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sw5w · 1 year
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Artoo-Detoo
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STAR WARS EPISODE I: The Phantom Menace 00:25:57
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Blood and Thorns Chapter 17 (Part 1)
Chapter 17 (Part 1): Consequences and Rewards (Read Chapter 1 (part one) here) - (See here for a complete list of chapters)
The authorities were called as soon as Marcus’ gun was shot. Servants ran in to see what the commotion had been to find Sapphire bleeding, Rosalind unconscious, Frigga injured, and Marcus in the centre of it all, shotgun at his feet. The magical light from the floor had faded completely, the chalk circle along with it, so the man’s guilt was easily inferred.
When Razi returned with the household nurse, Sapphire was promptly seen to and did not have lasting damage. She’d collapsed, and she’d need surgery, but she was strong enough to wait in her private chamber for the doctor. Rosalind, however, was immediately taken to the Thorneheart infirmary. Their condition was declining and their breathing was shallow. Once Rosalind was seen to under Marcus’ supervision, Frigga and Razi were also seen by the family nurse, but outside of headaches, some burns, and some stitches, they both were in good shape considering. Soon after, the authorities arrived and they had no choice but to take Marcus away with them. He had been the one to bring the weapon, and he made no attempt to deny it. Razi tried to explain to the guard captain Marcus had saved them and Sapphire had attempted to murder Rosalind, but, with the promise that Rosalind would be properly looked after, Marcus went with them. The family’s physician was brought in immediately and stabilized Rosalind. He also saw to Sapphire and confirmed the family nurse’s diagnosis. She would need surgery to extract the projectile, but would be alright to stay in the bedchamber where the authorities confined her, a guard stationed outside her door. Once she was well enough, she would likely be taken into custody, but until then she would remain under lock and key. Frigga and Razi were questioned. The head of the guard interviewed both of them separately, though Frigga wasn’t much help. The events of the evening were cloudy. She remembered casting the circle with Rosalind and being discovered by her aunt. She remembered being attacked and after that details were foggy. They had succeeded, and Frigga scarcely believed it. She even had her magic intact! But Rosalind said there would still be some effect on her, she just couldn’t figure out what had changed. Razi was not shy with details in her own chat with the guard captain. She remembered quite a lot, which was surprising considering she’d been assailed and knocked out at the beginning of the encounter. But she wasted no time in throwing Sapphire to the dogs, providing graphic and intricate detail about every assault she could recall. Once they were both finished their talks with the captain of the guard, Frigga and Razi sat together in Rosalind’s room, watching as the Thorneheart staff attended to them. They were covered in welts and burns, their neck was bruised, their hands and arms were shredded. “They’ve a cracked rib and arm also,” said the nurse as she finished taking their pulse again. “Likely will need heavy pain medication upon waking which was not at all certain an hour ago.” Frigga stared at Rosalind’s sleeping face as her tears welled up. “I don’t know what I’d have done,” she choked, and Razi gently rubbed the witch’s back in comfort. Frigga sat next to Rosalind and her love stood behind her. The nurse, a young woman with black hair pulled back into a neat bun and an apron that was just a bit stained noted Rosalind’s pulse on her clipboard. “I doubt they’ll be able to talk much either.” “Not that that’ll be much differen’ than usual,” Razi said. “Goldie’s the talker. Prolly talks enough for two.” Frigga peered over at the nurse’s notes. “I wonder how Marcus found out.” “Lucky ‘e did,” Razi replied. “I would’a definitely been next on your ol’ lady’s list. I was just comin’ to when he shot her.” The nurse looked at Razi with a concerned expression. “You were knocked out, right? Did someone look at you?” “Oh, yeah, I got checked.” “The shotgun didn't wake you up?” Frigga asked, looking to her love.
