#growth arrest、

[chinesegreenteagoldentriangle]

Mechanism of EGCG binding to p53 revealed: Polyphenolic compounds in green tea may enhance anti-tumor activity by stabilizing p53.

A new study has found that epigallocatechin gallate (EGCG), a polyphenolic compound found in green tea, can induce apoptosis in cancer cells, but its potential molecular mechanisms are not well understood. Recently, a team led by Chunyu Wang at Rensselaer Polytechnic Institute (with China Agricultural University as the first author's affiliation and Jing Zhao as the first author of the paper) published a study in Nature Communications titled "EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction". The study used SPR and NMR to report the direct interaction between EGCG and the tumor suppressor p53 (KD = 1.6 ± 1.4 μM), with the disordered N-terminal domain (NTD) identified as the main binding site (KD = 4 ± 2 μM). Large-scale atomic simulations (>100 μs), SAXS, and AUC showed that the EGCG-NTD interaction is dynamic, with EGCG leading to a subpopulation of compact bound conformations. The EGCG-p53 interaction disrupted the interaction between p53 and its regulatory E3 ligase MDM2 and inhibited MDM2-mediated ubiquitination of p53 in vitro, potentially stabilizing p53's anti-tumor activity. Overall, this study provides insights into the anti-cancer mechanism of EGCG and identifies the p53 NTD as a target for cancer drug discovery through dynamic interactions with small molecules.

In recent years, diet-based cancer prevention and treatment have received considerable attention. Green tea is a popular beverage worldwide and has been reported to have inhibitory effects on various types of cancers, such as breast cancer, lung cancer, prostate cancer, and colon cancer. Most of the chemopreventive effects of green tea on cancer are attributed to polyphenolic compounds, with epigallocatechin-3-gallate (EGCG) being the most important. EGCG accounts for 50-80% of the catechins in green tea. A cup of brewed green tea (240 mL) contains 200-300 mg of EGCG. A serum concentration of 0.1-1 μM EGCG can be achieved by drinking a cup of green tea or taking an EGCG tablet. The anticancer effects of EGCG have been confirmed in epidemiological, cell culture and animal studies, as well as clinical trials.

A 10-year prospective study by Nakachi and Imai reported that people who drink more than 10 cups of green tea per day have a lower risk of cancer compared to those who drink less than 3 cups per day. Recently, Shin et al. found in a randomized clinical trial in Korea that green tea extract can reduce the recurrence rate of colorectal adenomas by 44.2%. In vitro, EGCG has been shown to promote growth arrest and induce apoptosis in a variety of human cancer cell lines, including prostate cancer cells, epidermoid carcinoma cells, bladder cancer cells, and colon cancer cells.

In mice, oral administration of green tea or intravenous injection of purified EGCG can inhibit angiogenesis and suppress the growth of solid tumors. At the molecular level, EGCG has been shown to interact with cancer-associated proteins, such as glucose-regulated protein 78 (GRP78) and Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1), with an affinity of approximately μM.

In EGCG-induced apoptosis and growth arrest, p53 plays an important role. p53, often referred to as the "guardian of the genome," is a critical tumor suppressor that is mutated in over 50% of human cancers. p53 promotes cell cycle arrest or apoptosis as a response to cellular stress stimuli such as oxidative stress, oncogene activation, and DNA damage. As a transcription factor, p53 is tightly regulated and has a short half-life. p53 protein is typically maintained at low levels in healthy mammalian cells through continuous ubiquitination and subsequent degradation.

Under cellular stress, ubiquitination of p53 is inhibited, and p53 is stabilized. Then p53 accumulates in the cell nucleus and activates the expression of target genes, thereby triggering cell cycle arrest, apoptosis, and DNA repair processes. In addition to serving as a transcription factor, p53 can also be translocated to the cytoplasm or mitochondria. p53 directly interacts with anti-apoptotic proteins such as Bax and Bcl2 to induce apoptosis and also participates in the anti-aging effects of EGCG.

Full-length p53 consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a tetramerization domain (TET), and a C-terminal regulatory domain (REG). The NTD is further divided into two transcription activation domains (TAD1 and TAD2) and a proline-rich domain (PRD). The NTD is an intrinsically disordered protein (IDP) that interacts with many proteins and serves as a hub for cellular signal transduction. The NTD is not only necessary for transactivation but also interacts with MDM2 to mediate the ubiquitination and degradation of p53.

