HAIR CUTS #3

CosmeRNA: Hope or Cope

The launch of CosmeRNA’s androgen receptor (AR) inhibitor ignited a great deal of hope and cope within the hair loss community We are desperate for better options, and the ability to buy one deemed safe and effective by the reputable European and UK regulatory agencies is a dopamine rush only similar to ordering TM on WhatsApp (for research use only). The bulls and the bhairs of the novel treatment each laid their claims to the global hair loss community

The bulls pointed to the results of CosmeRNA’s flagship study–a 4.5% increase in total hair count across a double-blind placebo study with 43 par ticipants. AR–after all–is a known actor in several prominent hair loss pathways, and so inhibiting it by even a small percentage should render a clinical effect. Additionally, CosmeRNA’s approval as a cosmeceutical–even at its high 5 mg/ml dose–leads us to believe that the treatment will likely not have side effects. The bulls are left to exclaim that we may achieve a gold standard in the hair loss market: a growth promoter with very low side effect risk.

The bhairs lament the study’s breadth and depth. Only 22 patients received the 5mg/ml dose, at a significantly different dosing schedule than what CosmeRNA is currently adver tising (1x per week vs 1x per 2 weeks). Three of the four tested disease models–LNCaP cells; human dermal papilla cells; plucked human hair follicles–are worse than the scalp skin model used in our T3/T4 study The study also completely failed to measure the in vivo penetration or genomic changes of CosmeRNA’s active ingredient (AR68)–we don’t know if the treatment reaches or has any effect on our hair bulbs. Standard biopsies of the patients par ticipating in their

human unofficial clinical trial–as Dr. Barghouthi conducted for his Ver teporfin tests–would have provided answers for both questions, thus significantly strengthening CosmeRNA’s small dataset.

The biopsies we outline above would have cost no more than $50,000–a small add-on to the likely multi-hundred thousand dollar study run by Bioneer–the nearly billion dollar corporation behind CosmeRNA. Due to CosmeRNA’s inability to produce adequate data, we are left to test it ourselves. We recommend testing CosmeRNA only if one has the money to spend. If you generate the data, please share it with us in the Patient Por tal for HAIR. Those who buy the product have the ability to better evaluate the efficacy of the treatment than any institution today

Contributors: Visangle, BradMish, FollicleThought, Jumpman, Herber t, Tigris, Romeo, Macaque, Pointlol, Andy1, Cook, Copernacus, Endana, Averbs123, Dragan Dabic, Ghter, Gurgeh, Benjels, Fgsfds, and Potential Dingo

Disease Model Validit y

As we decide how to allocate our treasury, the testing models we use have fallen under question. The conversation began with our dutasteride delivery vehicle research, led by Herber t. Dr. Cornelia Keck pitched us on running our delivery vehicle study on ex vivo porcine ear, highlighting the pig ear’s similarity to in vivo human skin She doesn’t like the Franz diffusion model, as stretching the skin changes its mechanical proper ties Geoff Hamilton fur ther advised on the pig model, warning us to beware of Epibiotech’s recent pig results–their paper failed to disclose the drug used to immuno-suppress the pigs, a significant omission for any reputable research organization While perfected drug delivery–achieving a localized effect with no systemic exposure–remains of utmost impor tance, our model to test a drugs’ clinical efficacy differs substantially.

In drug efficacy, Jumpman, Ralf, Herber t, Bob allen, and Benjels continue to lead us. The animal whose balding genetics most closely mirrors ours is the stumptail macaque, with Bob allen highlighting that both Minoxidil’s and Finasteride’s efficacy in macaques approximately mirrored their human results. A pressing question in the hair loss community remains whether HMI-115’s Phase 1 clinical trials will mirror their macaque study Potential Dingo, Macaque, and Tigris repor ted we should receive their results in September or October RU58841 also successfully passed the

macaque test, although we still do not have its official, yet unreleased, Phase 2 trial data (Phase 2 trials show efficacy; Phase 1 trials show safety). If only someone would build the tools for us to aggregate patient treatment data.

