#Cell disruption

[idexindia]

What is Cell Disruption?

Cell disruption, also known as cell lysis, refers to the breakdown of the cell membrane and/or cell wall to release its contents. This process is crucial for accessing biomolecules such as proteins, enzymes, and nucleic acids that play roles in various biological processes. Centrifugation is a step in downstream applications within the life sciences, including protein purification for research purposes; nucleic acid extraction for genetic analysis or vaccine development; and metabolite analysis to understand cellular mechanisms and identify biomarkers. The effectiveness of cell disruption depends on factors like the type of cells involved, where the target molecules are located within the cells, and the specific applications being pursued.

visit: https://medium.com/@idexindia/what-is-cell-disruption-c8e2c6aaaf22

[linny-of-the-lakes]

The Blacklist 10.3 - Herbie aka Science Dad “What the hell, nobody at home screams at me when I ruin the prosecution’s case... I mean Sue screams at me but I can usually fix that with a goofy face.”

[kikun]

bites his finger :3c

kills him.

[tobrodachi]

i've come to bring you cursed knowledge about microbiology and antibiotics

colistin

super antibiotic, usually reserved as a last resort treatment for bacterial infections that are resistant to everything

it's literally the gundam hammer and works the same, just bash the fucking bacteria dead until it bursts open lmao

[jcmarchi]

A protein found in human sweat may protect against Lyme disease

New Post has been published on https://thedigitalinsider.com/a-protein-found-in-human-sweat-may-protect-against-lyme-disease/

A protein found in human sweat may protect against Lyme disease

Lyme disease, a bacterial infection transmitted by ticks, affects nearly half a million people in the United States every year. In most cases, antibiotics effectively clear the infection, but for some patients, symptoms linger for months or years.

Researchers at MIT and the University of Helsinki have now discovered that human sweat contains a protein that can protect against Lyme disease. They also found that about one-third of the population carries a genetic variant of this protein that is associated with Lyme disease in genome-wide association studies.

It’s unknown exactly how the protein inhibits the growth of the bacteria that cause Lyme disease, but the researchers hope to harness the protein’s protective abilities to create skin creams that could help prevent the disease, or to treat infections that don’t respond to antibiotics.

“This protein may provide some protection from Lyme disease, and we think there are real implications here for a preventative and possibly a therapeutic based on this protein,” says Michal Caspi Tal, a principal research scientist in MIT’s Department of Biological Engineering and one of the senior authors of the new study.

Hanna Ollila, a senior researcher at the Institute for Molecular Medicine at the University of Helsinki and a researcher at the Broad Institute of MIT and Harvard, is also a senior author of the paper, which appears today in Nature Communications. The paper’s lead author is Satu Strausz, a postdoc at the Institute for Molecular Medicine at the University of Helsinki.

A surprising link

Lyme disease is most often caused by a bacterium called Borrelia burgdorferi. In the United States, this bacterium is spread by ticks that are carried by mice, deer, and other animals. Symptoms include fever, headache, fatigue, and a distinctive bulls-eye rash.

Most patients receive doxycycline, an antibiotic that usually clears up the infection. In some patients, however, symptoms such as fatigue, memory problems, sleep disruption, and body aches can persist for months or years.

Tal and Ollila, who were postdocs together at Stanford University, began this study a few years ago in hopes of finding genetic markers of susceptibility to Lyme disease. To that end, they decided to run a genome-wide association study (GWAS) on a Finnish dataset that contains genome sequences for 410,000 people, along with detailed information on their medical histories.

This dataset includes about 7,000 people who had been diagnosed with Lyme disease, allowing the researchers to look for genetic variants that were more frequently found in people who had had Lyme disease, compared with those who hadn’t.

This analysis revealed three hits, including two found in immune molecules that had been previously linked with Lyme disease. However, their third hit was a complete surprise — a secretoglobin called SCGB1D2.

Secretoglobins are a family of proteins found in tissues that line the lungs and other organs, where they play a role in immune responses to infection. The researchers discovered that this particular secretoglobin is produced primarily by cells in the sweat glands.

To find out how this protein might influence Lyme disease, the researchers created normal and mutated versions of SCGB1D2 and exposed them to Borrelia burgdorferi grown in the lab. They found that the normal version of the protein significantly inhibited the growth of Borrelia burgdorferi. However, when they exposed bacteria to the mutated version, twice as much protein was required to suppress bacterial growth.

