Β Sheet Puns

Journal of the American Chemical SocietyDOI: 10.1021/jacs.1c03314

Aurelio J. Dregni, Harrison K. Wang, Haifan Wu, Pu Duan, Jia Jin, William F. DeGrado, and Mei Hong

https://ift.tt/3boYT8F

Starting from a 52 amino acid protein binding epitope, a bicyclic β‐hairpin structure was developed to bind the transcriptional coactivator β‐catenin. Our structure‐based design approach was supported by screening a focused library of bicyclic mimetics which was generated via late‐stage diversification. The most active bicyclic β‐hairpin shows cell‐penetration and inhibits Wnt signaling in a cell‐based assay.

Abstract

Protein complexes are defined by the three‐dimensional structure of participating binding partners. Knowledge about these structures can facilitate the design of peptidomimetics which have been applied for example, as inhibitors of protein–protein interactions (PPIs). Even though β‐sheets participate widely in PPIs, they have only rarely served as the basis for peptidomimetic PPI inhibitors, in particular when addressing intracellular targets. Here, we present the structure‐based design of β‐sheet mimetics targeting the intracellular protein β‐catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of β‐catenin, a macrocyclic peptide was designed and its crystal structure in complex with β‐catenin obtained. Using this structure, we designed a library of bicyclic β‐sheet mimetics employing a late‐stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to β‐catenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other β‐sheet‐mediated PPIs.

https://ift.tt/31vMAC5

Bicyclic peptidomimetics bind the transcriptional coactivator β‐catenin. A structure‐based design strategy has been applied to minimize a 52 amino acid binding motif into bicyclic 16‐mer β‐sheet mimetics. The biologically most active mimetic exhibits robust cellular uptake and inhibits Wnt signaling in a cell‐based assay, as reported by Tom N. Grossmann et al. in their Research Article (DOI: 10.1002/anie.202102082).

https://ift.tt/32wtk84

• DOI/PMID/ISBN: 10.1073/pnas.2015567117

• [URL] https://www.pnas.org/content/117/52/32902

Protein‐mimics are of great interest in the contexts of their structure, stability and properties. We are interested in the synthesis of protein‐mimics containing triazole linkage as peptide‐bond surrogate via topochemical azide‐alkyne cycloaddition (TAAC) polymerization of azide‐and‐alkyne‐modified peptides. The rationally designed dipeptide N3‐CH2CO‐Phe‐NHCH2CCH (1) crystallized such that the molecules are arranged in β‐sheet arrangement in one direction and in head‐to‐tail fashion in perpendicular direction. Upon heating, crystals of 1 underwent single‐crystal‐to‐single‐crystal polymerization forming triazole‐linked pseudoprotein having Gly‐Phe‐Gly repeats. Though the dipeptide adopted β‐sheet‐like alignment, the pseudoprotein has evolved into a helix as a consequence of TAAC polymerization. These helical pseudoprotein chains are laterally assembled via backbone H‐bonding in a direction perpendicular to the helical axis to form helical sheets. This interesting helical‐sheet orientation in crystal resembles the interesting cross‐α‐amyloids, where α‐helical proteins are arranged laterally as sheets. This is the first example of a pseudoprotein mimicking this interesting topology.

https://ift.tt/2vRbcsL

I don't want to step on anybody's toes here, but the amount of non-dad jokes here in this subreddit really annoys me. First of all, dad jokes CAN be NSFW, it clearly says so in the sub rules. Secondly, it doesn't automatically make it a dad joke if it's from a conversation between you and your child. Most importantly, the jokes that your CHILDREN tell YOU are not dad jokes. The point of a dad joke is that it's so cheesy only a dad who's trying to be funny would make such a joke. That's it. They are stupid plays on words, lame puns and so on. There has to be a clever pun or wordplay for it to be considered a dad joke.

Again, to all the fellow dads, I apologise if I'm sounding too harsh. But I just needed to get it off my chest.

