#myc talks design

[mixupmycota]

anyway

im not doing a full big sourced post about it and im not gonna link it to the others cause im simply too exhausted but vis a vis my letters analysis:

ferelden has a massive power vacuum after thegame. fergus cousland is potentially set to become one of the most influential people in the south, already having a personal and subsequently diplomatic connection to the Chasind after they saved his life in Origins. If Orzammar gets its shit together and abolishes the caste system in the wake of this, it may see an influx of trade and cultural exchange as some surface dwarves choose to return. with the information uncovered by solas's memories and even in the case of harding's death, bellara pledging to spread the truth of what happened with the titans, we are set to see a lot of different conflicts very quickly.

if the caste system is not abolished as just a consequence of the devastation in the south, and the miners were to refuse to gather lyrium to export to the surface, that could do it.

the revelation that making use of lyrium counts as a form of blood magic will likely have drastic implications on the southern chantry, particularly the templar order. a secondary schism is likely, between those who insist it doesn't count and those that push for abolishment of the practice

the academic ramifications are immense as they relate to the study of and understanding of magic, even if the origins of the elves as spirits is not revealed for the sake of protecting the people.

with orlais radio silent, we can expect their nobility to have scattered, probably pushing up into nevarra if they are allowed in. renegade chevalier forces will be a massive problem to be reckoned with.

the free marches are set to experience a surge of fresh refugees, so how varric's work at kirkwall went will be pretty vital.

the dalish clans could potentially push back towards reclaiming important cultural sites across the south and potentially establish more permanent presences if they were inclined.

there's not a lot of important characters who cannot die in some form across all the games.

in ferelden it's anora, fergus, and teagan

in orlais it's Vivienne and if she continues being the narrative's fave princess despite her potential death, Leliana

in the free marches we get sebastian and aveline

nevarra is set to fill the power vacuum where it straddles the north and south, getting out relatively unscathed. it can be expected to absorb a lot of refugees, both common and noble, and subsequent problems.

tevinter also set to take a place as a major diplomatic hub in the wake of the rise of the new archon

i wanted to format this all properly and gesture at maps but the fandom has made me fucking tired regardless of what positions people hold so that's the best that's coming from me

[swanpyart]

This is so cool! Andre’s especially sounds metal

What do you think the gang's subconscious' would look like? We got to see Reagan's, but I'm curious what you think their would be

OH FUCK THIS LITERALLY TOOK SO LONG TYSM FOR THIS

all sfw!! tw for religion and sacrilege, surgery mentions (glenn’s), drug use + intrusive thoughts (andre’s), existential concepts + death (myc’s), unreality, 

THESE ALL TOOK. SUCH A MASSIVE NOSEDIVE INTO VERY PRETENTIOUS ANGST. IM SO SORRY ANGST JUST FLOWS NATURALLY FOR THESE POOR BASTARDS.

'hypnagogic self-projection of your own mind - it's how you see your own thoughts" WHICH,, ALRIGHT GIVES A LOT TO WORK WITH. Based on Rand + Reagan's it gives the vibe of,, partially based on personality and self-identification, with a little bit of Familiarity in em?? 

SO OH BOISE THIS IS GONNA BE A DOOZY SMDNS. Lots of misc stuff, no real specific plotting? OKIE ENOUGH PRECURSORS LETS  GO

Brett

THEME PARK BABEY

every ride is a different memory!!

it all happens so fast he doesn’t even notice the transition’s happened? Like one second he’ll be on one of those Smaller Rollercoasters and when he blinks hes,, in his 11th grade band practice?

OH and it is,,,, MASSIVE. Like if he gets up high on the ferris wheel he can see it stretch on and on for miles.

It’s also so apparent that something is,, Wrong. Nothing too overt - its not like theres Evil Metaphor Monsters chasing him around but,, its got that Weird Liminal Feel?

There’s all these rides, but nobody but him. Its a ghost town. He didn’t think his mind would feel this lonely.

It doesn’t help that it’s always sunset - at first its super fun and calming but eventually it just feels... Bad. He starts jumping at his shadows pretty fast.

The steps to get up to some of the sadder rides feel like they go on forever - like his own subconscious is actively fighting back against letting him access memories that upset him.

Like if he just really, really, really believes that everything okay, it’ll tamp down that Overwhelming Sense Of Dread. ohyeah babey his Forced Positivity is DEEP IN HIS SUBCONSCIOUS TOO SMDNSD

There’s a house of mirrors and he can’t see his own reflection. It constantly shifts into static. he doesn’t stay in there very long.

Gigi

THIS WAS SO FUN. We don’t get a lotta info on her so,,, ehehehe >:)))) time for Outis to go bananas

from what we see,,  her life is very structured, very organized - she’s got all her shit together!! 

She’s got everything she ‘should’ want, but,,, its not actually making her happy? 

She says herself that she feels completely ignored in the position she’s in right now, despite presumably working for years to get where shes at!!

SO

its a castle - a big, bright, luminescent castle, like the ones she dreamed of when she was a kid. Pristine marble and gold, these big fluffy curtains everywhere <3

its beautiful. she hates it.

she feels bad for hating it? She’s built it from the ground up, right? shouldn’t feel so disconnected from what supposed to be the ‘basis of her entire self’, but she does. 

It’s like stepping back from an artwork you’ve spent years on, only to realize you don’t like how it turned out.

TBH it takes her,, a little while to actually find her memories.

She doesn’t like to think of the past a lot - she’s learned its not good to dwell

tucked away in this,, little corner of a small hallway is this giant darkroom with this big pool of Misc Chemicals in the middle.

RED LIGHTS AND ALL, ITS.... VERY CREEPY. 

She used to spent a lot of time in them, developing photos she’d take,,,,,, in this dinky little darkroom her highschool had. kept using it even as she progressed into more professional journalism!!

she supposes its,, pretty apt? It has that same,, disquieting familiarity that thinking of the past does. ,, nostalgia, but icky.

YEP ALL HER MEMORIES ARE PHOTOS!! she’s gotta toss the photo into the chemical pool and have a hop inside. 

It smells like,, peroxide and cleaning chemicals and that alone brings back unpleasant memories but it passes fairly quickly!!

the more recently she’s thought of the memory, the clearer it is!! If she hasn’t thought of it in years, everythings,, super grainy black-and-white with lots of static around the edges of her vision. If its smth she things of regularly, its,, vivid and bright and,, a little overexposed.

Glenn

At first I was gonna be like ‘well its a warzone bc,, its HIM’ BUT ALSO THATS TOO SIMPLE,,, MM,,, NO.

It’s a war museum

it reminds him a lot of the ones in his hometown AND FUCK THERE WAS A LOT OF EM SMDNSMDN

there was this,, massive military base, barely a mile out of the town he grew up in - one of those places that are created from a necessity for houses for ppl working there, yk? 

The base came first, a long time ago, and houses were built for the families. As farmers began to set, up it became less of ‘vague habitation’ and more of a town!!

that also meant that,,, smdsnd it was drenched in military influence - extremely patriotic, everyone was military, or knew someone who was military, etc

SO YEAH, WAR MUSEUMS FEEL SUPER FAMILIAR. it has almost a religious sacredness for him.

It isn’t as solid as the others - like it isn’t a Specific Type Of Object associated to memories, they’re all different!!

Medals, paintings, dioramas - theres this,, sleek while hallway with framed surgical equipment, and all his memories of medical operations are there. A lot of stuff his from his point of view, others look like someone hid in a corner and sculpted him out. Touching them puts him into the memory!

He’s alright for,, maybe 1/4. Until he comes upon a memory that,, actually shows him. From an outside/third person perspective.

His face is covered in every single memory of his pre-surgery self. He wanders for nearly an hour, tracing back - his wedding, getting the letter saying he was drafted, nothing.

paintings have this thick, tar-like sludge smeared over sections that have his face. Sculptures are decapitated. 

more recent memories, after the surgery? sure! he can see himself perfectly. Everything before then?

:/

yep you’ve got it its because he literally hasn’t looked at a photo of himself since he got the surgery :) and he’s forgotten what he used to look like.

needless to say, he doesn’t linger very long.

Myc

OH THIS WAS HARD. The irony isn’t lost on me that,,, the one who’s a mind reader is also one who’s internal motives and thoughts and feelings we see the least of MSNDMSNDS.

LITERALLY I BLANKED SO HARD ON THIS. BUT I THINK I’VE GOT ONE THAT VIBES?

He’s what he’s always been babey! a stranger in the crowd!

‘crowd’ is generous smdnsmd

its a lot more of a,,, street. This long, infinite street lined with buildings in the middle of spring-summer - it has that nice fresh smell.

A vague combination of all the places he’s been. 

While people do shuffle about a bit, nobody really moves - they aren’t gonna start walking down the street or anything.

Memories are accessed by finding a key person who was in those memories - as usual, the transition to a memory is done through touch!

his mindscape isn’t,,, upsetting in the traditional way? Like there’s no scary room or weird atmosphere. If anything, it feels too nice. Anybody else would feel completely chill in his subconscious.

It feels wrong specifically for him.

It’s like,,,, when you look at a really old black-and-white photo and you’re like ‘damn, all those people are dead, that feels weird. that’s kinda fucked my guy’

except imagine you got to meet those people - that you saw them, a hundred, two hundred years ago.

Not only that, but you could see inside their heads.

Current thoughts and the way they think them, their favorite things - their family and friends. Every hope and dream they had, everything they wanted to accomplish. Their deepest fears. The things that make up a person. All in the time it would take to glance at them, or brush shoulders on the subway.

now come back. look at that photo.

of course, you weren’t friends - you hadn’t even talked to them, but you knew them. Everything about them. Maybe better than anybody who did actually talk to them, because you didn’t have the filter of language and unsaid words.

Do you have the right to mourn someone when you’ve never even heard their voice?