The researchers then exposed bacteria to either the normal or mutated variant of SCGB1D2 and injected them into mice. Mice injected with the bacteria exposed to the mutant protein became infected with Lyme disease, but mice injected with bacteria exposed to the normal version of SCGB1D2 did not.

“In the paper we show they stayed healthy until day 10, but we followed the mice for over a month, and they never got infected. This wasn’t a delay, this was a full stop. That was really exciting,” Tal says.

Preventing infection

After the MIT and University of Helsinki researchers posted their initial findings on a preprint server, researchers in Estonia replicated the results of the genome-wide association study, using data from the Estonian Biobank. These data, from about 210,000 people, including 18,000 with Lyme disease, were later added to the final Nature Communications study.

The researchers aren’t sure yet how SCGB1D2 inhibits bacterial growth, or why the variant is less effective. However, they did find that the variant causes a shift from the amino acid proline to leucine, which may interfere with the formation of a helix found in the normal version.

They now plan to investigate whether applying the protein to the skin of mice, which do not naturally produce SCGB1D2, could prevent them from being infected by Borrelia burgdorferi. They also plan to explore the protein’s potential as a treatment for infections that don’t respond to antibiotics.

“We have fantastic antibiotics that work for 90 percent of people, but in the 40 years we’ve known about Lyme disease, we have not budged that,” Tal says. “Ten percent of people don’t recover after having antibiotics, and there’s no treatment for them.”

“This finding opens the door to a completely new approach to preventing Lyme disease in the first place, and it will be interesting to see if it could be useful for preventing other types of skin infections too,” says Kara Spiller, a professor of biomedical innovation in the School of Biomedical Engineering at Drexel University, who was not involved in the study.

The researchers note that people who have the protective version of SCGB1D2 can still develop Lyme disease, and they should not assume that they won’t. One factor that may play a role is whether the person happens to be sweating when they’re bitten by a tick carrying Borrelia burgdorferi.

SCGB1D2 is just one of 11 secretoglobin proteins produced by the human body, and Tal also plans to study what some of those other secretoglobins may be doing in the body, especially in the lungs, where many of them are found.

“The thing I’m most excited about is this idea that secretoglobins might be a class of antimicrobial proteins that we haven’t thought about. As immunologists, we talk nonstop about immunoglobulins, but I had never heard of a secretoglobin before this popped up in our GWAS study. This is why it’s so fun for me now. I want to know what they all do,” she says.

The research was funded, in part, by Emily and Malcolm Fairbairn, the Instrumentarium Science Foundation, the Academy of Finland, the Finnish Medical Foundation, the Younger Family, and the Bay Area Lyme Foundation.

[bahoreal]

i was tryna buy myself some drinkies cos im bored of drinking water and absolutely fucking everything has sucralose (GENOTOXIC) in it

[detnu-a-h]

I know I said biological siblings with Mak... BUT... my brain keeps going back to artificially created Atom since that's the story I had given him, and I'm like... okay, so I'm leaning towards making him have the base of a certain politician's genes instead and not actually be a biological part of the family but basically a modified copy of that man.

[abyssmalice]

Your brother was declared guilty for the case of the disappearance of young ladies in Fontaine. What do you make of it, miss Tartaglia?

"What do I think? Simple: that machine is fucking stupid, my brother is innocent, and if I have to beat up the Hydro Archon and that Chief Justice at the same time to fix this, then so be it."

"I know for a fact that my brother isn't guilty - not with these disappearances, at least. Does it even look like he would kidnap random ladies? This battle-hungry, stupid-headed idiot? As if! Anything else, though? Even I wouldn't be able to say if he's innocent of any other crimes. We're Harbingers, after all. But you can rule out pointless kidnapping, that's for sure."

[susanlabnic]

The Labnic High Speed Homogenizer is equipped with an LED digital display to view speed. Provided with an AC carbon brush motor with stepless speed regulation. which has large torque and output power with stable operation. The high-speed homogenizer operates with a power output of 220 watts. The high-speed homogenizer features a simple frame structure and an easy-to-clean internal suction area.