Do your worst!

I'm surprised it hasn't decade.

Throwaway for privacy

I (M26) have been dating my girlfriend (F24) for about a year now, and we recently moved in together. She didn't have a lot of furniture and such, so it's mostly mine in our apartment including my bed (frame, mattress, sheets). I am a bit of a neat freak, and she generally is too, so we get along pretty well living together.

Now I'm not one of those guys that gets grossed out over a woman having her menstrual cycle. I've had sex with my girlfriend on lighter days with a towel down. I'll go buy her feminine products. I don't get weirded out if she mentions it. I will say though, it totally grosses me out getting on my bed though.

Well a few days ago when we woke up I noticed a blood spot on the bed and got totally grossed out. I knew she had been on her period for 3 days already so it wasn't any sort of surprise accident. I asked how it happened and she was upset and said she thought she didn't need to sleep with anything on. I told her that was absurd, why would you go without wearing anything and get blood all over my bed. I told her that was irresponsible and that she needed to pay me for new sheets. She agreed to pay for new sheets but got upset with me for getting angry and calling her irresponsible. She said that she likes to not wear anything when she can. She said she thought her flow was light and she wouldn't bleed over night. She says I have no reason to be angry to talk down to her over something I don't experience. I said that she should've been more careful with where we sleep and that it was unhygienic

AITA for getting upset and wanting her to pay?

ETA: A lot of people seemed confused by what I said 'not wearing anything". She was wearing her normal pajamas, just no menstrual products. She said since she's on birth control she is very light on day 3 and doesn't ever bleed on the sheets. It still seems unreasonable to me to not have something for extra coverage just in case. To everyone saying to just wash the sheets, she did, but I just don't like the thought of it.

Second Edit: I obviously see that I was a prick for being condescending towards her and not being sensitive to her embarrassment. I told her I was going to replace the sheets myself. She got upset again saying she didn't want to financially burden me every time she could potentially have a leak and that washing them was good enough. I told her I obviously just have a weird phobia with it I need to work through. I did ask her to wear products every night

For context I'm a Refuse Driver (Garbage man) & today I was on food waste. After I'd tipped I was checking the wagon for any defects when I spotted a lone pea balanced on the lifts.

I said "hey look, an escaPEA"

No one near me but it didn't half make me laugh for a good hour or so!

Edit: I can't believe how much this has blown up. Thank you everyone I've had a blast reading through the replies 😂

It really does, I swear!

So I’m honestly just not sure at this point. I once lent some white basketball shorts to my dad when he wasn’t doing so great financially, and was living with me at my apartment. When I finally got them back after literal weeks (he’s the opposite of a punctual person) there were… um… well 💩 stains on the back area of them. Thoroughly grossed out, trying to be understanding, I proceeded to wash them 4 times, ended up under my bed folded up, stains still there, just to be washed again every now and then because I’m kinda afraid to wear them.

At first, I thought this is something that was an odd ‘my dad thing’, until I got my hands on my boyfriend’s white, Naruto boxer briefs. They’re absolutely adorable but I felt pretty awkward when putting them in the wash, only to notice there were skid marks in his underwear too.

I also remember seeing them in various places like visiting my brother and accidentally noticing his underwear thrown over the side of the hamper, as well as some bedrooms of guy friends’ of my boyfriend’s, when I’d be invited to go hang with them.

This honestly, and completely undisrespectfully, troubles me. Idk about EVERYONE, but every woman I know wipes that bum over and over again until the paper is as bright as, well, paper, even if it takes 25 sheets… and my mom agrees. None of us have had that problem in our underwear since we were 6 at the very latest.

So, my question is, are you guys just spending your entire lives wiping your bootyhole incorrectly and no one ever correcting you? Did your mothers not teach you how to do it right, or are y’all just slowly forgetting over the years?…because I honestly can’t think of any logical reason that I know this many people with skid marks in nearly every pair of underwear, and they’re all men.

