#myc talks design

[mixupmycota]

also just gonna chime in as someone with some narrative dev experience and who has studied their games for a long time

three games in an rpg franchise with continuous rolling forward decisions is barely sustainable as it is, and we can see that in the reception to the mass effect 3 original ending.

i would like everyone to imagine for me if every choice you can make in these games generates a new timeline. if you've ever written fanfiction i want you to think about this really hard.

consider this. character A asks character B what they should do in a tense situation. Character B selections option 1 of 3. In this version of the chapter.

You also need to write Character B selecting options 2 and 3. From there you need to adjust the trajectory of the rest of their character arc, and you're writing a new timeline for every major choice made.

I need people to understand that branching RPG's are multiverse experiences. I'm not joking. This is why we won't get anything like Origins exactly from the series again unless they swept the board COMPLETELY clean and started building from scratch. Save importing was breathtaking. Taking into account variables from prior games is a herculean exercise. It's hard enough to write one branching game, but players want their choices to Matter:tm:, and that often means three things:

big worldstate alterations that appear to meaningfully impact the overall plot of a given game

cameos

callbacks

It can seem so easy to do up a quick fix it fic for things we don't like about a given title. Comparatively, it is. Because we aren't needing to generate dozens of alternate and valid timelines for every variation that can be made.

This is why RPG's will often have narrative chokepoints, where big choices are made that pull all the different timelines in together and trim down the number of potential branches.

There are a lot of tricks to create the illusion of greater depth than there is when writing a nonlinear narrative, and they're all really neat!

But also like. Veilguard's script is estimated to be around 140k lines long. About 60k of those are Rook's lines, 15k per voice from an interview i read - and this is another reason we're probably not going to get design like Origins again. Players expect AAA games to have voiced protagonists. Since Bioware cares deeply about trying to make their games accessible for as wide an audience as possible, they set aside resources for this game to have multiple voice actors available to select from. That's an immense use of resources.

I see a lot of comparisons made to BG3 and I cannot overstate how deeply, utterly unfair that is. Multiple dev friends of mine held their heads in despair after that game out, because they knew that exactly that would happen to any big RPG that was released afterwards.

Larian's dev process was wildly atypical, and not sustainable under different models. You will note that they did NOT have voiced protagonists, which allowed them a great deal more freedom, but it is also worth remembering that when that game launched the upper city was barely playable because storing so many variables was causing save files to balloon and slow down computers.

Game development is really, really hard. The fact that any game gets released is a marvel. The credits for Veilguard are atypical in that they made an effort to credit as far as I can tell anyone who had worked on any version of the game. A lot of the Quick Fixes I've seen proposed for things pointed at are situations that would add at least 20-30k to the script.

That doesn't mean it's beyond rebuke or critique at all, but I really want people to understand that "choices must matter" style complaints over the years have led to exactly this point. This is where that goes. The demand for increasing escalation, for the faves to come back always and they must matter but must not suffer too much or that's bad writing that needs a window to be undone in the future, for higher fidelity graphics and more intricate animations - all of that leads to the situation of the beancounters putting the devs in a hydraulic press.

Veilguard pushes for a narrative structure that's a blend of everything that came before and pulls heavily from DA2 in particular. It's an incredible achievement, I genuinely never expected it to actually release. Valid to not enjoy it, everyone can feel how they feel, but I hope like.

Additional information about the difficulty of making these kinds of games helps a little bit because genuinely it is a completely different skillset to writing linear prose. They used a program called Twine to check the script from end to end - bless them for that, most RPG studios have bespoke narrative software and Bioware are using the equiv of a physical corkboard and string here.

They chose to prioritize their greatest strength of companion writing and interaction, and also really tighten up and work on the greatest *weakness*: overall plot and stakes. They left as much undefined about the overall worldstate as possible and moved us to the opposite side of the world, where genuinely, many of our previous choices WOULDN'T matter. Thedas is really big, and Veilguard has a sense of scale there. If faves don't come back and their fate is not confirmed, that means they can be alive and maybe pulled back into different titles.

But they also expressly wanted to avoid making the world feel very small by ensuring that like the same 30 people are always at the middle of everything going on.

We all miss our characters but we can just think about what they would be doing in this situation. If we bring in the hero of ferelden to fight - what about those who have decided their HoF is dead, or retired? Those choices also deserve to be respected, if they're going to invoke that character again.