Outside of the macaque, the two most impor tant models remain human scalp skin ex vivo tests, either on murine back or cultured in a dish Additional models, such as skin organoid models and dermal papilla cells in a dish, often fall shor t, as the transcriptomes and intercellular communications–or lack thereof–deviate too far from human in vivo The community’s final conclusion is that Jumpman’s gigabrain knows best–there is no model better than human in vivo. The only question is when is most economical–both for patient safety and hair regrowth efficacy–to turn on the switch.

Contributors: Jumpman, Ralf Paus, Herber t, Potential Dingo, Bob allen, Geoff Hamilton, Andy1, Macaque, Vincent, Benjels, Tigris, Visangle, Averbs123, and Ghter

HMI-115

Synthetic Pug discovered that only a few dermal papilla cells can make all the difference–answering our questions on the ability for HMI-115 to sufficiently regrow hair within only six months of use in macaques. HMI-115’s treatment works as a prolactin (PRL) receptor blocker, administered as a monoclonal antibody injection in the stomach. There has been significant speculation on the success of HMI-115, due to repor ted results from its ongoing Phase 1 clinical trial and its impressive pre-clinical macaque study As Dingo, Macaque, and Tigris repor ted, we should receive our results of the Phase 1 androgenetic alopecia trial in September or October of this year.

Despite HMI-115’s success thus far, one can have upregulated prolactin levels and still experience significant hair regrowth–in fact, prolactin stimulates hair growth in females Ghter has been taking 2mg of prolactin a day and his hair is looking way better We thus are left to question whether PRLR is either a sustainable long-term treatment or a co-activator in another, more impor tant pathway. Jumpman ideated a study on the measurement of the downstream genomic changes of PRLR inhibition on the novel pathway’s mechanism of action.

We also remain cautious of the systemic effects of the drug and thus advise

self-experimenters to exercise caution at home. Prolactin helps maintain healthy neurochemistr y, protection against fatty liver disease, and is necessary for sexual function. HMI-115 is also in Phase 2 trials for endometriosis, a female reproductive disease, eerily similar to Finasteride’s use in the male reproductive system. We need more data to understand PRLR’s science, due to its truly novel approach in the treatment of androgenic alopecia.

Fun fact: Patients currently in HMI-115’s clinical trial are paid $2k USD

Contributors: Jumpman, Synthetic Pug, Tigris, Macaque, Visangle, Potential Dingo, Ghter, Andy1, Herber t, BradMish, and Endana

The Mesenchyme Command Factor y

Hair follicle loss is directly due to a decrease in the number of functioning dermal papilla cells, a stem cell group at the bottommost par t of our follicles. Dermal papilla cells are generated from hair follicle dermal stem cells (hfDSCs), a stem cell group capable of differentiating into both dermal papilla and dermal sheath cells. The dermal sheath surrounds the hair follicle, touching the dermal papilla in all hair cycles, while always separated from our outer root sheath cells (ORS) by the basement membrane formally titled the basal lamina.

Dynamic remodeling and morphology of the dermal sheath during the hair cycle During the growth phase (anagen), expanding DS tightly wraps the follicle and is closely juxtaposed with the epithelial ORS progenitors During the regression phase (catagen), the DS more loosely encases the epithelial strand around which restructuring of the basement membrane occurs (referred to as “glassy”) Apoptotic DS cells trail the regressing follicle in the DS “sleeve,” and by the resting phase (telogen), only a few DS cells persist and intimately surround the DP, which are bipotent stem cells termed hair follicle dermal stem cells (hfDSCs). Source: Rendl et. al (2020).

Throughout hair follicle cycles, there is a flow of mesenchyme stem cells between the dermal papilla and the dermal sheath. Jumpman outlined the flux between the two groups, discovering that both endothelin signalling (ET) and alpha smooth muscle actin (αSMA) act as pivotal pathways in the dermal sheath’s healthy contraction during catagen. Fur ther in catagen, Synthetic Pug presented that the senescence or displacement of dermal sheath cells may worsen the outflux of dermal papilla cells. Herber t shared terrific background of the two cell groups groups in several papers.

