[Sciences/BBB] T Lymphocytes and Cytotoxic Astrocyte Blebs Correlate across Autism Brains (DiStasio et al., Ann Neurol 2019)

I  have been recently approached on social media to discuss about the recent study published by Anderson and colleagues in Annals of Neurology (https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25610), in which the authors reported the presence of residing CD8 cytotoxic T-cells in the perivascular space of brain samples from ASD patients. I wrote about it, and gave my first impressions about reading the study. After such discussion, I realized that I have an interesting review that worth being shared here on my blog.
Here is the summary of my review of this paper as I wrote it on social media. I made some corrections (mostly spelling and grammar), as well as some changes in the writing style (I wrote these comments on the spur of the moment, as I went through the paper). Also due to copyrights, I will not show any figures and tables from the study.

About the authors: The first author is Dr. Marcello DiStasio (MD/PhD) and the senior author is Dr. Matthew P. Anderson, MD/PhD. He is a clinical faculty of Harvard Medical School and member of the Department of Neurology and Pathology a Beth Israel Deaconess Medical Center, with an affiliation with Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center.  So we have some high profile and experts in neurodevelopment disabilities.

About the journal: The journal is published under Wiley, and is the official journal of the American Neurological Association and the Child Neurological Society. It has an impact factor of 9.49 and is in the top quartiles of neurology and neurosciences journal. Therefore, we have a study published in a very good journal that is relevant to the topic.

About the study design: The study is mostly observational and relies mostly on histological methods (tissue sections followed by staining using chemical dyes and/or antibodies targeting specific proteins). Tissue samples are freshly isolated from postmortem patients (which is a big plus compared to formalin-fixed samples, and opens up the ability to perform protein and RNA analysis if the samples are immediately treated for extraction). The sample size is pretty decent (N=25-30) with a large age spectrum and various types of ASD represented. First interesting to note, 50% of the ASD brain (N=25, not bad) have a history of seizures. Less than 30% of control brains (N=30) have history of seizures. Important thing to consider as a comorbidities and evenutally as a cofounding factor.