Razi shook her head and then immediately winced, a palm covering her eyes. “Nah, I was about to try an’ get up, but I don’ know how much good I’d’ve been.” A knock at the door announced the physician. “Miss Thorneheart?” he said as Frigga turned to look at him. She tried to stand when he held out his hand, “No, please, sit. You both should be resting too.” He pointedly looked at Razi who did nothing in reply, ignoring his admonishment. “I just needed to let you know that your aunt is stable and will be fine.” “Shame,” Razi muttered, earning the doctor’s obvious disapproval. “Thank you,” Frigga answered with genuine relief. “You said earlier she would need surgery?” “Yes, I’ve booked her in for my first available slot. She’ll be fine until then, I think, but she’s not allowed to move too much. Now, your nurse gave you a look over, but I’d like to double-check.” Frigga submitted to his examination which was certainly more invasive than the nurse’s had been. Lights were shone in her eyes, her head rotated in all kinds of uncomfortable ways, and the cut on her arm was stitched up with practiced easiness. Razi hesitantly submitted to a second examination as well. “You both have mild concussions,” he dryly stated. “But rest and taking it easy should be sufficient. If you notice your symptoms worsening, headache, memory issues, fatigue, et cetera, you can call for me and I’ll come straight back. I’ll need to see you in about a week anyway for those stitches, Miss, and I’ll be back tomorrow when the young Master wakes, but don’t wait if you notice anything amiss with your head.” “Thank you, doctor,” Frigga said as she stifled a yawn. “And thank you for taking care of my aunt and Rosalind.” “Not at all, I’m glad to be at your service,” he replied as he gathered his tools back into his bag. “See you tomorrow, or I guess, later today.” He left the room, shown out by Gertrude. When the door closed, Frigga started sobbing, the weight of the night bearing down on her. Razi immediately wrapped her arms around Frigga who responded by returning the embrace. “Everyone’s fine,” Razi comforted. “You’re fine, I’m fine, Vampire’s fine, we’re gon’ be free soon, Frigg.” Frigga nodded, burying her face in Razi’s chest. “Yes,” she breathed, but still couldn’t let go of the nagging feeling something was wrong. She knew Rosalind was right, something was different but she couldn’t quite put her finger on it. But it could wait. Frigga and Razi were too relieved and exhausted to bother cleaning themselves up too much, or even getting into bed properly. They fell asleep on top of Frigga’s bed still in their clothes, holding each other tightly.
Frigga was stirred the next morning by Doris’ knock at her door. She usually was awake before her breakfast made it to her room, but this morning she found her arms and legs sluggish. She moved to rise but was immediately tugged back down by Razi who was starting to wake as well, and the woman nestled in close. Frigga didn’t have the heart to separate from Razi, but she also needed to help Doris in with the tray. “Raz,” Frigga whispered, “I need to-“ “Nah,” Razi mumbled. “Y’don’ need to do nothin’.” “Eat?” Razi grunted. “I guess tha’s a thing we gotta do, you’re right.” Frigga sleepily giggled. “I have to let Doris in, then.” “S’long as you come back right away.” “I promise,” Frigga murmured, placing a kiss on Razi’s forehead who winced slightly before releasing her captive. Frigga slid from the bed and whined as her head throbbed. She shuffled to her door and opened it, letting Doris in. “Good morning, Doris,” she greeted sleepily. “Just by the bed is fine.” “Oh!” the attendant exclaimed causing Razi to groan and cover her head with a pillow in protest. “Sorry,” she whispered, “I wasn’t aware you had company, Miss Thorneheart.” Frigga doubted that. “Not a problem.” The servant placed the tray on the bedside table and curtsied, though Frigga didn’t miss the glint in her eye. “I’ll go fetch another, if you’d like.” “Yes, please,” Frigga replied as she crawled back onto her bed and gently pried her pillow from Razi’s grip. “And if you can keep the door open a little so I don’t have to get back up, I’d appreciate it. I’m not well, this morning.” “Yes, Miss Thorneheart.” Doris scurried out of the room as quickly as if her skirts hems were on fire. “Congrats,” Razi moaned beside her. “The entire town knows in an hour, two if we’re lucky.” Frigga chuckled as she plucked a bowl of apple slices off the tray to nibble at. Her hands felt heavy and slow, like they weren’t quite getting her commands right away. She was probably just tired. “It’s fine. It’s not important anymore. Here,” she offered Razi an apple slice. Razi took it and ate it in a single bite. “Lemme guess, apples an’ toast?” “And a side of yogurt.” Razi snorted. “Guess they weren’t told I was fired. Tha’s what they usually do when they gotta throw breakfast together in a rush.” She slowly sat up, her eyes screwed closed. Frigga reached a shaking hand to rest at the base of Razi’s head and focused her magic, directing healing energy into it. She didn’t have a lot of energy to spare, but Razi was clearly in a lot of