Ndimension highlighted that hair follicle dermal stem cells (hfDSCs) with upregulated levels of β-catenin experience senescence, leading us to question the long-term efficacy of the ever-mentioned Wnt pathway However, Jumpman, Herber t, and Tigris reminded us that DHT downregulates β-catenin and Wnt through DKK1–and perhaps additional inhibitors–posing that we need to only bring Wnt’s activation back to healthy levels Going beyond healthy Wnt levels results in senescence, as the body recognizes high levels as tumor growth and overactivates mTOR Much of our discussion on the dermal sheath’s role in hair follicle tissue remodeling remains open-ended

Contributors: Jumpman, Synthetic Pug, Ralf, Ndimension, Herber t, Tigris, Andy1, and Pubehead

DHT’s Mechanism of Action

Scalp dihydrotestosterone (DHT) reduction remains one of the few clinically proven ways to regrow hair. However, the hormonal treatment often causes significant side effects–through DHT downregulation, estrogen upregulation, and modification of androgen receptors. The side effects themselves have caused many of us to question whether systemic DHT inhibition is wor thwhile, as membrane androgen receptors (mAR) and NADPH oxidase (NOX)--the two most prominent co-activators in intracellular DHT pathways–are highly implicated in neurological function

The community’s most prolific researchers have found that DHT in small amounts is good for hair follicles. Jumpman poses his theory on DHT’s biphasic nature–DHT upregulates uPA up until a threshold is crossed, at which point PAI-1 becomes upregulated, causing cellular senescence downstream. Vincent agrees, finding that DHT in low levels is necessary for hair follicle functioning in vitro. In tandem, Synthetic Pug and Herber t pose that DHT’s effects are due to its co-activators rather than the hormone itself–evidenced through DHT’s ability to promote growth in our beard and body hair during puber ty. In fur ther agreement, Jumpman repor ts that transgenders seem to get better hair growth from spironolactone, which is a par tial agonist of androgen receptors, than from bicalutamide, a potent antagonist

DHT’s story becomes fur ther muddled when considering the relative failures of androgen receptor treatments. Numerous stories of failed androgen receptor blockers and degraders were shared, both in standard clinical trials–Visangle scoffed at Pyrilutamide’s results–and group buys. Herber t believes that this may either be due to the many binding domains of the androgen receptor, or the androgen receptor’s ability to mutate in the presence of low androgens

At the same time, DHT’s significance in hair loss is unmatched RU58841–a potent AR blocker–remains the market’s most effective treatment anecdotally, other than potent DHT reducers Finasteride and Dutasteride. More questions remain of DHT’s complete mechanism of action, specifically the downstream effects of its co-activators. Androgens are still poorly understood in hair, the brain, and the rest of the human body.

Contributors: Herber t, Synthetic Pug, Jumpman, Visangle, Tigris, Andy1, Endana, Ghter, BradMish, BenjamTD, Benjels, Macaque, Vincent, Romeo, Averbs123, Murder Fox, GregLurik, and Aspectx

On the Arrector Pili

Jumpman explains the arrector pilli’s relevance to healthy hair follicle functioning The arrector pili muscle (APM) promotes growth via sympathetic nerve connection, transmitting norepinephrine and, in turn, activating Beta-2 adrenergic receptors in the hair bulge. The downstream activity of these receptors inhibits FOXP1 and FGF18, as well as promoting cell-cycle related genes. The arrector pili is maintained by Sonic hedgehog (Shh) emitted from Transit Amplifying Cells (TACs)--progenitor cells in the hair matrix that also maintain the dermal papilla

After Shh is downregulated over a prolonged period, the arrector pili muscle is lost. Jumpman doesn’t think the APM is necessary to re-enter anagen, but believes we can still obtain the benefits of the APM through Beta-2 agonists, such as procaterol. It remains to be seen how effective Beta-2 agonists are as a treatment, although they are hypothesized to work through the GPCR-cAMP-CREB pathway

Contributors: Jumpman

Convhairsations

Synthetic Pug’s Theory of Balding: Synthetic Pug argues that TGFb downregulates SOD2, inducing senescence in dermal papilla cells (DPCs). In a positive feedback loop, senescent cells emit SASP factors, which cause TGFb upregulation, which increases SASP factor production, and the cycle continues. The compounding effects of TGFb is why hair loss is progressive and not immediate, but still tends to happen in one hair cycle. Higher expression of AR may also play a role, as higher expression leads to more Dkk1, which inhibits Wnt, but it doesn’t appear to be causative.

