas). Additionally, increased connectivity was found in regions associated with emotional processing and value-guided decision-making (VMPFC, OFC, and amygdala), but only when sounds gain reward values. When added to the dopamine findings, the activity in these brain regions suggests that when you hear new music your brain looks at its stored information about sound relationships and makes a decision on whether or not to like it based on previous listening experiences and the expectations of tonal events associated with that type of music. If you like it, then your brain gives you a pleasure reward and you end up using your money to buy the song (or otherwise find ways to hear it again). If you like it better than you expected, you get even more delight.Now we know why we like the song and want to hear it again (and again and again…).In the next post we will go further and explore what turns this likeable song into an earworm. Or is it its likeablity at all? (insert cliffhanger music here…dun dun duuuunnnn…)Salimpoor, V., Benovoy, M., Larcher, K., Dagher, A., & Zatorre, R. (2011). Anatomically distinct dopamine release during anticipation and experience of peak emotion to music Nature Neuroscience, 14 (2), 257-262 DOI: 10.1038/nn.2726Salimpoor, V., van den Bosch, I., Kovacevic, N., McIntosh, A., Dagher, A., & Zatorre, R. (2013). Interactions Between the Nucleus Accumbens and Auditory Cortices Predict Music Reward Value Science, 340 (6129), 216-219 DOI: 10.1126/science.1231059...and an article in ScienceNOW "Why Your Brain Loves That New Song"(image via rockandtheology) ... Read more »
Salimpoor, V., Benovoy, M., Larcher, K., Dagher, A., & Zatorre, R. (2011) Anatomically distinct dopamine release during anticipation and experience of peak emotion to music. Nature Neuroscience, 14(2), 257-262. DOI: 10.1038/nn.2726
Salimpoor, V., van den Bosch, I., Kovacevic, N., McIntosh, A., Dagher, A., & Zatorre, R. (2013) Interactions Between the Nucleus Accumbens and Auditory Cortices Predict Music Reward Value. Science, 340(6129), 216-219. DOI: 10.1126/science.1231059
Shakespeare wasn't kidding about the "winter of our discontent." In the colder and darker months, people do more internet searches for mental health terms, from anxiety and ADHD all the way to suicide. Search patterns also promise that like a refreshed browser window, better times are due to arrive soon.
John Ayers, of the Center for Behavioral Epidemiology and Community Health in San Diego, and other researchers dove into Google Trends to explore whether certain searches vary by season. "Seasonal affective disorder is one of the most studied phenomena in mental health," Ayers says, "with many individuals suffering mood changes from summer to winter due to changes in solar intensity." He wanted to find out whether any other mental health complaints changed with the seasons, as some studies had hinted.
Since Google Trends breaks down searches by category, the researchers started in the "mental health" section. Looking at all mental health searches in the United States between 2006 and 2011, they saw a consistent cycle with peaks in the winter and troughs in the summer. (If you do this search yourself, you'll see that there's also a dip around the December holidays—but the curve reliably bottoms out in July of each year.)
The team did some statistical smoothing and found that mental health searches overall were about 14% higher in the winter than in the summer. To confirm that the difference was due to the season, they ran the same analysis on data from Australia. Searches cycled in the same way—about 11% higher in winter than summer—but the peaks in the southern-hemisphere country were almost exactly 6 months out of sync with the United States.
When the scientists broke down searches by specific symptoms or illnesses, the seasonal cycle remained—and in some cases got much stronger. "We were very surprised" to see this, Ayers says. Searches including the terms ADHD, anxiety, bipolar, depression, anorexia or bulimia, OCD, schizophrenia, and suicide all rose in the winter and fell in the summer.
One of the most dramatically cycling search terms was schizophrenia, at 37% higher in the winter. Eating disorder terms varied just as strongly. (The smallest seasonal difference was for anxiety, which was just 7% higher in the winter in the United States, and 15% in Australia.)
Some of this seasonality might be due to the schedule of the school year, Ayers points out. Referrals for kids with ADHD and eating disorders may come from their schools.
Other explanations involve winter itself. The effect of shorter days on our circadian rhythms and hormone levels might be a factor, the authors write, as in seasonal affective disorder. They speculate that a lack of vitamin D (which we make using sunlight) in the winter might contribute. Even omega 3 fatty acids might matter: we consume less of them in winter, and omega 3 deficiency has been linked to some mental illnesses.
There's also the question of what we're doing all season. People hunkered indoors during the colder months may have fewer chances for socializing, which is "a well-known health emollient," the authors write. The same goes for physical activity.
"There is a lot more we need to learn about mental health and seasonality," Ayers says. "For instance, is there a universal mechanism that impacts our mental health?"
Of course, sometimes our malaise isn't about the season.
Whatever portion of mental health is predictable, though, doctors would love to know about it and use that information to help.
This study doesn't give reveal much about low-income or elderly populations who aren't online. And knowing what people are searching for isn't exactly the same as knowing what symptoms they're experiencing. "We are actively working to address these limitations," Ayers says. Working with Google.org, the charitable branch of Google, he hopes to develop systems similar to Google Flu Trends that can track a population's mental health.
"Intuition suggests that these results are reflective of an important link between the seasons and mental health," Ayers says. For now, we have the reassurance of computer algorithms that skies will be clearer soon.