pain this morning. The moan of relief that escaped the woman made the struggle worth it. “Better?” “Yeah, a bit. Still got it, but s’less now,” she mumbled as she stole another apple slice. Razi then leaned over and placed a smiling kiss to Frigga’s shoulder, her hand covering the witch’s playing with Rosalind’s corded crystal that still hung around her neck. “Good mornin’, beautiful.” Doris brought up a second tray a few minutes later as well as a pot of tea large enough for two people to have multiple cups. She set the tray down in front of Razi with a sanitized and entirely too innocent, “I suppose you won’t be working today, Wood?” Razi levelled a tired glare at her but Frigga rescued her. “Razi resigned yesterday, so no.” Her brows quirked but the attendant’s face remained carefully neutral. “Oh, I see. Shall I inform the rest of the staff for you, then?” “Like you need my permission,” Razi replied flatly. “You’ve already blabbed for sure.” Frigga chuckled and rubbed at the hand that was tingling somewhat painfully. “Yes, Doris, if you could inform…” Frigga blanked. She couldn’t for the life of her remember the head of staff’s name. She looked at Razi, her brows knit tightly. “Um, Raz?” Razi looked to the witch with a puzzled frown and watched as Frigga floundered. She seemed to be making a calculation before offering, “Gert?”
“Yes!” Frigga breathed, still unnerved by her sudden amnesia. She looked back at Doris, smiling to conceal her alarm. “Yes, let Gertrude know for us, I’d appreciate it. And I won’t need help dressing this morning.” Doris curtsied again. “Yes, Miss Thorneheart, I’ll come up for your trays in an hour, then.” She left, leaving Razi and Frigga blessedly alone. Frigga looked back at Razi who was looking at her grimly. “What was tha’?” “What?” “You forgot Gert’s name?” Frigga looked away from Razi to hide her embarrassment. “No, I didn’t forget. It just escaped me for a minute.” “Right,” Razi did not sound convinced but continued picking at the tray Doris had brought for her. “Didn’ the doctor say somethin’ ‘bout memory loss?” “He did. Maybe that’s all this is and it’ll go away.” Razi didn’t respond to that, opting instead to turn the conversation to a lighter topic for the remainder of breakfast for which Frigga was grateful. The two of them ate at their leisure, though a bit faster than maybe the would have; Frigga was anxious to check in on Rosalind. The witch finished eating and went to her wardrobe to pick something out. That was new, she usually just put on whatever was chosen for her that day, but now she stared at the wardrobe, unsure what to do. Frigga ran her hands over the options and winced as her headache began screaming again. How do people do this every day? The fabrics all blended together, she tried to remember which dress was which, but, strangely, that knowledge alluded her. Surely she wasn't this inept at dressing herself? Surely she wasn’t this helpless? But as she stood in front of all these options, a haze paralyzed her. She tried, really tried, but she couldn’t pick something. Razi made her way over. “You alright?” she asked, concern evident by the woman’s tone. Frigga shook her head. “Yes, I just… I don’t know, I guess. Maybe I’m still shellshocked from last night.” “Grab somethin’ comfortable, we’re probably not goin’ anywhere today.” Comfort, something Frigga could focus on. She picked a simple, loose-fit blue dress, something she could easily do up herself, even if her hands weren’t co-operating for some reason. She’d worn it a hundred times, it was familiar and comforting. It also had pockets which was nice. The two women brought Frigga’s clothes into her bathroom and started the process of cleaning Frigga up; she was desperate to wash the terror and violence off of her, to feel the water carry away the horror from the night before. The bath was short and pragmatic, but it was still nice to spend time getting clean with Razi. Once bathed, dressed, and wounds re-wrapped, Razi had Frigga sit at her dressing table and stood behind her, running her fingers through the hoard of red curls. “I asked Doris to teach me,” she said. Frigga noticed Razi’s hands moving with more confidence than she had the week previous. Her chest filled with warmth and she relished the feeling of the woman’s hand in her hair. “I’m impressed.” “Don’ be, I’m still not great. But at least I kinda got a better grip on it now.” “At least you know how to take a bath on your own,” Frigga muttered, bitter at how much help she’d needed. “Hey, don’t do tha’,” Razi said with a command that demanded Frigga’s attention. “And besides, I’ll be happy to help you with bath and your curls as much as y’need.” Frigga looked up at her in the mirror. Of course she was used to someone doing her hair but… This felt different, more intimate, Razi’s hands were stronger but less practiced. It warmed Frigga’s heart, reminded her of how her love had taken care of her these last few months. “Thank you, Razi.” Razi tied off the braid and pressed a kiss onto the top of Frigga’s head. “Of course, Princess.” The title was usually for teasing, but there was no teasing today, just fondness.
