[Sciences/Neurosciences] International/European Society of Neurochemistry (ISN-ESN) Meeting 2017 – Paris (France). A summary

Today is the last day of the ISN-ESN biannual meeting taking place this year in Paris (France). The venue was taking place at the Palais Des Congres near Porte Maillot (right on the periphery of Paris). I thought it was a great place for the venue, first by its location (excentered from inner Paris, giving more affordable options for lodging), but also by hosting a shopping mall in the basement level (with affordable lunch options including a Galeries Gourmandes and a Paul Patisserie). Another special perk was the presence of complimentary coffee during the morning and afternoon session breaks.
The presence of vendors was fairly minimal but the welcome package provided by ISN was fairly nice. It included:

A mug of your choice (I took molecular basis of disease of course),
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And a set of 10 RATP tickets allowing you to wander inside Paris when the urge of sightseeing overcomes your thirst of science:
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This is a first time I am attending a ISN meeting, following the acceptance of my paper by the Journal of Neurochemistry. It is a small conference (maybe 500 attendees, this is a high estimate) but it does not mean the quality of science was small too. The conference was taking place on four full days (21-24 August) with morning plenary lectures including a senior keynote speaker and a junior keynote speaker, followed by two breakout sessions (one morning, one afternoon) covering different topics including development, gene and genetics, synapses and neurotransmission, molecular basis of diseases, neurodegeneration or cell energetics.

One of the nice thing was this huge crowd-sourced timeline in which attendees could fill it with stickers indicating their first publication in Journal of Neurochemistry, their first enrollment in one of the different societies.
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Interesting fact, the first ISN took place in Strasbourg (my hometown) in 1967 and 50 years later, one attendee was still attending the same ISN meeting! Hail to the elders!

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Senior keynote lectures were very instructive including a keynote lecture by Pr. Tamas Horvath (Yale University, USA) on the selective depletion of Agouti-gene related protein neurons and its impact on feeding behavior. These neurons are present are very few numbers (3000-6000) but play important role in feeding. The take home message? Resistance (to chocolate cake) is futile!
Another interesting keynote lecture was from Pr. Yoshi Hirabayashi (RIKEN, Japan) on glycolipids, their known impact on Gaucher’s disease and more interestingly their contribution into Parkinson’s disease. One slide to highlight the complexity of the topic is this one summarizing the different types of glycosphingolipids present in mammalian brains. Yes, this will be part of your next biochemistry quiz.

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Finally, todays senior keynote lecture by Pr. Giovanna Malluci (Cambridge University, UK) on the importance of unfolded-protein response stress and its contribution to several neurodegenerative diseases (in particular on prion diseases), with the importance of elongation factor 2E (elF2E) as a rescue pathway in neurodegeneration. More interestingly was the description in the second part of the cold-shock response and the contribution of RBM3 as a neuroprotective agent. I was aware of the importance of cold in hypoxia tolerance (drowning in frigid water decreases the gravity of brain injury inflicted by hypoxia compared to warm water) but I was always skeptical on the use of cooling blanket on stroke patients to cool their body down. It seems there is some vestigial molecular pathways initially used in evolutionary adaptation in hibernating animals that maybe still present in non-hibernating animals via RBM3. It would be interesting to see how this pathway cross-talk with the HIF-1 pathway.

Other concurrent sessions were interesting including one on transporters in the CNS (especially one on glutathione handling in astrocytes through MRPs), the importance of TDP-43 in ALS and other diseases, SIRT6 and its importance in neurodegenerative (including the possible involvement of Wnt and HIF-1 pathways), mitochondria bioenergetics and the discussion and debate on mitochondria movements in astrocytes and neurons (with even the discussion on Eng Lo’s paper on mitochondria transfer following stroke injury) or novel aspects of neural development and neurogenesis.

The poster sessions were well designed with the exception of the manned poster sessions. Poster sessions were initially scheduled between the morning and afternoon concurrent sessions but the presence of poster authors was requested only during the evening socials after 6:00PM. By principle, I am done with science by 5:00PM if I have been bathing in since the morning, so I ended up seeing a lot of “empty” posters and wished I could have a chance to chat and talk to the poster authors. I think this is were SfN poster session is more adapted: you have half-day to showcase your poster and have a time period (2 hours) to stand next your poster. Maybe the organizers could take this into account for ISN2019 taking place in Montreal.