About the results: This is my summary of the different figures. By copyright concerns I am not showing the actual figures, but you can overlap my comments to the figures as I have separated them into sections.
Figure 1: Me being cranky, I wanted to see control brain pictures, but not avail. Also with immuno pictures, you have to be super-precautious because there is a high risk of cherry-picking a brain slice, and claim it is representative of all brain. Nevertheless lets discuss it here. On the left panel, we have an H&E staining. Pretty much a vanilla staining. Now, if you want to show a certain protein, you can do it with the right antibody and staining (DAB/peroxidase stain). It appears as the dark brown color. We can see a strong GFAP staining around the vasculature (hollow structure). Astrocytes usually line up blood vessels by forming end-feet process. S100B and ALDH1L1 are pretty standard proteins for astrocytes. However seeing GFAP expression in human astrocytes means these cells are stressed out and are reactive. This is what the quantitative bar graph is telling us. We can also see some CD8 in this perivascular space. These are the cytotoxic T-cells. I wonder what they are doing there, as they can cross the BBB only during brain injury, as microglial cells will äctivate” these endothelial cells and allow white blood cells to adhere on their surface and cross the BBB into a complicated tango dance.
Figure 2: Here there is an attempt of some matrix correlation. GFAP versus CD8 cells. And we can see there is some (expected) correlation between these two (see linear regression and R2) with ASD brains have higher rates of both compared to controls. Interestingly we see similar pattern between ASD that are genetic versus the idiopathic.
Figure 3: digs in more about the immune cells and some correlations (although the scatter of the ASD brains is less convincing here). Overall it seems we have a higher number of lymphocytes in the ASD brain compared to control, both in the white matter (WM, this is where our cables go through) and grey matter (GM, this is where our processing units are) and lepomeningeal (LM, this is our brain surface protective skin, basically the meninges, pours the CSF into the veinous blood). What seems interesting is that at young age we have lymphocytes sitting in our perivascular space, doing nothing(?) and decrease as we age (thats interesting for the non-neuroimmunologist that I am). However, these number at best slightly increase in ASD brain as we age (and I guess not convincingly enough, otherwise the authors would have reported the R2 value), or at least remain the same. With the exception of the medulla (brain stem) most blood vessels show a higher number in ASD brains versus control brains. Interestingly, cortical blood vessels being the predominant population harboring such feature. Very few NK cells to be honest on the panel.
Figure 4: Again this one makes me cringe a bit as a reviewer, because the author do not show the controls data. Yeah, I am pissed. Anyway. Again, perivascular space. Again immune cells highly present (CD3+), CD8 lymphocytes being the predominant type of T cells, in contrast not many CD4 lymphocytes (usually the T helpers, but my immunology is outdated for 20 years at least). Granzyme staining denotes the presence of natural killer (NK) cells. CD20 is a marker for B cells. What is interesting is mostly not much B-cells in either ASD and control brains, the graph more like a refried version of what we already know (higher number of immune cells and CD8 cells).
Figure 5:  is a bit of a useless graph, I don’t see anything that brings us more information than before.
Figure 6: It shows us a Masson trichrome staining. It is a chemical (histological) staining aimed to make collagen fibers visible under a certain color compared to other tissues. Collagens exist in different forms (based on their alpha-fibrils) but the one you expect to see around the vasculature is Collagen Type IV (COL4A1). This one forms a basement membrane (BM) that is like a net around blood vessels. Think about standing on a trampoline. Thats it. Collagen IV forms the net that supports the BBB. Normally, you would expect the BM to be thinned out, this is the case after stroke as cells secrete protein-degrading enzymes (like matrix metalloproteinases MMP2 and MMP9) that will break it down into pieces. But here it is thickened and hhad a bigger thickness than normally. Why so? What does not mean? I dont know. The only time I have seen such things was in transgenic mice overexpression erythropoietin (EPO). These mice had a such high hematocrit that would make blood be like Aunt Jemima corn syrup. If I remember, my former PhD adviser had a collaboration with an electron microscopist and observed similar thickening. Why this is happening is a good question that is likely the next study.
Figure 7: See Figure 5 comment.
Overall thoughts, limitations and outlook: Overall, it is very interesting study, that has some methodological limitations to be noted. First, we are missing any information about the BBB integrity in general, as I wish the authors would have shown some immunofluorescence to compare changes in tight junction (TJ) proteins expression (claudin-5, occludin) in blood vessels and assess differences in TJ strands. The second problem is the lack of information about microglia activation (that would be done by Iba1 staining. The authors noted they performed it, observed a higher expression in ASD brain but decided not to show the data) and more importantly the status of endothelial cell activation (using ICAM1, VCAM1 staining). Are these residing CD8 T cells freshly migrated or just being duck sitting for a while? Is the inflammation status in the brain (and the BBB) ON or OFF at the time of autopsy? What about pro-inflammatory cytokines levels between ASD and control patients? As usual, studies like that opens much more questions that it answers. The second problem is that the study by itself fairly descriptive and observational. It would be interesting how this would compare to clinical findings done in patients. Do we see flares on the MRI indicating of the BBB opening? How does that data compares to patients with MS?
I would also be very careful on making any claim about a “leaky” or “down-regulated” BBB at this point. There is no data about the barrier integrity (TJ complexes integrity) or assessment of the barrier function (for example an MRI scan with gadolinium as contrasting agent) to support the claim. I have seen this claim floating around in non peer-reviewed articles (including in The Scientist), as a BBB expert I would not jump into that conclusion quickly until I see real data on that
This is the type of interesting study, because it opens 100 questions that incentivize to further look down the road. I hope that the authors were able to prepare RNA and protein samples for transcriptome analysis (RNAseq) and proteome analysis (2D-electrophoresis coupled with MALDI) that could help us learn more.

 

 

[Sciences/Junk Sciences] Anti-influenza activity of elderberry (Sambucus nigra)

First blog post of 2020, after taking a holiday break to reinvigorate and prepare myself for the second half of the academic semester, a semester with a lot of items on the menu.
It is also, for those living in the Northern Hemisphere, time for the flu season. Unfortunately this year, it is not looking good and seems to be a very bad year for Winter 2019-2020 as we have already an early spike in the number of cases about flu and already a certain number of fatalities.
For some reasons, the flu shot drag a very bad reputation amongst the population. We blame it gives you the flu (which is impossible since you are injecting a dead virus into your deltoid muscle, not even in your nasal cavity) and some prefer downplaying the danger of influenza (“It is just a cold!”) or claiming you can prevent it by using some grandma remedies such as elderberry syrup. If you wander around some “wellness” websites, you will see these website touting about the benefits of elderberry syrup, claiming it as a “cure-it-all” remedy and even will give you how to make your own.
To sugarcoat it with a layer of “scientific literacy”, they will cite studies showing its antiviral properties and therefore giving it credentials to other treatments. Back off Tamiflu(R), we have a serious challenger right here, and it is natural!
One study that I have seen becoming viral is this one:
Anti-influenza activity of elderberry (Sambucus nigra)” by Dehghani and colleagues, published last year in Journal of Functional Foods, a journal that aims on publishing any studies on nutraceuticals (studies showing the biological activity of food and food-derived products). It is a journal published by Elsevier with an okay impact factor (3.19 as of 2019).