They went to Razi’s room so she too could briefly wash up and find a change of clothes. While she was changing Frigga noticed the rosewood block from the arcane supply shop on the table by Razi’s armchair. Whatever she was working was small but nowhere near finished. Once Razi was freshened up, the two made their way to see Rosalind, hand in hand. The nurse informed them as they entered the room that the young Head of Household was still unconscious and hadn’t woken up at all in the night. Their bandages had been refreshed and their left arm was wrapped more securely due to the break. Frigga’s heart broke seeing them in such a horrible state, and guilt threatened to overtake her. She took off the corded necklace they’d put on her the night before and slung it over Rosalind’s head to rest on their neck before she sat at their right side and gently took hold of their hand. “Wow.” Razi mumbled taking in the gravity of their condition from her spot standing behind Frigga. “That’s… just, wow.” Frigga nodded, and they sat in silence. The nurse came in once to check in, but there was no sign of change. Eventually there was a distant knock on the home’s front door and Razi went to investigate leaving Frigga alone. She rubbed Rosalind’s hand with her thumb gently and took in a deep breath. How had she gotten off so easily and they had not? It wasn’t fair. She tried to push the guilt down, Rosalind had volunteered and prepared themself for this possibility, she should respect their choice. But it didn’t matter, she had put them in danger, they were suffering because of her. Before she could ruminate further, the door opened. Razi had returned with a guest. Frigga jumped up and rushed to him, meeting him in a warm hug. “Thank you, Marcus, how did you know we needed help last night?” Marcus gave her a quick squeeze before stealing the spot she’d been sitting in and grabbing Rosalind’s hand. He was a mess, his mascara smudged into rings around his eyes and a few streams on his cheeks from tears he hadn’t managed to wipe away. His skin was paler than usual and his eyes darker. “I had a feeling,” he replied with a hoarse voice barely resembling his own, “when your aunt said you were sick. Ros was scared of something yesterday morning too, so when you weren’t at dinner, I figured you guys were doing something. How are they?” Frigga put a hand on Marcus’ shoulder comfortingly. “They’re alright, the doctor says my aunt nearly killed them but, because you showed up, they will recover.” Marcus pressed his forehead to Rosalind’s hand, and a shuddering sigh escaped. “I had to get back, I can’t fucking believe this.” “Thought you were arrested,” Razi questioned as she shoved her hands in pockets. “No, my dad knows the captain and Frigga vouched for me. I did what they wanted but…” He didn’t finish his statement, his voice cracking with the strain of holding back the tears he was obviously fighting. Frigga placed a hand on his shoulder gently. “They’re alright, Marcus. They’re going to be fine.”
Marcus lost his battle and broke into tears, sobbing into Rosalind’s bed and bandaged hand. Cuts and scrapes were mostly dressed but a few of the more superficial ones on finger tips poked out from dressings. Razi and Frigga found other seats and stayed with Marcus for a while. The three were mostly silent, though Marcus asked them for more details about what had happened. The women were pulled away to deal with the authorities again shortly after Marcus arrived, so they left him alone. The nurse or a servant would drop in periodically to check if Rosalind was awake or if Marcus needed something, but nothing changed. At some point he did ask for someone to send his father a note on his behalf, but eventually Marcus drifted off, leaning on the bed. He hadn’t slept all night and, while he was a night owl, he usually followed his late nights with late mornings. But he never let go of Rosalind’s hand.