Genuinely I hope that if they do make additional Dragon Age games - which I do not expect, especially after the pre-release layoffs and how those let go had to fight to get their severance - they are smaller scale titles without ties to any returning characters, all over the world. Veilguard has the scent of a setup for another trilogy, but I hope they are not pushed into doing that, because with escalating story stakes being demanded and increased spectacle and threats called for they'll end up having to reveal ALL the secrets of the setting.

Just, basically. Veilguard IS that thicker tome. If the choices from the last games were all pulled in, we'd be looking at a script that's around two million words at least, I would ballpark it at, and would have taken all ten years to develop with a supportive publisher in a single product. The variable cinematics required with bespoke animations and character models, the endless hours of voice acting on top of that, it just.

If we want that, we need too as players push for better working conditions for developers, and for a push away from infinite growth models. Because this problem isn't unique to bioware, and the games industry is actively collapsing at this time under its own weight. There's a reason Larian skipped away from the BG license and have ruled out doing an expansion or a sequel.

[mixupmycota]

we have reached the point i look forward to the most every new bioware release where my engine activates and i begin pouring over the narrative design as if it is a whalefall and im a hungry, hungry deep sea worm

there is always intentionality in the design, bioware has been pushing towards writing People as well as Characters as companions for like. the life of the studio. this isn't a formal gamedev classification it's just how i've been theorizing about their design process since i was a kid wanting to grow up to work for them.

i think veilguard has some of the best People writing they've ever done.

the distinction i am making here is that People writing allows for a lot more apparent inconsistencies, for a lot of depth and subtlety and it expects a lot from your audience. It benefits from analysis of interpersonal dynamics and from evaluating the actions of characters like you would a real person and using that to inform the roleplay.

It's something that the art form really lends itself too! The arc a given character has can be different between playthroughs, but they all come from the same person. Branching paths are potentiality, windows into how people react under different conditions.

Character writing can seem too - or sometimes actually - suffer when the focus is on trying to present companions as more independent, realized people, because there will be moments of stilted delivery or seemingly out of character reactions that rely on looking for context beyond the limits of the scene or the themes of the character arc. When writing People is done well it ensures there's always more to think about and is a huge reason for the enduring love for companions across games and time!! and i think that's so cool, actually.

if you just analyze companions through literary lenses, things will be missed, because they won't always play to type. if you just analyze them through focusing on their interpersonal relationships, things will be missed, because there will be thematic throughlines and subtext that has also been woven into their writing. the two pronged approach is so, so rewarding.

i think a lot about the reactions i am seeing to lucanis and neve's banter and the hate for that and the hate i've learned (i somehow missed it at the time) people had for isabela and fenris's interactions along the same line. a common point of contention is not liking how the characters "behave differently with each other than with rook/hawke."

I find that fascinating because that's the point, they're written to be people. Do you interact the same way with everyone you know?

The differences between Rook and Lucanis and Neve inform their dynamics with each other! Neve and Lucanis have a lot of mannerisms in common, they each have deep social attachments to their communities in a way the other characters do not, and both of them have trust issues. It is incredibly natural that they have a much different dynamic with each other, and that they can develop a friendship or more in the aftermath of choices that affect both of them very personally, and that influence how they see Rook.

They're written as people, as well as characters.

This is evident in Lucanis's romance as well, which leaves a lot to the player to put together. While it's fair that some feel his romance is "empty" along a character writing line, when you approach it from an interpersonal analysis standpoint, grounded in considering the realities of the events of the game and historical context and how they would affect a real person in that position: the fact that a romance even happens is breathtaking, and really elevates the events.

the game is really going to benefit from repeat playthroughs, from building a deeper understanding of each of the *people* in rook's team, and how they respond to different events under pressure and when they get a break from it, and i'm so, so excited to dig around in it for ages

[tacobellabeanburrito]

so... are we like.... not going to talk about Myc’s human form or???

Edit: People in the comments told me they designed him to look more like his voice actor, that is so cool! I really like that Easter egg.

[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

[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

General resources I recommend at the current time:

gazafunds.com

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.

[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).'