About the conflict of interest:
The first thing I am checking when reading papers is the affiliation of the authors and the possible conflict of interests in the funding of the study. The authors are all affiliated with the University of Sydney (NSW, Australia) with the exception of Qayyum Adil that has an affiliation with PharmaCare Laboratories. This is the first item of interest. If you lookup PharmaCare Laboratories, you will find out that one of their product is Sambucol(R) (elderberry extract). Sambucol(R) is sold at any grocery chains like Wal-Mart as a dietary supplement (which means it was not approved by the FDA to diagnose, treat or prevent any illnesses) and natural remedy to “stay healthy through the year”. It is sold as syrup, or tablets, or gels with some packages claiming “homeopathic cold and flu relief”. There is also the disclosure of financial support by PharmaCare to the study, which accounts for a conflict of interest. A conflict of interest is not inherently bad and evil. But it is important to disclose it, as the authors may have a possible bias to present their study in a too much favorable and positive way that is supported by the data.

About the study:
This study aims to look at the antiviral property of elderberry extract (here mentioned as juice) as a potential antiviral against influenza virus (in this case H1N1 strain, and only the H1N1).  To address this activity, the authors have solely conducted an in vitro (aka in a Petri dish) study using two cell lines to assess the antiviral activity (A549 cell line which derives from a lung cancer) and MDCK (Mavin-Darby Canine Kidney cells, a cell line derived from a dog kidney). It is important to note that the A549 is only good at assessing adhesion and internationalization of the influenza virus (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692684/), but is not a great at allowing the virus to spread. In the other hand, MDCK is one of the cell line commonly used to grow the influenza virus for industrial production, as these cells are perfectly suited for large-scale culture in bio-reactors, and provide source of viral material including for vaccines production.

Like any plant-derived products, elderberry extract is reach in plant chemical products originating from the plant primary metabolism and secondary metabolism. Amongst them, polyphenols represent a major class of phytochemical found in elderberry. Polyphenols share the same chemical structure revolving around a benzopyrane structure (see below).
1280px-4H-Chromen.svg

Elderberry extract is indeed rich of a certain class of polyphenols called “anthocyanins”.
Examples-of-anthocyanins-found-in-different-foods.ppm

These anthocyanin share a common structure, with the presence of an “oxonium” (positively charged oxygen atom) in their structures. They differ from each other by the nature of the radical groups surrounding the aromatic rings (hydrogen, hydroxyl, or methyl groups) and being present either as their aglycone (no sugar moiety) or glycoside form (with a sugar moiety, quite often a glucose).
As I have mentioned, this “oxonium” is very unstable yet very useful. It gives these polyphenols a pigmented color usually in the blue-purple range, which gives the colorful blue-purple of red grades, roses and berries. The maintenance of the structure is indeed pH dependent and remains stable only under acidic condition (pH<5). At higher pH, these compounds quickly disintegrate into a chalcone.
Structure-change-of-anthocyanin-with-pH-in-aqueous-solution_W640

I know this to happen personally very fast, as I have been working on measuring levels of delphinidin in cell culture medium during my Master’s degree……and failed. Upon aqueous solution at physiological pH (7.4), it degraded into a chalcone, making it near impossible to detect on my HPLC-UV instrument. Without an internal standard, I could establish a validation method for its analysis. I lost half of my Master thesis on that issue.

About the method:
For the study, the authors extracted 200g of elderberries and obtained a juice at undocumented concentration, which they diluted via serial dilution for the study. A quick lookup of some data in Figure 1 allows us to estimate that 1:5 of elderberry dilution maybe representing 100mg of anthocyanin/100ml juice.
That would conclude that the stock (1X) solution would contain 500mg anthocyanin/100mL juice or a concentration of 5000mg/L (5g/L) of anthocyanins.
A lookup on the Sambucol(R) datasheet suggests that 10mL of serving (2 teaspoons) contains 3.8g of elderberry extract (assuming that his extract is 100% anthocyanins). This would correspond to about 0.38g/mL or 380g/L solution (which is roughly the same of a 76X concentrated juice). In parallel, the authors also used cyanidin-3-glucoside (C3G) as a standard. The authors used two cell lines (A546 and MDCK), measured cell viability via WST-1 assay, assayed the antiviral activity by measuring the inhibition of hemagglutinin (the H in H1N1) using red blood cells, H1N1 infectious level by measure plaque formation assay (which denotes cell death from viral infection, leaving the area empty), measurement of H1N1 infection in MDCK cells by flow cytometry (and using a FITC-labelled anti-H1N1) and measurement of cytokines using a cytometric bead array (CBA). This last experiment is a bit weird as usually an ELISA (direct measurement of cytokines release) being a more accurate choice.

