Updated Research and Knowledge - Cutting Edge

[SuicidalTraveler]

Fedex created. Check HGR.

[SuicidalTraveler]

I have an account. Can't I pay you through PayPal though?

I don't have a credit card really.

[SuicidalTraveler]

Ugh. Sorry, I wrote this to the wrong forum. Admin please delete my messages. Thanks.

[forgottenwarrior]

Amalgam is an alloy 50% mercury, which stops elongation of microtubules, which are needed to maintain and grow nerve cells. Sooooo....
It is recommended to take DMSA or IV EDTA immediately prior to and after an amalgam filling extraction so as to avoid Central Nervous System (Headache, poor memory, sleep etc) side effects of the pieces of the filling (microscopic ) going into the stomach and getting absorbed.
Also the dental and cranial nerves suffer from the mercury vapors from drilling etc. but it should pass when mercury gets evenly distributed in the body, but do you really want that?
Not sure why HA is one-sided, maybe you do have a plaque on an artery like Middle Meningeal, that renders that bottleneck ore sensitive to transient bacterial LPS (although LPS is usually vasodilatory), or mercury, who knows? Better go get checked before a clot forms on the bacteria-roughened endothelium (if that is the case of course)

Oh yeah, also, there is more of an urgency to get checked, if you have ever had Rheumatic fever, prosthetic heart valve, or even any foreign surgical material or shrapnel in your body. Or if you have intermittent fevers, unless you are on immunosuppressants. Anyways, take my advice with a grain of salt.

I've noticed since getting my amalgam fillng removed I've had testicular pain, and I noticed my semen become more watery. This was not a good sign at all as this occurred to me in the middle of the day.

I'm very sure the heavy metals from the filling are affecting my hair to some extent. However it's the bacterial side I want to address as well. If I had bacteria clump up around my skull due to the heavy metals what would you believe to be my options?

[Swooping]

Yeah I agree with you guys. My line of thought is that AGA seems to incorporate oxidative stress too. I don't know for sure though.

@InBeforeTheCure,

Interesting. So what do you guys suggest on a practical level. Do we even have a chance for reversibility or is it a pipe-dream and do we need to work on a preventative level?

Looking at that box of potentially differential regulated TF's. I see that estrogen interacts with many of those. For example, FOX, HOX, AP-1, SP-1, MYC, AHR.. See; http://press.endocrine.org/doi/full/...0/er.2006-0020.

Senescence would be catastrophic imo. I can see why estrogen would be good in reversing senescence if damage is not too severe though (myc, fos, jun, cyclin d1 etc), in other words making sure the cells re-enter the cell cycle.

If damage is too severe though, it might be irreversible?

Besides like I mentioned a while ago, the inflammatory aspect of AGA would correlate with SASP the inflammatory phenomena that is a sometimes but not always a hallmark of senescence, and even worse fibrosis which is also a hallmark of senescence which also has been shown in studies for AGA.

There have been several studies associating senescence with AGA like this one; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828374/.

To make another example, overexpression of AR for has been associated with oxidative stress too in other studies not related to AGA.

AGA remains a mystery to me though, but it is a b*tch that's for sure.

[InBeforeTheCure]

tofacitinib results in decreased secretion of CXCL10 protein <== I have already trialled Tofacitinib 2 years back. It doesnt work and made my scalp very itchy. a possible reason could be that the Th response was swifted to Th2.

What concentration of tofa did you use?

inbeforethecure:

Im not too sure about minoxidil 'growing hair everywhere' it doesnt seems to have any noticeable results on my scalp at all- while it did help grow my eyebrows

What I mean is that generally, minox has an effect on all types of hair (it causes hypertrichosis), rather than growing hair in one spot and suppressing it in another like sex hormones do.

Inbeforethecure:

helps my gyno. But the problem is while it inhibits DKK1;

Clomiphene results in decreased expression of DKK1 protein

http://ctdbase.org/detail.go?type=ch...02996&view=ixn

it worsens my hairloss and increased sebum secretion. This stuff agonises/antagonises Estrogen receptors, depending on the tissue. So my guess that it's a very good indicator that Estrogen receptors are deeply involved with AGA.

caused me whole body itch where there's hair- but amazingly, it doesnt seems to bother my scalp. It's an Estrogen receptor Beta agonist. I stopped this becos i switched to Estradiol itself.

