Here are the articles I thought were tweet-worthy in July 2012. If you find the topics interesting, follow me on twitter. I really appreciate your support.
July was an interesting month, including: unconscious passwords stored in procedural memory, neuroethics of the “gay gene,” Virtually THC-free (but CBD-rich) marijuana, oh and lets not forget the Higgs Boson (puts things in historical context).
Brain: The precuneus: review – involved in self-consciousness, engaged in self-related mental representations - http://bit.ly/LO2lnZ
http://scienceblog.com/55711/children-in-foster-care-develop-resilience-through-compassion/ … children in foster care develop resilience through compassion meditation
List of movies with psychological or cognitive science themes – Indiana http://bit.ly/PIANW8
A Single Brain Structure May Give Winners That Extra Physical Edge: Scientific American – t http://bit.ly/LNKb5Q
The American Scholar: Living With Voices – T. M. Luhrmannhttp://bit.ly/PBJ1iN - Thought-provoking alternative view on auditory hallucinations
Continue reading ‘Month in Review: July – Unconscious passwords, “gay genes,” high-less pot, and the Higgs Boson’
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5-hydroxy-methyl CpGs (5-hmCs) were first discovered in 2009 and shown to be enriched in the brain, but remain a mysterious epigenetic mark, despite intriguing functional findings such as: environmental enrichment’s reduction of it, MeCP2′s preference for 5mc over 5hmc, and it’s possible role as an intermediate in demethylation. This new technique will aid their characterization by allowing absolute quantification and base-resolution localization of the marks. The technique also serves as a reminder of why you should pay attention in orgo, or at least why you should collaborate with people who did!
Now, Emory’s Peng Jin, has collaborated with University of Chicago chemist He Chuan to develop a new derivative of bisulfite sequencing, Tet-Assisted Bisulfite Sequencing (TAB-Seq) that distinguishes 5-hmcs from 5-mcs, as they describe in cell.
Traditional bisulfite sequencing (MethylC-Seq):
- Sequence the sample
- Treat the sample with bisulfite, which converts all non-methylated cytosines to uracils, but leaves 5-mCs and 5-hmCs as cytosines. (The even rarer base 5-carboxy-C (5-caC), is converted by bisulfite into 5-caU.)
- Compare your first sequence to your second. You know the unmethylated cytosines from the first sequence will show up as Ts in the second sequence (because when they are amplified, they will be amplified as Thymidine not Uracil). The methylated and hydroxy-methylated cytosines which show up as Cytosines in both sequences.
So, how can we differentiate 5-hmCs from 5-mCs? In a process that may remind you of all those organic chemistry synthesis problems, TAB-seq involves an extra step to protect the hydroxy-methylated cytosines from TET oxidation.
- Glucosylate 5hmC using β-glucosyltransferase (βGT).
- 5mC is oxidized to 5caC by with an excess of recombinant Tet1. (The blocked 5hmCs (β-glucosyl-5-hydroxymethylcytosine (5gmC) ) are not oxidized.)
- Treat the sample with bisulfite. This converts the Cs and 5-caCs to Us, but doesn’t effect the 5gmC.
- Compare back with traditional bisulfite sequencing. The 5-hmCs are the bases that show up as Cs in these two sequences. (5-mCs will show up as Ts in TAB-seq, but Cs in traditional. Unmodified Cs and CaCs will show up as Ts in both sequences.)
Validation and Findings
Validation of new techniques (proof that they work), is always important, and the paper shows that it works using mass spectrometry.
They validated it’s practicality, by using the technique to map 5-hmCs in human embryonic stem cells (hESCs) and mouse embryonic stem cells (mESCs). In hESCs they found 691,414 5hmCs with a false discovery rate of 5%. Interestingly, though mice have similarly sized genomes, they found much higher levels of 5hmCs–2,057,636–which they hypothesize is also due to the higher levels of Tet1 and Tet2 proteins.