Herber t ’s Theory of Balding: Herber t believes that at least one co-activator in the androgen receptor pathway experiences expression changes.

Metabobbly’s Theory of balding: Metabobbly believes there is shor tage of acetyl-CoA, which causes the RNA II polymerase complex to be terminated most likely by a HDAC. As such, longer genes are no longer expressed and cells eventually become senescent.

Ndimension’s Theory of Balding: Ndimension argues that our hair stem cells have a set number of cycles based on our genetics and epigenetics.

Jumpman’s Theory of Balding: Jumpman illustrates how PAI-1 and Twist-1 modify FGFR signaling to downregulate R-spondins and Wnt-signaling.

On Models: Jack Scannell advised us to look at Markhov models, due to the flux state of hair loss–both phenotypically as our hair transitions from anagen to catagen to telogen, and microscopically as some of our dermal papilla move to the dermal sheath in late anagen and return in late telogen.

On ALK5: Jumpman repor ts that methylation of cer tain genes cause TGFb to signal more to ALK5 than ALK1 ALK5 knockouts have been shown to reduce TGFb-induced growth inhibition of outer root sheath (ORS) stem cells

On Microneedling: The best microneedling technique, according to Follica, is 0.8mm deep every two weeks. Jumpman writes, “People got this idea in their head that deeper is better, but density>depth.” Microneedling’s mechanism of action is believed to be from increased Wnt proteins and HGF receptor expression.

Natural 5ar Inhibitors: Molotov Ribbentrot identifies a naturally derived AR inhibitor from mangrove trees. Macaque shares Fenubreek as a natural 5-ar inhibitor, recommended by Nick Sangrove–rumor has it can drop DHT by 10%. Andrew Huberman tells us how he just couldn’t stand the side effects of DHT inhibition in circumin. Just imagine if he tried Finasteride–Herber t shares his analysis of the molecule Salugi states that better delivery vehicle is better than nutraceuticals, although it would be nice to know for sure if natural 5ar inhibitors are hope or cope.

TGFb and Reactive Oxygen Species: Herber t, Synthetic Pug, and Ghter question the chicken and egg problem of TGFb and reactive oxygen species (ROS). Which comes first?

C3A and Procyanidin: Herber t and Synthetic Pug continues to push forward C3A, which they believe likely has the same mechanism of action as procyanidin but in stronger amplitude. If we can get a clinical dose of C3A in scalp skin, we can hypothetically

scavenge ROS and reduce TGFb. Synthetic Pug points out, however, that high amounts of antioxidants can lead to other health problems.

Jumpman on Alopecia Areata: If you are like andy1 and have a genetic predisposition to alopecia areata, Jumpman advises to not take JAK inhibitors as a prophylactic. Most people who are predisposed to alopecia areata will never actually develop it.

JWPharma and YAP: Jumpman repor ts that JWPharma was granted its first oversees patent for its GDNF activator. GDNF upregulates YAP signaling, the same pathway that Ver teporfin suppresses for its scar prevention treatment. Jumpman, Endana, Tigris, and Ghter debated whether we want to upregulate or downregulate YAP. Tigris provided studies of YAP’s upregulation in tissue regeneration, while Jumpman countered with YAP silencing’s ability to upregulate TRPS1 and RSPO1 in wound healing–two desirable growth genes.

DMSO At Home: Visangle and Jumpman repor t that placebo groups that use 100% dimethylsulfoxide (DMSO) tend to grow hair. The compound is less toxic than ethanol, if you’re conducting at-home research.

siRNA Treatments: If Herber t could design a drug, it would be a nano-formulated siRNA that is able to keep the iRNA in the par ticle in the skin, but then releases the par ticle once it hits blood, leading to degradation. Jumpman ideated a Twist-1 siRNA knock-out, which would pair very nicely with Herber t’s model.