About the results:
The first result is the presentation of the cytotoxicity. A common trope that flies over anti-vaccines and alternative medicine is the good old axiom of Paracelsus known as “the dose makes the poison”. Figure 1 is about that, assessing which dilution of elderberry juie makes the poison.1-s2.0-S1756464619300313-gr1

A caveat here is the absence of control (untreated cells) that would have helped set the baseline and determine which amount is toxic. If we take the highest dilution as control,  we can guess which dose is toxic. Usually if you achieve over 30% decrease, you can expect the difference is statistically meaningful. If we look at the values extrGapolated from the absorbance and normalized to the 1/20th dilution,  we have about 75% and 50% viability at 1/15th and 1/10th dilution for MDCK; 80% and 50% viability for A549 respectively. Similar outcome for panel b. Interestingly, is the absence of statistical significance (as reported as “*” which is indicative of a P-value lesser than 0.05), which is bizarre that no reviewers asked for.  One thing is certain, by 1:5th dilution, we have 0% viability. Both cell lines are dead. The dose makes the poison. It can be due to the extreme acidity (elderberry juice is pH 4.4, 1000x more acidic than the physiological pH).
If we look at the dilution (1/5th) and the amount of anthocyanin (~100mg/100mL or 1000mg/L juice or 1g/L juice), we can estimate that the average concentration of this elderberry juice is about 5g/L. I would assume dilution of 1/15th and higher can be considered not toxic.
Then comes trouble. And trouble came with the form of the IC50. In pharmacology, the IC50 is the concentration of a drug by which you obtain 50% of inhibition. From the IC50, you can deduct that you should achieve a very good inhibition at 10x to 100x this value.
In pharmacology this concentration has to remain under a certain level, usually below 1micromoles/L to avoid off-target effects (lack of selectivity, which is the basis behind drug side effects). Usually, we cap the maximum concentration to 100micromoles/L. If you cannot achieve a significant inhibition, you can toss your drug candidate in the trash or bring it back to the bench and let medicinal chemists tinker it.
The authors give us two values: A for during and after infection, B for during infection only. The average values provided are 6mg/100mL and 17mg/100mL.

Screen Shot 2020-01-09 at 2.20.43 PM

These equate to 60mg/L and 170mg/L respectively. If we assume that all this elderberry juice is 100% made of cyanidin-3-glucoside (C3G, which is the compound they consider bioactive) and harbors a molecular weight ~450g/mol, we can estimate IC50 values of 0.133-0.377mmoles/L or 133-377micromoles/L. We are talking here IC50 values, which means we have to factor in we will likely need 10x these concentrations to have an antiviral activity. These put us about 1.33-3.77mmoles/L. This assuming we have a concentration in tissues equal to the concentration in plasma (blood). Assuming a blood volume of about 5L in humans, we are talking about 6.65-18.8mmoles to enter the body.
The oral bioavailability of anthocyanins is indeed very small and reported to occur between 0.26-1.8% (based on comparative PK to IV administration) according to this review. If we assume a 2% bioavailability, this puts us to the consumption of at least 332.5-940 mmoles of anthocyanins. Assuming we are talking about C3G, that would represent a mininum intake of  150’000mg or 150g of C3G. If we had to put into perspective, that would be about 400mL of Sambucol to swallow, or 40 teaspoons or about 3 bottles at 4oz each. This would require to repeat it 4 times a day, which brings us to 1.6L of Sambucol(R) swallowed by an adult every day to achieve the same results than obtained in a Petri dish. With a price tag of $12.99/0.12L ($108.25/L) on Sambucol(R) website, it would cost you almost $200/day/person to have a chance in reducing your flu symptoms (if it works). Assuming a week-long treatment? About $1400 per week per person!
And BigPharma is here for their money, one $15 to get a flu shot you get once per season! The maths is here.
Now let’s reverse it. The company tells you to take 10mL four times a day. Thats 3.8g per serving. Out of it, 2% is bioavailable and ends in the circulation. Thats 0.076g circulating in your blood, with about 0.0152g/L(15.2mg/L) of average plasma concentration. Assuming it is 100% C3G, thats a plasma concentration 0.0337mmoles/L or 33.7 micromoles/L.  Or 25% of the IC50 values. In other words, you cannot achieve any antiviral effects with the dose recommended by the company. In both ways you lose.
A) The posology written on the insert for Sambucol(R) is too low to be efficient
B) To achieve the efficacy as reported in a Petri dish, you will have to drink gallons of it, with a price tag exceeding far more the cost of a flu shot.