So where are 5hmCs enriched, now that we can identify them precisely? H1 distal-regulatory elements including p300-binding sites (observed/expected [o/e] = 7.6), predicted enhancers (o/e = 7.8), CTCF-binding sites (o/e = 5.1)–CTCF is a transcriptional repressor that blocks interactions between promoters and enhancers and also plays a role in stopping the spread of heterochromatin, and DNase I hypersensitive sites (o/e = 3.4) which are associated with active gene expression. Because, 5-hmCs are enriched at enhancers, the authors speculate that 5-hmC may be specifically recognized by transcription factors as a core base in binding motifs.
Many genes had significant enrichment of 5hmC, but lowly expressed genes had more than highly expressed. 5hmCs showed asymmetry, with more hydroxylation on strands where the CpG was surrounded by Gs. (A similar pattern wasn’t observed for 5mCs.)
5hmCs also tended to be enriched near low CpG areas
Previous findings that identified 5hmCs in high CpG areas, such as CpG island-containing promoters, but these findings are likely do to the bias of mapping techniques which can amplify frequent weak signals and overshadow sparse but strong ones. The present study, found that 5hmCs tended to be enriched in lower CpG areas, especially those with H3K4me3 or bivalent (H3K4Me3 and H3K27ac) chromatin modifications, but how 5hmC interacts with the histone code is still up in the air.
It will be interesting to see if the findings from, generalize to different cell-types, but since hESCs and mESCs showed similar patterns, it suggests that the regulation at least in stem cells is evolutionarily conserved.
It seems this tree will have bountiful fruit, weighing down the branches for some time. I’ll leave a final summary in the authors’ own words:
“We have developed a genome-wide approach to determine 5hmC distribution at base resolution and have generated base-resolution maps of 5hmC in both hESCs and mESCs. These maps provide a template for further understanding the biological roles of 5hmC in stem cells as well as gene regulation in general. In conjunction with methylC-Seq, the TAB-Seq method described here represents a general approach to measure the absolute abundance of 5mC and 5hmC at specific sites or genome-wide, which could be widely applied to various cell types and tissues.”
Kriaucionis, S., & Heintz, N. (2009). The nuclear DNA base , 5-hydroxymethylcytosine is present in brain and enriched in Purkinje neurons. Science, 324(5929), 929-930. (Free full text.)
Szulwach, K. E., Li, X., Li, Y., Song, C.-X., Wu, H., Dai, Q., Irier, H., et al. (2011). 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nature neuroscience, 14(12), 1607-16. Nature Publishing Group. doi:10.1038/nn.2959
Yu M, Hon GC, Szulwach KE, Song CX, Zhang L, Kim A, Li X, Dai Q, Shen Y, Park B, Min JH, Jin P, Ren B, & He C (2012). Base-resolution analysis of 5-hydroxymethylcytosine in the Mammalian genome. Cell, 149 (6), 1368-80 PMID: 22608086
Guo, J. U., Su, Y., Zhong, C., Ming, G.-li, & Song, H. (2011). Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond. Cell Cycle, 10(16), 2662-2668. doi:10.4161/cc.10.16.17093
You may also be interested in the brief article I wrote previously about 5-hmCs and a paper that showed that they are highly enriched in the cerebellum and hippocampus (10x higher than in stem cells), and they increase with age. Further, the authors showed that MeCP2–which strongly binds the unhydroxylated and more ubiquitously expressed version, 5-methyl CpGs–does not bind 5-hmCs. Overexpression of MeCP2 even seems to block TETs from converting 5-mCs into 5-hmCs.
Just learned about oxBS-Seq another method for sequencing, need to look into this. Does anyone know off-hand advantages/disadvantages of either?
Filed under: Epigenetics, Genetics, Human, Molecular, Mouse | 1 Comment
Why Conspiracy thinks he’s possessed by two intergalactic space demons – an Interview with Jonathan Balazs director of Mars Project
You may have seen my tweet about the upcoming documentary Mars Project, which tackles complex issues such as mental illness, drug use, psychiatry, race, and stigma. When director Jonathan Balazs contacted me about his film, I got really excited about it.
If you liked the teaser but want to learn more about the project, check out Balazs’s Indie-Go-Go page (the film is still in production and could really use your help). You might also be interested in the original short film, and my interview with Balazs below.