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govindhtech · 7 months
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MSI Pulse 16 AI C1V: Ultimate AI Gaming Laptop
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Chapter 49: Assembling and Dissembling
Becoming The Mask
Bold italics are trollish.
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There were, Barbara learned, two possible meanings for the word 'troll', depending on the context.
A Brief Recapitulation of Troll Lore, Volume 1 of 47 sat open on the table, along with a dictionary, and a sheet of paper where Jim had written out the trollish alphabet and the phonetic equivalent of each letter's sound in English.
Blinky had offered to teach Barbara to read trollish, so they could set up a book swap. He was intrigued by her medical textbooks. She was keen to learn more about this strange magical world she had found herself tied to. Jim had volunteered to teach Barbara instead, since living together would make it easier to work lessons around Barbara's unfixed schedule.
Trolls had a mostly phonetic alphabet. They didn't seem to use capitalization, but did have accents that appeared around certain words to indicate significance. Jim and Barbara had gotten onto this tangent when she noticed 'troll' was written in two different ways.
There was 'troll' meaning 'a person, a member of the species', which was the kind of troll meant by Jim's title 'Troll-Who-Is-The-Hunter'.
And then there was 'troll', usually prefixed by a tribe name, which meant 'member of the tribe'.
"The pronunciation is the same for both," said Jim. "The second one is probably what most trolls mean when they say Changelings aren't trolls, since we've been disowned and the Gumm-Gumms don't acknowledge us as full tribe members. Up till we get a Familiar we can't exactly pass as being a different species."
"Disowned?" Barbara repeated. No one had mentioned that part when she'd asked where Changelings came from.
(It might explain what Jim had said about not having a name before getting a Familiar, though, if trollish disowning involved stripping the person of their entire name rather than just the family name.)
Jim made an uncertain noise and wiggled his hand. "Sort of disowned, sort of presumed dead. Basically, after we're taken and altered, we can't go back to our first families even if we do find out who they were."
… What?
"I'm going to need you explain all of that. Starting with the –" god, which bit to even start with? "– with the 'taken' part."
"Okay?"
Jim shrugged and turned in his chair to face her more directly.
"So, Gumm-Gumms used to raid other troll communities, and sometimes they would take babies who would then be adopted into the tribe and raised as Gumm-Gumms. That sort of thing's happened with humans, too, right? And after the Gumm-Gumms allied with Pale Lady, they started giving some of those whelps to her, and she'd turn us into Changelings and swear us back into Gumm-Gumm service."
"Who's the Pale Lady? And why babies?" What was it with trolls and stealing babies?!
"Our Creator. You don't just get Changelings naturally; you have to turn a troll into one. It's safer the younger we are but it's still really hard. She's the only one powerful enough to do it."
Jim sighed.
"She disappeared centuries ago. There probably aren't going to be anymore Changelings after my generation."
That didn't exactly sound like a bad thing, from Barbara's perspective. No more kidnapped children, magically mutated to a point where members of their own species hesitated to acknowledge them as being the same species, kidnapping and stealing the faces and lives of other children in order to blend in …
"Anyway," Jim continued, "after a raid, any parents who'd lost their kids would declare them dead, since the Gumm-Gumms were too strong to launch a rescue mission against, and 'my whelp is dead' was easier emotionally – you know, for closure – than dealing with, 'if I ever see my whelp again, it will be as an enemy'. Since we're not old enough to remember our first families clearly, we can't track them down later, and since we're enemy agents by that point, it isn't safe to try."
He hooked an arm over his chair's backrest, which was beside him with the way he was sitting.
"I mean, that doesn't stop everybody, but those stories all end badly."
Barbara felt her breathing get faster and shallower. Oh no. Oh no. Had she – she had – no wonder Jim hesitated to call her 'Mom' anymore – pushing him away like she did must've stomped right on that sense of rejection, that fear of a parent seeing him as an enemy.
"We're getting way off-topic, though," said Jim.
His tone had stayed light and casual the entire time. He turned back to the table and the book and the page of notes.