It seems silly, but it’s a legitimate question I just can’t get out of my head 😂😂😂

EDIT: Sooooo um y’all I’m beyond absolutely beyond amazed at the FEW THOUSAND people I’ve got talking about bootyholes in the comments rn. I’ve never gotten this much feedback on any post anywhere, not just Reddit. Thank you verrr much for the feedback and help, each and every one of you have been helpful and kind.

When I first posted this, I was doing my best to respond to every single new comment but it seems that may be impossible at this point as there’s a new comment quite literally every two seconds. Thank you for everyone’s suggestions and thoughts though ❤️ I needs to go have quite the interesting yet

Because she wanted to see the task manager.

I started to live with my girlfiend almost 6 months ago (I'm 34 male, she's 35 female) and we have this ongoing issue that just escalated. She has this weird obsession with planning food like it's the most important topic in the world. She constantly asks me what my plans for food are the moment I wake up, she wanted to have discussions about us doing a weekly "chart" (wtf) with meals, asks me for lists whenever she goes to the store, and is just super pushy.

My stance is this - we're two adults. I have zero expectations of her to cook. I was never in a situation where I was unable to eat because I didn't plan food in advance. I really can't decide what I want before I'm actually hungry, and I don't see any need to limit myself to these choices. I never spent more than 30 min cooking, I'm fine with us ordering if we're not in the mood, we have so many options. Stores is near so we can always buy stuff, there's always something at home, and we can always do our own thing. Shortly, the topic bores me to death and started to annoy the shit out of me.

The other day she again made a speech that I need to tell her what I want to eat so that we can plan and I just bluntly told her that by now isn't it clear that I can't and don't want to decide on these things in advance, that she can just do what she wants and I'll figure out my own shit the way I did all this time. She said that if I don't communicate what I want to eat to her we can't plan or get all the necessary ingredients. I asked her when did we ever experience an issue because I expected to eat something I didn't have ingredients for, and also that I don't expect her to make food - we can see who is in the mood to cook, order, have something simple...

I finally told her to just never ask this again, that I'm never going to do fucking excel sheets with weekly meal plans, to relax and do what she wants. She is now pissed and ignoring me. I don't get it. The whole thing seems like such a made up issue

Some additional info : both of us are fit, we're not on any special diets, we eat fine, no health issues... that would make her particularly concerned.

I'm at the point when I want to walk out of the room whenever she asks anything about food.

They’re on standbi

Pilot on me!!

Nothing, he was gladiator.

Dad jokes are supposed to be jokes you can tell a kid and they will understand it and find it funny.

This sub is mostly just NSFW puns now.

If it needs a NSFW tag it's not a dad joke. There should just be a NSFW puns subreddit for that.

Edit* I'm not replying any longer and turning off notifications but to all those that say "no one cares", there sure are a lot of you arguing about it. Maybe I'm wrong but you people don't need to be rude about it. If you really don't care, don't comment.

What did 0 say to 8 ?

" Nice Belt "

So What did 3 say to 8 ?

" Hey, you two stop making out "

When I got home, they were still there.

I won't be doing that today!

[Removed]

EDIT: repost cause I accidently deleted the first one and the issue still stands.

My f34 husband m32 has a medical condition (heart problems) and we sleep separately, he sleeps in the bedroom while I am on the couch.

he's become partially reliant on me to care for him wether it be cleaning, cooking for him, supervising his medication intake and managing side effects. He's on a number of medications and one of them causes excessive urination (it is essentially to treat the swelling of his feet and abdomen) as a result he urines a lot which's an issue cause he just keeps wetting the bed. Previoysly, he was catheterized so I didn't worry about the bed wetting issue, but he went against the doctor's recommendation and had the catheter taken out and the problem of him wetting the bed started. As a reasonable alternative to taking the catheter out, adult diapers had been recommended but he was 100% against it. We had arguments about it cause it wasn't like he had an allergy preventing him from using diapers.