*jazz hands* so yeah Myc’s having a whole time in his subconscious.

 He really has never moved faster in his LLIIIIIFFFFEEEE. He just wants to get in and out as fast as possible.

As miserable as it is, It’s at least a refresher as to why he doesn’t get attached. Those are needed sometimes. He’s been getting a bit too chummy.

Andre

His drug use is implied to be how he copes with his OCD and Tourettes and possible religious trauma? Which gives so much to work with when crafting his subconscious smnsmd

Catholic Guilt x Eyestrain

Just,, this towering, omnipresent cathedral that's been vandalized to all hell? The pews all have these neon stickers and UV lights underneath em? Someone took a giant paintbrush and just dragged it behind them, making streaks of color on the walls? The candles on the walls are replaced with these super bright, colorful flood lights?

The holy water fond has jungle juice in it and that makes him laugh WAY longer than it should have lmao

It's kinda like when you're watching a 3D movie and you take the glasses off and there's that,, Fuzzy Aura that makes your eyes hurt?? Yeah that but its Neon Green-And-Pink and fucking EVERWHERE sdmnsmd

these long, stretching hallways that no matter what will always bring him back to the start. It's super dusty, but the apse is scarily clean.

OH and there's these,, angel statues everywhere around the room - Kinda like the ones you'd see in a cemetery? Their heads are wrapped all the way around with neon tape and glittery chains but he can still hear them whispering.

His memories are depicted in stain-glass windows - stepping through em feels like jumping in a cold lake.

JR Scheimpough

His office. 

I had a few ideas for him, but he's so thoroughly entrenched in Cognito day-in, day-out that I can't imagine it being anything else. 

even HE isn't surprised when he opens his eyes and he's just,, sitting in his office again. just feels like some kind of sick joke. Of course, the thing his mind would conjure is his office, as if his life isn’t already some surreal tragi-comedy smdnsmd.

LIKE,, TANGENT HERE BUT,,

 it isn't even a case like Reagan's, where he cares about Cognito and WANTS to improve it and WANTS to make it the best it can be LIKE NOPE NOPE /ABSOLUTELY/ NOT

Cognito Inc is a beast that's eaten him from the inside out and filled in the gaps and is now shambling around in the body of what used to be JR Scheimpough. It’s a parasite and he is a host unto it.

OH and his mini golf set is still there though so that's fun :)

When he opens the door, it's an endless void. There's a red rotary phone on his desk with a phone book beside it.

Memories are each associated to a phone number bc even his subconscious can't make shit easy for him smdnsmdns

YEP THIS POOR BITCH IS GONNA BE SITTING AT HIS DESK, FLIPPING THROUGH THOSE THIN, FIDDLY LITTLE PAGES FOR LIKE THREE HOURS TRYING TO FIND THE RIGHT MEMORY SMSMNDSMD BECAUSE FUCK HIM I GUESS

when he dials the number, the scene outside changes!! He can step out of his office, into the memory, or he can just open the blinds up and observe from a distance.

He likes the distance. lots of memories have Rand - the less he has to interact with him, the better.

GOD THAT TOOK SO LONG IM GONNA EAT MY OWN SHOE <3333 MDNSMDS IT WAS SUPER FUN THO. lmk if you had smth else in mind!! I may come back and rework some elements one day but who knows smdnsd

[ignocubo]

Inside Job Preference #1

< What They're Like As A Partner >

Reagan

distant

it's not you, that's just the way she is

the most affection you'll get from her is her legs in your lap or her leaning on your arm if she's really tired

usually puts work before the relationship but does try to involve herself in things that you find important

doesn't like hanging out with you at her house bc of her dad

will want to go to your house a lot if you live alone

dislikes talking about the relationship with her coworkers

gets aggravated when they bring it up anyways but it's kinda funny to you

idk i feel like dating reagan is like being her best friend except you get to know more about her personal life

Brett

clingy

you know he needs constant validation soooo

he's a pretty basic partner lol

very supportive of your interests and quirks

likes doing stuff for you like cooking and taking you shopping

his love language is definitely acts of service

surprisingly he gets jealous easily because he's worried you'll meet someone and end up liking them better

anyways, expect lots of exercise in the relationship

he finds it romantic, don't ask why

if you work at cognito inc he finds every opportunity to work with you

he'll come to you whenever he gets injured and kindly ask for help even if you have no medical experience

if you don't work at cognito inc he feels bad that he can't tell you about his job and why he has to work unpredictable, typically long hours that cause him to miss more dates than he can count

he'll probably find a way to make it up to you though

or he'll just try his best to get you a job at cognito inc as well

Gigi

i don't have many head canons for dating her

she likes showing you off

so that means you'll most likely be one of those couples that takes a ton of selfies together

i think she'd be a little demanding at times but not to the point that it aggravates you

her love language is gift giving. you get a gift almost every week, sometimes multiple days throughout

she doesn't make a big deal of asking you for things though

is probably more distant than reagan at times because she loves partying

but if you call her for ANYTHING she'll be there in a heartbeat

Myc

first of all, yes that's how his name is spelled, i hope this doesn't become a big thing in the fandom where people misspell it as 'mike' for some reason

anyways, i may be biased but i feel like he'd be the best partner out of these four

gives great advise, you know, when he cares about your problems

likes making you laugh and has spent a lot of time deciphering your sense of humor

is very touchy feely but i feel like that's expected considering what type of alien myc is

isn't as flirty in public as you think he would be

after it's made clear that you two are a couple, he saves the couple stuff for alone time

kinda lazy? like most of time the dates are just y'all sitting on the couch and watching seinfield

i've never watched seinfield but i feel like myc would like either that or rick and morty

after a certain point in the relationship, myc wants you to be his designated 'milker'

i mean it's a two-person job but he wants you to be one of those people, always

[imaginemycroftholmes]

Imagine mycroft becoming very concerned with the work load his girlfriend has from University. And trying to help her (but she's independent and can do it all her self!) And he plans a day out for her to have a break and in the evening his plans continue ( ;) )

"Mycroft what the hell is this?" you ask upon entering the his office with a paper packet in hand.

Mycroft hardly looks up from documents as he answers, "Why your schedule for tomorrow."

"My schedule?" you parrot dumbly.

"Yes," Mycroft confirms, "I designed one for you so that way you get optimal preparation for classes, studying-you were complaining about it the other day remember?"

To be fair you've been pretty strung out with your courses and workload. So close to graduating you were pretty much riding on coffee fumes and Redbull trying to make it on your own that you even neglected your own boyfriend.

"Um, sort of?"

Sighing you take the seat across from Mycroft and go over the time table.

"So it says here I get up at 6:00 a.m. for a jog around the house with you?"

"Nothing helps jog the mind than with a little exercise," Mycroft explains continuing his paperwork.

"Then around 8:45 a.m. it talks about personalized studying?"

Mycroft reaches for one of the stacks closest to you and you push it closer to help. "I called in a few favors to have some professors come in to help tutor you for some of the more sticky problems that have been causing you sleepless nights as of late," Mycroft states getting a bit peeved when his pen won't write shaking it before abandoning it for a new one.

he begins writing something fierce as if he's nervous about something but you'd chalk that off to having his deadlines to meet.

"Ah Myc, you didn't have to," you begin before you look further down on the list to see 9:30 p.m.

"Mycroft what's this 'extracurricular activities' listed on here for 9:30 p.m.?" you ask curiously.

All pen motion stops and you can't help the wide grin that's growing on your face.

Mycroft's face looks as hot as the sudden sound of having extracurricular activities at night  scheduled by your own boyfriend. My poor baby you think as Mycroft still fidgets with a plausible answer.

Like the minx that you are you put the schedule down and swagger over to Mycroft and push the chair away from the desk in order to get a spot on his lap.

"Mycroft, you could've of told me I was neglecting you," you coo bringing him ever closer and farer away from his work.

"But your education-"

"There are necessary times when every student needs a break," you say shushing him with a gentle finger.

 "Do you think I could get a head start on my extracurricular activities now?" you ask so innocently that it makes Mycroft shudder.

"It can be penciled in," Mycroft says weakly before he lets lust overtake him.

[mariajustinteriordesigns]

MYCS Furniture Makes My Home More Beautiful

Hello friends and happy Friday! I was talking to my friend Agata this morning because she’s looking for a marble surface in her home and she loves my coffee table. And of course she asked me where I got it and I happily told her MYCS, a company in Germany that I just love and would shop from again and again. MYCS worked with me in 2018 on a little collaboration in which I received a lovely closet for my hallway to store jackets and things and my favorite piece of all - my white Carrara marble sofa table in my living room, shown below. Have you seen it!?! It’s one of my favorite pieces in my home at the moment.

I really love this sofa table, it’s beautiful and big, I can even shoot on it when my clients ask for something to be shown on a marble background so it doubles for work and for play. It’s also very sturdy and looks so pretty when I’m entertaining, especially if I lay out all of my pretty things on it - candles, string of lights, nuts, fruit, cheese, prosecco, stemware… THE perfect table for an girls party that okay, you always want to Instagram because everything looks so damn pretty when combined with white marble! Yes?!

AND good news for YOU. At the moment, this table “Beistelltisch” is 30% off and you can get it in many different variations, including brown and black marble, glass, wood, or 18 different solid colors and the base can also be changed to suit your wishes. I honestly want to buy extra tops in different colors so I can use it more for flat lays and shoots because the dimensions of this table are just perfect for photography and I take a lot of photos over the past two years than ever before.

As for the company itself, MYCS is just great - friendly, fast, their setup and delivery service is 100% professional and great, and I really like their price point and also how you can customize many of their products to suit your design and lifestyle. It’s affordable, functional, beautiful design for all budgets, but definitely NOT IKEA, it’s extremely well made so it’s perfect for when you are ready to graduate from IKEA systems and furniture and purchase lasting pieces that you’ll keep a lot longer. For instance, my IKEA closet is falling apart so I won’t replace it with an IKEA closet… When I am ready, I’ll replace it with a system like those that MYCS carries.