Independent of ubiquitination, MDM2 also inhibits transcription by preventing the general transcription factors from binding to the NTD. The apoptotic effect of EGCG on human cancer cells is related to its interference with MDM2-mediated ubiquitination of p53. It has been reported that EGCG can also stabilize p53 and increase the phosphorylation of critical serine residues. In a recent study, EGCG was identified as an inhibitor of the p53-MDM2 interaction from a library of 2,295 plant chemicals. However, the molecular mechanism by which EGCG disrupts the MDM2-p53 interaction is not yet clear.

In this work, direct binding between EGCG and p53 mediated by the NTD of p53 was demonstrated. The study suggests that the EGCG-p53 interaction disrupts the MDM2-p53 interaction and inhibits the ubiquitination of p53, potentially stabilizing p53's anti-tumor activity and providing a structural mechanism for the anti-cancer effects of EGCG.

[doctorstarlock]

Taking a vacation from personal growth. Gonna indulge in a little arrested development for a while. As a treat.

[crystallllines]

my god churro is the lone woman performing amid a bunch of men saturday night

what a brave girl! ugh i’m so proud of her and also fuckin terrified that i’ll hate the set. it’s supposed to be edgy humor, so i’ll just brace myself to expect what i hear from josh on the regular, i guess. but churro also said she was doing a couple jokes about our grandfather (the bad one), and frankly THAT makes me worried about how i’ll respond to someone making jokes about… about what? what he did? the trial? my god, charity was just a little baby when all of that happened.

i want tomorrow night to be about her, though, not about how i feel about someone making light of an ordeal that tore our family apart and hurt so many people i love— including churro— you know? so, like, while i was definitely encouraged to only ever look upon that issue with the utmost seriousness (you have to be serious if you’re testifying in a criminal trial, uh, helloooo), i will do my best to have a sense of humor about it

[mabelsguidetolife]

i can get pretty emotional but somehow i’m pretty good at therapeutic self-examination because if i could afford a real therapist i would probably be uncomfortable sharing with them, and if i didn’t train myself to be resilient and non-impulsive i would probably be dead

[m0tel6mxzzy]

also bro i’m literally soooo easy to be friends w the bar is like….basic human respect. i’m nice to ppl i meet bc it’s the decent thing to do. i will gush abt ur creative interests bc it brings me joy something personal to u makes you happy. it fulfills me to be nice to ppl im so tired of having my kindness treated as me being conniving or weak or flirty!!! that is not my heart. if i like someone i say it. to me it’s the strongest thing to have been through pain and still find beauty and good in other people. let me be kind without some projected ulterior motive. if u can’t enjoy kindness with me what’s the point. i love being kind

[smilesleepandspeak]

If bvb win today, I'm going to use it as anti-haaland propaganda like oh dortmund won the season after he left, FRAUDland much 🤨🤨🤨

[anonymous-tals]

Gob kind of just crashes through life with little regard for those around him. Ya know, he’s not the most self aware guy. He doesn’t always consider how his actions will affect those around him. Or if he does, he just does what he wants anyway. Which makes his interactions with his son kind of interesting cause we see some sense of self awareness from him in his interactions. When Gob first meets Steve, unaware that Steve is his son, they really get along. He says, “Kid's amazing, though. It's almost like I wish he could be my Dad.” On top of this being somewhat of a roundabout criticism of George, something we don’t usually hear from Gob, we can understand from this that Gob kind of looks up to Steve. He sees himself in the kid, a better version of himself, really, and he wishes he could’ve had someone like that who he could look up to when he was a kid. But as soon as he learns Steve is his son, his face falls and he’s silent before saying he’s made “huge tiny mistake,” before promptly running off.

While obviously, this isn’t the right thing to do, from Gob’s perspective, he’s thinking it’s for the best. As stated, he looks up to Steve and clearly cares about him. When talking about Steve, he says, “It’s like my heart is getting hard. Maybe I am ready to be a father,” before promptly ducking under the desk when he hears George Michael say, “Dad?” thinking it to be Steve. Bringing back the point from earlier, Gob isn’t very self aware. But what we see here is him realizing he cares about this kid but at the same time realizing that he’s afraid of hurting the kid like George did to him. He doesn’t want this kid to turn out like he did. He doesn’t want Steve’s admirable traits, what he wished his father could’ve been like, to disappear because of something he did. And so he runs.