Should we continue? Sure let’s continue. In the later stage of the study, the author use C3G as a comparator as they mention it being “the primary anthocyanin in elderberry,showed a strong anti-influenza effect with the IC50“. The IC50 reported is 0.069mg/mL or 69mg/L (or 153micromoles/L).  What is bizzare is the nature of the contradictory of the data shown.
One of them is the flow data hidden in the supplementary figures (which you have to download separately). First, the design of this figure is very convoluted and needed to rearrange the panels to become more readable. Putting aside the concern that the number of events are not equal between the different histograms (the authors should have presented as % max for the y-axis), you can see something that is not looking good for the authors.
If we compare between the two infected groups, we can see without hard numbers that elderberry syrup (at 1/20th dilution) was not changing the outcome of infected population. In the opposite, treatment with anti-H1N1 antibody completely blocked the infection. Guess what makes you produce anti-H1N1 antibodies? A $15 flu shot!

Slide1
What is even more bizarre is the cytokine expression profile. I personally not much confident in this method, and I would have much more preferred a good old ELISA, which gives you absolute values. But lets go through the figure 6.1-s2.0-S1756464619300313-gr6

Cytokines are important molecules that serve as communication methods for immune cells. Some are pro-inflammatory, some are anti-inflammatory. In this case, the cytokines measured are most pro-inflammatory (IL-1beta, IL-6, IL-8, TNF), with IL-10 being anti-inflammatory and IL-12p70 being involved in T cells differentiation into Th1 cells.
Under normal conditions, cells do not produce pro-inflammatory cytokines.
LPS is the acronym for lipopolysaccharide, a biomolecule present in Gram-negative bacteria. LPS is considered as the most potent bacterial stimulator of immune response during sepsis, and commonly refered as endotoxin which can induce a septic shock.
We can see that LPS alone induce the production of IL-6 by 50 fold and in lesser extent IL-8 (15-20 fold).
Interestingly, elderberry juice (1/15th dilution) triggered the expression of TNF-alpha by 50-fold and IL-6 by 200-fold. IL-8 by contrast was increased by 30-fold. Here is the problem. If C3G is the main anthocyanin in elderberry juice, why he could not achieve the same profile then elderry juice (which is about 5g/L anthocyanins) at a concentration half of it (C3G was given at 2.5g/L)?
The second issue is the extent of the release of pro-inflammatory molecules. This release can be high enough to cause what we call a “cytokine storm”, the equivalent of the nuclear option for the immune system by inducing a major immune response leading to the death of the patient. Cytokine storm is accepted now as the worst outcome of the flu pathphysiology (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711683/), with current goals is to save patients with flu by trying to avoid the nuclear option using immunomodulators.
As I said, the last thing you want is to worsen the immune response. With such an increase in pro-inflammatory cytokines, you may indeed worsen the outcomes of flu rather than treating the flu.

Conclusion:
This study albeit interesting suffers from major flaws that unfortunately will not deter woo peddlers. But lets resume it here:
1. It has some skin in the game as one author is affiliated with a company making a living of elderberry syrup as dietary supplement.
2. The amount used to show some effects requires a ridiculous amount to see any effects.
3. Inversingly, the dosing regimen of the Sambucol as written on the package is way below the dose needed to see a semblant of biological effect.
4. The data is overall of poor quality and contradicts each other making the paper pretty unreliable.
5. And if you think you can save money by making your own, think twice. You can poison yourself to death with elderberry juice. I guess flu will have no chance…if you are dead.
https://www.cdc.gov/mmwr/preview/mmwrhtml/00000311.htm

[Metal/Melodic Death] Insomnium -Heart Like A Grave (90%)

Finally, the last review of my streak of overdue reviews. The last one in the list is the Finnish melodic death metal band Insomnium. I got into them late in the game through their album (and fairly controversial album within the community) “Winter’s Gate”.
What I like about the band is their ability to perfectly blend the brutality of death and powerful melodic, that give me the sense of mental escapism and serendipity of the Finland wild, green and white vast lands of wilderness.
This is an album containing 10 tracks (+2 bonus tracks, iTunes version) spinning about 70 minutes. We got introduced by “Wail of The North”, giving us this floating feeling, that melodies I have been talking but this one mostly driven by pianos and keyboards, followed by fast guitar riffs. It nicely serve as a primer for the official opening track “Valediction”. This is where the “attach your seat belt” sign should be blinking because we start brutally, only to get free flying within 30 seconds. Enjoy the video clip:

“Neverlast” brings us more to classical Insomnium stuff, but that does not a downgrading. We are still flying on the awesomeness with the band, again very good track. “Pale Morning Star”, we keep on a perfect streak with the band and this perfect blend of heavy riffs and melodic that makes your soul escape into beautiful Finnish landscapes. “And Bells They Toll” is my favorite song of the album. The quintessential track that makes in my opinion the band being the flagship of the whole Finnish Melodic Death Metal scene. “The Offering” is in contrast, tuning to heavier and faster riffs, making it more aggressive and yet enjoyable, rapidly followed by “Mute is My Sorrow” and “Twilight Trails” that in my opinion almost acts as a bridge between “Winter’s Gate” and this album.
“Heart Like A Grave” brings us more down to Earth and simply beautiful to listen, my second favorite of the album by its enriched sensory experience. Watch the video, close your eyes, focus on the auditory stimulus and enjoy this mental escapism.