Finally, the ISN see themselves through the Neurochemistry consortium as funny people and hell yeah they know how to bring fun with a complimentary funny photomaton booth. Another opportunity for me to let the weird and funny coming out of me 🙂

See you in probably the ASN meeting 2018 in Riverside, CA and ISN2019 in Montreal (Quebec, Canada)!

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[Sciences/Junk Sciences] Remember the deadly turmeric IV infusion done in a holistic clinic? Lessons from the FDA report

You have remember this story of this young woman that died shortly after recieving an IV infusion of turmeric acid (aka curcumin, a bioactive compound found in Curcuma) in a holistic clinic in California few months ago (http://www.10news.com/news/team-10/encinitas-woman-dead-after-i-v-infusion-of-turmeric).
This story baffled me for many reasons. First, it was really puzzling me on how quack medicine (rebranding itself as “holistic” and “integrative” to appear more sciencey) have been moving slowly but surely into medical procedures normally held by medical staff, with some dubious claims of “IV therapy” in which the onset of an IV line and pumping up vitamins straight into your systemic circulation will help you “detox” or “rejunevate”.
Second, how turmeric acid that have been bounced by some “health/food gurus” as superfood (move on kale and quinoa, you are so 2015!) quickly moved on as therapeutics without even having the right science to back it up (until now only preclinical studies done in cells grown on Petri dishes and in rodents), with the glittery “cures-it-all” sticker all over it.
You see, turmeric acid is way far from being the next wonder drug as sold by woo peddlers. Why? Lets see some of its features (https://pubchem.ncbi.nlm.nih.gov/compound/curcumin#section=Top).
First thing, turmeric acid has a problem. A huge problem. This problem is solubility. It has a calculated xLogP of 3.2, this is already telling us this compounds is lipophilic (likes fat). It will dissolve well in oil, but not well in water (less than 0.1mg/mL according to Santa Cruz Biotechnology data sheet). If you try to go beyond that value, you will have a saturated solution with turmeric acid precipitates. These precipitates can have serious effect if injected into an IV line, if these particles are big enough to clog some capillaries.
You can circumvent things around by tweaking nanoparticles carriers. Still, even from food intake, turmeric has a very low bioavailability. From 100g of pure turmeric acid swallowed, only 1g will effectively reach the circulation and circulate through your body.
The second problem with turmeric is its pharmacokinetic profile. According to the reference cited by the FDA report, turmeric is highly unstable at physiological pH (7.4). According to this review, the elimination half-life (t1/2) for turmeric is very low (1.7+/-0.5h). By 6 hours, most of the turmeric injected via IV route will be gone. Therefore, if turmeric was considering for therapeutic, it would require multiple dosing that are either ridiculous (Dosing interval of about ~2 hours, therefore swallowing a pill every two hours) or being on a constant IV infusion (that is not realistic for everyday life).
Third problem with turmeric? Its pharmacological activity. Two important parameters have to be accounted for a drug candidate: its selectivity (does the drug targets one or several proteins?) and IC50 (what is the concentration needed to achieve 50% inhibition).
The problem with turmeric is that it is considered as a “dirty” molecule because it hits a bit of everything, with many signaling pathways affected by it. The second problem is its very high IC50. Anti-cancerous activity of turmeric swings around 10microM in various cancer cell lines in a Petri dish and have other targets at higher doses. This is not a horrible value, not a good value either. Usually we want to reach an IC50 in the nanoM range (10’000 less concentration than 10µM). Thats not the case for turmeric. Maybe by tweaking the chemical structure we may improve its IC50, but since the compound itself has so many targets trying to optimize it for therapeutic purposes maybe simply a waste of time.