It’s great topic for Balazs to have chosen, and extremely courageous of “Conspiracy” to discuss and publicize his diagnosis of schizophrenia–a heterogenous disorder that is often swept under the rug, despite the fact that ~1% of the human population suffers from it’s symptoms. There is are a lot of misconceptions surrounding schizophrenia, and I think Mars Project will reach a lot of people that might otherwise be misinformed about the disorder. Further, with a neurotypical identical twin, I think “Conspiracy” is an especially great example of the complexity of psychiatric disease–although schizophrenia has a genetic component, it is far less heritable than autism, and GWAS studies have failed to turn up likely candidate genes.
Despite the difficulty of the problem, I think that genetics will give us the insights to explain schizophrenia biologically within my lifetime. But it will be important for psychiatrists and neuroscientists to remember the other side of biological reductionism–our experiences and thoughts are constantly affected the biochemistry of our brain. We need to explore the whole bio-psycho-social environment for therapies in addition to looking for cleaner drugs.
|What inspired you to make a film where schizophrenia and mental illness plays such a central role?I felt like this whole process was an exercise in self-discovery. The whole process was cumulative, one that developed quite opposite of an Archimedean moment. I had some academic influences sure, but my education came from an innate sense of curiosity toward this mysterious and sometimes terrifying mental disorder called Schizophrenia. As I tried to pin down what it meant to me or how to make sense of it, the more elusive a definition came. I’m probably more confused by that label now than I was when I first began my inquiry.|
In doing research for the film, did you find any good resources explaining schizophrenia, mental illness, etc.?
Yes and no. Symptoms of Schizophrenia (and pretty much any mental disorder) are not so cut-and-dried like a knee-scrape or heart condition, as these are easily observable medical phenomenon. Schizophrenia on the other hand seems more like a philosophical concept, rather than a medical one – a split between a shared universally accepted human reality (if there is such a thing) and someone who’s simply too involved in their own mind. The dimensions of human expression are too complex, unpredictable and culturally influenced that there can be no concrete definition as they currently stand. I was quite surprised to discover a growing number of psychiatrist doctors who agreed with this and who defined people by their identity vs. their brain organ.
My research into these issues is ongoing, but I have found a great deal of value in the work of Dr. R.D. Laing (someone I wish I could have shared a drink with) and Dr. Thomas Szasz. I think it’s unfortunate that they have been labeled as patriarchs of the “Anti-Psychiatry” movement because there is value in what they have written. One of our interview subjects Dr. Gordon Warme has been a defining influence in my study of mental illness and on Mars Project. I’ve been trudging through Michel Foucault’s writings and wonder where the popular philosophers are in 2012 – it seems like they’ve been replaced by the theoretical physicists and astronomers.
What was it like to meet “Conspiracy” for the first time?
Loud, I think we were at a rap show.
How did you find the psychiatrists you interviewed for the film? Was it difficult finding academics willing to go on camera?
I have to give credit where it’s due; executive producer David Reville was instrumental in those interviews as I’m still very “green” with respect to disabilities studies and psychiatry. He was the one who put together the interviews with Dr. Gordon Warme, Dr. Kwame McKenzie and disabilities scholar Erick Fabris. We were very fortunate to receive insight from these people all doing important work in their area(s). I think the most difficult aspect of interviewing them was scheduling them all on the same day. I don’t think it could have been more successful honestly.
Do you think mental illness can be explained entirely through biology? Are you, yourself, a spiritual person?
Those are two different questions, I think. No, I don’t think the biological argument is entirely sufficient to explain these mental illness phenomena. I don’t think I’m qualified to say that there could never be a biological explanation, though I will note that ‘biology’ seems to be a primer for something that can’t be explained fully. I have too much respect for human culture to chalk up society as a vast network of neurons farting out serotonin and dopamine. For some people the medical model might ring true; those who do follow the path of the shaman in the white lab-coat are free to do so because the path of “recovery” (or more aptly management) lies within the individual.
I am not a spiritual person by most definitions and definitely not religious, I sometimes refer to myself as a rational agnostic.
What role do artists play in spreading scientific information?