[mortalityplays]

"how do you just know this" is a question I get asked a lot, because I tend to be someone who can contribute unusual facts or insight on whatever topic a casual conversation turns to, and I never know how to answer because "I pay attention" sounds rude and isn't super actionable. but that is really it, I just take an active interest when I encounter something curious or unusual.

like recently one of my friends linked me a funny paragraph from a very badly written erotic novel. it was so bad that I thought "I wonder if this is real", so we looked up the book it was from and learned it was a vintage horny housewife type story by someone who wrote a lot of shitty cheap porn back in the 80s, all of which now seems to be completely out of print.

in the course of googling the author, I discovered that one of their works had been cited in a 2004 court case over a prisoner's right to keep erotic novels in his personal library after the prison confiscated them. a bit more googling turned up the case details in a legal database. the guy had received the books by mail and kept them, among others, in his cell. the prison seized them, citing a policy against prisoners having pornography. his lawyers argued that 1. erotic novels are distinct from pornography because they have artistic and expressive content beyond the depiction of sex acts, and 2. since he received them by mail they are therefore protected under his constitutional right to freely access non-disruptive information from outside the prison. I don't know if he got his books back, but he won his case.

then we googled the defendant and found out he was in prison for helping a woman to drug and murder his boss (who she lived with), mutilate the body with acid and dump him in a ravine.

anyway my point is, take an interest. that's how you learn weird stuff.

[reasonsforhope]

Green energy is in its heyday. 

Renewable energy sources now account for 22% of the nation’s electricity, and solar has skyrocketed eight times over in the last decade. This spring in California, wind, water, and solar power energy sources exceeded expectations, accounting for an average of 61.5 percent of the state's electricity demand across 52 days. 

But green energy has a lithium problem. Lithium batteries control more than 90% of the global grid battery storage market. 

That’s not just cell phones, laptops, electric toothbrushes, and tools. Scooters, e-bikes, hybrids, and electric vehicles all rely on rechargeable lithium batteries to get going. 

Fortunately, this past week, Natron Energy launched its first-ever commercial-scale production of sodium-ion batteries in the U.S. 

“Sodium-ion batteries offer a unique alternative to lithium-ion, with higher power, faster recharge, longer lifecycle and a completely safe and stable chemistry,” said Colin Wessells — Natron Founder and Co-CEO — at the kick-off event in Michigan. 

The new sodium-ion batteries charge and discharge at rates 10 times faster than lithium-ion, with an estimated lifespan of 50,000 cycles.

Wessells said that using sodium as a primary mineral alternative eliminates industry-wide issues of worker negligence, geopolitical disruption, and the “questionable environmental impacts” inextricably linked to lithium mining. 

“The electrification of our economy is dependent on the development and production of new, innovative energy storage solutions,” Wessells said. 

Why are sodium batteries a better alternative to lithium?

The birth and death cycle of lithium is shadowed in environmental destruction. The process of extracting lithium pollutes the water, air, and soil, and when it’s eventually discarded, the flammable batteries are prone to bursting into flames and burning out in landfills. 

There’s also a human cost. Lithium-ion materials like cobalt and nickel are not only harder to source and procure, but their supply chains are also overwhelmingly attributed to hazardous working conditions and child labor law violations. 

Sodium, on the other hand, is estimated to be 1,000 times more abundant in the earth’s crust than lithium. 

“Unlike lithium, sodium can be produced from an abundant material: salt,” engineer Casey Crownhart wrote ​​in the MIT Technology Review. “Because the raw ingredients are cheap and widely available, there’s potential for sodium-ion batteries to be significantly less expensive than their lithium-ion counterparts if more companies start making more of them.”

What will these batteries be used for?

Right now, Natron has its focus set on AI models and data storage centers, which consume hefty amounts of energy. In 2023, the MIT Technology Review reported that one AI model can emit more than 626,00 pounds of carbon dioxide equivalent. 

“We expect our battery solutions will be used to power the explosive growth in data centers used for Artificial Intelligence,” said Wendell Brooks, co-CEO of Natron. 

“With the start of commercial-scale production here in Michigan, we are well-positioned to capitalize on the growing demand for efficient, safe, and reliable battery energy storage.”

The fast-charging energy alternative also has limitless potential on a consumer level, and Natron is eying telecommunications and EV fast-charging once it begins servicing AI data storage centers in June. 

On a larger scale, sodium-ion batteries could radically change the manufacturing and production sectors — from housing energy to lower electricity costs in warehouses, to charging backup stations and powering electric vehicles, trucks, forklifts, and so on. 

“I founded Natron because we saw climate change as the defining problem of our time,” Wessells said. “We believe batteries have a role to play.”