If we could avoid systemic absorption of estrogen, that would be nice -- otherwise, it's obviously not viable. Maybe someone should work on formulating something like that.

increased sebum secretion and itch, despite being an anti-inflammatory. My guess tells me that Th response switches are caused by https://en.wikipedia.org/wiki/Cannabinoid_receptor receptors- in the context of AGA. That's why Tofacitinib(i binned it already) didnt work for me. Its about the appropriatehttps://en.wikipedia.org/wiki/Chemokine ligands in the scalp that brings hair growth. misexpress the wrong 1s and AGA occurs(as seen in the diagram u've linked)

inbeforethecure:

If we look@ page 21, there are a few genes that are significantly differentiated between balding and non-balding scalp DPCs:

1)COL18A1 16.750 15.675 <== downregulated in balding scalp when compared to non-balding scalp by more than a whopping 15 fold

Estradiol promotes the reaction [ESR2 protein affects the expression of COL18A1 mRNA]
Estradiol results in increased expression of COL18A1 mRNA

This means the https://en.wikipedia.org/wiki/Estrogen_receptor_beta (aka ESR2) is downregulated in balding scalp. Also, the ESR2 inhibits AR's expression.

2)DHCR7 23.464 20.353 <=== more than 20 fold

Acetaminophen results in decreased expression of DHCR7 mRNA <=== Panadol
Estradiol results in increased expression of DHCR7 mRNA
Caffeine results in decreased expression of DHCR7 mRNA
Copper results in decreased expression of DHCR7 mRNA <== we've got copper toxicity in the balding scalp- and it's 1 of the effectors in Parkinson's
Ethanol results in increased expression of DHCR7 mRNA

3)HTATIP2 6.764 6.038 <== more than 6 fold

Valproic Acid results in increased expression of HTATIP2 mRNA
epigallocatechin gallate results in decreased expression of HTATIP2 mRNA <=== EGCG
Finasteride results in increased expression of HTATIP2 mRNA
Flutamide results in increased expression of HTATIP2 mRNA
Antirheumatic Agents results in decreased expression of HTATIP2 mRNA

4)SCG2 5.365 5.938 <=== more than 5 fold

Valproic Acid results in increased expression of SCG2 mRNA
8-Bromo Cyclic Adenosine Monophosphate results in increased expression of SCG2 mRNA <== cAMP (Bambuterol, Forskolin, etc)

5)COL1A1 5.069 4.926 <=== Collagen type 1, by around 5 fold

Tons of common chemicals ups it

inbeforethecure:

on Stat3:

based on the data from the study regarding the https://en.wikipedia.org/wiki/Chemokine, my opinion is we need the right kind of inflammation to grow hair.

CXCl2 and CXCl6 is probably the 'wrong' type of inflammatory ligands that are upregulated in AGA-affected scalps.

What is ur take on this?

inbeforethecure:

so based on the data, Vitamin C and Zinc would be 2 simple chemicals for aiding hair growth- probably influenicng the ROS pathway.

What I'm looking to do is run a genetic network analysis like the one described in this paper. This will hopefully give us some insight into the complex relationships and help us see what the connections might be; otherwise, it's a nightmare to figure out the relationships among several thousand genes. Most likely they arise from a small subset of interactions.

This is very computationally intensive though, and I'm running into problems because I only have 8GB of RAM.

inbeforethecure:

[FOXO1 protein results in increased expression of SOD2 mRNA]

FOXO1's target gene is SOD2- to remove ROS and improve cell survival. I have read the zebrafish pax1/pax9 study. Like u've mentioned- it states pax1 and Foxo1's interaction increases during hypoxia.

It is highly like due to the 20p11 AGA locus that this interaction is altered- and this is further evident that FOX01's expression is only present in non-balding scalp DPCs

Yeah, if it is PAX1, it's possible that this interaction is where it plays its role, although how it would change FoxO's behavior I have no idea. It could also play a role through its interaction with homeobox genes.

Yeah I agree with you guys. My line of thought is that AGA seems to incorporate oxidative stress too. I don't know for sure though.

@InBeforeTheCure,

Interesting. So what do you guys suggest on a practical level. Do we even have a chance for reversibility or is it a pipe-dream and do we need to work on a preventative level?