NMR Verification: Verifying a compound’s structure at home? Using an NMR spectrometer could be helpful. Benjels and Jumpman tackle TM's structure.

On Anagen: Herber t repor ts that the hair follicle is not fixed during anagen. Synthetic Pug argues that prolonging anagen may not change hair miniaturization, if it doesn’t also solve for senescence. Pug claims anagen prolongation may regrow hair in areas with viable DPC amounts, but follicles with too many senescent DPCs would not return from a vellus state. Pug’s theory may explain why HMI-115 may not regrow hair in fully bald areas. He also poses an interesting study idea: can we quantify the amount of miniaturization reversal, if we know the percentage of anagen prolongation?

Dynamic Melanocytes: Melanocytes are a dynamic stem cell group, constantly differentiating and moving between the hair bulge and germ. Jumpman teaches that if the colorful cell group returns to the germ, they should be able to differentiate normally If they become stuck in the bulge, the patient will experience hair graying, and potentially hair loss in some, as senescent melanocytes may signal SASP to adjacent hair cell groups.

Minoxidil’s Mechanism: In Hair Cuts #2, we repor ted that “Alongside angiogenesis, Jumpman pointed out that Minoxidil inhibits GSK3b and SFRP1, upregulates LHX2, and promotes keratinocyte differentiation - mostly mediated through the upregulation of Hepatocyte Growth Factor (HGF), an executor pathway outlined by Ralf as good for hair growth.” This month, Synthetic Pug supplemented our minoxidil research with more fuel. Minoxidil acts on DPCs to stimulate VEGF and may also upregulate androgen metabolism through 17b-hydroxysteroid dehydrogenase upregulation Herber t hypothesizes that the drug may be countering oxidative stress-induced senescence from androgens.

Patient Por tal Data: Herber t wants to analyze genomes from patients who have experienced side effects from finasteride even in microdoses. He also wants to see data from researchers trying RU58841 and CosmeRNA.

Market Briefing: Visangle provides a market overview of hair loss star t-ups, as well as a warning to beware of fake papers Up to 34% of neuroscience papers and 24% of medical papers published in 2020 were probably fake.

New Targets: Drug Hunters Assemble

Jumpman finds five new targets with a 2017 genetics-based approach: SP1, HDAC2, NR3C1 (GCR-alpha), BCL2, and PTGIR

Our favorite mouse Ghter teaches us IGFBP3 is upregulated in balding scalps

Jumpman repor ts RSPO3 is downregulated 8-fold by DHT exposure in DPC cells, granted it’s measured in a 2D cell culture

Ndimension wonders what would happen if he upregulated PGE2 four teen times above his current level

Synthetic Pug, Jumpman, and Metabobbly teach us IL-6 may promote hair loss exclusively through TGFb TGFb is required for hair growth too though, and so shouldn’t be a direct target

Jumpman thinks PGD2 is a money sink, for a bunch of diseases

Jumpman shoots down GSKb3 as a target It's probably not a great mechanism because it's downstream of Wnt receptors, and may actually result in the degradation of Fzd Wnt receptors by recruiting Fzd degrading proteins, par ticularly in AGA scalp where the protein (RSPO) that suppresses Fzd degrading proteins is already low.

Visangle and Jumpman identify that IRX5 knockout causes hair loss by downregulating DNA repair regulators BRCA1 and FOXM1 and upregulating FGF18 In tandem, differentially-open chromatin regions in IRX5+ cells include NFATc1, LHX2, and JUND. Are any of the targets wor th our pursuit?