"So, when 'troll' is spelled with this accent, you can infer that the word right before it is a tribe name, but the tribe names can also appear on their own. They all seem to have this same accent by the first rune," pointing to it. "At first, I thought it translated as a Significant Capital Letter, and it probably does, but it only seems to be used in this context, so it probably means 'this is the name of a tribe'."
+=+
AAARRRGGHH tapped the wall of the tunnel leading into Vendel's workshop, a hollowed-out space just within the Heartstone.
He tried to smile reassuringly at the younglings he and Blinky escorting. Mary and Toby smiled back. Claire and Darci tried, but their smiles looked as strained as AAARRRGGHH's felt. Jim was looking the other way, keeping AAARRRGGHH and Blinky and the humans in his peripheral vision while he watched for anyone else approaching where they were.
"Enter."
Darci had her arms crossed over the book the younglings had been writing, with stories about their families. AAARRRGGHH and Blinky had read it already. AAARRRGGHH didn't think it would sway Vendel on letting more humans know trolls existed, but the humans wanted to try anyway.
AAARRRGGHH was ready to physically carry all five of them back out again if they started pushing Trollmarket's Elder too hard, before Vendel could outright ban further discussion of the matter.
(They didn't have the other Changeling with them this time, so if it came to that point, AAARRRGGHH would be able to put Jim on his shoulders with the rest. Jim seemed protective of his fellow Changelings, so AAARRRGGHH had figured last time that Jim would be more comfortable being carried where he could keep an eye on – Enrique? Not Enrique? – and ensure the smaller one was being well-treated, and AAARRRGGHH didn't think he couldn't keep that strange canopied rolling chair secure on his back.)
Vendel was standing in front of his favourite chair, with a drink and a book on the armrest. Uh-oh. This might not be the best time to start asking favours.
"This is – about – what we asked before," said Mary. "About telling our families where we go, and who we see, here."
"I am still against it," said Vendel flatly.
"We hoping – we hope you will be more – more open to think about it," said Toby, "if you know more about our families. To know they can be trusted. Trusting?"
"Trusted," said Blinky. "You had it right the first time."
The humans would also have to be trusting, to accept that their whelps were safe among trolls, but AAARRRGGHH didn't think this was the right time to say, 'both work'.
"So we made a book," said Darci, holding it out, "with family stories. For you to read. To know them without meeting."
Vendel made no move to take the book.
"It's in trollish," said Claire.
There was another awkward pause.
Claire took the book from Darci and put it on Vendel's workbench.
"Will you read it?" she pressed.
"If I agree to read your book," said Vendel slowly, looking at each youngling in turn, "and once I do, I still refuse to expose trollkind to additional humans, you will accept my decision and cease to push this issue."
It was not so much an offer as a declaration.
AAARRRGGHH probably should've scouted out what Vendel was doing in advance, or something. Or maybe Blinky should've officially set up a meeting. Or AAARRRGGHH should've pulled them all out of there as soon as he realized they were intruding on Vendel's rare leisure time and so Vendel was going into the conversation already irritated.
The humans exchanged looks between themselves. He couldn't read most human expressions easily. AAARRRGGHH could recognize 'distress' from sheer exposure, and there was some of that, but there was something else mixed in as well.
"We accept your terms," said Claire and Darci, not quite overlapping. Claire continued. "If you give our reasoning full consideration and still find it lacking, we will not keep asking for permission."
Vendel picked up the book. "Then I will read it."
"So, to be clear," said Jim, after they left the Heartstone, "when he says 'no', you're just going to tell them without permission."
"Yeah," said Mary easily. Blinky spluttered.
"Just making sure we're all on the same page." Jim's jaw was tense. The lines on his armour pulsed closer to blue than silver. AAARRRGGHH wanted to reach over and pat his back, but Daylight hung there, and AAARRRGGHH had no desire to burn his hand on the magical sword.
Moving slow, so the Changeling could see him coming, AAARRRGGHH nudged Jim's side. Jim veered away.
+=+
"And Jim, stop by my office after school, please," Mr Strickler had said when class ended that morning. It was now afternoon, and Jim was dutifully reporting in.
Stricklander opened his pen to reveal the hidden key, and opened the partition between the mundane and magical sides of his office.