Obviously prevention is ideal, but as for some sort of reversal protocol, I don't understand it well enough yet to suggest anything. We still need more data on epithelial signaling networks and so on first. That data isn't available yet, but hopefully will be soon. The new study you linked from the Chew/Philpott group, which I realize now is actually a new study with microarray data from epithelial hair bulbs could be helpful. Also, Rendl should be coming out with some new data on gene expression patterns in mice at different stages of the hair cycle. If we understand it well, then maybe we can "hack" it if possible (which I'd guess probably isn't to any great degree with current technology).

Looking at that box of potentially differential regulated TF's. I see that estrogen interacts with many of those. For example, FOX, HOX, AP-1, SP-1, MYC, AHR.. See; http://press.endocrine.org/doi/full/...0/er.2006-0020.

Senescence would be catastrophic imo. I can see why estrogen would be good in reversing senescence if damage is not too severe though (myc, fos, jun, cyclin d1 etc), in other words making sure the cells re-enter the cell cycle.

If damage is too severe though, it might be irreversible?

After some point, senescent cells undergo irreversible chromatin remodeling, so maybe that's the "point of no return"? One question I have is whether if, under the right circumstances, dermal stem cells can come in and replace the damaged ones. Even a small increase in senescent cells can suppress stem cell activity nearby, so I'd be curious to see what would happen if they were purged. Are the dermal stem cells depleted, or are they just suppressed?

Besides like I mentioned a while ago, the inflammatory aspect of AGA would correlate with SASP the inflammatory phenomena that is a sometimes but not always a hallmark of senescence, and even worse fibrosis which is also a hallmark of senescence which also has been shown in studies for AGA.

There have been several studies associating senescence with AGA like this one; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828374/.

Yeah, I've read that paper. Kind of interesting too how the cells progressively lose their AR expression. AR is basically a DP signature gene and loses its expression in culture it seems. I suppose like other DP signature genes, it needs epithelial signals to maintain its expression?

To make another example, overexpression of AR for has been associated with oxidative stress too in other studies not related to AGA.

AGA remains a mystery to me though, but it is a b*tch that's for sure.

Mystery is fine. I like a good puzzle.

By the way, I also ran another Opossum gene signature analysis, this time on the top 1000 downregulated genes (maybe that's too many) after 30 minutes of DHT exposure in BAB-A. Several FOX genes showed up at the top (I guess they tend to cluster together because of similar binding sequences or something) and of all the genes that are actually expressed in DPCs, FOXO3 was the highest on the list. This hints again that AR is acting through a non-genomic pathway -- probably mTOR/Akt/SGK -- to interfere with FoxO transcriptional activity. This would expose the cells to bursts of damaging ROS.

[kuba197]

What do you think guys about proteasome inhibitors (PSI)?

[Swooping]

@InBeforeTheCure,

I pm'ed you, let's get you some extra RAM so you can make that analysis. We need those computational methods indeed to make something of it all.

Btw;

http://www.ncbi.nlm.nih.gov/pubmed/24064061 (rat though)

Further interesting read between the interplay (Skip to 5. TGF-B and ROS interplay) ; http://www.hindawi.com/journals/omcl/2015/654594/

Btw, there are people walking around with either loss of function or gain of function mutation of STAT3. No hair alterations are observed in those people. Interestingly tooth and bone development is altered.

Can we say based on this that STAT3 doesn't seem to function a big role in hair follicle biology? I would think so.... One would expect at least some hair alterations right?

Take loss of function in the VDR and alopecia very often develops; http://www.nature.com/bonekeyreports...ekey20145.html

Other example is loss of function in HR; http://onlinelibrary.wiley.com/doi/1...09.01042.x/pdf

Then you have APCDD1 etc....


Lastly, is it fair to say in terms of damage control a "primary" anti-oxidant might help? Something like orgotein (SOD)? Did you ever try it TheKingOfFighters? Seems you have a whole lab at home lol. Might be troublesome with a 30kDa protein though.. Not really practical to regularly inject into the scalp.

[InBeforeTheCure]

@InBeforeTheCure,

I pm'ed you, let's get you some extra RAM so you can make that analysis. We need those computational methods indeed to make something of it all.

Right now I'm looking at algorithms that use prior knowledge and incorporate post-translational regulation, as I think that would be better suited for our purposes. Maybe miRNAs too, we'll see.