He was completely fine hanging out when it was a son and son camping trip or a father and son camping trip where Steve was the representative father but a father and son camping trip where Gob was the father? And not just the representative father but Steve’s actual father? That’s too much for Gob to handle. There’s pressure to that title. Earlier, we see Gob break down, sobbing over how George didn’t tell him about the cabin or promise him they’d go camping, which on it’s own, sounds silly to be this upset over but in reality is representative of the great neglect Gob experienced over the course of his life. He is aware of just how awful it is to treated the way his dad treated him. His dad is supposed to be someone he can to look up to. Someone who’s supposed to be there for him. Someone who’s supposed to teach him how to play catch and take him camping. As discussed, he’s afraid of hurting his son in the same way he was. He’s most likely thought about how he’d never want to be a dad for that reason. He’s probably also had the thought that if his dad wasn’t around, he’d probably be better off. So once he realizes that he is Steve’s dad, his actual dad, the pressure of being the dad he always wanted weighs on him and he runs. An action, although wordless, contains acknowledgment of his faults. And while running off from responsibility and leaving his son in the parking lot was not a good thing to do, his logic is fueled by the idea that it’s better for Steve to have no dad than to have him as a dad. Steve’s been doing generally okay for himself up until this point and the less time Gob spends around him, the less likely Steve is to be poisoned by his presence, become damaged goods just like him.

Anyway, I don’t have much else to say(oops, turns out I do). Just that Gob’s moments of self awareness are interesting, ya know? Moments where he dares to really look at himself in the mirror and face what’s underneath the paper thin facade of confidence and act accordingly. And even then, he doesn’t usually make the best choices but you can see in his actions what he really thinks of himself. How he’s internalized a lot of his parent’s words about him. How he’ll never do anything right. In spite of encouragement from Michael, he still avoids his son like the plague most of the time. Perhaps- No, not even perhaps. He’d for certain feel more confident in taking responsibility and being this kid’s dad without having experienced the perpetual reinforcement of the idea that he is incapable of doing anything right. Or if he had a proper support system that could reassure him about the whole thing and ease his doubts. Cause, remember, he had a moment where he for a split second was like, “Yeah, maybe I could be this kid’s dad.” And then he was so afraid screwing things up, an apparent “inevitability” that his father continues to instill in him, that he hid behind the desk a second later when he thought Steve was there. He is capable of development, growing as a person, and in season five and in the latter half of his arc in season four, he does actually begin grow in the right direction, but in those earlier seasons, like we see so many times, it’s hard for that development to stick when he doesn’t have an ample support system(which he has with Tony in season four and five, where his growth begins to bud).

It’s all very interesting.

[sirbob-thebread]

You walk free. After everything you did, you walk free. Cut off everyone that would try to make you accountable, you walk free. Almost two years since I heard your voice yet some key words echo in my mind. You made it known I was never meant to share my story with another. You walk free and I can't help the next people you hurt. I hope one day, somehow, you'll realize the consequences of those actions. Until then, you'll walk free and I'll wish my heart was never so accepting of 'love'.

~Love, The Leech ❤️

[dh5ryxhgbctgr]

Composite Jacket Arrester Market Review and Future Growth Estimates 2024 - 2031

The composite jacket arrester market is projected to grow significantly, with an estimated size of $1.1 billion in 2023. By 2024, this market is expected to reach $1.2 billion, and it could surge to $2.5 billion by 2032. This growth translates to a compound annual growth rate (CAGR) of approximately 9.59% during the forecast period from 2024 to 2032. As demand for reliable protection systems continues to rise, the composite jacket arrester market presents substantial opportunities for industry stakeholders.

The composite jacket arrester market has been gaining traction in recent years, driven by the increasing demand for efficient lightning protection systems across various industries. This article explores the key aspects of the composite jacket arrester market, including market dynamics, applications, and future trends.

Understanding Composite Jacket Arresters

What is a Composite Jacket Arrester?

A composite jacket arrester is a type of surge protective device designed to safeguard electrical equipment from voltage spikes caused by lightning strikes or switching surges. The composite material offers enhanced durability and resistance to environmental factors, making these arresters suitable for outdoor applications.

Key Features of Composite Jacket Arresters

High Surge Capacity: Designed to handle significant voltage spikes.

Durability: Resistant to harsh weather conditions and corrosion.

Lightweight Design: Easier to install and maintain compared to traditional metal counterparts.

Versatility: Applicable in various industries, from telecommunications to renewable energy.

Market Dynamics

Drivers of Market Growth

Rising Incidence of Lightning Strikes: Increased frequency of severe weather events has heightened the need for effective lightning protection systems.

Technological Advancements: Innovations in materials and design are enhancing the performance of composite jacket arresters.

Regulatory Compliance: Stricter regulations regarding electrical safety are driving demand for reliable surge protection devices.

Challenges Facing the Market

High Initial Costs: The upfront investment for composite jacket arresters can be significant, which may deter some potential users.

Market Competition: The presence of established manufacturers can create intense competition, affecting pricing strategies.