"How does that not mess up everything on your shelves?" Jim asked, gesturing to where the wall had slid away, to be hidden inside a hollow wall on a different story.
"It moves smoothly, and most of my curios have wide bases. I also added a few stability enchantments when I set everything up, in case of earthquakes, and those take care of the rest … Ask Dr Lake if she'd like some around the house, along with those security spells on the tunnel."
Stricklander opened the front panel of a box with an ornate, glowing crystal on the lid. He murmured while stroking the air around the crystal. Jim might have thought it was an incantation to unlock to box if he didn't recognize the crystal as an antramonstrum shell.
"I'm with Nomura," Jim said when Stricklander stopped chanting. "That seems like a risky thing to have in a school."
"It's well-behaved and well-contained," said Stricklander. "And it's not why you're here. You're here for this."
He held a blue stone, faintly glowing, with a colder light than the Amulet gave off. It was shaped like a pyramid with spikes near the point. Jim accepted the crystal and looked at the pyramid's base.
It had a pupil. Hazy, but there. Jim gasped and closed his hand around it. Stricklander did say he had access to …
"The Eye?"
"His Eye."
"It's … still living stone." Definitely not a sphere; were trolls' eyes not eyeballs or was the shape distorted from how it had been cut out of his face? "Can he still see out of it?"
"That would take very specific enchantments, which would need to be planned and cast before the eye was removed."
"… Have you ever done that?"
"No."
Jim stole a tissue from the box on Stricklander's desk to wrap the crystal, got his pencil case out of his sweatshirt's stomach pocket, and zipped Gunmar's Eye inside.
"I'm going to be out of town for a short while," said Stricklander. "The school is under the impression a distant relative of mine has passed on and I'm needed for the reading of the will and so on; nothing so time sensitive I couldn't arrange lesson plans for the substitute, but also something that might drag on unexpectedly."
To a more experienced agent, this might sound condescending, but Jim appreciated when Stricklander explained the reasoning behind his chosen cover stories. It gave Jim a better understanding of how to craft his own.
"The Janus Order will be answerable to Jennifer Smith in my absence. She'll likely continue the lockdown of the main base. I expect to return within two weeks … hopefully having acquired something else of use."
Maybe he has a lead on the Birthstone, Jim thought hopefully.
+=+
The Trollhunter came to Vendel's workroom alone the following night.
"Vendel, Elder of Trollmarket," he greeted.
Vendel braced himself; the last time the Trollhunter had used that stilted, formal tone, Vendel had been presented with a severed head, and the boy seemed honestly surprised not to be praised for such … Gumm-Gumm-ish behaviour.
Vendel had done his best to accommodate him later – it was an important victory, after all – and ensure the rest of Trollmarket would not panic over what their Trollhunter had done.
"I have the first of the Triumbric Stones, the Eye of Gunmar."
At least he had it wrapped in some kind of satchel this time, rather than flaunting the severed body part.
"Blinky said you would know what to do with it."
Vendel considered this. It was a few decades early in the Trollhunter's training, but it would be apropos. He went to a shelf and retrieved a black leather box, which he placed on his worktable.
"The Triumbric Stones, once gathered, must be cleaved. Humans cleave stones to unlock their beauty. I presume you already have some concept of cleaving stones to unlock their power."
"How you groom the Heartstone for healthy growth," said Jim. "Or the body, symbolically." He touched his own arm, indicating where one of Vendel's carvings encircled his bicep. Or did the Changeling have a carving there, too, in his troll form? "Or the body, literally, when a troll is transgender. Glug told us about King Quag. Or like when a troll is made a Changeling."
Vendel scowled at that – that obscene, blasphemous comparison to a sacred skill – but held his tongue.
"I guess that one is more like metamorphosis," Jim added, more quietly. Vendel took it as a peace offering.
"There are exponentially more elements than the humans have yet discovered. Their properties account for much of how magic works. Merlin's Amulet is a relic of unfathomable power. It is said, when he forged it, he made it malleable, so that each Trollhunter could combat dangers that even its creator could not foresee. I have, under my guardianship, a few remaining stones that Trollhunters past have used to unlock their potential."