[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]

another fun thing is that we only see what we see, but that doesn't mean that what we didn't see didn't happen

by which i mean the game demonstrates that conversations between companions at the lighthouse are still treated as if they fired even if rook was not there to see them. interpersonal storylines between the companions advance over time, and depending on how often you go home and check in you can miss things!

i missed an interaction between neve and bellara in my first run for instance that i only learned existed when talking to a friend - and i didn't realize this because when kalin walked into bellara's room the conversation was flowing like it does when you encounter two friends who are already talking about something they did together recently.

the more antagonistic moments clearly also happen too! it's a huge part of giving the companions more fully realized lives and agency that doesn't rely on the protagonist personally solving all of their problems.

it makes me so excited to do the Worst Run. I see people saying we can't be mean at all in this game and while Bioware has given us comparatively few levers to pull to be directly a little shit in dialogue - because Rook is an authored but open character - they have provided us with the only way they could be a true asshole to their team through the mechanics and structure of the game itself: ignoring them.

we have three different relationship state indicators put in front of us in the game: approval, bond and what im calling the "influence" points for now. I need to do a lot of experimentation and keep notes across runs because I have a theory I need to test for that last one. the main way we get bond up is by doing character quests and also taking them out on the field with us.

so the structure of the Worst Run would be to just mainline the plot without paying any attention to the companions. Ignoring their lighthouse conversation opportunities. Not doing any more with them than is mandated to progress. Having either just one team you use the whole time or rotating only to be optimal. I will need to roleplay as a game guy who doesn't care about the story in order to do this.

I know bond does have a direct impact on a few things, and I'm still mulling over the purpose of approval because I think it's much more subtle this time around and that we potentially have a much more delicately balanced version of the friends/rivals system than da2? will remain to be seen. The "influence" points that i would point too for consideration would be how character storylines can be drastically influenced by rook's background and potentially race lining up with a companion's (mourn watch mage to mourn watch mage communication really influences a lot).

the cruellest thing you could do as Rook in this game that repeatedly directly tells you how important team cohesion and solidarity is, is to only treat them as tools. i have to see what it looks like when you do.

we have reached the point i look forward to the most every new bioware release where my engine activates and i begin pouring over the narrative design as if it is a whalefall and im a hungry, hungry deep sea worm

there is always intentionality in the design, bioware has been pushing towards writing People as well as Characters as companions for like. the life of the studio. this isn't a formal gamedev classification it's just how i've been theorizing about their design process since i was a kid wanting to grow up to work for them.

i think veilguard has some of the best People writing they've ever done.

the distinction i am making here is that People writing allows for a lot more apparent inconsistencies, for a lot of depth and subtlety and it expects a lot from your audience. It benefits from analysis of interpersonal dynamics and from evaluating the actions of characters like you would a real person and using that to inform the roleplay.

It's something that the art form really lends itself too! The arc a given character has can be different between playthroughs, but they all come from the same person. Branching paths are potentiality, windows into how people react under different conditions.

Character writing can seem too - or sometimes actually - suffer when the focus is on trying to present companions as more independent, realized people, because there will be moments of stilted delivery or seemingly out of character reactions that rely on looking for context beyond the limits of the scene or the themes of the character arc. When writing People is done well it ensures there's always more to think about and is a huge reason for the enduring love for companions across games and time!! and i think that's so cool, actually.

if you just analyze companions through literary lenses, things will be missed, because they won't always play to type. if you just analyze them through focusing on their interpersonal relationships, things will be missed, because there will be thematic throughlines and subtext that has also been woven into their writing. the two pronged approach is so, so rewarding.

i think a lot about the reactions i am seeing to lucanis and neve's banter and the hate for that and the hate i've learned (i somehow missed it at the time) people had for isabela and fenris's interactions along the same line. a common point of contention is not liking how the characters "behave differently with each other than with rook/hawke."

I find that fascinating because that's the point, they're written to be people. Do you interact the same way with everyone you know?

The differences between Rook and Lucanis and Neve inform their dynamics with each other! Neve and Lucanis have a lot of mannerisms in common, they each have deep social attachments to their communities in a way the other characters do not, and both of them have trust issues. It is incredibly natural that they have a much different dynamic with each other, and that they can develop a friendship or more in the aftermath of choices that affect both of them very personally, and that influence how they see Rook.

They're written as people, as well as characters.

This is evident in Lucanis's romance as well, which leaves a lot to the player to put together. While it's fair that some feel his romance is "empty" along a character writing line, when you approach it from an interpersonal analysis standpoint, grounded in considering the realities of the events of the game and historical context and how they would affect a real person in that position: the fact that a romance even happens is breathtaking, and really elevates the events.

the game is really going to benefit from repeat playthroughs, from building a deeper understanding of each of the *people* in rook's team, and how they respond to different events under pressure and when they get a break from it, and i'm so, so excited to dig around in it for ages