I think it’s important that more artists recognize and value the influence of scientific discourse, though I admit that there is a concern with this information being presented accurately (and to an extent objectively) while still keeping with the identity of the artist. I would add that art and science are far too often pitted against each other when they’re essentially cut from the same cloth. It encouraged me to hear Dr. Kwame McKenzie discuss the art of psychiatric medicine in our interview.
After getting to know “Conspiracy” so well, are there parts of the psychiatric system or the way we address these illness,that you personally think need to be changed?
I can only say what I might do for myself, because fixing the mind lies with the patient alone – psychiatry is just one of the tools available. If I ever suffer from prolonged psychosis, who knows what I’d do? My feeling though, is that many of these potent, mind-altering psychiatric drugs are prescribed too freely – as if the answer to your crisis can be sought through a little pill. Some of these drugs essentially dull every aspect of your spirit and not just those undesirable or offensive aspects of behavior. The systematic, state-imposed ‘zombification’ of vulnerable individuals doesn’t seem like the best path; some might read this and ask what business a filmmaker has on mental health policies.
When will the movie be released, and do you have other upcoming projects?
The film will be completed by the fall and hopefully it will hit festival screens in the autumn. I hope that we’ll be able to negotiate wide distribution in theatres and certain online and V.O.D. platforms. With the amount of cussing in the film, I doubt that many networks will want to program it on their channels.
I’m working on a short documentary featuring the work of illustrator Pearl Rachinsky and I’m hoping to shop around an expanded treatment based on a short film I wrote a few years ago called Thane Spa on the monetization of suicide.
For more information on Mars Project see www.marsprojectmovie.com, ‘like’ us on Facebook, check our Youtube channel and please help us support our indiegogo campaign. I’m a little too serious on Twitter, but you can follow me just the same @BrandoBalazs.
Know of any good movies or documentaries out there about mental illness or schizophrenia? I need to watch something while I wait for Mars Project, so suggestions would be great!
Filed under: Antipsychotics, Antipsychotics, Drugs, Film, Genetics, Human, Psychiatric, Schizophrenia | Leave a Comment
|Rank||Brand Name||Generic Name||# of U.S. Prescriptions||Use|
|10||Valium||Diazepam||14,009,000||Anxiety, Panic disorder|
|Benzodiazapene – Positive allosteric modulation of GabaA Receptors – (Facilitates GabaA inhibition in use dependent manner)|
|9||Effexor XR||Venlafaxine||14,992,000||Depression,Anxiety, Panic disorder – “Off-label” for diabetic neuropathy and migrane|
|Serotonin-norepinephrine reuptake inhibitor (SNRI) – increases serotonine and norepinephrine|
|8||Seroquel||Quetiapine||15,814,000||Schizophrenia, Bipolar disorder, “add-on” for Depression|
|“Atypical antipsychotic” – Blocks dopamine, serotonin, adrenergic and histamine receptors|
|7||Cymbalta||Duloxetine||16,626,000||Depression,Anxiety, fibromyalgia, diabetic neuropathy|
|Serotonin-norepinephrine reuptake inhibitor (SNRI) – increases serotonine and norepinephrine in a use dependent manner|
|6||Desyrel||Trazodone||18,873,000||Depression, Bipolar Depression (sometimes), Anxiety|
|Predominantly a 5-HT2A receptor antagonist, also 5-HT1A partial agonist and Selective Serotonin Reuptake inhibitor (SSRI)|
|5||Prozac||Fluoxetine||19,499,000||Depression, Anxiety, OCD, Bulemia, PMDD|
|Selective Serotonin Reuptake inhibitor (SSRI), 5-HT2C receptor antagonist, σ1 Receptor agonist|
|4||Zoloft||Sertraline||19,500,000||Depression,Anxiety, OCD,PTSD, PMDD|
|Selective Serotonin Reuptake inhibitor (SSRI) – Weak σ1 receptor agonist and α1-adrenoreceptor antagonist|
|3||Ativan||Lorazepam||25,868,000||Anxiety, panic disorder|
|Benzodiazapene – Positive allosteric modulation of GabaA Receptors – (Facilitates GabaA inhibition in use dependent manner)|
|Selective Serotonin Reuptake inhibitor (SSRI)|
|Benzodiazapene – Positive allosteric modulation of GabaA Receptors – (Facilitates GabaA inhibition in use dependent manner)|
It’s a little crazy, pun totally intended, how much we’re prescribing SSRIs, when some meta analyses say they aren’t much better than placebo. Placebo effects are probably doing something very physiological in this case, by relieving anxiety. I would say that sugar pills would be a lot cheaper and save us money, but I don’t think we need more sugar either. Maybe, we should go Germany’s route and prescribe St. John’s Wort for mild depression?