-via GoodGoodGood, May 3, 2024

--

Note: I wanted to make sure this was legit (scientifically and in general), and I'm happy to report that it really is! x, x, x, x

[stellavista]

Marc Almond - Tears Run Rings (Disrupt Dub)

[deebris]

From annoying to beloved

Homelander x fem!Reader

Synopsis: The new member of the Seven annoys Captain Patria with their habit of doodling in the corners all the time, but he didn't expect to end up liking it.

During the fourth season, it can be read as both romantic and platonic.

Warnings: Swearing, mentions of murder, the reader has the power to control plasma, fluffy.

The reader is also kind of anxious.

Word count: 2.9k

"You gotta be fucking kidding with me." Homelander interrupted abruptly upon hearing snores in the room. "Is Noir sleeping?"

"Mmhmm," Firecracker murmured in agreement, but the masked superhero jolted awake when The Deep kicked his chair.

"Oh, shit! Sorry, guys." Black Noir straightened up, while the Captain shook his head in disbelief, unable to fathom what he had just witnessed.

"Ah, what the fuck." The blonde furrowed his brows, eyes darting around the room quickly, then fixing on a specific point when something else caught his attention. He had noticed you earlier with a notebook and pencil, but now you're not writing but drawing. The irritating sound of the graphite scraping against the paper had been bothering him for some time, but he had tried to ignore it, assuming as a newcomer you were taking notes.

He wouldn't lie. Though he found taking notes utterly stupid, he liked to think someone was that focused on what he said. Not that he needed it, just opening his lips and everyone would be watching him. But as if that weren't enough, he finally realized you were dressed in regular civilian clothes.

"Radiance, where's your suit?" He asked slowly, but angrily. "Can't anyone do anything right around here?"

You finally tore your attention from the paper, meeting Homelander gaze directly. It's not that you weren't paying attention—in fact, you were, maybe more than anyone else there. It was easier to absorb things while doodling, a way to calm your nerves. Well, that or rubbing your sweaty fingers together until they hurt.

No one ever understood. Even back in school, your parents used to receive complaints about you drawing during class, no matter how high your grades were or the fact that you were the top student.

This was your first meeting with the Seven, and the last thing you wanted was to give the impression of being careless or not caring about being there. It could be said that one of the best days of your life was yesterday when Vought sent you a notice, letting you know that the greatest superhero of all had personally chosen you to join the team. After so many "retarded" - in his words - he had been forced to accept into the Seven, Homelander saw in you, above all, the opportunity to make up for Firecracker's ridiculous weakness.

When Ashley began talking about your powers, he had no doubt the last spot was yours. It was simply brilliant. Who the hell would have imagined someone would have powers to control a state of matter? You could maneuver fire, generate electrical discharges, disrupt magnetic fields, and damn it, you could split atoms as if slicing butter.

Vought's scientists said they didn't know if it was possible, but you could destroy the damn out of a star one day. Homelander wasn't a science guy, but in one of his moments of boredom, he got curious and did some research. He didn't even know that plasma crap was all that, he thought it was a cell thing or whatever.

He always thought someone with a power as peculiar as yours, and at your age, would be arrogant or just plain dumb. But you were actually the complete opposite. You didn't speak unnecessarily, and while you seemed very aware of your own actions, you had no clue how powerful you were, or perhaps ignored that fact. The blonde thought you were an idiot for it, but he appreciated the inferiority you submitted to, especially in relation to himself.

"I don't have one, sir," you replied to his question, feeling small with everyone looking.

"What the hell?" He continued, focusing on you with incredulous voice, he couldn't believe it. How did someone end up here without even having a superhero suit?

The truth was, you had never been part of any team before, nor had you received any sponsorship during your life, or even attended Godolkin University. The only thing you had were your powers, which were indeed impressive. You never chased after any position, nor were you ever obsessed with being a famous superheroine, but lately you thought it would be a good adventure to radicalize your life. That's when you applied to join the Seven.

"How do you have a name and not have a fucking suit?" He asked, boiling with anger, fists clenching tightly behind his back.

"They gave me a name when I filled out the application," you answered honestly. That day, after they chose to call you Radiance, a random and easily commercial name, you couldn't complain much and didn't want to bother, so you left it at that.

"You'll be introduced as an official member of the Seven tomorrow, how do you not have a suit?" He took his hands off his back, moving them as he spoke to express his confusion, and for a few moments you followed it movement like a child who can't keep their attention on anything for long. "Who's handling your marketing?"