“Karelia” is a melodic ballad, 100% instrumental track that closes the album magnificently.
The two bonus tracks are good. The first one, “The True Morning Star” is an instrumental acoustic guitar track that is okay but does not feel we are missing much. The second one, “Karelia 2049” is much more electronic, giving place to the keyboards. Oh boy as I love the prime electronic sounds of the early synthesizers, I like that track giving a much colder and electric sound to the homonym track.
With this album, Insomnium is showing us that they are reaching their pinnacle of their artistic talent, over 10 years in the refining and improving, giving us this perfect album that is a pleasure to listen and has been spinning almost daily in the last two months. Rarely we are given a chance to hear a nicely blended form of melodic death metal that embrace this “Fire and Ice” analogy. If I have to summarize the beauty and wilderness of the Finnish metal scene, that would be using this album I would showcase. Finland gave us one of the best symphonic metal band (Nightwish), one of the best melodic doom metal band (Swallow The Sun) and just offered us one of the best melodic death metal band in the presence of Insomnium.

[Metal] Lacuna Coil – Black Anima (80%)

October was also the same month of the release of the latest album by Lacuna Coil “Black Anima”. At the helm, we have Cristina Scabbia and Andrea Ferro as usual keeping the ship exploring and wandering over the years. It is a 14 tracks album (iTunes version, that is inclusive of three bonus tracks in the total I provided) spanning over 59 minutes of music.
We get into it with “Anima Mera”, a cryptic song that is pretty interesting and setting sort of the whole album. The second track, “Sword of Anger” is pretty okay but nothing really hooking much, as well as the third track “Reckless”. For some reason, I find this track pretty unattractive to my ears and even would sound like one of the weakest of the album. The band has a videoclip, so you can judge by yourself. The videoclip is indeed much better and is deeply inspired by Dario Argento’s “Suspiria”:

Fortunately things become interesting for me “Layers of Time”, the fourth track. Tha’ts the Lacuna Coil stuff I was looking for, that’s a song I really like that it became an earworm through these last two months. Again a videoclip to share, so enjoy the listening of that track:

The fifth track “Apocalypse”, is also a decent track and straight into the band direction. “Now and Never” reminds me a lot like “The House of Shame” of their previous album, so good stuff again from the band. “Under The Surface” is also pretty good overall. “Veneficium” is probably my second favorite track. It starts with Cristina starting a capella into a sort of chorale, following by Andreas lyrics, some of the heavy stuff that has something connecting the old fans to their old stuff, it has this wavy feeling that is so pleasant to my ears. “The End Is All I can See” is a bit strange but very fascinating to my ears. Another good track of the album.  “Save Me”, the 10th track, is pretty okay but in my opinion nothing too pretencious, something more like alternative metal. “Black Anima”, the last official track is another good one, with Cristina in my opinion being the best of her in this album, with hitting the highest notes she can.
What about the three bonus tracks? “Black Feathers”, the first of the three extra tracks, is a damn good one, I would like to have this one in the regular album in place of some weaker songs. Same for “Through The Flames”, very good one. “Black Dried Up Heart”, the last track (and the last of the bonus tracks) is also pretty decent and wished was part of the regular album tracklist.
As this album marks about 20 years of discography of the band, where does it stand? I would say still pretty well. The band went back to their heavyness a scale higher, they also embraced darkness at a higher level than their discography of their second decades. There are some good songs, and some weak songs. It is not the crush album, it takes some times to get into in and appreciate. It is overall a pretty good album and love to see the band after 20 years still being dynamic and produce some quality albums, where other bands crashed on the shores or simply let the wrenched sea become their graveyard. My only regret was missing on their North American tour that was not clearly advertised and that’s honestly disappointing. Lacuna Coil is one of these bands that performs well both in studio and live and wished I could finally see them live after this incessant game of cat and mouse.