Key Applications of Composite Jacket Arresters

Telecommunications

In the telecommunications sector, composite jacket arresters protect sensitive equipment from voltage spikes that can disrupt service and lead to costly downtime.

Renewable Energy

With the rise of solar and wind energy installations, these arresters play a crucial role in safeguarding inverters and other electrical components from lightning-induced surges.

Industrial Applications

Industries such as manufacturing and oil and gas rely on composite jacket arresters to protect critical machinery and control systems from electrical disturbances.

Regional Analysis

North America

North America holds a significant share of the composite jacket arrester market, driven by stringent safety regulations and the increasing deployment of renewable energy projects.

Europe

In Europe, the market is fueled by a strong emphasis on infrastructure development and sustainability, with many countries investing in advanced lightning protection systems.

Asia-Pacific

The Asia-Pacific region is witnessing rapid industrialization and urbanization, leading to a surge in demand for composite jacket arresters, particularly in emerging economies like India and China.

Future Trends

Innovations in Materials

The future of the composite jacket arrester market lies in continued innovations in materials, which will enhance performance and reduce costs.

Integration with Smart Technologies

As smart grids and IoT applications become more prevalent, integrating composite jacket arresters with smart technologies will offer improved monitoring and management of electrical systems.

Sustainability Focus

With a growing emphasis on sustainability, manufacturers are likely to focus on eco-friendly materials and production processes, appealing to environmentally conscious consumers.

Conclusion

The composite jacket arrester market is poised for significant growth, driven by increasing demand for reliable surge protection across various sectors. As technology evolves and industries adapt to changing environmental conditions, composite jacket arresters will play a vital role in ensuring the safety and efficiency of electrical systems worldwide. As we look to the future, continuous innovation and a focus on sustainability will shape the direction of this promising market.

[weterpete]

mad props to the arrested development seasons 4&5 writers for creating a very long, interconnected and convoluted story that goes absolutely nowhere at all. also for having to dub-over half the lines. also for both reviving and tarnishing the legacy of an iconic tv show

[strewbi]

So we know Louis is continually trapped in the emotional experience of grief over a beloved family member, and whenever someone he cares about seems like they’re leaving in some way that nerve gets pulled.

I don’t know Lestat’s business

And Claudia, I don’t know what her human life was like but the period surrounding her death was a moment of acceptance of her coming death, and then joyful wonder and love for these two angels. So eventually those angels prove themselves to be fallible it’s like her god dying in front of her, or a realizing a parent doesn’t know everything. She kills her gods mentally, before she does it physically, and then it’s as natural to her as eating. I think maybe that blend of philosophical acceptance on top of discovery, and then the betrayal and death of that wonder is her nerve that gets pulled.

If the sanctity of her life is fallible and there’s nothing she can do, fine, oh shit there’s more to know. —>There are angels and powers and more must be discovered about their limits. —> their limits are that they are just men, and men are killable.—> There is a wide world of people who know more and more discoveries need to be made and surmounted and eaten—oh the extra hunger is part of the rush of discovery, the curiosity is a hunger.

She’s leveling constantly, and it would have been fascinating if she had continued growing. If for her, the last human died with Charlie, what would happen to her if the last vampire died with someone else?

[autogyne-redacted]

Let's Talk About Security Culture: Why Keeping Secrets is Cool and Sexy

It's a natural impulse -- if you love crime -- to want to talk about how great it is. And if you hate America, it's only natural to want to share your dreams for its future with the rest of tumblr dot com. It can feel brave and transgressive. And there is a drive to share your soul with the world at the heart of social media. Surely I should be posting the most concrete implications of my politics, right? This is the poster's curse.

Security Culture refers to a set of "best practices" developed over the past several decades, largely (in a US context) coming out of radical environmental groups as they faced intense state repression, infiltration and entrapment. If you're not familiar, there's some fascinating crimethinc write ups to give you a window into that world:

Much of it boils down to: don't talk about crimes, past or forthcoming with people who don't need to know about them, and be mindful of the possibility of surveillance and infiltration. And, we can support each other as a community in minimizing risks, with an eye towards enabling bold action rather than getting bogged down in fears and anxieties. The guidelines that make sense for AG-based trouble-makers are different from the guidelines that make sense for posters, but plenty of common principles apply. To speak briefly to our position here as posters:

First, it bears saying that long term anonymity is nearly impossible to maintain. Unless you've never accessed Tumblr without a vpn, and avoided connections with other ppl who can be associated with you/your location, and never shared pictures without scrubbing metadata, and a bunch of other 100% consistent steps, it's trivial for the state to know who you are.