You couldn't answer, so you stayed silent and no one else dared to say a word either. You had no idea who was handling your marketing, not knowing you should even have that. You glanced quickly around the table, perhaps seeking some kind of help for the situation, but everyone looked down when they realized you were staring at them. They were enjoying themselves, and that made you exhale through your nose in embarrassment.

"You know what? Fuck it, doesn't matter." Homelander brought his fingers to his furrowed forehead, letting out a loud sigh as he calmed down. "Just... don't show up like this in public until someone gives you a suit."

"Yes, sir," you replied tensely, relieved that he had resolved the matter.

Sister Sage widened her eyes in relief when she finally saw the superhero sitting beside her. She opened her mouth to begin speaking, as she had intended from the beginning, but when some sound was about to come out of her mouth, Homelander spoke to you again, this time pointing an accusatory finger at you:

"And stop drawing, damn it," he ordered, causing you to slowly drop the pencil on the table, as if caught doing something wrong with the weapon of the crime in hand. You stared at your lap throughout the entire meeting, embarrassed for messing everything up on your first day.

When the meeting ended, you followed most people out of the room, but stopped nearby in one of the hallways. You slid down the wall, crouching in a hidden corner, and lightly tapped the sketchbook against your forehead in annoyance.

"Stupid," you murmured softly to yourself. It was so ridiculous, yet it embarrassed you so much. Maybe this first day wasn't so bad after all. You would have plenty of time to prove your worth to everyone, no need to dwell on this situation. Even though you had been corrected in front of some of the most iconic supers by Homelander himself, this situation could be overcome. It was thinking about it that kept you from letting the burning tears fall.

"I can hear you whining," Homelander voice made you jump to your feet, startled to be caught once again doing something you shouldn't. He didn't seem happy, and his expression was so intimidating that you felt like Mariah Carey performing for a crowd of Eminem fans.

He approached you in slow steps and you held the sketchtebook protectively to your chest, as if that could protect you from something. He glanced down to briefly see the object in your hands and looked at you with disgust.

"If you don't straighten up, I'll kick you out. Got it?" Everything about him exuded threat. Maybe if he weren't so imposing and powerful, that sentence would have sounded a bit like the janitor from your old school scolding you for spending too much time in the bathroom during class.

You were paralyzed standing there and all you could do was a nod. But your gesture made him more aggressive.

"Answer with your mouth. Are you mute or something?" And there he was, hands behind his back again. He seemed to enjoy that pose.

"I won't mess up, sir," you said, swallowing your saliva.

"And get rid of that. Or burn it, do whatever, just get rid of it. And I better not see you with that again," he said referring to your notebook, walking away faster than before. "These kids..." you heard him mutter distantly.

After that happened, you didn't destroy the sketchtebook, but you were afraid of being caught and kept it safely tucked away in the back of a drawer in your room. What the eyes don't see, the heart doesn't feel, right? You mentally made a promise to yourself not to use it anywhere else but here, to avoid causing more trouble.

It's been a week since you've been with the Seven, and several strange things have happened. You quickly realized that Homelander wasn't the pristine and merciful hero everyone believed him to be. But the truth was that deep down you already expected that. Everything about heroes always seemed too perfect and pure, there had to be a catch. Despite everything, you still remained yourself, never intentionally hurting anyone or getting involved in murders and conspiracies.

You were comfortable helping out with some minor crimes that Vought sent you to solve, but by now you suspected that sooner or later Homelander would ask you to do some of his atrocities. It was still hard to think about how to feel about it, but you weren't naive, you were already mentally preparing to submit to it or else be killed.

During that time, as you adjusted and interacted with the team, it didn't go unnoticed by Homelander that you were drawing on your own hand, or on napkins and on random sheets you found lying around, even though you hadn't shown up with your sketchtebook again. This was starting to wear on his last nerve, but he tried to ignore it. As long stayed as you were, without asking too many questions and obedient, he made an effort to continue overlooking your makeshift drawings.

"Meeting's over," the blond suddenly declared, interrupting another of the Seven's weekly gatherings while cutting off The Deep's rambling about his ideas.

"But I haven't even talked about the flying shark yet," he tried to defend himself.

"Shut up," Homelander's voice rang out sternly in the room, issuing a warning that the man promptly obeyed.