This is my exact closet from MYCS below (photo/room not mine):

I am so happy with my MYCS experience from start to finish and highly recommend this company to shop from for your home, it has my official Holly stamp of approval. :) ha ha. They also have 5 showrooms in Germany, one in Paris and another in Zurich. You can also shop their online site in the UK - or buy online from other European countries, of course.

In other news… It’s boiling hot in Germany right now, it was 104 yesterday, so I’m indoors blogging and working on a photo shoot for issue two of my magazine, out 26 September on news stands all over German speaking Europe and not long after, a digital English version will be available to buy online. It’s a lot of work to make magazines, but it’s the most exciting project I’ve ever been on, and I’m loving every minute of it. As I finish up the magazine in boiling weather and no A/C, I am reminded that I must really love my job. :)

I’ll be back later with a lovely home tour.

Hugs,

Holly

(Images: Holly Becker except of closet.)

[SPONSORED by MYCS however ALL opinions and words are my own. I am never paid to “like” something. If I don’t like it, I won’t write about it and the products get returned. With this collaboration, I was only gifted with product, not compensated to write about it. I love the product and am happy to share this brand with my fans and friends.]

[cognitosclowns]

....Would you be interested in doing Glenn headcannons? Glenn x Reader headcannons? He is very special to me.

IMMACULATE TASTE ANON I WILL GLADLY SIMP OVER THIS MAN W/ YOU 

All sfw!! just a very cute dolphin man <3 

Oh god oh fuck the moment he realizes he’s fallen for you he starts losing his shit.

it hits him like an absolute semi-truck too. It isn’t a passive ‘oh, they’re pretty sweet’, that would be too easy for him, right?

Nope, it’s head-over-heels, completely forgetting his own name when you make a comment on his new artillery designs.

Your eyes are just,, so kind?? and you’re smiling so sweetly at him? Like genuine excitement while you pour over his designs?? dear god he’s a mess?????

He thinks its stupid to even consider, because

He’s the most abrasive mf on this hemisphere, and he knows it

Have you fucking seen him lately dear god he doesn’t have a shot in hell huh (the self hatred is Deep huh smdnsd)

~Repression time~

He’s repressed every other positive feeling in his life and by golly is he gonna do it again! Because the idea of asking you on a date is somehow the most terrifying thing he’s ever experienced, and he’s fought in actual wars

Be merciful, ask him

Because it’s gonna take him weeks to even consider getting the teams input for advice about this. The shame is unbearable.

Yea sure they’re gonna tease him a bit, but they’ll definitely lend a hand!

When you ask him he might just,, fucking bolt. Make up an excuse and find the nearest exit because he is Panicking

Gigi and Myc will physically drag his ass back to talk to you if they have to smdnsd bc they are not letting him pass up this opportunity.

DATING HIM?? TO KISS THE DOLPHIN MAN?? <3 <3 <3 <3 THE DREAM

AT FIRST HE IS A COMPLETE MESS PLEASE BE PATIENT WITH HIM OK

he’s terrified of initiating anything bc he doesn’t wanna scare you away?? Insecurity is a pain in the ass, and you’re definitely gonna have to get him used to hand holding/hugs/kisses!! 

It’s gonna take time for him to accept that you love him, but he’ll get there eventually <3

He honestly loves affection!!!! He’s kinda gotten used to tamping down All Those Warm Fuzzy Feelings (tm),, but he secretly loves cuddling. <3 <3 Please hold him <3

He might cry if you call him handsome. Or pretty. Any genuine compliment about his physical appearance and hes,, gone.

(bonus : his accent gets thick as molasses when he’s flustered)

he loves feeling you trace the webbing on his fingers!!! it’s very comforting <3 

EEEE I LOVE HIM IM LOSING MY MIND <3 TYSM FOR THIS ASK ANON

[azveille]

Protein-slaying drugs could be the next blockbuster therapies

When Craig Crews first managed to make proteins disappear on command with a bizarre new compound, the biochemist says that he considered it a “parlour trick”, a “cute chemical curiosity”.

Today, that cute trick is driving billions of US dollars in investment from pharmaceutical companies such as Roche, Pfizer, Merck, Novartis and GlaxoSmithKline. “I think you can infer that pretty much every company has programmes in this area,” says Raymond Deshaies, senior vice-president of global research at Amgen in Thousand Oaks, California, and one of Crews’s early collaborators.

The drug strategy, called targeted protein degradation, capitalizes on the cell’s natural system for clearing unwanted or damaged proteins. These protein degraders take many forms, but the type that is heading for clinical trials this year is one that Crews, based at Yale University in New Haven, Connecticut, has spent more than 20 years developing: proteolysis-targeting chimaeras, or PROTACs.

Large and unwieldy, PROTACs defy conventional wisdom on what a drug should be. But they also raise the possibility of tackling some of the most indomitable diseases around. Because they destroy rather than inhibit proteins, and can bind to them where other drugs can’t, protein degraders could conceivably be used to go after targets that drug developers have long considered ‘undruggable’: cancer-fuelling villains such as the protein MYC, or the tau protein that tangles up in Alzheimer’s disease.

“This is new territory,” says Alessio Ciulli, a biochemist at the University of Dundee, UK. “We’re breaking the rules of what we thought would be druggable.”

The field has reason to be optimistic. In 2014, scientists discovered that the myeloma treatment lenalidomide (Revlimid), one of the world’s best-selling drugs, works in a similar way to protein degraders to chew up two formerly untouchable proteins1,2.

Yet the field lacks published data confirming that PROTACs and other emerging compounds can make undruggable proteins disappear. And there are questions about where and how these odd-looking molecules will work in the body.

For now, all eyes are on Arvinas, a biotech company in New Haven, Connecticut, founded by Crews. It’s scheduled to begin testing a PROTAC for prostate cancer, albeit attacking a protein that’s been targeted successfully by other drugs. “We’re on the cusp of proving these PROTACs can be drugs,” says Ian Taylor, senior vice-president of biology at Arvinas. “Right behind that will be: can we do this with an undruggable?”

An academic exercise

In diagrams, PROTACs often look like dumb-bells. They are molecules made up of two binding ends connected by a thin tether.

The action happens on the ends. One grabs on to the target protein, while the other latches on to a ubiquitin ligase — part of the cell’s natural rubbish-disposal system that labels defective or damaged proteins by slapping a small protein called ubiquitin onto them (see ‘Marked for destruction’). Ubiquitin tags act as sort of ‘Please collect’ stickers that instruct the cell’s protein shredder, called the proteasome, to do its thing.

Proximity accounts for a lot in biology, so by simply bringing together the ligase and the target protein, a PROTAC ensures that the target will get marked for destruction. Ligases are efficient and ubiquitin, as the name suggests, is plentiful, so a single PROTAC should be able to perform its catch-and-release function repeatedly throughout the cell, suggesting that only a small amount of such a drug is needed for potent activity.

The earliest-known published description of a PROTAC-like molecule is in a patent filed in 1999 by two scientists at Proteinix, a biotechnology company in Gaithersburg, Maryland. In the patent (see go.nature.com/2vyjf9l), John Kenten and Steven Roberts proposed co-opting the cell’s protein-degradation system. Colleagues dismissed the idea, saying that Kenten and Roberts were complicating drug discovery by trying to bind to two proteins — the unwanted protein and the ligase — at once. “There was not a lot of enthusiasm internally for it,” recalls Kenten, now research director at Meso Scale Diagnostics in Rockville, Maryland. Proteinix did not pursue the approach.

But on the other side of the United States, another pair of minds was mulling the same idea. During a research retreat in 1998 at a scenic resort on Semiahmoo Bay in northwest Washington, Deshaies paused in front of a poster by Crews to listen to him talk about using small molecules to link two proteins together. Deshaies, then a biochemist at the California Institute of Technology in Pasadena, was knee-deep in the study of ubiquitin ligases. The human genome encodes roughly 600 of them, which need to form a complex with other proteins to do the tagging. About a year earlier, Deshaies had co-discovered3 a protein family now known to contain 250 ubiquitin ligases.

“It wasn’t that big of a leap to come to the idea of, well, gee, if you could link things to ubiquitin ligases then you could potentially drive the ubiquitination of a protein — and its degradation,” recalls Deshaies. He and Crews continued to chat all weekend and parted ways with a plan to find funding to explore the idea.

At the time, Crews was developing a drug that worked in the opposite way to PROTACs. It blocked the ubiquitin system in cells, causing proteins to build up to dangerous levels and eventually trigger cell death. The result of that work, carfilzomib (Kyprolis), is now used to treat the blood cancer multiple myeloma. “I thought the flip side would be equally as interesting,” says Crews. “That certainly has turned out to be the case.”

Crews and Deshaies soon published a study demonstrating that their first PROTAC, Protac-1, successfully grabbed and led to the degradation of a cancer-associated protein called METAP2 in extracts from Xenopusfrog eggs4.

Still, Protac-1 was far from being a drug, says Crews, who called the paper an “academic exercise”. First-generation PROTACs had low activity in human cells, probably because the compounds struggled to get inside. They relied on big, unwieldly peptides to bind to the ligases. The scientists had to find a way to make the ligase-binding ends more drug-like — “Something that had potential to be a pharmaceutical,” says Crews. Or they needed to move on.

With funding and research support from GlaxoSmithKline in London, Crews pushed ahead, mainly targeting one particular ligase, the von Hippel–Lindau disease tumour suppressor (VHL). In 2012, Crews, together with his graduate student Dennis Buckley and Ciulli, a former visiting fellow in Crews’ lab, reported on a small-molecule binder for VHL5. Crews finally began to believe that PROTACs really could become drugs.