Second, just because something isn't actively being prosecuted now doesn't mean it can't be prosecuted later. The priorities of the state change and a shift in power towards the right or a growth in radical action from the left can suddenly make it a priority to destroy anarchist networks or just find a few ppl to prosecute as examples (who probably weren't that plugged into larger networks before getting arrested). Advocating for specific anti-government crimes or declarations of intent to commit such crimes are likely prosecutable, and even if charges don't stick, they're an easy vector for legal harassment.

Third, it's worth thinking about heat as separate from prosecutability. There are modes of engagement that may not be directly criminalized but signal that you are someone worth watching. Some people choose to be public in ways that make heat unavoidable. But it's worth noting that heat isn't strictly individualized, that it persists over time but also is going to shrink over time.

It's easy on here, ime, to see yourself as a proud member of the crime fandom but not much of a content creator. And it's easy to feel like you've generated an amount of heat where you're locked into that role. But heat you generated 10 years ago is probably pretty well gone. Heat you generated 5 years ago has faded substantially. It's worth thinking about how the world might shift in the coming years and what doors you want to keep open.

The non-individualized nature of heat also means that leaning into the spiciest of anti-state positions will make it a bad idea for people who are acting out those positions end up tied to you. Loudly talking about how "more people should be doing [X/Y/Z]" unfortunately sets you up to remain distant from people who might be doing or thinking about doing such things.

Which brings me back to: keeping secrets is sexy. Not spelling everything out builds intrigue. You can lay out a theoretical position and leave working out the practical implications of that as an exercise for the reader. There's value in opacity. The poster's curse and the drive to confess are extremely convenient for the state, but we can resist them. We can hold dreams in our hearts that we refuse to offer up to the posting spectacle.

[shrimp1y]

"wrio isn't a cop hes a king"

Can someone with brains please please PLEASE talk about the disgusting portrayal of cops, crime, court proceedings, justice system and prison incarceration in genshin impact's fontaine update because I cannot SIT HERE and see people completely destroy their brain cells just so they could play a mediocre game and make some fictional men fuck in their mind

I'm deadass surprised there isn't more people talking about it??? I'm honestly so ??? It's literally presenting prison labour as a good thing. Wriothesley, the prison administrator, got rich off of making his inmates build police robots for the state AND HE'S PRAISED FOR IT. AND THEY'RE PAID IN COUPONS THAT CAN ONLY BE USED IN JAIL. HE WAS REWARDED FOR IT WITH HIS DUKE STATUS.

The fact that the fucking MC's mascot was like "oh the prisoners get one free meal a day? you're making life too good down here what if no one wants to leave :(" what in the bullshit. What in the. There's also a fighting ring in the prison, by the way, and you can bet on it with your coupons you just can't bet on both fighters.

The. This is a scene people think is hot. "But that's a bad guy!" THAT'S HOW THE NARRATIVE IS WRITTEN. THEY ARE ALWAYS THE BAD GUY IN FICTION. THAT'S HOW COPAGANDA WORKS, they make you think people in power can just beat the shit outta anyone and of course the person deserves it because they are clearly always the bad guys! And the people in power are always right! This is sarcasm btw.

Neuvillette and the magic judgement machine are literally seen as undeniable justice ordained by magic and NO ONE KNOWS HOW IT WORKS. NEUVILLETTE HIMSELF HAS NO CLUE WHAT HE'S DOING HE'S ACTIVELY FIGURING SHIT OUT AS WE SPEAK. And yet it's what sends people to The Worst Most Dangerous Super Scary Prison Ever Where There's No Laws [but 1 meal a day's great /s].

"But he feels bad!" Genshin has repeatedly chosen to highlight the pains and troubles of the oppressors [Eula] [Ei/Shogun] and there's literally never any repercussions for them aside from when they portray The Haterz clearly as villains or they turn it around and say "Well it was a misunderstanding all along! No one's to blame here!"

I'm not smart enough to go into details I'm just saying. This. needs to be talked about. I'm not telling you to stop the game bc Hyperfixations not really smth that can be controlled or whatever I get It I Got Back into the game when the first trailer dropped I drew neuvillette fanart and then everything just went downhill since then and I'm like why the fuck did I expect anything better than racist, pro cop dogshit from Mihoyo It needs to be talked about ESPECIALLY by people who still cares about it to critically. assess what the fuck you are absorbing because this shit isn't okay. This is literally paw patrol for weebs they just didn't call anyone a "cop"

PLEASE. TALK ABOUT IT.

[newsbites]

Charges laid against the protesters are starting to collapse.