[Metal] The Agonist – Orphans (90%)

Thanksgiving is finally here, meaning for me the end of the frenetic fall semester and able to take some time on my blod and foremost write reviews on the albums I have purchased and listened during my grants and manuscript writing . Because of the glut of albums to reviews I will keep them sweet and short.
Among the pile of albums, came the latest one from the Canadian metal band The Agonist titled “Orphans”. After facing some issues I would not enter into details, it finally came out mid-October and available on the Bandcamp webpage of the album.
Third album with Vicky Psarakis at the helm, I have to say this is an album that marks a maturation of both the band and from Vicky. It is brutal, harsh, bombing and pretty homogenous just like I like them!
It is a pretty short album (45 minutes) but sweet albums with 10 strong tracks. We start into it by ramming the big door with “In Vertigo” that for some reasons reminded me some tracks of the band from the early days with Alissa. The band makes us a gift of a videoclip for the song, so listen and enjoy:

A pretty good introduction track that ramps up towards to track 2 “As One We Survive”. Here comes the cannons of Navaronne, some of the firepower of the band in combining the brutality and the melodics, while Vicky show her able to steer both cleans and growls in a same track.  My favorite part? The second half of the song, this crescendo of riffs bringing an increase in tension as the music become heavier until it peaks. The brutality of the song is nicely translated into the videoclip of it, check it out:

The third track is “The Gift of Silence”, keeping up into the frenzy of the second track, this time bringing the pace to a much faster pace, also a damn good song. And another clip for your eyes and ears:

The fourth track is a continuing streak of good track from the band, with “Blood As My Guide”. What I can say? It is the gift that keeps on giving with good stuff, with special mention on Vicky singing a whole verse in Greek (I would assume from her Greek heritage), if anyone can give me the translation of the words that would be great. I did my best to guess using my French to do some bastardized translation but nothing speaked much as a  tragedy unforlding than listening to Vicky singing.
The rest of the album is also damn solid with “Mr. Cold”, a bit much chill than the rest;  “Dust To Dust” which also quite good only got me into it by the second-half of the song (I hate the first-half, like the second-half); “A Devil Made Me Do It”, a sick as hell track by its sheer speed and brutal drums ; “The Killing” which is pretty good but kind of left hungry; “Orphans” (9th track) that is my second favorite song of the album, starting soft and building momentum as we go through. “Burn It Down”, the 10th track of the album, concludes this almost perfect streak from the band.
What I can say? Man I love to see how the band came together over the years by constantly refining their artistic direction and getting this unique sound making them standing out from the crowd. Vicky certainly reached a point of maturation making her a definitive asset in the band. This winning formula is certainly the one that should and must make this band becoming a flagship for the Montreal metal scene, and the Canadian metal band. It is so good to see the band unleashing itself after navigating tumultuous waters in the last few years. The band came out of it stronger than ever and ready to conquer new lands.

[Metal/Power Metal] Sonata Arctica – Ecliptica (20th anniversary)

Today marks the 20th anniversary release of the first full-length album “Ecliptica” by the Finnish power metal band Sonata Arctica. Power metal, never a metal genre was making so much polarization within the community. Some love it, some hate it. I found it is interesting that the divide espouse the Atlantic rift with the North American continent predominantly driven towards death metal and its sub-genres (hardcore, metalcore, grind core), whereas Power Metal being really a popular feature in Europe.
What I like about Power Metal? Ultra-fast riffs, high-speed drums, and this whole adrenaline pumped out by embracing lyrics. And Sonata Arctica counts in my favorite Power Metal bands, in particular when it comes to their old stuff. And how does “Ecliptica” holds on after 20 years? Awesomely well. With certain cynicism, I would say the old SA stuff ages much better than their new stuff.
The album is short (47 minutes), but damn intensely packed, with certainly a very strong foundation with 10 tracks holding overall very well. We get into it with “Blank File” that quickly sucks us into an intense and fast tempo giving the tone: it will be loud, it will be fast and it will be epic. The second track, “My Land” is kind of more relaxed and more like a power ballad. But the third track, “8th Commandment”, oh boy, thats some densely packed steroids right here. Super-fast riffs, super-fast pace, with very engaging and dueling keyboards/guitars. The very essence of Sonata Arctica. Give it a try and listen to it:

One power metal track like this one over 10’000 death metal songs, anytime. Where death metal songs sounds mostly the same, power metal gives you this energy and complexity never experienced. Every time this song is played in a concert, it is such a pleasure.
The fourth track, “Replica”, gives us some resting and offers us another of these nice power ballad, one of these sing-along songs that makes SA concerts great. “Kingdom for a Heart”, the fifth track, is good but for some reason not putting me into ecstasy.

Then comes “Fullmoon”. The Sonata Arctica Power Ballad, the stuff you want to sing-along in concert. It is an epic power ballad that I have rarely seen equaled by other bands I have listened.

“Letter to Dana” is a beautiful power ballad story about this love story that never occurred to happen and ends up tragically.  Yes, the writing is a bit cheesy, a bit goofy but thats the charm of power metal.