Fishing for small molecules

Crews wasn’t the only one chasing protein degraders. In 2010, while at the Dana-Farber Cancer Institute in Boston, Massachusetts, chemical biologist James Bradner read a paper by a team of researchers in Japan, led by Hiroshi Handa, then at the Tokyo Institute of Technology in Yokohama6. Handa had been trying to understand why the infamous drug thalidomide, approved in some countries in the late 1950s and early 1960s to help with nausea in pregnancy, caused problems with limb development. (It is now approved to treat multiple myeloma and a skin condition.) Using thalidomide as the bait to fish for proteins in cells, Handa discovered that the drug hooks on to and blocks the activity of a ubiquitin ligase called cereblon. That inhibition, his team found, affects limb growth and development in zebrafish and chicks6.

Bradner realized that if thalidomide binds to a ubiquitin ligase — no easy feat, because such enzymes are notoriously difficult to grab — then perhaps he could find a way to bind to the same ligase but target it to proteins implicated in disease. In 2013, Buckley joined Bradner’s team as a postdoctoral researcher, and they began the search for small molecules that bind to cereblon.

In May and June 2015, three teams — led by Bradner, Ciulli and Crews — published five separate papers describing small-molecule PROTACs with potent, drug-like activity7–11. With Ian Churcher at GlaxoSmithKline, Crews bound a PROTAC to VHL and used it to degrade the levels of several proteins to less than 10% of those present in untreated cells7. Bradner and his colleagues bound cereblon to their PROTAC to reduce levels of a cancer-causing protein8, and Ciulli, by then at the University of Dundee, and his team degraded the same protein, using VHL as the ligase9. The protein degraders worked both in cells in a dish and in human tumours in mice.

As well as designing drug-like protein degraders, Crews and Bradner’s teams have both built systems — HaloPROTACs10 and dTAG12, respectively — that enable researchers to put targeted protein degradation to work as a tool in the laboratory, using genetic tags to mark proteins for destruction in cultured cells and in mice. With dTAG, “you can deplete a protein in minutes or hours and monitor what happens”, says Behnam Nabet, a chemical biologist who led development of the system with Nathanael Gray at the Dana-Farber Cancer Institute. “This gives you a lot of power to study oncogenes and kinases and proteins that have very rapid activity.” The dTAG materials are currently freely available: more than 150 academic labs use the probe to investigate the effects of depleting specific proteins in cells, says Nabet.

Bradner, who left Dana-Farber in 2016 to become president of the Novartis Institutes for Biomedical Research, estimates that around 30 separate tools already incorporate the technology. “The path to chemical probes is now well established,” he says. “But the challenge to make real-world medicines from these ligands is significant.”

Gold rush

Following the 2015 flurry of small-molecule PROTACs, Deshaies, who had left the field, penned an opinion piece declaring that PROTACs had the potential to become a major new class of drug, possibly surpassing two of the hottest drug-development areas of all time — protein kinase inhibitors and monoclonal antibodies13. “The gold rush is on!” Deshaies wrote at the time.

Since then, he says, it has only intensified. He joined Amgen in 2017 and now oversees the company’s work in the area.

The Arvinas trial, expected to begin by mid-2019, will include 28–36 men with metastatic prostate cancer and will last around 9 months, says Taylor. It is usual for any new class of drug to go after a well-known target, where the biology and toxicology are well-understood, and Arvinas’s first candidate is no exception. It degrades the androgen receptor, a protein that is already targeted by a handful of approved drugs. The company hopes that by degrading rather than inhibiting the receptor, its PROTAC will be able to treat people who have become resistant to or see no benefit from existing drugs. And if the candidate succeeds, the field will finally have the clinical data that everyone is looking for. Arvinas will have shown that a PROTAC can be a drug.

That’s crucial because there has been considerable doubt about whether protein degraders can work in humans. Fully assembled PROTACs break well-known rules of thumb for drugs. Chief among them is size. A good small-molecule drug typically has a mass of less than 500 daltons. Current PROTACs range upwards of 1,000 daltons. Yet the molecules can still enter cells7,10,11. Crews suspects that this is because they are probably recognized by the cell membrane as two smaller molecules that happen to be tethered together, rather than a single large one.

“We’re throwing out preconceived notions we’ve had about larger-than-average small molecules,” says Taylor.

Also out of the window are preconceived ideas about undruggables. The problem with many of these tough protein targets is that most small-molecule drugs or monoclonal antibodies need to bind to an active site on an enzyme or a receptor to work. But an estimated 80% of proteins in human cells lack such a site. PROTACs, however, can grab a protein by any nook, cranny or crevice — they don’t need to be sitting in an active pocket to work. So they could make those proteins accessible.

There’s already some evidence to support this approach. Last year, a team at the Institute of Cancer Research in London produced a small molecule that can bind to a transcription-factor regulator that doesn’t have an active site14. They were able to create a potent PROTAC by attaching a binder for the ubiquitin ligase cereblon.

The field still lacks published evidence of a PROTAC that can target and degrade a valuable undruggable protein. Deshaies says that Amgen has a PROTAC effective in both cultured cells and animals against an unnamed high-value cancer target that has been historically tough to bind. Arvinas claims to have in vivo evidence of PROTACs degrading tau in the brains of mice. On its website, the company says that injecting its tau-protein degrader directly into the mouse hippocampus reduced levels of tau by 50%.

By developing PROTACs for an array of diseases, including those that affect the brain, Taylor says that many researchers hope to show that the technology is “therapeutic-area agnostic”. Various teams are also working to expand the pool of ligases that protein degraders can recruit. There are only four main ones used at present, including VHL and cereblon, and a wider variety of available ligases could enable drug developers to match the most potent ligase–PROTAC combination with their cell type or protein of interest. “Potentially, any ligase can be hijacked through this approach,” says Ciulli, who is collaborating with German pharmaceutical company Boehringer Ingelheim on the development of PROTACs.

Buoyed by fresh targets, improved potency, and a clinical trial about to begin, researchers are ready to prove that protein degraders can be more than a parlour trick. “The sky is the limit,” says Ciulli. “It is just a question of when.

[cancersfakianakis1]

A novel hedgehog inhibitor for the treatment of hematological malignancies

The hedgehog-smoothened (HH/SMO) pathway has been proposed as a potential therapeutic target for hematological malignancies. Our previous studies designed a series of HH inhibitors with novel scaffolds distinctive from vismodegib, the first Food and Drug Administration-approved HH inhibitor for the treatment of basal-cell carcinoma and medulloblastoma. In the present study, we evaluated these HH inhibitors against blood cancers and found that HH78 displayed potent activity in suppressing the HH signaling pathway. HH78 competitively bound to SMO and suppressed the transcriptional activity of GLI by the luciferase reporter gene assay and the measurement of HH/SMO-downregulated genes, including cyclin D2, cyclin E, PTCH1, PTCH2, and GLI. HH78 at low micromolar concentrations induced significant cancer cell apoptosis showed by increased caspase-3 activation, annexin V-staining and downregulated prosurvival proteins, including c-Myc, Bcl-2, Mcl-1, and Bcl-xL. In contrast, vismodegib did not show any effects on these apoptotic events. HH78 also suppressed the activation of the AKT/mTOR pathway, which cross-talks with the HH/SMO pathway. Finally, HH78 inhibited the growth of human leukemia K562 in nude mice xenografts with no overt toxicity. Collectively, the present study identified a novel HH inhibitor with great potential for the treatment of hematological malignancies. https://ift.tt/2PHGoPS

[irishmuseumofmodernart]

  When the Ceiling Meets the Floor, Acrylic paint, 900x450cm approx., The Lab, Dublin, 2015

  ‘…when an artist sits down to write about another artist, he (she) is also writing about himself (herself).’

– D. Salle, How to See, W. W. Norton & Company Ltd, 2016, p.8.

The area of investigation within my own work explores the ‘extendable paint surface’ and the provisionality this causes within traditional views of painting. Through extensive research followed by the setting of boundaries to work within (for example using only 3 colours, Magenta/Cyan/Lemon, and 3 Shapes, Square/Circle/Triangle) I find possibilities to make painting for now. Consequently, the visual outcomes found in my work are often biomorphic in appearance; playfully teasing some form of beauty out of a self- conscious awareness of the paint and its own material hybridity.

MYC- neon, Something about some thing to do with Paint, Acrylic paint, medium gel, canvas, wooden structure and steel supports, 200x185cm, The Mac, Belfast, 2014, Photo credit: Simon Mills

MYC- neon, Something about some thing to do with Paint, Acrylic paint, medium gel, canvas, wooden structure and steel supports, 200x185cm, The Mac, Belfast, 2014, Photo credit: Simon Mills

What has become increasingly important within the work I make is how to systematically challenge painting without sacrificing the medium of paint. Peeled and removed paint within my paintings thus acts to reveal the canvases innards while concealing it at the same time, inviting the viewer in to examine its fragments (history) and out: to experience its wholeness (now-ness), making it indeed mysterious and curious as an object of painting.

  Y_M_C_C_Y_M_M_C_Y_YMCCYMMCY_YMC_CYM_MCY, Acrylic paint, medium gel, wood support, 450x200cm approx., Highlanes Gallery, Drogheda, Photo credit: Davey Moor

  Hence it will come as no surprise that what struck me most about my first encounter with the Freud paintings at IMMA was not the normal frontality of his subject matter but rather the way he constructed his paint upon the surface of his supports.

Detail image from Two Irishmen in W11, Oil on canvas, 172.7×141.6cm, 1984-85, Private Collection

  Lucian Freud is an artist who has been long celebrated for his painted flesh, but I am not talking about flesh; that meaty and weighty plasma. Rather when confronted with the work in IMMA what I found myself wondering about was the way his paint handling had now become a kind of skin. Skins, which are not of the human variety even though they are suggestive of it, but rather a skin, which has been created touch-by-touch [1], brushstroke by brushstroke, layer over upon layer and within the rectangular confinements of the canvas and beyond.