Ayers, J., Althouse, B., Allem, J., Rosenquist, J., & Ford, D. (2013). Seasonality in Seeking Mental Health Information on Google American Journal of Preventive Medicine, 44 (5), 520-525 DOI: 10.1016/j.amepre.2013.01.012
Image: Skaneateles, NY, by me.
... Read more »
Ayers, J., Althouse, B., Allem, J., Rosenquist, J., & Ford, D. (2013) Seasonality in Seeking Mental Health Information on Google. American Journal of Preventive Medicine, 44(5), 520-525. DOI: 10.1016/j.amepre.2013.01.012
Several signalling pathways – namely the mTOR, HIF and insulin signalling pathways – are known to slow ageing and increase longevity under certain conditions. This is a topic of much research, and was discussed at the recent “Talks about TORCs” … Continue reading →... Read more »
Gharbi H, Fabretti F, Bharill P, Rinschen M, Brinkkötter S, Frommolt P, Burst V, Schermer B, Benzing T, & Müller RU. (2013) Loss of the Birt-Hogg-Dubé gene product Folliculin induces longevity in a hypoxia-inducible factor dependent manner. Aging cell. PMID: 23566034
Like lungfish, the other surviving lineage of lobe-finned fishes, coelacanths are actually more closely related to humans and other mammals than to ray-finned fishes such as tuna and trout. Ancient lobe fins were the first vertebrates to brave the land, and the coelacanth genome is expected to reveal much about the origins of tetrapods, the evolutionary line that gave rise to amphibians, reptiles, birds and mammals, says lead author Chris Amemiya, a biologist at the University of Washington in Seattle. “The coelacanth is a cornerstone for our attempt to understand tetrapod evolution,” he says.... Read more »
Lazarus sign, also known as Lazarus reflex, is a complex form of reflex movement of the arms in brain dead patients.
In this phenomenon, the arms of the brain dead patients or the patients with brainstem failure raises to the chest and often fall crossed on to the body (in a place that you may have seen in some of the Egyptian mummies). “The arms flex quickly to the chest from the patient's side, the shoulders adduct, and in some patients, the hands cross or oppose just below the chin. The limbs then return to the patient's side, sometimes asymmetrically,” Researchers reported.
Even weirder is the presence of minor shaky movements of the arms of the patients or the presence of goose bumps on the arms and torso in some cases. Researchers have also reported "respiratory-like movement in a patient with brain death" along with Lazarus sign.
This reflex is a kind of reflex arc generated by the spine that is why it can occur even after brain death, while the other organs are still working. Researchers have found that this phenomenon occurs after several minutes of the removal of the medical ventilators that helped to pump air in and out of brain-dead patients, so that the bodies of the patients would stay alive.
Researchers have also found the presence of Lazarus sign during the testing for apnea - brief pause in breathing - that is one of the criteria for the determination of brain death used by the neurologists.
You can see a video of this reflex here.
Calixto Machado (2007). Brain death: a reappraisal. Springer. p. 79. ISBN 978-0-387-38975-2.
"Practice Parameters: Determining Brain Death in Adults". American Academy of Neurology. 1994. Retrieved 12 July 2009.
Urasaki E, Fukumura A, Itho Y, Itoyama Y, Yamada M, Ushio Y, Wada S, Yokota A, (1988). [Lazarus' sign and respiratory-like movement in a patient with brain death]. [Article in Japanese]. No To Shinkei, 40(12):1111-1116.
Ropper, A. (1984). Unusual spontaneous movements in brain-dead patients Neurology, 34 (8), 1089-1089 DOI: 10.1212/WNL.34.8.1089... Read more »
Ropper, A. (1984) Unusual spontaneous movements in brain-dead patients. Neurology, 34(8), 1089-1089. DOI: 10.1212/WNL.34.8.1089
A new paper could prompt a rethink of a technique that’s become very hot in neuroscience lately: Confounds in multivariate pattern analysis The authors are Princetonians Michael T. Todd and colleagues, and the method in question is multivariate pattern analysis (MVPA). I’ve written about this before and there’s a blog dedicated to it. MVPA searches [...]... Read more »
Todd, M., Nystrom, L., & Cohen, J. (2013) Confounds in multivariate pattern analysis: Theory and rule representation case study. NeuroImage. DOI: 10.1016/j.neuroimage.2013.03.039
In a new study on mice, researchers from the RIKEN Institute, Japan have discovered a compound that could be used to prevent cancer relapse in acute myeloid leukaemia (AML) patients, especially the ones carrying the FLT3-ITD mutation.Read More... Read more »
Saito, Y., Yuki, H., Kuratani, M., Hashizume, Y., Takagi, S., Honma, T., Tanaka, A., Shirouzu, M., Mikuni, J., Handa, N.... (2013) A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo. Science Translational Medicine, 5(181), 181-181. DOI: 10.1126/scitranslmed.3004387
Posted by: Kasra Application of exosomes for therapeutic, especially as drug delivery agents has been always an interest. However, there is limited knowledge on how these vesicles interact with the variety of the cells inside the body and how does the body react to their presence. Takahashi et al. have used exosomes released by a [...]... Read more »
Takahashi Y, Nishikawa M, Shinotsuka H, Matsui Y, Ohara S, Imai T, & Takakura Y. (2013) Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. Journal of biotechnology. PMID: 23562828
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