If we stick to the 10µM concentration and an average molecular weight of 328g.mol-1 for turmeric, we need a concentration of 3mg/L or (0.003mg/mL) to expect some biological activity. Now the problems come in with the FDA report. There are two reported cases of adverse events, including the fatal cases. In both cases, patient had an IV line of turmeric acid. In both cases, both patients were mentioned an IV infusion of turmeric acid at 10mg/mL. First, this concentration would have made no sense. It is 300 times higher than the hypothetical dose needed to achieve a biological activity in vivo. Second, the final concentration in the IV bag was much less than this concentration, as the FDA reported only 1% of the prescribed concentration was found in the IV bag (0.00235mg/mL).
Someone has been not only been deceiving their customers by selling you less product than advertised (1% net content is honestly a huge rip-off) but also had absolutely no clues on what they were injecting. So we can blame two actors: either the compounding company that prepared the turmeric or the holistic clinic (I guess you can point who is the crook in the story).
Both cases involved ImprimisRX, a compounding pharmacy. These are laboratories under the responsibility of a pharmacist holding a specialization in compounding. He or she has to follow established rules and protocols, adhere to good manufacturing procedures in compliance with the FDA. It seems there is no wrongdoing from the compounding. The compounding produced an emulsified form of turmeric (to increase its solubility). Yet, the final concentration in the vial was about 0.205mg/mL or about 2% of the amount put on the label. Since turmeric is highly unstable under aqueous solution (even in its emulsified form) we cannot exclude a degradation of the product from the time it got compounded to the time it was administered. In aqueous protein-free solution, 90% of turmeric acid is degraded within 30 minutes (https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM466380.pdf).
Now comes an another problem: was there any deception between ImprimisRX and the holistic clinic? One of the reason is the use of polyethylene glycol 40 (PEG40) castor oil in the compounding process. PEG40 may contain traces of diethylene glycol (DEG), a very well known toxic compound if ingested, with a toxicity of about 1mg/kg. DEG is a byproduct of PEG production, therefore the FDA has different quality grades of PEG whether it is destined for non-medical usage or for human consumption. DEG was found at a concentration of 0.21% (0.21g pure DEG in 100g of PEG40). The PEG40 used for the compounding was 1.25% with the clear label “CAUTION: For manufacturing or laboratory use only.” Why the compounding pharmacy used that ungraded PEG40? We don’t know yet.
PEG40 oils are used for cosmetics and considered safe for cosmetics usage  because the bioavailability of this compound is small and suited for topical application (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505343/). But you have to remember that a product that is considered safe in an administration mode is not in another administration route. This is probably explaining the adverse effect observed.
The second possible issues is a possible allergic reaction to PEG40, as the FDA cited previous reports of allergic reactions of patients exposed to PEG formulations following IV infusion of anti-cancerous agents.
By now, your enthusiasm for cur turmeric should (rightly) wind down. Turmeric is certainly great for spicing your food, not much for your health. But most of all, don’t let a “holistic clinic” perform any type of IV infusion.
IV infusion is a very delicate procedure, used for restricted applications (chemotherapy, anesthesia, infectious disease……) by a trained personnel in a medical environment (hospital or medical clinic).