Freud’s paint surfaces, these skins, are made from and contain huge amounts of paint, paint often arduously yet somehow instinctually applied. The paint skins in each individual painting now hold all manner of evidence such as that of the artist’s hand, his touch, his intensity and importantly his struggle to make an image from this liquid and its fugitivity. Freud’s skins thus make visible not just a specific ‘medium’ (paint), but also content, ideas, and his very process.

Details image from Reflection (Self-Protrait), Oil on canvas, 56.2×51.2cm, 1985, Private Collection

Details image from Reflection (Self-Protrait), Oil on canvas, 56.2×51.2cm, 1985, Private Collection

Upon close-up inspection what becomes noticeable is just how much Freud’s paint skins hold all manner of nuance. They are full of contradictions, somehow appearing both delicate and frenzied within their construction, both abstract and figurative within their picturing. They are beautiful and they make visible so many aspects of Freud’s material inquiry, understanding and long pre-occupation with both colour and medium.

What Freud’s surfaces allow to unfold before the viewer’s eye could be compared to what art historian and theorist Isabelle Graw would refer to as traces of an (his) activity [2]. Freud does this through his very many and varied brushstrokes. Those exquisitely, and more often than not laboured signature marks both embedded within and making visible these very paint skins I find myself gazing upon.

Yet for all of Freud’s frontal seduction and the juiciness of his medium, these paintings are hard won. There are so many paradoxes at play with the evidence of Freud’s own painting battles made visible within the lumpy, scratchy, blobby, melting pigmentation…hands are too big, angles are all wrong, the likeness is clumsy, wonky, weird, compositions are often ever so slightly off and lacking in optical harmony. There is no glamour to his work, only a single-mindedness and he repeatedly makes you aware of this through the dingy and shabby surrounds deliberately left on view of his artist workplace…the studio.

Freud encourages his viewer to enter this world to look beyond his sitters, to peer into and around, to be nosy. His juxtaposition of colours upon each unvarnished canvas draws you inward and invites close up inspection with the image defining the terms of its own making [3] to see how the skin has ‘actually’ arisen. Repetition, and often a lack of sentimentality for his subject matter or site reveal an obsessive tactility. A tactility in the paint handling, in the paint construction, in the many and varied methods of mark making Freud, employed and made visible upon the surfaces of his work. With this tactility in itself also becoming a form of doubling.

Details from Photograph of Freud’s Studio

Details from Photograph of Freud’s Studio

This becomes evident through the expanded nature of his painting beyond the surface of the canvas, beyond and into the world Freud actually inhabited.  His daily painting pursuit and importantly his obsessiveness with paint becomes both visual and unmistakable upon the actual ‘Paint-Walls’ [4] he created through years upon years of the smearing of the excess of his paint mixing upon the walls of his studio.

Detail from Photograph of Freud’s Studio

  ‘Paint-Walls’ now inhabit both the imagined and the embodied world. Eventually, Freud would camouflage his whole existence and being in this second skin. And if you look closely at the paintings themselves in IMMA you can see traces and fragments of the paint-walls/skin growing, you can almost feel it taking over every available surface, breathing and multiplying, sitter after sitter, canvas after canvas. The painterly slowly becomes more about paint and painting, than the images of the flesh.

About the Author

Susan Connolly is an artist based in between Ireland and the UK, she is a graduate of Limerick School of Art and Design, she holds an MFA from the University of Ulster and a first class honours MA from ACW at NCAD, Dublin. Connolly is currently a PhD candidate at Ulster University (2014-2018) where her practice lead research is looking at the slippage and traces within contemporary abstract painting practices.

Connolly has exhibited her work extensively and has work in many private and public collections. She is a Lecturer at WIT and an Associate Lecturer at Ulster University. More information about her work can be found on http://www.susanconnolly.com

Footnotes

[1] R. Shiff, Paint-Wall, in C. Debray, (ed.), Lucian Freud: The Studio, Hirmer Verlag, 2010, p. 64-71.

[2] Isabelle Graw, The Value of Liveliness: Painting as an Index of Agency in the New Economy, Painting beyond Itself: The Medium in the Post-medium Condition, Sternberg Press, 2016, p.79.

[3] Ibid, p. 29.

[4] Ibid, p. 64-71.

Paint Skin? – a blog by Irish Artist Susan Connolly ‘…when an artist sits down to write about another artist, he (she) is also writing about himself (herself).'

[thedissonantverses]

Your background and your game dev chops are really shining with this one. This really taps into why the battle with the Evanuris needs to be dealt with quickly and with a small team and why it takes less time to defeat them than Corypheus. They’re a much larger threat and the longer they’re allowed to divide and conquer the easier it’ll be for them to take power forever.

On the importance of morale, the opportunism of Empire, and the value of supply lines.

This is part 3 of a series of posts in which I closely examine the letters my character received from the Inquisitor across Veilguard, and talk about the strategic and political implications of what we see within them.

I strongly suggest reading parts 1 and 2 before proceeding with this one, they contain vital context!

Part 1 can be found here!

Part 2 can be found here!

With that said, I will get into it:

Morale is critical to sustained conflicts. Underestimating this is lethal, and Elgar'nan and Ghilan'nain clearly understand its value per the last letter.

They have been concentrating on symbolic attacks as well as strategically significant ones, often weaving these together with devastating effect for the South, as outlined in the last letter.

In this one, we see how critical Rook's actions will be for the outcome of this entire conflict: because we goad Ghilan'nain into making mistakes. And we do this via hits to her morale.

For all the strategic value of her victory at Weisshaupt, it pales to her in the face of the loss of her Archdemon. That's her baby, her perfect creation. The mother of monsters mourns her daughter. We reminded her immediately that she is now mortal, which is another devastating morale hit.

When we take out her blighted dragons at Hossberg it only compounds. She is overcome by her anger and grief, a situation so dangerous for them that it prompts Elgar'nan's direct intervention to soothe and retrieve her.

The war against the Evanuris will not and cannot be won in a numbers game. Both sides are keenly aware of this. Our attacks are instead personally targeted and blisteringly effective.

We see some of that in the course of playing, but it is driven home additionally very firmly here.

As the letter makes clear - to the people of Thedas, this is not just Rook's victory, this is a victory for the Wardens, who desperately needed a win to demonstrate that their Order was not robbed of power and agency in the wake of the Fall of Weisshaupt.

Hossberg sends a message: we will survive, we will endure, and we will win and rebuild.

And not just here, in this victory, either - as we progress through the game this is driven home thematically when Antoine tells us that flowers will bloom again there. No matter how bad it seems, some form of life will cling on.

Morale is everything, and this victory has encouraged enlistment in the overall struggle. The stakes are clear: we will fight together, or die alone.

However. Empires, are Empires.

Empires tend to die alone. Imperialism isolates you from everywhere that isn't another Empire, and while collaboration does happen, and is happening here, there is a constant friction when two expansionist Empires are rubbing up against each other.

We see here confirmation of the speculation from part 1: the Venatori are on the ground and providing direct military aid to the Orlesian rebels and their forces. The taking of Val Royeaux is a significant blow, and one that grants naval access to the Free Marches, which seems to have been immediately made use of by launching attacks eastward.

While they could make use of the overland route I've put on here for good measure, there's not much meaningful opposition to controlling this stretch of the Waking Sea. Attempting to take Kirkwall is the next move in stepping up aggression.

It is another goal with multiple strategic purposes and morale consequences.

To the people of the city, which finally had reconstructed under Varric's tenure as Viscount, the attacks threaten what they have just regained and would create desperation, which we all know historically goes great in Kirkwall.

To the Venatori, taking the City of Chains back would be a significant morale victory and affirmation of Elgar'nan and Ghilan'nain's 'commitment' to their cause. Reclaiming the ancient powerful sites of Empire would do a lot to bolster their political influence back home, and also be a blow against the Shadow Dragons - regardless of what their current status is.

Kirkwall is the source of almost all the trade that flows between the Free Marches and Ferelden. Take it out? Ferelden is completely isolated, and the additional morale hit from this realization and starvation tactics will begin to also do their work.

If you take Kirkwall, you have consolidated naval control up to the mouth of the Waking Sea, with the Antaam intended to be performing a pincer here to lock down control of the coastlines. I'm being handed a note, we'll get to that.

Meanwhile, Orlais is dying on the hill of standing alone. We can see in the Trespasser DLC that regardless of who is in control, tensions between Ferelden and Orlais flared again when it came time to talk about what to do with the Inquisition. It is a substantial concession for Ferelden to send any military aid to Orlais, but its rejection is to be expected.

To an Empire that is governed with revolving door betrayals and power plays, accepting help and coordinating tactics with a former territory is an unacceptable display of weakness, and the sending will likely be regarded as a display of opportunism from Ferelden, rather than genuine solidarity in the face of the current existential threat.

After all, it would be opportunistic for Orlais to send aid to them, no? As it was in Inquisition? Why would this be any different?

The Inquisitor also points to the generational trauma of the war directly here, just to further drive it home. But this is a systemic cultural barrier that even an hypothetical edict from the Divine herself would not be able to overcome - the work has not been done to enable it too. All of this, incidentally, is why we will be working with the Shadow Dragons rather than appealing to the Magisterium directly. The vast bulk of Magisters have nothing to gain by working with us, and all of them have everything to lose. What support we get can only come through underground channels, lest it risk a complete purge, and depending on our actions that can occur as it is. Empire is often a game of sunk cost, and we cannot expect meaningful aid in overthrowing a corrupt system from the vast majority of those who are personally invested in it.

I have been handed the rest of the note. Again, our work up in the North is critical to the stability of the South.

I've marked with red X's the locations we know for sure are almost entirely out of commission at this point: Denerim, Orzammar, and Val Royeaux. Kirkwall is being harried, and so was Ostwick, so those are circled in orange.