Btw;

http://www.ncbi.nlm.nih.gov/pubmed/24064061 (rat though)

Further interesting read between the interplay (Skip to 5. TGF-B and ROS interplay) ; http://www.hindawi.com/journals/omcl/2015/654594/

A nasty positive feed back loop. ROS -> TGFbeta -> ROS

TGFbeta probably contributes to HF fibrosis too (Foitzik et. al, 2000).

Btw, there are people walking around with either loss of function or gain of function mutation of STAT3. No hair alterations are observed in those people. Interestingly tooth and bone development is altered.

Can we say based on this that STAT3 doesn't seem to function a big role in hair follicle biology? I would think so.... One would expect at least some hair alterations right?

I guess the argument then would be that there are multiple STATs at work, and maybe there are some that are more important to AGA than STAT3, or there are redundancies between them that compensate for the knockout of one of them. Either way, according to the Chew data, all STATs are downregulated* at the mRNA level in balding DPCs, but it's still possible that they are nevertheless phosphorylated at a higher rate. I'm far from convinced of the Jak-Stat hypothesis though.

* There was a study from 2004 that contradicts this one. Contrary to Chew et. al, they found STAT1 to be upregulated in balding DPCs.

Take loss of function in the VDR and alopecia very often develops; http://www.nature.com/bonekeyreports...ekey20145.html

Other example is loss of function in HR; http://onlinelibrary.wiley.com/doi/1...09.01042.x/pdf

Then you have APCDD1 etc....

Interesting then that "response to vitamin D" is the 2nd most enriched biological process for genes upregulated in balding DPCs in PANTHER. Chemical had some stuff on VDR earlier in this thread as well.

It has been hypothesized that the role of the VDR in the hair cycle is to repress the expression of a gene(s) in a ligand-independent manner.46, 55, 89, 91, 93 The ligand-independent activity requires that the VDR heterodimerize with RXRα and bind to DNA.46, 90 The corepressor actions of HR may also be required in order for the unliganded VDR to repress gene transcription during the hair cycle. Mutations in the VDR that disrupt the ability of the unliganded VDR to suppress gene transcription are hypothesized to lead to the derepression of a gene(s) whose product, when expressed inappropriately, disrupts the hair cycle that ultimately leads to alopecia.46, 55, 89, 91, 93 Inhibitors of the Wnt signaling pathway are possible candidates.13, 95, 96, 97

This is oPOSSUM for the top 1,000 downregulated genes in balding vs. non-balding DPCs:

TF	Z-score
NFATC2	17.98
ELF5	15.897
RXRA::VDR	15.677
Hand1::Tcfe2a	15.49
HOXA5	14.369
SPIB	13.276
TAL1::TCF3	12.972
FEV	12.58
REL	12.51
Tal1::Gata1	12.244
RELA	11.862
Gfi	11.796
MAX	11.792
RUNX1	10.994
AP1	10.697
Nobox	10.636
IRF1	10.348
SRY	10.206
ARID3A	9.57
RORA_2	9.492
Pdx1	9.492
SPI1	9.255
FOXF2	8.879
STAT1	8.819
Myf	8.689
MZF1_1-4	8.439
Nkx2-5	8.334
CEBPA	8.037
NF-kappaB	7.907
Myb	7.782
FOXO3	7.592
MZF1_5-13	7.444
IRF2	7.302
PBX1	7.297
Sox5	7.25
Prrx2	7.04
NHLH1	6.799
Nr2e3	6.794
NR4A2	6.589
Gata1	6.416
NR1H2::RXRA	6.404
Foxa2	6.043
Sox17	5.929
Stat3	5.891
Ddit3::Cebpa	5.625
FOXA1	5.237
Tcfcp2l1	5.062
Nkx3-2	4.999
Spz1	4.96
Arnt::Ahr	4.668
Sox2	4.658
USF1	4.477
HLF	4.441
NFKB1	4.252
MYC::MAX	4.13
NFIL3	4.088
CTCF	4.065
ZNF354C	4.062
TBP	3.998
SP1	3.955
Lhx3	3.926
INSM1	3.925
RORA_1	3.892
RREB1	3.806
Pou5f1	3.754
HNF4A	3.748
EBF1	3.642
CREB1	3.423
MEF2A	3.228
TEAD1	2.982
SRF	2.92
ELK1	2.828
ESR1	2.805
FOXI1	2.764
T	2.716
E2F1	2.366
HIF1A::ARNT	2.284
Klf4	2.03
SOX9	2.026
NR3C1	1.983
HNF1B	1.958
NR2F1	1.744
NFE2L2	1.424
RXR::RAR_DR5	1.279
TLX1::NFIC	1.11
FOXD1	1.074
Arnt	0.899
Foxq1	0.781
NKX3-1	0.478
Ar	0.308
Mycn	0.298
Foxd3	0.146
YY1	0.103
Esrrb	0.041
NFYA	-0.511
Pax4	-0.593
ESR2	-1.383
Evi1	-1.674
HNF1A	-1.712
PLAG1	-1.754
Myc	-2.201
Pax6	-2.239
EWSR1-FLI1	-2.322
Pax5	-2.345
PPARG	-2.566
TP53	-2.905
Egr1	-3.389
PPARG::RXRA	-3.586
ZEB1	-3.846
MIZF	-4.012
znf143	-4.448
Zfx	-4.475
GABPA	-5.105
ELK4	-5.993
Zfp423	-6.415
REST	-8.525