“Unopened”, “Picturing the Past” and “Destruction Preventer” nicely help finish the album by alternating power ballads and by power melodics making the album a perfect streak.
Now there are two versions of the albums: the original one and the revisited one published for the 15th anniversary. I personally prefer the original from the keyboard perspective. The revisited is kind of lacking flavor and punch of the original one. Please grab that version, you will thank me later.
Sonata Arctica, like it or not, is certainly one of the flagship of Finnish power metal and a must-have band to have in your power metal collection. It epitomizes for me what makes power metal a much better experience than death metal: epic, fast-faced, bombastic listening experience that brings this adrenaline rush that makes you feel much better after a listening session. I wish Sonata Arctica could look back at their early years and bring back this energy in their musical direction.

[Personal Log] Looking back at my 10 years in the US, from a French perspective

Today officially marks the 10th anniversary of landing here in the United States. It was on October 23rd 2009. After weeks and weeks of waiting on my H1-B visa to be processed (it took about three months between the time I have got the I-797 notification and the time I have landed in the US), I finally got the magic pass to start my career in the US.
I officially handed over my keys of my efficiency in Zurich, the same efficiency that was my place during my graduate study. Yet, I started to experience the long process of the US administration.
I thought I would be in the US by August, it would take me almost 3 months to get there. I had my family (my wife and two daughters, 3 and 2) send back to France, cluttered in 1BR in my parents house. And I spent the whole summer couch-surfing in student dorms sub-leased for a month at the time (because the rental market in Zurich back then was insane, less than 1% vacancy rate). I lived most of my days in the lab and the office, finishing up crucial experiments.
I remember when I got the visa stamp, I hastily booked a flight to the US. I could not get picky with the flight and it was a whole journey. I had packed 2 baggages of 50lbs each (it was just at the time when airlines removed the 2 checked-in bag allowance), filled with basic necessity stuff. I had arranged my rental all over the internet and using Craigslist. I left on a Friday morning from my hometown. From there a domestic flight from CDG to DTW, then DTW to IAH and finally a shuttle from IAH to Aggie-land. I spent the first night late in a Knight Inn at close proximity of my rental.
Nicely, the landlord was here to greet me the next morning. He picked up with his Chevy Suburban. That was my first experience with SUV. Everything is bigger in Texas, even the cars. Gave the deposit, the first month of rent in cash and that was the first pictures I took with my Macbook:

 

Here I was. An empty house and some basic necessity in my baggage: some linen sheets, a pillow, my computer, some kitchen utensils, my clothes. And not furniture, no bed…..yet. Fortunately, I was able to grab some free Internet (I think it was from the nearby Motel 6, hehe), at least enough for a week. I had made arrangement to have a guy selling mattresses deliver one of them in my place, I also made arrangement for a round table with four chairs and finally a sofa and loveseat. I was lucky enough to find an Albertson’s 10 minutes walking. I discovered Philadelphia cream cheese, Folgers coffee and donuts!
That afternoon felt like going on a run like in the Walking Dead: secure glassware, dishes, small appliances (coffee machine, toaster….). And I walked west, towards Goodwill. A 2 miles walk. 38 minutes walk. It was all about learning. Me and my backpack. I remember crossing a pawn shop (first time I ever entered a pawn shop) and bought an Xbox360 (that will serve me for a DVD player and videogames). I later got from Goodwill a small frying pan, a couple of glass, a alarm radio, and some stuff.
Sunday was my second day. That time I explored the East side of my neighborhood. I went to the Dollar Tree that was two miles East. That’s what I bought the necessary stuff to the house and cleaning supplies, some basic necessity. And finally on my back, passed by Best Guy. Bought my first prepaid phone (AT&T Pay as you Go or something like that), and my first TV. An Insignia 32″ LED TV that as of today is still working :). I still have it and use it in my man cave. This fellow followed me through my journey. Finally in the afternoon, Greg my mentor picked me up and drove me to Walmart. Having a car ride would be my luxury in the next three months, especially in Texas!
For three months, my radius of action was 1 mile at best. The only way for me was the Aggies bus shuttles that would take a whole hour to bring you from A to B, a bicycle I bought, and that basically it. The things that were around me were Albertson’s, Denny’s, Pizza Hut, and Sonic. And Blockbuster. That closed within a month of me arriving here.
My first week was discovering a whole different way to do research, learn about things you don’t know, setting my first bank account, applying for my SSN number. getting cable, connecting the utilities…….It was a steep learning curve. I still remember my first Halloween (unfortunately no Halloween in a college town if you live in a student neighborhood), my first Thanksgiving. I remember how sidewalks became my bike lane because it honestly feel suicidal to drive on a major avenue.
But heck it was an unforgettable experience. Looking back 10 years, I learnt a lot and now feel part of the country.
Howdy y’all!