[Music/Gothic Metal] Seven Spires – Solveig (80%)

Fresh from the press, a band that came out of nowhere in my disc library: Seven Spires, a FFM band from Boston, Massachusetts. Their first album “Solveig” was released this Friday and of course it ends up being reviewed by me. I have been listening several times, interrupted by the livestream of “Wacken Open Air 2017” (thats very nice from the organizers to have a livestream of the main line-up).
This is a 15-track album, lasting 75 minutes. iTunes classified it as death metal/black metal and fairly I disagree with it. Because this album does not fit in one category. It is definitely metal but explores different facets with some gothic, some symphonic, some even sounding like some black symphonic a la “Dimmu Borgir”. So yes, it is a very schizophrenic album but it also a kind of a good showcase for Adrienne Cowan, allowing her to hear her vocal range from clean to growls.
We get into “The Siren” an introduction that really sounds like a Danny Elfman track, you know something like straight from a gothic ambience of a “Nightmare Before Christmas”. It seamlessly brings to “Encounter” blending this Elfman tunes with heavy riffs. Good stuff, really gives you a good grip on the ride. Some fresh air, it has a been a while we did not hear a good gothic metal band and Seven Spires is kind of baiting with that appeal. Then we move to “The Siren (Reprise)” that rather sounds like a revisited opening sequence for “Encounter”. I found it odd to have right in the third track, I would have put as a bonus track. The fourth “Cabaret of Dreams”, sounds a bit more rock giving this kind of abruptness in the ride. Certainly not my favorite. “Choices” sets the train back on its track, brining on some symphonic elements with a heavier tone. A very engaging song that should have been in my opinion right after “Encounter”. “Closure” continues into this very enjoying emotional riding experience, with a slower tone supported by orchestral arrangements and maybe an annoying presence of the bass guitar. Thats one thing I noted, the presence of the bass was too much accentuated in this album. I know the bass player has bad rep but the bass is part of the background unless you are Iron Maiden or Lemmy Kilmister. “100 days” is this nice melodic ballad giving a nice interlude in the album, right in the middle of the album. “Stay” brings us a power melodic tone that is very engaging, a good one. “The Paradox” brings us for the first time Adrienne on the growls into this track that brings on the excitement of a symphonic black metal straight out of a good “Dimmu Borgir” album. You know this kind of track that put your auditive and limbic cortices into fritz, with this rush of dopamine that wants to mosh into your living room by this brutal riffs blended with awesome melodics. Oh yeah! Thats my favorite! This is kind of a title that tells you this band with the right direction that breaks some charts. “Serenity” is falling into more conventional genres, even sounding like metal core. “Depths” brings us back to calmer tracks, a nice one, something similar to the chords of Alissa or Vicky style encountered in “The Agonist”. “Distant Lights” brings on the melodic power metal. Nice but nothing that impressed me. “Burn”, brings on back this “Dimmu Borgir” feels with a good spoon of power metal, sending again into a rollercoaster ride from Hell.  “Ashes” brings on this what I call “anime metal”. Dont ask me why, but this is the kind of metal that would match very well with a opening sequence of an anime. Nice! “Reflections” brings back the orchestral sounding like a ending sequence.
The overall album is good, pretty good. But it kind of misses the overall excitement that some other albums have sparked in the previous months. Maybe it is this mix of different styles and some questionable tracks. Sometimes, lesser is better.
However, this album is a great showcase of Adrienne’s vocal range and ability to sing both in clean and growls. The band also have shown its comfort in playing in different styles with ease. But lets be honest, Seven Spires enters a market highly competitive, especially if they think to take the Symphonic metal direction. Right now, melodic death and power metal are very good niches for entering FFMs. Really, their black symphonic metal composition of “The Paradox” and “Burn” really felt taking a rollercoaster from Hell, giving the thrills and chills of an adrenaline rush only to kick in the endorphins at the end of the ride, sending you in this musical euphoria.

[Metal/Melodic Death] Exalt The Throne Last Show @ Dallas, TX (O’Rileys Bar – 07/29/2017)

We are born, we live and we die. Some people call it the circle of life. I don’t, i prefer the allusion of the thread of life metaphorized by the Ancient Greek through as the Moirai (or Fates) Clotho, Lachesis and Atropos. We exist as a thread with our beginning and our end. We cease to exist with the continuum but we remains as part of the fabric (history).
Same applies for our intellectual endeavors, scientific and artistic alike.
I have seen bands being born bringing the joy and the excitement with their innocence and novelty. I have bands that have been following me through my life, becoming a sort of travel companions through my own journey. Sadly, I also have seen bands giving their last breath and close their eyes.
The announcement of a band going into hiatus or disbanding is always a sad news to hear because you know that you will not experience anymore that auditory and visual stimuli that made them listen and like their work, over and over.
One of the band that lately gave their final curtain, their “barroud d’honneur” was Exalt The Throne (Dallas, TX). I discovered the band very recently as their supported Epica second leg North American Tour following the release of “The Quantum Enigma”. It was love at first sight because of this very interesting blend of melodic death (with high-paced guitars of Charles, Tim and Kanyon and drums) with symphonic metal (clean female vocals performed by Courtney). It was neither the former nor the latter. It was its own blend that made them unique. When the band announced their final show a month ago, it was unexpected and a very sad moment to experience.
However, I decided to drive all the way to attend their final show and have a chance to collect a last souvenir from the band. The gig was short but oh boy you could feel how the band matured over the last 18 months, refining their performance.  The band played three of their songs present in their album “Long Live the King” (“Long Live The King”; “Perpetual Agony” and “Rampant Idolatry”) and one cover from Amon Amarth (I ain’t fan of folk metal but if someone can help identify the song, I would be more than happy to update this post).

If I have to find a silver lining into this final show, I would definitely cite the first law of thermodynamics that stipulates “energy is not created nor destroyed in a closed system, it is only transformed and transferred”. Same applies to the artistic energy. It is only transformed and transferred. I wish to the band members all the best and success in their endeavors and in their personal and professional careers. The king is dead! Long live the king!