If RXRA::VDR acts mostly as a repressor, then interestingly enough, it seems like it may be more active in AGA DPCs. Also, the PPARG::RXRA complex is underrepresented in the same set. It makes me wonder if, for some reason, RXRA is associating with VDR at the expense of PPARG. Of course, this is just in DPCs and VDR expression is much higher in ORS cells according to the Hair-Gel site, so things may be different there.

Also a side point...In PANTHER, the top 3 categories in the downregulated genes are

1. response to interferon-alpha
2. response to interferon-beta
3. type I interferon signaling pathway



Perhaps this is something we could investigate. In fact, the first paper I've landed on (this one) says the following:



I know you're aware of this paper:

We detected the significant upregulation of miR-221, miR-125b, miR-106a and miR-410 in balding papilla cells.

The paper mentions the three bolded ones.

"miR221/222 can target STAT1 and STAT2"...Reference chasing takes us here:

Unlike miR-145 which is commonly down-regulated in tumors, miR-221/222 are often up-regulated in cancers [23, 27, 28]. Among the genes whose expression levels are altered by antisense-mediated knockdown of miRs-221/222 in U251 glioma cells, ones in the IFN-α signaling pathway are the most significantly modulated, and this observation is dependent on increased expression of STAT1 and STAT2 [23]. Consistently, overexpression of miR-221/222 in U251 glioma cells interferes with IFN signaling by down-regulating STAT1 and STAT2 [23].

Our very own STAT1/STAT2 inhibitor. That's nice.

"and there are numerous miRNA regulators of STAT3, including...miR106a...and miR125b"

More reference chasing:

In addition, we identified 2 potential miR-125b-binding sites within the 3′UTR of Stat3 (Figure 4B), a transcription factor strongly involved in granulocytic differentiation.35,36 To demonstrate direct regulation by miR-125b, luciferase reporter containing wild-type Stat3 3′UTR sequences or their mutant-derivates with deletion of the putative miR-125b-binding sites were transfected into NIH3T3 cells stably over-expressing miR-125b (NIH3T3/miR-125b; Figure 4B and supplemental Figure 3A). As shown in Figure 4C, miR-125b represses luciferase activity by approximately 40% depending on the presence of miR-125b binding in the Stat3 3′UTR. Finally, Western blotting revealed an approximately 30%-40% reduction of STAT3 protein expression in 32D/miR-125b compared with 32D/miR-ctrl cells (Figure 4D).

(link)

Quantitative real-time PCR and Western blotting demonstrated that miR-106a was upregulated, and STAT3 and phospho-STAT3 were downregulated in the hippocampus at 12 weeks post-OVX, compared with age matched controls and the 6 and 8 weeks post-OVX groups. Transfection of human neuroblastoma SH-SY5Y cells with a miR-106a mimic reduced the expression of STAT3 mRNA, compared to control cells transfected with a scrambled mimic. STAT3 and phospho-STAT3 protein expression was upregulated or downregulated by a miR-106a inhibitor or miR-106a mimic, respectively, indicating that miR-106a negatively regulates STAT3. Luciferase reporter gene assays confirmed that miR-106a directly targets the 3' untranslated region (UTR) of STAT3.