"Right. Meeting's over." Ashley nervously moved to gather the portfolios on the new soda advertisement she had come to present, but as soon as she touched the first folder, specifically the A-Train one, the superhero exploded in rage:

"Ashley! Get out!" She immediately dropped the folder in place and hurried out in her heels, unable to run in them. "All of you! Get out of here."

Everyone got up from their chairs, even you, and filed out through the front door, leaving the folders on the table. Sister Sage hesitated, thinking she might be an exception, but when his scowl deepened, she understood she should leave too.

With the room empty, Captain Patria took a few minutes to admire the view from the tower. He enjoyed staring at it sometimes, even when bored.

"Bunch of idiots," he muttered to himself, shaking his head in denial, indignant. If he had to spend one more minute with these morons, he would have a heart attack, even though that was technically impossible for him.

He threw his cape back as he turned to leave, looking down and not focusing on anything in particular. But his eyes caught something different from the other folders. It was obviously yours, with a huge drawing covering the text and images printed on it.

That was the first time he actually saw something you had scribbled. And damn, it was perfect. It was a drawing of everyone in the room, with him in the center looking angry. Just as he was. His ego flared up as he noticed that his figure was more detailed than the others'. You must have started drawing him first, hence had more time to detail him. The idea of you making him the main focus of this particular drawing made his pupils dilate. He used his super hearing to check if anyone else was around and secretly took that sheet for himself.

The next time he saw you drawing in the Seven's room, he couldn't help but wonder if you were drawing him again. As soon as he noticed you sneakily reaching for a pen that belonged to Ashley, he looked in your direction. The noise that used to annoy him now sparked curiosity. And after staring at you for so long, it didn't take long for you to look back at him too. The blond thought you would be embarrassed, like most people, but you just grinned as if you were used to being caught looking. And indeed, you were.

You began drawing Homelander more frequently when you realized he never caught you watching him. It was easier and avoided awkward situations with other people. After two whole weeks of drawing him continuously while taking advantage of this freedom, you felt capable of drawing his face without even needing to see a photo, having memorized most of his distinctive features.

Well, it seems he's finally noticed you.

Sometimes, when alone in your room, you took out your sketchbook and started practicing the memory of his facial features you had developed. Just like every other time, you became absorbed in the drawing, focusing only on the voices around you to understand what was being said. This was also a way to keep yourself engaged during conversations, so you wouldn't get restless from being still while being a mere spectator of everything. After all, you never participated much or gave opinions; Deep already did enough for two.

The meeting had already ended, but you stayed in your chair, even as everyone else left, to finish just a part of the hair. You thought no one would mind, and then you would leave as usual, but a voice caught you by surprise:

"Can I take a look?" Homelander asked, for the first time, using a gentle voice beside you. His expression was enigmatic, somewhat relaxed, and shy at the same time.

You turned the stack of post-it notes, also taken from Ashley, for him to see what you had drawn, fearing what he would say. You weren't ashamed of drawing people, much less of them catching you doing it. You feared because he found your habit annoying.

He observed the drawing, seeing his posture from the side, upright and imposing. He wondered if you drew him exactly as you saw him, or if it was just another caricature of reality, like those Photoshopped pictures spread around. He looked much better than he imagined, though he had that superiority complex that made him see himself as a god.

For a moment, he was offended to see his image stamped on such despicable things as scraps of paper and these damn post-it notes. Your fingerprints were also visible stains, and the paper was slightly wrinkled from his sweat. He had noticed that sometimes you drew calmly, as if you had all the time in the world, and other times it was like drawing on a boat in a storm. Today seemed to be the latter situation.

"Do you like drawing me?" He glanced at you.

"I do," you shrugged. That was the simplest and most truthful answer you could give. "Sorry, I won't do it anymore," you said, thinking he was bothered by it.

"Why?" He ignored your apology.

"You're drawable... I guess," you stared at the table, not understanding the flow of the conversation.

"And what the fuck does that mean?" He asked in a louder voice, turning to face you, obviously confused. "Is this some artistic shit?"

"It's just that you're easy to draw because you have unusual characteristics. It's a good thing," was your answer, and it inflated his chest with narcissistic pride. Unusual, that's what you said, but to him, it was like being called extraordinary.

"Next time you draw me, try using a sketchbook," he said sternly, pretending to reject your work, but deep down, he just didn't want to show that he really liked it. That statement was his way of encouraging you to continue, but at the same time, it was so ironic, considering he got mad at you just when you were drawing him in the sketchtebook that day.