FGF targeting needs to be done correctly, warns Jumpman: “FGFR inhibition is not great. It needs to be modulated in just the right way You want to block the negative regulators FGF5 and maybe FGF18 Downregulate FGF23 and maybe FGF21 but not block them Blocking FGF18 only par tially

rescued anagen delay in IRX5 knockout ” Benjels wants to inhibit FGF-18

Synthetic Pug wants to look at NOX2 inhibition using GSK2795039 Downregulating NOX reduces ROS, consequently mitigating cellular senescence The paper identifies DPI, VAS2870, VAS3947, and tat-gp91ds as the most convincing NOX antagonists. Potential Dingo wonders about the safety profile of NOX inhibitor Isuzinaxib–it’s about $600 for a 6 month oral supply

Jumpman identifies that AC010789.1, a long non-coding RNA, delays androgenic alopecia progression by promoting the proliferation and differentiation of hair follicle stem cells (HFSCs) and downregulating miR-21-5p and TGF-β1 expression, while upregulating the Wnt/β-catenin signaling pathway

SyntheticPug identifies elastin as a potential marker to monitor, highlighting that normalizing the protein is key Elastin is essential for the tissue remodeling that takes place at the intersection of the arrector pilli and outer root sheath (ORS). Its overregulation likely blocks follicle growth and upregulates inflammation, while its underregulation causes detachment from the arrector pilli muscle

Ndimension found that Nanog could have positive effects on hair follicle stemness through bone morphogenetic protein (BMP) signaling and well-known growth factors Sox2 and Oct4)

Benjels drops new study design for 3aHSD. Long live sulforaphane

We receive our monthly PAI-1 update from Pubehead: Eirion made a royalty milestone payment to Renaissance six weeks ago, earning clearance to begin Phase 1 clinical trials Any day now–the trial should show up in the registry. To achieve maximum PAI-1 inhibition, Jumpman recommends apj agonist along with a pde5 inhibitor. Vincent repor ts on TM5441’s metabolites and mechanisms of action in non-hair diseases

New Treatments

Finerenone blocks angiotensin II-induced aldosterone from binding to MR. This results in upregulation of NO, which inhibits angiotensin II The drug holds a similar mechanism of action as spironolactone, but may be safer due to having less affinity to other steroid hormone receptors.

Gorilla Head thinks salicylic acid may work as a direct AMPK activator.

Herber t repor ts that caffeine has only been shown to work in vitro.

DukeNuke thinks topical cetirizine seems like a low risk for good chance of ROI as a product or compounded treatment for HairDAO to sell.

Melatonin topically makes sense as lipophilic molecule, says Herber t. If it becomes metabolized in skin as opposed to liver, the natural compound may have a very different effect.

Zoon and Pevjo analyze antioxidant Tocotrienol, which upregulates Wnt co-activator B-catenin.

Herber t lists a series of natural WNT upregulators in this general WNT background. On the list are: alpinetin, baicalin, morroniside, Aconitie Ciliare Tuber extract, Centipeda minima extract, linoleic acid, and Prunus mira seed oil.

Herber t investigated the protective effects of epigallocatechin gallate (EGCG) from green tea on human dermal papilla cells (DPCs) when treated with dihydrotestosterone (DHT).

Metabobbly seeing good progress with his treatment. What is his stack? It’s patent pending, he claims.

ROS scavenger Allium Hookeri activates B-catenin and NRF2 in a new paper drop.

NDimension and Synthetic Pug tell us we may be able to suppress TGFb1 with NAC, a ROS scavenger that is widely available.

HairDAO Prescriptions and High Thoughts

HairDAO Association, nor any other entity or person, endorses or recommends the treatments below. This is for enter tainment and research purposes only

Flaming Taco recommends looking at zinc deficiency

Aspectx: Not all finasteride generics are created equal. A reputation system is very impor tant here.

Endana, Potential Dingo, and Averbs debate if are hair transplants are permanent. Joe Buck’s gotten at least 8 of them.

TeQuiero needs to up his Vitamin D

Mna shares a dutasteride mesotherapy study, where only 15% of patients completed the year-long treatment, 38% of which saw results.

GregLurik’s recommends star ting with 5ar inhibitors before moving to androgen receptor blockers.

RawSkin is on 1% spironolactone (1.5ml daily) and is happy so far.

Murder Fox is on Bicalutamide 50mg daily for her androgen sensitivity, which seems to be caused by a previous regimen: low dose cyproterone acetate–an AR receptor blocker–and a weekly dose of dutasteride. Impeding androgen production and interaction levels caused increased sensitivity to androgens, so much so that 0.6 nmol/L of testosterone would resume her hair loss. She’s only on Bicalutamide for the last 3 months–shedding has slowed, but not stopped entirely yet.