The Felicisima Armada historically close ranks when under attack by outsiders, and our work in Rivain and Treviso provides ancillary support to the overall fight against the Antaam, sowing division between two of their leaders and dividing their attention back down to the warband level.

The Armada's work draws the Antaam away from the mouth of the Waking Sea, opening up supply lines.

Per volume 1 of The World of Thedas, pages 72 and 82, we can also get a sense of the likely situation.

I've circled Treviso in yellow as well, since we know it is having a bad time. I saved Treviso in this run, so I don't know if anything changes at this point if Minrathous has been prioritized - but it's use in this situation is limited regardless while the occupation continues. Llomerryn and Estwatch, circled here in magenta, are stronghold locations for the Armada. Taking them would require significant commitment of resources and a well oiled logistics network, and I expect attempts are being made.

Even with begrudging Venatori aid, however, we see at this point in the game there are substantial cracks, as Rook's and the faction's efforts popping up all around the North are dividing attentions and interrupting supply and disrupting morale there. The Antaam cannot take to the open ocean, which means they have no choice but to travel up the coast, getting harried every step of the way.

As the Inquisitor points out, it's much needed relief. But this is also a dangerous moment, because we have driven our enemies to desperation that they cannot afford to wear on their sleeves.

After the loss of the Archdemon and the two Blighted dragons, Ghilan'nain and Elgar'nan need to consolidate their power and reassert their divinity and right to rule, or else they risk losing control of the Venatori and the Antaam. That means they need another major symbolic victory, and that means another act of targeted terror. I was!

Very frightened at this point!

That wraps up this round!! I'm glad these are being enjoyed, they are fun for me to write out.

[mixupmycota]

people are following me now so since you're here i guess i should make a pinned

i don't tag nsfw generally though if anyone really wants me too i'll make an effort on it

i DO tag for any posts discussing real world atrocities. Usually the place and relevant content warnings.

Lit analysis of works dealing with serious subjects will also have relevant content warnings.

Common tags:

#In The Mud Ditch About It This tag is for posts that remind me of @.feniksido's oc's in his original work Strings of the Forgotten, who are my favourites.

#myc talks design probably not that common but if im rambling about game development, particularly narrative design, that's where that goes

#myc talks politics what it says on the tin, will try to remember to append to any given expressly political post

Dragon Age meta I've written that I want to be able to find again later:

Veilguard companion analysis posts, collected here

On the letters from the Inquisitor to my Rook across the course of the game, analyzing the implications and talking about what I like about them and what they have to say about the state of the world and the themes of the game.

Part 1: On solidarity, and it's lack

Part 2: On the pitfalls of relying on myth and historic, faded strength during an international emergency.

Part 3: On the importance of morale, the opportunism of Empire, and the value of supply lines.

Part 4: On logistical concerns, and dread anticipation.

Part 5: On collaborators, desertion, and the consequences of morale collapse.

Part 6: On decisive action, hope, and the consequences of going it alone.

General resources I recommend at the current time:

gazafunds.com

the sameer project, providing tents and resources directly to displaced populations in gaza

the anarchist library

the disability visibility project

the haymarket books youtube channel

Feminist Giant, Mona Eltahawy's newsletter

The People's CDC for continued covid safety

I keep asks closed and messaging off outside of small windows for ask games while I am <50 followers.

I had a previous account some might know me from but I have been in a cascading mental health crisis for most of the year and I iced it during an anxiety attack. The same may happen for this one, we will see.

[cancersfakianakis1]

A novel hedgehog inhibitor for the treatment of hematological malignancies

The hedgehog-smoothened (HH/SMO) pathway has been proposed as a potential therapeutic target for hematological malignancies. Our previous studies designed a series of HH inhibitors with novel scaffolds distinctive from vismodegib, the first Food and Drug Administration-approved HH inhibitor for the treatment of basal-cell carcinoma and medulloblastoma. In the present study, we evaluated these HH inhibitors against blood cancers and found that HH78 displayed potent activity in suppressing the HH signaling pathway. HH78 competitively bound to SMO and suppressed the transcriptional activity of GLI by the luciferase reporter gene assay and the measurement of HH/SMO-downregulated genes, including cyclin D2, cyclin E, PTCH1, PTCH2, and GLI. HH78 at low micromolar concentrations induced significant cancer cell apoptosis showed by increased caspase-3 activation, annexin V-staining and downregulated prosurvival proteins, including c-Myc, Bcl-2, Mcl-1, and Bcl-xL. In contrast, vismodegib did not show any effects on these apoptotic events. HH78 also suppressed the activation of the AKT/mTOR pathway, which cross-talks with the HH/SMO pathway. Finally, HH78 inhibited the growth of human leukemia K562 in nude mice xenografts with no overt toxicity. Collectively, the present study identified a novel HH inhibitor with great potential for the treatment of hematological malignancies. *Peng Lin, Yuanming He, and Guodong Chen contributed equally to the writing of this article. Correspondence to Xinliang Mao, MD, PhD, College of Pharmaceutical Sciences, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, 215123 Suzhou, People’s Republic of China Tel/fax: +86 512 6588 2152; e-mail: xinliangmao@suda.edu.cn Received March 5, 2018 Accepted July 10, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. https://ift.tt/2MQadw3

[mixupmycota]

This does mean for the last part of this series im going to need to think really hard and pour over the wiki and take into account major political players who we know with certainty are alive or could be because their deaths have not been confirmed anywhere in the series.

Critical to remember that the odds of a character coming back in a future title sharply decrease if it is possible for them to die, and if they do come back it's liable to be in a cameo role most of the time. this is a narrative design logistics decision and does not inherently reflect dev attachment to a character.

And I specify narrative design rather than just writing because those are two different things, even when the game industry is still in active debate about the full extents and limits of a narrative designer's job as opposed to someone who does work only as a writer.

From my perspective as one, I consider narrative design to be about ensuring the whole experience is cohesive and builds towards the desired themes and motifs. It involves considering the rhythm of the narrative, the ebbs and flows and emotional peaks. It's about making decisions to set tone and writing priority, like the choice to have companions interacting in the lighthouse rather than on the field.

I know a lot of people reflexively hate that call, but from a logistical and design perspective I was just nodding along. If all of those conversations were relegated to battlefield banter, we would never see all of them without easily 6 playthroughs, and it would make the Lighthouse feel *dead* if companions didn't interact among themselves outside of companion quests.

It's less of a problem in previous titles - in Origins we have a camp, and everyone is in sight of each other. In DA2, we have a house, and the house is in a city, and our companions have places they live also that we visit.

In Inquisition, we have Skyhold, which is bustling with npcs that give the illusion of life and activity.

Not so in the Lighthouse. So the call was made to prioritize naturalistic relationships between the companions that provide the opportunity to learn more about them in how they interact in their downtime with others, with more events than we would otherwise have where Rook gets to interact with multiple party members.

Is it a bit stilted? Yes. Would I have liked to have both options personally? Yes.

Do I understand as a designer why they did it this way? Extremely yes. I would have made the same call.

Narrative design can cover what is cut, what compromises are made to avoid diluting the pacing and overall messaging you're going for. A lot of writers end up doing narrative design, especially if there aren't dedicated narrative designers on staff. It involves active communication with all the other departments to build towards an experience that has resonance between all its components.

But yeah. Gotta look over who is still standing, who can potentially step up and become a major player, and what based on past behaviour and political circumstances and interpersonal ones I predict for them going forward and I'm EXTREMELY looking forward to it.

[mixupmycota]

Perhaps if I rephrase!! If people genuinely are assuming I'm attacking criticism with that post, which I was not, I can do better.

Proposal for a writing exercise. It has literally nothing to do with whether you liked Veilguard or hated it. I am not saying you cannot feel one way or another. There is no value judgement attached to this concept.

I am proposing a writing exercise for those who are interested in branching narrative and video game writing, and learning more about how it can work through first-hand experience.

If you have an idea for a conversation with one of the companions, make a list of what it is for, and what potential outcomes you want for each point that it branches. Consider what animations you will need, what location you will use, and if any custom props are required.

For example, using one of my ancient joke oc's to further get some distance from this game specifically.

Say I want to write a conversation featuring my character Soup Daniel.

Soup Daniel has been feeling insecure about himself in the wake of his teammates complaining about the menu he offers whenever it is his turn to cook.

Potential outcomes:

Soup Daniel agrees to diversify the menu (with chowders).

Soup Daniel decides to learn how to cook the specialty of one of two different companions, Litigious Jeff or Ray Abelone. LJ makes incredible lemon slices. Ray makes Mystery Lasagna.

Soup Daniel is reassured that he is providing a valuable service in diversifying the tragically solids based palettes of the team, and doesn't change anything.

To borrow VG's structure, the player character needs to have at least three tones in possible response to anything Soup has to say: Supportive; Playful; No-Nonsense.

I'll skip faction specific dialogue largely because I'm tired right now and the only joke I can come up with for one off the top of my head is "Broth-er In Arms" and I will spare everyone more iteration on that.

Location notes:

Soup Daniel's Soup Kitchen, the dead of night. Lit initially by the glow of the heating element. Lights are turned on after the player character first speaks.

Prop notes:

Tall cookpot, filled with nondescript dark red liquid. Some chunks that suggest vegetables if someone is feeling fancy.

Ladle.

Two ceramic bowls. One has the word "Soup Boy" written on the rim.

Animation notes:

Soup Daniel stirs the ladle in the cookpot in a circle on loop. At the end of the conversation, an animation suggesting he is ladling soup into the bowls.

No custom facial animations required.

Music notes:

Normal Soup Daniel theme, fading after the first conversation branch, resuming at the second before last.

Branching notes:

Only dialogue choice that has a consequence on the game state is the final one.

With all this written out, and this is just my personal process, I could then write the conversation. I would have to be careful to keep each conversation branch approximately the same length in both call and response. This is supposed to be a small conversation, so it shouldn't take more than a couple of minutes.