"But you asked me to get rid of mine," you said simply, your voice dwindling with each word of the sentence, not wanting him to find out that you had never thrown it away.

"I'll get you a new one," he said dismissively, taking the entire stack of post-it notes with him, including the drawing, as if you wouldn't notice.

[madness-of-void]

People who play shit on their phone loudly in public (or, say, the tiny ass breakroom at your work) are obnoxious. Not everyone wants to hear your stuff. And it's rude. Doubly so if it's in a pharmacy, personally speaking.

[tothearx]

so i'm not saying my mutuals should make blackout club verses for their muses, but --

[jcmarchi]

Study models how ketamine’s molecular action leads to its effects on the brain

New Post has been published on https://thedigitalinsider.com/study-models-how-ketamines-molecular-action-leads-to-its-effects-on-the-brain/

Study models how ketamine’s molecular action leads to its effects on the brain

Ketamine, a World Health Organization Essential Medicine, is widely used at varying doses for sedation, pain control, general anesthesia, and as a therapy for treatment-resistant depression. While scientists know its target in brain cells and have observed how it affects brain-wide activity, they haven’t known entirely how the two are connected. A new study by a research team spanning four Boston-area institutions uses computational modeling of previously unappreciated physiological details to fill that gap and offer new insights into how ketamine works.

“This modeling work has helped decipher likely mechanisms through which ketamine produces altered arousal states as well as its therapeutic benefits for treating depression,” says co-senior author Emery N. Brown, the Edward Hood Taplin Professor of Computational Neuroscience and Medical Engineering at The Picower Institute for Learning and Memory at MIT, as well as an anesthesiologist at Massachusetts General Hospital and a professor at Harvard Medical School.

The researchers from MIT, Boston University (BU), MGH, and Harvard University say the predictions of their model, published May 20 in Proceedings of the National Academy of Sciences, could help physicians make better use of the drug.

“When physicians understand what’s mechanistically happening when they administer a drug, they can possibly leverage that mechanism and manipulate it,” says study lead author Elie Adam, a research scientist at MIT who will soon join the Harvard Medical School faculty and launch a lab at MGH. “They gain a sense of how to enhance the good effects of the drug and how to mitigate the bad ones.”

Blocking the door

The core advance of the study involved biophysically modeling what happens when ketamine blocks the “NMDA” receptors in the brain’s cortex — the outer layer where key functions such as sensory processing and cognition take place. Blocking the NMDA receptors modulates the release of excitatory neurotransmitter glutamate.

When the neuronal channels (or doorways) regulated by the NMDA receptors open, they typically close slowly (like a doorway with a hydraulic closer that keeps it from slamming), allowing ions to go in and out of neurons, thereby regulating their electrical properties, Adam says. But, the channels of the receptor can be blocked by a molecule. Blocking by magnesium helps to naturally regulate ion flow. Ketamine, however, is an especially effective blocker.

Blocking slows the voltage build-up across the neuron’s membrane that eventually leads a neuron to “spike,” or send an electrochemical message to other neurons. The NMDA doorway becomes unblocked when the voltage gets high. This interdependence between voltage, spiking, and blocking can equip NMDA receptors with faster activity than its slow closing speed might suggest. The team’s model goes further than ones before by representing how ketamine’s blocking and unblocking affect neural activity.

“Physiological details that are usually ignored can sometimes be central to understanding cognitive phenomena,” says co-corresponding author Nancy Kopell, a professor of mathematics at BU. “The dynamics of NMDA receptors have more impact on network dynamics than has previously been appreciated.”

With their model, the scientists simulated how different doses of ketamine affecting NMDA receptors would alter the activity of a model brain network. The simulated network included key neuron types found in the cortex: one excitatory type and two inhibitory types. It distinguishes between “tonic” interneurons that tamp down network activity and “phasic” interneurons that react more to excitatory neurons.

The team’s simulations successfully recapitulated the real brain waves that have been measured via EEG electrodes on the scalp of a human volunteer who received various ketamine doses and the neural spiking that has been measured in similarly treated animals that had implanted electrode arrays. At low doses, ketamine increased brain wave power in the fast gamma frequency range (30-40 Hz). At the higher doses that cause unconsciousness, those gamma waves became periodically interrupted by “down” states where only very slow frequency delta waves occur. This repeated disruption of the higher frequency waves is what can disrupt communication across the cortex enough to disrupt consciousness.