Bpq asks if anyone has tried Regenera Activa or knows much about it.

Ryann updates us on Turn Biotech, an epigenetic reprogramming company, has moved to in vivo models for skin regeneration. Hair would be next, we hope.

RawSkin asks: “What if you transplanted beard hair to scalp, dermarolled the fuck out it, would they become native hairs?”

GregLurik wonders: “What is a nutrafol ad doing during the NBA playoffs?”

Ndimension ponders: “Should we downregulate anagen at the star t of anagen, to prolong anagen?”

Racias asks: “Will androgen receptor blockers cause higher levels of DHT in scalp/blood–worsening effects on follicles that don’t receive AR inhibition?”

Zoon is currently on spironolactone, opzalura topical, ketoconazole shampoo, and some vitamins.

BradMish is going to light Ghter’s tail on fire if we don’t have Hairy Matters 3.

Is Olix dead? They at least have some expensive patents.

Herber t asks Jumpman: “Do you think there could exist an anti-androgen that can only be active in the follicle, not by delivery mechanism, but purely by design?”

HAIRy Matters

**Once received, all HAIRy rewards will be vested monthly over a two-year period**

● Ralf: 730.16, per our contract.

● Jumpman: 730.16. The only language model that supersedes HairGPT is JumpGPT. Jumpman’s work this month highlights PAI-1, Twist-1, Beta-2, Shh, E T, αSMA, COL17A1, ALK5, and AR–among theories on anagen, DHT, prolactin, senescence, and the arrector pilli. The VisionHair y continues to garner data that no one else in the hair loss industry has.

● Benjels: 421.55. Benjels continues to execute both mission-critical operations and gigabrain research. His operations include co-developing Discord data scraping and securitization (more on the hack in Hair Cuts #4–the world will never lose Jumpman’s research again), HairGPT, Grow, and treasury signing execution. His research includes model validity, senescence, PAI-1, epigenetics, and 3aHSD

● Herber t: 399.08. Herber t continues to lead our delivery vehicle study, while senescence, model validity, prolactin, dermal sheath, DHT, WNT, AR, NOX, and siRNA research. Visangle was especially grateful for his contributions, conferring to him the most prestigious invite a hair loss researcher can receive.

● Schmakofant: 321.61. Schmakofant carried the development of HairGPT, the first hair-focused research bot, and continues to monitor the Patient Por tal, which we could use at any day to aggregate our CosmeRNA or RU58841 data. He has more updates for HairGPT on the way–including scaling the product into a Hair Wiki that Endana wants to use to create more researchers.

● Synthetic Pug: 252.48. Synthetic Pug led research in the mesenchyme command center, hair stage cycling, cellular senescence, TGFb, ROS, AR, VEGF, NOX, and elastin.

● Endana: 179.72. Endana continues to execute on-the-ground research and operational work at a high-level. He leads our Ver teporfin research, ideates content to uplevel more researchers, and executes ad-hoc business development.

● FollicleThought: 159.92. FollicleThought continues to execute high-level business development, this month putting us in touch with Cage Bio and Zylo Therapeutics for our delivery vehicle study. He’s reached out to some bigger names too, although there’s nothing he can say yet.

HAIRy Matters

● Ghter: 117.44. Our favorite mouse contributed to our research of TGFb, reactive oxygen species, YAP signalling, CosmeRNA, prolactin, and presented IGFBP3 as a new target.

● Tigris: 113.68. Tigris contribute to our research on CosmeRNA, prolactin, the mesenchyme command factory, YAP signalling, and WNT.

● Visangle: 106.42. Visangle led our research on CosmeRNA, AR, IRX5, DMSO, and PAI-1.

● PotentialDingo: 91.31. PotentialDingo contributed to our research on CosmeRNA, prolactin, model validity, PAI-1, and NOX.