Just trying something like this out, actually writing these branches and experimenting, can give you a real sense of the joys and limitations of working with branching narrative structures as opposed to linear prose. I recommend it, it's fun!

[mixupmycota]

On the pitfalls of relying on myth and historic, faded strength during an international emergency.

Part 2 of a series of posts talking about the letters my first character received from the Inquisitor during the events of Veilguard, and why I am very excited about them and personally really enjoy what they have to say about the political and strategic situations in the South.

I am going to strongly recommend that you read part 1 first, especially if you find this post in isolation! I go into a lot of context there that sets the stage for this one.

However long this series winds up being, in the final post I will wrap up how I feel the letters tie into the overarching themes of both this game and the series as a whole, and my feelings as a narrative designer on how Bioware used these letters to thread an impossibly small needle. If I make any lore mistakes, my apologies! But I'm mainly going to be talking about strategy and political ramifications here.

So!

The first letter, with a load bearing middle paragraph, told us a lot about the starting position of the South, in particular, of Ferelden and Orlais, during the events of Veilguard.

In that paragraph, it evoked a LOT of history. Both in-world historical events prior to the games, and of our actions within each title.

The second letter, received after the fall of Weisshaupt, is even more densely packed than the first. I'll be presenting it in chunks and going through it bit by bit as a result.

From the title of this letter, it sets the tone. The fall of Weisshaupt, capitalized as The Fall of Weisshaupt, reflecting that this is an event of immediate major consequence in the now and historic record.

Weisshaupt, as a fortress that was constructed in the First Blight, and that has never fallen in all that time, is a location shrouded in legend.

Before we can go through this letter, we need to consider the circumstances in which it was built, and why.

To do that, we need to consider the first Grey Wardens. Per the codex entry from Origins of, The Grey Wardens, the original Wardens were former soldiers of the Tevinter Imperium. Their lived experience had been nothing but endless war and Blight, and they met in the newly constructed Weisshaupt fortress to discuss their options. Per World of Thedas, p. 156, Weisshaupt was built in an area strategically close to Tevinter, but not hit as hard by the Blight.

In a time when the Blight had been an omnipresent reality for 90 years, that's a very significant starting position for a new order to have. They renounced their nationality and political ties.

Weisshaupt becomes their base of operations, and while it is a considerably larger fortress, we can consider it analogous to Skyhold in Inquisition in several ways - both in Inquisition itself and in Veilguard.

Per the codex entry gained in Origins, The First Blight: Chapter 4, one of the first if not THE first major victory the Grey Wardens won was at the city of Nordbotten, circled in the screenshot above.

Reports of each Warden taking down 10-20 Darkspawn at a time - a number that seems almost ludicrously low compared to the expectations on them in current Thedas.

But the first Blight, while very long, also saw the Darkspawn divided heavily between their surface and underground activity. There were less of them overall, and they had to cut their way through the Dwarves in order to establish their underground hives that would allow them to become an exponentially multiplying threat.

Over the next hundred years, the first Wardens fought to establish themselves. They made treaties, they established conscription and did not discriminate by race or class or background. In many ways, their actions mirror those the Dwarves took in creating the first Golems, but that's a subject for a different post, maybe.

All of this builds up to saying:

Weisshaupt was critical as a strategic location when it was first used as a base of operations. That victory cemented it as the ancestral headquarters of the Grey Wardens in all the time that follows, but as time marched on it became less and less strategically relevant to subsequent Blights.

Its main value became symbolic - the last refuge, the place to make a last stand. Weisshaupt has never fallen, and while it remains standing, there is hope.

I am being handed a note. It's this note. We can talk about the rest of this note now.

With all that prior context established, we can look at the actions the First Warden takes here with a critical eye. Leaving aside the merit of some of the things he has to say to Rook in the game, when we consider the actual underlying positions that the First Warden holds, he is deeply conservative, and a hardline traditionalist. He is an old soldier, yes, but as has been seen by references to his actions in previous titles and in this one: he is largely a figurehead, caught up in politicking.

As a political figurehead, but one fully on board with the death-cult tendencies of the modern Wardens (obsession with past glory and future heroic, destined death; deeply secretive to its own organizational detriment; rife with paranoia), First Warden Glastrum is faced with a deeply unenviable burden: constant darkspawn activity and multiple Blights across what we can assume is his entire tenure in the position, since no reference I can find is made to his having been a newcomer to the role.

Already quite old, both by normal standards and ESPECIALLY Warden ones, the First Warden displays some irrational behaviours that made me suspect he was actively experiencing his Calling from our first meeting with him.

His fixation on due process struck me as a desperate attempt to seek control in the face of that, and the actions that followed reinforced my feelings that this was a man who wants to cement his own legacy while he still can.

Calling the Wardens back to Weisshaupt is a strategic choice that does not make sense outside of that framework, and it is reinforced as what is probably going on by the Veilguard codex entry: Every Warden's Journey.

Viewed through this lens, and with him experiencing the Calling later confirmed if you reason with the First Warden, we can see that calling the Wardens back to Weisshaupt was less about meaningfully combatting the new Blight, and more about forcing a last stand.

We know that all the Wardens are having a bad time once Ghilan'nain takes control of the Blight. We know, per Dorian, that the First Warden signed off on the plan to raise a demon army in Inquisition, a plan which involved active collaboration with the Venatori. It is not the first time he has approved Glorious Last Stands.

The First Warden is a perfect target to subvert if you are Elgar'nan and Ghilan'nain, and the Grey Wardens are a potential obstruction to your plans to consolidate control over the entirety of Thedas.

He wants to do right. He wants to fulfill his duty. He wants to die with honor, and make his mark in a way he has not been able too across the rest of the games, trapped as he is in the role of a figurehead.

And so he calls the Wardens, en masse, back to Weisshaupt. And we all know how that goes.

He concentrates them all in one place, which at this time in history, is a strategically useful location, but not for what we see it used for. Not as a border fort with immediate access to the worst off areas in this new Blight.

Weisshaupt would have been the perfect place to house refugees, and to use as a counterpart to Skyhold in the South. An information and logistics center.

Baiting the First Warden into a suicidal last stand serves multiple strategic purposes:

It consolidates the bulk of the Grey Warden order in a single, isolated location.

It pisses off everyone who currently really needs Grey Warden support.

It denies those people and places Grey Warden support, which as we will go over in the letter has devastating consequences.

It denies the forces in the North a powerful base of operations, as just outlined.

A victory at Weisshaupt is a devastating blow to morale across all of Thedas. It's fall robs everyone of the comforting myth that no matter what happens, they can always fall back to Weisshaupt and know that they will be safe. It sends a message: nowhere is outside of our reach, and there is nobody who can protect you.

We see how this unfolds in the next lines of the letter. The Grey Wardens withdraw, and it results in immediate losses of ground, particularly for Orzammar. It is a betrayal of one of the oldest alliances that the Wardens have, and one that will stoke the isolationist tendencies of Orzammar's ruling class.

If they are abandoned, once again, why should they show up for anyone else? And, indeed, I did not hear of them again until the final letter.

Orzammar has been dying a slow death across all of the games. The humans - and then the Qunari, in the events of Trespasser - have been trying to circumvent reliance on the Dwarves for access to the lyrium trade across all of the games and in the historical record.

There is a horrifying mirroring of the true history of the Dwarven people we learn about in the Descent DLC and the things we learn in Veilguard that we can see in these efforts.

And no matter who we made King, Orzammar has up until now refused to adapt and make the systemic change needed to reverse this slide into obliteration: the abolishment of the caste system. I want to go into the differences between Orzammar's approach and that of Kal-Sharok, but that will have to be a different post I think. Suffice it to say, based on everything we have seen of that city in prior titles, I expected exactly this result. Now Orzammar will have to contend with the same set of circumstances that Kal-Sharok was once forced into:

The unaddressed systemic cultural issues and generational trauma of the Dwarves of Orazmmar led to them becoming increasingly isolationist and reliant on the lyrium trade in order to tend to their daily needs. And without Grey Warden allies, and with their supply lines also affected by the same issues hitting Ferelden, their options dwindle sharply.

And a thousand or so Wardens die at Weisshaupt.

That is a devastating loss. We see what even a pair of Grey Wardens can do multiple times across the series.

With the loss of the Wardens and Weisshaupt both, Ghilan'nain and Elgar'nan can launch the next stage of their offensives. Remembering that aside from being known as the mother of the halla, Ghil is the elven goddess of guides and navigation. We can subsequently intuit that she probably has a very firm understanding of how long it takes to get places, and she has control of the Blight and the Darkspawn - which means she now controls the Deep Roads near entirely unopposed. She's got the subway.

Coordinating an eruption of Darkspawn at historic sites terrorizes Thedas with what the Dwarves already knew: the Darkspawn are everywhere, in seething hordes, and surfacers will reckon with those numbers when Orzammar no longer holds them back.

So!

Per the last letter, the border with Orlais is being harried. The Darkspawn horde at Ostagar appears to have made directly for Denerim - another strong strategic move. Take out the capital, and theoretically you undermine the ability of the nation to organize and field meaningful resistance. Except, here, the less centralized structure of Ferelden society does it a firm favour. As we have seen in prior games, Denerim is not the only key location to locking Ferelden down. Redcliffe is also critical. I'm being handed another note, but that's a problem for future me and for future Ferelden.

The situation in the capital is grim, yes, but not currently totally lost. We have seen how stubborn and determined the people of Denerim are in the face of adversity in Origins firsthand.

Next up is the one part of this that I did not see coming after receiving the first letter - though I should have! I overlooked the implications of the Jaws of Hakkon dlc, having only viewed it through for the first time shortly before Veilguard's release.

When the political process is failing, when the establishments are tearing themselves apart, when civilians lives are on the line and there is an existential threat to everyone: the sorely neglected and othered often step up to provide the most critical support. So it is here, with the Chasind and the Avvar.