A spectrogram of brain rhythm frequencies over time predicted by the team’s model. After a first, moderate dose of ketamine, gamma brain rhythm power (warmer colors) emerges. Then as the dose increases, the gamma rhythms become periodically interrupted, leaving only very low-frequency waves, and then resume.

Image courtesy of Adam, Kopell, McCarthy, et. al.

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But how? Key findings

Importantly, through simulations, they explained several key mechanisms in the network that would produce exactly these dynamics.

The first prediction is that ketamine can disinhibit network activity by shutting down certain inhibitory interneurons. The modeling shows that natural blocking and unblocking kinetics of NMDA-receptors can let in a small current when neurons are not spiking. Many neurons in the network that are at the right level of excitation would rely on this current to spontaneously spike. But when ketamine impairs the kinetics of the NMDA receptors, it quenches that current, leaving these neurons suppressed. In the model, while ketamine equally impairs all neurons, it is the tonic inhibitory neurons that get shut down because they happen to be at that level of excitation. This releases other neurons, excitatory or inhibitory, from their inhibition allowing them to spike vigorously and leading to ketamine’s excited brain state. The network’s increased excitation can then enable quick unblocking (and reblocking) of the neurons’ NMDA receptors, causing bursts of spiking.

Another prediction is that these bursts become synchronized into the gamma frequency waves seen with ketamine. How? The team found that the phasic inhibitory interneurons become stimulated by lots of input of the neurotransmitter glutamate from the excitatory neurons and vigorously spike, or fire. When they do, they send an inhibitory signal of the neurotransmitter GABA to the excitatory neurons that squelches the excitatory firing, almost like a kindergarten teacher calming down a whole classroom of excited children. That stop signal, which reaches all the excitatory neurons simultaneously, only lasts so long, ends up synchronizing their activity, producing a coordinated gamma brain wave.

A schematic of the brain network model. Tonic Inhibitory neurons (blue) use GABA to inhibit the other neuron types. Pyramidal excitatory neurons stimulate each other and the phasic inhibitory neurons (red), which, in turn, inhibit the excitatory neurons.

Image courtesy of Adam, Kopell, McCarthy, et. al.

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“The finding that an individual synaptic receptor (NMDA) can produce gamma oscillations and that these gamma oscillations can influence network-level gamma was unexpected,” says co-corresponding author Michelle McCarthy, a research assistant professor of math at BU. “This was found only by using a detailed physiological model of the NMDA receptor. This level of physiological detail revealed a gamma time scale not usually associated with an NMDA receptor.”

So what about the periodic down states that emerge at higher, unconsciousness-inducing ketamine doses? In the simulation, the gamma-frequency activity of the excitatory neurons can’t be sustained for too long by the impaired NMDA-receptor kinetics. The excitatory neurons essentially become exhausted under GABA inhibition from the phasic interneurons. That produces the down state. But then, after they have stopped sending glutamate to the phasic interneurons, those cells stop producing their inhibitory GABA signals. That enables the excitatory neurons to recover, starting a cycle anew.

Antidepressant connection?

The model makes another prediction that might help explain how ketamine exerts its antidepressant effects. It suggests that the increased gamma activity of ketamine could entrain gamma activity among neurons expressing a peptide called VIP. This peptide has been found to have health-promoting effects, such as reducing inflammation, that last much longer than ketamine���s effects on NMDA receptors. The research team proposes that the entrainment of these neurons under ketamine could increase the release of the beneficial peptide, as observed when these cells are stimulated in experiments. This also hints at therapeutic features of ketamine that may go beyond antidepressant effects. The research team acknowledges, however, that this connection is speculative and awaits specific experimental validation.

“The understanding that the subcellular details of the NMDA receptor can lead to increased gamma oscillations was the basis for a new theory about how ketamine may work for treating depression,” Kopell says.

Additional co-authors of the study are Marek Kowalski, Oluwaseun Akeju, and Earl K. Miller.

The work was supported by the JPB Foundation; The Picower Institute for Learning and Memory; The Simons Center for The Social Brain; the National Institutes of Health; George J. Elbaum ’59, SM ’63, PhD ’67; Mimi Jensen; Diane B. Greene SM ’78; Mendel Rosenblum; Bill Swanson; and annual donors to the Anesthesia Initiative Fund.