He promised he'd be careful but every time he'd end up wetting the bed and expecting me to clean it, clean everything the sheets, the mattress, the floor even. So far I've cleaned the bed for over 40+ times middle of the night and he still said no whenever I urge him to just wear diapers.

It all came to head nights ago, he woke me up shouting from the bedroom that he wet the bed again and needed me to get up and clean it right then, I'm talking 2am!. I expected that and was maddened so I ignored him and remained sleeping. He kept shouting demanding I come clean up then started calling my phone but I turned it off.

I got up at 6, found him sleeping on the floor on a spare mattress and the bed was a mess, he woke up and blew up at me calling me nasty and heartless for not rushing to help and clean up the bed for him after he wetted it. I stated that it was his fault for refusing to wear diapers after willingly removing the catheter. He yelled saying the catheter thing caused him suffering, then said he'd never wear diapers cause of his "hurt ego" and "manhood", also said I had a job and I neglected it and acted petty by punishing him this way and causing him to sleep on the floor.

I said I was done doing unnecessary chore in the middle of nigh almost every night when he could just use diapers, he was astonished by what I said and called me a monster for enjoying his suffering like that then got SIL to come give me a stern talk about my attitu

Where ever you left it 🤷‍♀️🤭

This morning, my 4 year old daughter.

Daughter: I'm hungry

Me: nerves building, smile widening

Me: Hi hungry, I'm dad.

She had no idea what was going on but I finally did it.

Thank you all for listening.

There hasn't been a post all year!

You take away their little brooms

It was about a weak back.

Protein complexes are defined by the three‐dimensional structure of participating binding partners. Knowledge about these structures can facilitate the design of peptidomimetics which have been applied e.g. as inhibitors of protein‐protein interactions (PPIs). Even though β‐sheets participate widely in PPIs, they have only rarely served as the basis for peptidomimetic PPI inhibitors, in particular when addressing intracellular targets. Here, we present the structure‐based design of β‐sheet mimetics targeting the intracellular protein β‐catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of β‐catenin, a macrocyclic peptide was designed and its crystal structure in complex with β‐catenin obtained. Using this structure, we designed a library of bicyclic β‐sheet mimetics employing a late‐stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to β‐catenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other β‐sheet‐mediated PPIs.

https://ift.tt/31vMAC5

A designed dipeptide with azide and alkyne groups at its termini adopts β‐sheet packing in its crystal and undergoes single‐crystal‐to‐single‐crystal polymerization via topochemical azide‐alkyne cycloaddition to evolve into a pseudoprotein with interesting helical‐sheet packing in its crystals. This helical‐sheet orientation in the pseudoprotein crystal resembles the novel cross‐α‐amyloids, wherein α‐helical protein assembles laterally.

Abstract

Protein‐mimics are of great interest for their structure, stability, and properties. We are interested in the synthesis of protein‐mimics containing triazole linkages as peptide‐bond surrogate by topochemical azide‐alkyne cycloaddition (TAAC) polymerization of azide‐ and alkyne‐modified peptides. The rationally designed dipeptide N3‐CH2CO‐Phe‐NHCH2CCH (1) crystallized in a parallel β‐sheet arrangement and are head‐to‐tail aligned in a direction perpendicular to the β‐sheet‐direction. Upon heating, crystals of 1 underwent single‐crystal‐to‐single‐crystal polymerization forming a triazole‐linked pseudoprotein with Gly‐Phe‐Gly repeats. During TAAC polymerization, the pseudoprotein evolved as helical chains. These helical chains are laterally assembled by backbone hydrogen bonding in a direction perpendicular to the helical axis to form helical sheets. This interesting helical‐sheet orientation in the crystal resembles the cross‐α‐amyloids, where α‐helices are arranged laterally as sheets.

https://ift.tt/2vRbcsL