● NDimension: 77.36. Ndimension contributed to our research on the dermal sheath, cell cycling, PGE2, Nanog, TGFb, and Reactive Oxygen species.

● Macaque: 63.44. Macaque contributed to our research on CosmeRNA, prolactin, model validity, AR, and DHT Maybe we can test on it one day

● BradMish: 59.71. Brad contributed to our research on CosmeRNA, PAI-1, and prolactin.

● Vincent: 57.38. Vincent contributed to our research on model validity, the mesenchyme command factory, PAI-1, DHT, and ver teporfin.

● BenjamTD: 54.33. Benjam introduced us to Hemia Cosmetics and contributed to our research on DHT, AR, 5-ar inhibitors.

● Romeo: 50.42. Romeo contributed to our research on CosmeRNA, AR, and PAI-1.

● Metabobbly: 49.42. Metabobbly contributed to our research on cellular senescence and interleukins.

● Dragan Dabic: 46.22. Dragan Dabic contributed to our research on CosmeRNA and PAI-1.

● MurderFox: 42.21. MurderFox contributed to our research on androgens and DHT

● Aspectx: 36.21. Aspetcx contributed to our research on PAI-1, AR, and DHT, as well as social media reach-out.

● GregLurik: 34.17. GregLurik contributed to our research on microneedling, tretinoin, and minoxidil.

● DukeNuke: 33.21. DukeNuke contributed to our research on today’s best current treatments, our operations, and general pharma trends.

● GorillaHead: 32.81. GorillaHead contributed to our research on TGFb, AMPK, Twist-1 and thrombosis.

● Pubehead: 29.22. Pubehead contributed valuable insight on PAI-1.

● Cook: 28.29. Cook contributed to our research on CosmeRNA.

HAIRy Matters

● Bob_allen: 25.24. Bob_allen contributed to our model validity discussion.

● Pevjo: 24.21. Pevjo contributes to our research on melanocytes and tocotrienol.

● Gurgeh: 22.19 Gurgeh contributed to our research on CosmeRNA.

● Mna: 21.08. Mna contributed research on 5ar inhibitors, mesotherapy and microneedling.

● Zoon: 20.07. Zoon contributed to our research on spironolactone and tocotrienol.

● 20Club: Copernacus, Geoff Hamilton, Ryann, Pointlol, Fgsfds, RawSkin, Racias.

● 10Club: Sleuth, InfectedAztec, Sir Robin, oceanvibe, onix, Hathbanger, TeQuiero, Sg2000, daviboy, Yigitamkk, sohailinho, bpq, and Bendji.

● 5club: Coinflip, Shub25, Kolligant, and RalleyMonkey.

HairForce Update

Attention HairForce! We were attacked by an anon, who seemed to want nothing more than to ruin our day As if the universe wasn’t cruel enough for taking our luscious locks away, it took our server away too. For a community that just got nuked, we should be

Today, we stand 254 strong. Impor tantly, we were able to get most of the key members back. We would love to highlight those key members and show everyone how hard you are actually all killing it.

It should be no surprise who generated the most mentions in the

Contributor: Benjels

HairForce Update

community during the mid-April through mid-May period. Our lord and savior, his holiness, Jumpman generated 260 mentions. All hail. Herber t, a recent addition to the Hairforce, has quickly proven himself to be one of the top hair loss researchers in the world, with an acute interest and exper tise in drug delivery. We may have to star t calling him the Delivery Man. Speaking of delivery man, shoutout to Jumpman for his fire meme.

Other data we have been looking at is reactions (emojis) placed on

people’s messages. Shouldn’t be a massive surprise that his holiness is also at the top of that list. Coming in at third (of the Advanced Researchers) is Endana, an early-20s beastly options trader in the Midwest. If you think he’s a catch, just wait until you hear he’s a Norwood 6. Jokes aside, Endana has emerged as a clear leader within the community and we could not be more thankful for his suppor t, pushing the boundaries of the research, keeping things pragmatic and professional, and pushing us HairForce members to be our best selves. So much more we could get into here, but going to let you all go back to losing your hair If you have any suggestions on what other metrics you’d like to see, hit me up.

Contributor: Benjels