- 10. Hydrochlorothiazide (various brand names) lowers blood pressure — 47.8 million
- 9. Generic Glucophage (metformin) diabetes drug — 48.3 million
- 8. Amoxicillin (various brand names) antibiotic — 52.3 million
- 7. Azithromycin (brand names include Z-Pak and Zithromax), antibiotic — 52.6 million
- 6. Generic Prilosec (omeprazole), antacid drug — 53.4 million (does not include over-the-counter sales)
- 5. Generic Norvasc (amlodipine besylate), angina/blood pressure drug — 57.2 million
- 4. Generic Synthroid (levothyroxine sodium), synthetic thyroid hormone — 70.5 million
- 3. Lisinopril (brand names include Prinivil and Zestril), blood pressure drug — 87.4 million
- 2. Generic Zocor (simvastatin), cholesterol-lowering statin drug — 94.1 million
- 1. Hydrocodone (combined with acetaminophen), opiate/painkiller — 131.2 million
This list doesn’t contain any psychiatric drugs–Xanax just barely misses the cut–but the #1 drug, hydrocodone, is psychoactive. However, while our #1 psychiatric drug did not make it into the top 10 most prescribed, our #8 drug, the atypical antipsychotic Seroquel clocks in at #6 on the drugs we spend the most money on (shown bellow).
Also of note, is the #1 most prescribed drug for teenagers. Can you guess what it is? Methylphenidate, Ritalin, the ADHD medicine. I’m most surprised it’s not adderall at this point.
According to ABC news: “The United States makes up only 4.6 percent of the world’s population, but consumes 80 percent of its opioids — and 99 percent of the world’s hydrocodone, the opiate that is in Vicodin.” Our use of hydrocodone and other opiate painkillers has many issues: such as diversion and abuse and use as a bandage in chronic pain or injury instead of treating underlying issues (where it may even make pain worse in the long term). Another startling new trend, is the spike in newborns born dependent on opiates:
The best sellers are often generic drugs, so it is also interesting to see where “big pharma” is making the most money:
Top 10 drug we spend the most money on in the United States overall (according to IMS Institute for Healthcare Informatics in 2011)
- 10. Epogen, injectable anemia drug — $3.3 billion
- 9. Actos, diabetes drug — $3.5 billion
- 8. Crestor, cholesterol-lowering statin drug — $3.8 billion
- 7. Singulair, oral asthma drug — $4.1 billion
- 6. Seroquel, antipsychotic drug — $4.4 billion
- 5. Abilify, antipsychotic drug — $4.6 billion
- 4. Advair Diskus, asthma inhaler — $4.7 billion
- 3. Plavix, blood thinner — $6.1 billion
- 2. Nexium, antacid drug — $6.3 billion
- 1. Lipitor, cholesterol-lowering statin drug — $7.2 billion
Note the atypical antipsychotics Seroquel and Abilities. One meta-analysis of antipsychotics, showed they have questionable benefit over the now-generic typical antipsychotics, and were not a cost-effective answer. The studies analyzed all suffer from the same difficulties that genetics studies of schizophrenia do, because patients are so heterogeneous and diagnoses are somewhat subjective. Atypical prescriptions are probably too high, due to advertising and “newer is better” kind of thinking, but because the disorders are heterogeneous, I’m glad that we have more drugs to choose from and try out with individual patients.
Also, I’m also shocked that antacid drugs can make that much money, but I guess it’s in a different ballpark than Tums.