Relegated to the margins across all of the games, treated mostly by our viewpoint characters and those we interact with as backward and provincial at best, both the Chasind and the Avvar are substantial and mostly unrepresented groups in the franchise. They also occupy the most outwardly 'hostile' terrain in Ferelden, and know it like the back of their hands.

I got so, so excited when this popped up. The implications of this alliance were the most stirring thing to give me hope for the South. With access to the travel routes and supply lines, as well as remote and well protected territories, the potential to slip civilians out from the noose that Elgar'nan and Ghilan'nain are tightening around Ferelden shoots up.

Troops can be moved, and so long as the Blight is contained and harried at by those who at this point have a great deal of learned experience fighting Darkspawn, this alliance marks a potential turning point both in the immediate moment we receive the letter, and in the long-term arc of history that will go on far past the events of the game itself.

It's exciting to me, and I'm excited to also dig into the next letter! As with the last one, nobody else has to like what they've done here, but I think it's great, and I'm really excited to share more of why.

Part 3 here!

[mixupmycota]

On solidarity, and it's lack, and my raw horror and delight at seeing these missives pop up in my file across the game. This SUPER got away from me, so this is now part 1.

I disbanded the Inquisition in this run, and did not save Minrathous, and have not yet seen if that makes a difference to the content of these letters!

I am aware these letters are a controversial part of Veilguard for a lot of people, and it's fine for everyone to feel how they feel about it! I'm not telling anyone that they are wrong, I'm just offering my perspective on why I really love what they did here, and think it's an excellent way to unite disparate threads while also punctuating the theming of this game, respect the struggles of our previous protagonists, and also realistically represent what we could expect of the disparate nations of the South in the conditions we see in Veilguard.

Some personal context that I don't actually need to share, and you don't need to read, but does inform my perspective on this:

I keep a keen eye on international politics in the real world, have a lot of experience in doing so, and I was one of many disabled advocates who saw the danger of covid coming long before it was declared an official pandemic and started doing what I could with a platform I had at the time to keep as many people around me both tangibly and in an online network sense as safe as possible. I know for a fact that my efforts saved lives. But there were limits to what I could do as an individual, and especially one confined to my bed.

When it came to mobilizing individuals, to getting information into the hands of trusted people in influential positions - eg. librarians - and providing them with the resources to then educate and mobilize their workplaces and social circles, I did great. But the issues I and others faced were systemic, and our effectiveness was limited by this.

With that context said and either read or skipped past, let's talk about the state of Southern Thedas across Veilguard.

So, this first letter from the Inquisitor contains a lot of information, densely packed.

Discussion of Morrigan here alone could be another post, but suffice it to say that this tells us that in the last ten years she has succeeded Flemeth as a guardian advisor of the South, inheriting in spirit (heh) if not in name (yet) the mantle of Ashar'bellanar.

The key part here is that she was very firm with the Inquisitor, more so than Scout Harding is being and Varric had been, that Rook is someone to watch and rely on at this time in history. With her personal context of being a hero of the Fifth Blight, that makes Rook contextually a peer to the hero of Ferelden in her eyes. Which might seem unlikely - but we need to remember that Morrigan was there from the very beginning, when the HoF had no idea what they were doing, and in most worldstates she witnessed them unite the disparate groups of Thedas, including those among the margins, into a powerful (if mostly transitory) alliance to combat and ultimately defeat the Blight.

Her endorsement is invoking all of that history.

Next up: it is established that when Solas began his ritual, the consequences were felt everywhere. We can operate on the assumption that at least some fade tears were ripped open, and that demons escaped and wreaked a wave of initial havoc.

This is backed up by a detail in a later letter, about demons having occupied Skyhold, and by the consequences we see in Minrathous, despite the ritual taking place in Arlathan.

On their escape, the gods immediately began to make their moves, and one of the first is Elgar'nan's overtures to the Venatori, which become consolidated into firm control very quickly due to his appeal as a mythic figurehead for them in their own goals, and the power he promises.

That they quickly become extensions of his will, their original cause nothing more than deluded lip-service, is part of the design, as I have gone into elsewhere previously but will likely do so again in more detail after a few more playthroughs.

When we hear that a splinter group of nobles have made common cause with the Venatori, we can intuit that they will be openly Imperialistic, likely a blend of old guard who still carry resentment around Ferelden's independence and up and coming warhawks. They will be those who resent the declining influence of Orlais on the international stage; who resent the gains that have been made over the years in improving the rights of the elves; and that they will be incredibly stubborn individuals who will insist that Orlais needs no allies and can stand on its own.

They will be those who cry for a return to the glorious past, and who are easily swayed by the promises of personal power to do so, because these are all the traits Elgar'nan selects for when gathering pawns - and they are traits that we have seen on display in many Orlesian's across both the games and the extended media. That's not a unique to Orlais situation, it's a cultural marker of a sunsetting Empire.

No matter who is the sitting Emperor of Orlais from the options we have been able to influence in the past titles, these people would still exist. They would be those who are laughed at and dismissed as toothless relics and hotblooded upstarts in Celene's court, and the hawks that consider Gaspard to be weak and lacking in ambition, while likely forming a core part of his supporter group.

They receive backing from the Venatori - and we know that the Venatori are embedded deeply in the upper strata of Tevinter society, that they have long ceased being a fringe group as they were initially presented in Inquisition - and the writing was on the wall even then that they had already made great strides in entrenching themselves in the halls of power.

So, to have Venatori backing is to have Tevinter backing, at a time when they are for the first time across the games free from needing to devote their military resources to combating the Qunari - and, however deeply reluctantly, are actively working with the Antaam, so we can operate with the belief they are providing logistical support that canonically the Antaam have lacked since they performed their military coup and launched their invasions. This read is backed up across this and the rest of the letters, with discussion of the dreadnaughts and the role they are playing.

We can subsequently operate with the assumption that the Orlesian splinter faction is being provided money, logistical support, political influence (key, given the Game) and potentially tangible military backing.

They waste no time, and specifically target the Royal Guard and the border keeps of Ferelden.

What does this tell us?

It backs up who these people are, and what they want, and we can subsequently intuit the kind of populist right wing messaging they will be using. They launch attacks against the core forces of the current Emperor or Empress, signalling a rejection of the current status quo in doing so. The move against the border keeps is a promise to return to the golden era of expansionism, and one that also serves to harry and divide Ferelden's forces.

In the next sentence, we learn that an initial force of Antaam corsairs are harassing shipping out of Ostwick, and that location is very significant.

It, in conjunction with the coordinated attacks in Orlais, is the first move in cutting off core allied supply lines from the North to the South. We know from prior titles that the ocean proper is not navigable without disaster, and control of the Waking Sea is going to be very important in subsequent letters and how the tide (heh) shifts back and forth.

Immediately, the goal has been to attempt to cut off and isolate Ferelden from international support, replicating the conditions of the Fifth Blight. This, more than anything else at this point in the game, made me very scared of Elgar'nan. We know from the memories that he was a brilliant strategic mind, and that the Evanuris started out as generals.

Man wakes up, glances across the board, probably gets a tl;dr primer from his new associates and as someone familiar with the lines of hard and soft power quickly moves to shut down the biggest threat in the South: those fucking weirdos from Ferelden who keep kicking over the board. It's an excellent call.

Ghilan'nain is not idle either, with her control of both the Blight and the work she is doing with the Antaam. Massing the Darkspawn at Ostagar again is both an excellent strategic move - for the same reasons it was in Origins - and a highly effective terror tactic.

We can intuit that it's a terrible time to exist in Ferelden right now. You've just been reminded of the events of Inquisition and the last time the sky was split open, a wound which everyone has gotten used to seeing above them but healed, and now Orlais is harrying the border and the darkspawn are massing once again at the site of the major historical event that led to mass death and upheaval in the LAST Blight.

Every lever possible to invoke and then beat on generational trauma and create mass panic has been pulled at once. It will divide their forces, it will divide their political system - it's what Loghain was scared of in Origins, but this time it's actually happening for real.

But hey at least we have the Free Marches and Orzammar and the Grey Wardens! [I'm being handed a note, which I will open later.]

The rest of this letter is reassurance from the Inquisitor: all of this fucking sucks, but it's terrible things that the South has experienced before, and as it has in the past, so will it survive it again.

This single letter told me so much, immediately.

All of these situations that they put forth are ones that cannot be fixed by swapping people in and out of chairs in the high halls of power.

The vulnerabilities that Elgar'nan preys on are systemic, cultural issues, reflecting ancient wounds and vulnerabilities. The victories that we can potentially make across the games can breathe within this narrative space, but do not in themselves have enough power to override these core weak points.

Orlais is an Empire. Ferelden is geographically isolated and culturally scarred by the horrors of a brutal occupation by said Empire, by the events of the Fifth Blight, and the blows it received during the events of Inquisition. We know that getting the bannorn to agree on a course of action at the best of times is like pulling teeth, and they may as well have dropped a thousand live bee grenades into an active debate.

It's a brilliant opening move, and it isn't one that invalidates what has come before, but one that preys on the active weak points that we have seen remain active across all of the games. We cannot expect solidarity from Orlais in Ferelden. Orlais cannot expect solidarity from Orlais, because their political culture is one of backbiting, plotting, and endless sabotage: this is a feature, not a bug, to them. It is one that ordinary Orlesians have paid for time and again, and one that will continue to have incredibly predictable and dire consequences.

I was thrilled by this letter, because it lit my brain on fire. I began to consider next moves, what I would expect from each faction involved based on historical context and precedent. As I will get into in later parts, this speculation was rewarded for me, and it's one of my favourite things about Veilguard.

You don't have to like it personally, but I am excited to talk about why I do, and how I feel it reflects the best of Dragon Age's political writing.

Part 2 here!