(link)

We have our own STAT3 inhibitors too. Fascinating.

So does this mean the interferon/JAK-STAT pathway is suppressed, or is it actually overactive and we're seeing evidence of negative feedback? I guess we'll have to investigate further.

Lastly, is it fair to say in terms of damage control a "primary" anti-oxidant might help? Something like orgotein (SOD)?

Are there complications to using standard ROS scavengers for this? Something like N-acetylcysteine? I imagine people have tried them before, and if they don't work, either they don't combat oxidative stress in hair follicles effectively or oxidative stress is not necessary for AGA to develop.

[Trackster]

Can we say based on this that STAT3 doesn't seem to function a big role in hair follicle biology? I would think so.... One would expect at least some hair alterations right?

Interesting, I am not so knowledgable in this field, but I read alot of these comments with interest. It is funny how different some of the opinions are.

http://www.hairlosscure2020.com/jeff...comment-105085

Wow…. look at these articles in relation to all previous posts I and others have posted

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653025/

There is definitely something to this whole miRNA-22 and JAK/STAT pathway thing going on in hair. In this other cancerous t-cell population it looks like like JAK/STAT pathway is actually supressing miRNA-22. Specifically this article mentions JAK3/STAT3/STAT5…. Notice how Walker talked about developing a JAK3 inhibitor as apposed to the others…

miRNA-22 functions as a “tumor suppressor”. Aka it stunts the growth of cells. The exact thing we are seeing in the actual hair shaft part of the hair follicle in AGA. Difference between AGA and AA? One is an adaptive immune response (AGA) and the other is an innate response (AA). Which explains the different timescales to lose hair, and explains the pattern somewhat. We also know from above posts that STAT3 is a positive regulator of miRNA gene suppression. And it is known that miRNA-22 is androgen induced from previous posts. And you may look this up if you wish, but estrogen/estrogen receptor and androgen/androgen receptor are regulated differently by miRNA-22 in different cancers.

Based off of in human trials and on mice, we know that lowering/blocking of JAK/STAT signaling allows hair to grow. When it is high, it is a stop signal in the hair follicle. That much is obvious. This not only works in rodents but in humans. We also know that miRNA-22 functions in hair to stop it from growing by suppressing 50+ keratin genes (and probably others)…. see above article for that. Causing the follicle to regress according to above posted article… exactly like the parthenogenesis of AGA. Also the miRNA-22 promoter is located on the same DNA region in mice and in humans per the article I posted above.

miRNA22 is also implicated in endothelial cell cellular senescence…. We know this is going on in AGA dp cells, perhaps once again through the JAK/STAT pathway? Relieving this reverses senescence. See the below abstract

http://www.ncbi.nlm.nih.gov/pubmed/25323119

Also miRNA-22 regulates smooth muscle cell differentiation. Smooth muscle cell is what the erector pili muscle is made of, in which contact is lost in AGA. Could stopping miRNA-22 jak/stat signaling allow the erector pilli muscle to make contact again? See the below abstract.

http://www.ncbi.nlm.nih.gov/pubmed/25722434

Here is where this gets interesting to me….

http://www.genecards.org/cgi-bin/carddisp.pl?gene=MIR22

The gene coding for miRNA-22 is on chromosome 17. And it appears that the genes coding for stat3, stat5a, and stat5b are ALSO on chromosome 17.

http://www.genecards.org/cgi-bin/car...keywords=stat3

http://www.genecards.org/cgi-bin/car...keywords=stat5

http://www.genecards.org/cgi-bin/car...keywords=stat5

Note that stat1, stat2, stat4, and stat6 are not on the same chromosome…. So perhaps this micro RNA is promoting stat3 and stat5 over-expression in AGA.

miRNA’s main function is to post transcriptionally regulate gene expression.

STAT’s stands for “SIGNAL TRANSDUCER ACTIVATOR OF TRANSCRIPTION.” It would only make sense that something like this is the main problem in AGA. It looks super complicated from the outside because so much is going on. But perhaps it is one or two master switches causing the cascade of crap to happen. This is what I believe at least.

Man, I am more confident then ever that proper JAK/STAT inhibition via a topical is truly it. I could be completely wrong, but it sure looks like jak/stat signaling has a ton to do with all of hair biology (really, all of biology in general) not just AA.