References / Further Reading
Turner, E. H., Matthews, A. M., Linardatos, E., Tell, R. A., & Rosenthal, R. (2008). Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy. New England Journal of Medicine, 358(3), 252-260. Massachusetts Medical Society. doi:10.1056/NEJMsa065779
Hanrahan, P., Luchins, D. J., Fabian, R., & Tolley, G. (2006). Cost-effectiveness of atypical antipsychotic medications versus conventional medication. Expert Opinion on Pharmacotherapy, 7(13), 1749-1758. Expert Opinion. doi:10.1517/146565220.127.116.119
Filed under: Antipsychotics, Anxiety, Benzodiazepine, Depression, Dopamine, Pharmacology, Psychiatric, Public Health, Schizophrenia, Serotonin, SNRI, SSRI | 3 Comments
Tags: Drugs, Medicine, Pharmaceuticals, Pharmacology, Pharmacy, Prescription Drugs
COMT, Catechol-O-methyl transferase, is an enzyme that degrades catecholamines–such as dopamine, epinephrine, and norepinephrine (or adrenaline and noradrenaline as they are called in the UK). It was first discovered in the ’50s by Nobel laureate and pirate Julius Axelrod.
More recently, scientists discovered an evolutionarily recent nonsynonomous single-nucleotide polymorphism (SNP) in the protein-coding portion of the COMT gene–Val158Met or rs4680. This means that some people carry a version of the gene that differs by a single DNA basepair and alters the 158th amino acid in the protein, changing it from valine to methionine.
Just because an amino acid has been altered, doesn’t mean there will necessary be a functional change in the protein, that has to be studied explicitly, but in this case it was dramatic.
Scientists have studied the Val158Met polymorphism and found dramatic effects in its enzymatic activity, expression levels, and behavioral phenotypes for its carriers as well with influences on subjective well-being, emotional processing, and possibly even dopamine-related diseases such as schizophrenia and Parkinsons. It is an extremely well-studied polymorphism with 165 papers referencing it on pubmed.
COMT Val158Met’s biochemical effects
Filed under: Behavior, Cannabis, Dorsolateral PFC, Drugs, Genetics, Human, Schizophrenia, SNPs, Uncategorized | 5 Comments
Tags: Biology, cogsci, Genetics, neuro, Neuroscience, psychology, Science
Get those multimodal neurons firing! This is a followup to my post on the most popular neuroscience blogs. I realized that I left out some of my own favorite sources for neuroscience news and information–podcasts! Later on, I’ll make posts about online lectures and courses.
Podcasts have gotten me through a lot of boring lab work, and introduced me to and piqued my interest in many topics. My top 3 podcasts (in alphabetic order):
1. Brain Science Podcast – Hosted by an ER doctor, Ginger Campbell, who does a great job of getting big name neuroscientists, talking in depth on a topic, but keeping everything very accessible and easy to understand. The tagline for the show is the wonderful “The show for everyone who has a brain.” I find it especially good for finding books, and getting introduced to schools of psychology out neuroscience I hadn’t previously heard of. I also love that Ginger repeats and clarifies important points in the middle and end of episodes and always asks the guests to give advice to students interest in neuroscience. The website also features annotated transcripts of the episodes if you’d prefer to keep things occipital. Monthly episodes ~1 hr.
2. Neuropod – Nature’s official neuroscience podcast hosted by neuroscience journalist Kerri Smith. Each episode is around a half hour and usually features 3-4 pieces interviewing authors of recent papers and reviews. (The website also has links to the papers if they peak your interest.) The whole format is better produced than many podcasts and resembles feature pieces on public radio. Monthly episodes ~30 minutes.
3. Neuroscientist’s Talk Shop – As the name implies this one is a little more intense, speakers will assume you are at least a neuroscience graduate student, though I think you can still get a lot out of it, even if you aren’t. It usually has a more computational, electrophysiologal, and information processing slant. Each episode consists of an informal discussion between a few of University of San Antonio’s professors. They are all great speakers and it can often be a lively and funny discussion. I like that they are willing to speculate on topics (though like any good scientists, they make it more than clear when they are speculating). It’s a great way to see how professional neuroscientists think and talk. Frequency varies 1-3 weeks during the school year ~45 min.
Filed under: Blogs, Podcasts, Review, Talks | Leave a Comment