Vendel opened the box. Jim leaned in, eyes wide and gleaming in the reflected light from the crystals.
"Stones that will grant nimbleness," the Aequati Stone, used by Araknak the Agile to traverse any obstacle;"a glimpse into your enemy's mind," the Omniscien Stone, used by Deya the Deliverer to stop Merlin from being so damned cryptic all the time, according to what she'd told Vendel's father Rundle after returning from her quest to punch the wizard in the face;"even the power to walk in daylight."
"Wait, why isn't that one in the Amulet always?" Jim asked.
"The Umbra Stone is particularly temperamental and difficult to wield. Most Trollhunters do not have time to learn it."
"Shouldn't that one be first priority?"
"The Trollhunter is rarely aboveground during the day." The current one was, but he was an outlier to the pattern in every other respect as well.
"And when they are, they die. Kanjigar might still be alive if he'd had this stone with him." Jim looked away from the stones and up at Vendel. "Give me the Umbra Stone. I will make it part of the Amulet forever. No future Trollhunter will be killed by sunlight then."
Vendel closed the box.
"You should learn to properly cleave a stone before you start altering the Amulet. You do not need the Umbra Stone. Show me the Eye."
Jim glared. For a moment Vendel thought the boy would grab the box and try to steal the Umbra Stone from it, though he'd have to guess which one it was. Instead, Jim opened the satchel he still held, and extracted the Eye of Gunmar from its soft white wrapping. Some of the wrapping tore on the crystal's sharp protrusions.
Vendel put the box away, pretending he didn't notice the Changeling obviously making mental note of where he kept it. He led Jim over to his grindstone and picked up a stone about the size of the Eye with a set of tongs.
"You should be in troll form for this. The subtleties will be easier to observe."
Nothing he had read in human books suggested they had an understanding or interest in stone shaping for purposes other than aesthetics or building construction. Also, Vendel had some idea how squishy humans were – he'd feel less unnerved by a troll standing so close to the grindstone, where chips could fly.
Jim went rigid as stone without actually transforming.
"I don't think that's a good idea."
Vendel rolled his eyes. "Would you prefer to have Blinkous or Aarghaumont present as a chaperone?"
"It's not that I expect you would hurt me," though, from the way he was inching back, he obviously hadn't ruled it out either, "it's more, what if someone else comes in and sees?"
"Without your armour, there would be nothing to see. Trollmarket is highly populated and popular. I doubt you look so unusual that you stand out to a casual glance." Blending in was part of what the Changelings had been designed for, after all. "It would not be the first time I demonstrated proper cleaving techniques to a visiting student."
Jim instead closed the faceplate of his helmet and turned his head to the entrance of Vendel's workroom. The entire suit of armour flashed blue as he did, responding to its wearer's distress.
… No, Vendel realised a moment later, when Jim physically pulled the Amulet from his chest to dismiss the armour. That blue flash had been the Changeling's transformation.
He looked so young.
Too young, in fact – the Battle of Killahead had been just over 400 years ago, and the whelp standing before Vendel now couldn't be even 200 yet –
"How old are you?"
"What? Probably a bit less than 450, why?"
Jim's brow ridges crinkled adorably – a Changeling should not be cute, but whelps were without trying – and then he made a sound of realization.
"Oh – oh, the age distortion. You've never met a 'young Changeling', have you? This is how old my Familiar would be if we never swapped, not how old I am. I'll start aging like a troll again once I hit human adulthood. Or catch up to the age I would've been without the age pause. We don't exactly have ways of testing those theories."
"… This is how young your human friends are, then."
"16 for a human is about 240 for a troll if I've done the math right."
He hadn't – he looked about half that age – although maybe humans had a delayed puberty? That didn't make much sense, for creatures so short lived, but it could happen. If they hit puberty in their second century instead of it marking their first – or, the equivalent thereof – that would at least make Vendel feel better about how ridiculously young the Trollhunter looked, a child should never have been even considered by the Amulet –
"… Should I switch back?" Jim asked, in English. He was wearing a human-like style of clothing, too, Vendel noted, as he started to get over the initial shock and take in more of the boy's appearance.
"No," Vendel decided. He picked the sample stone back up, having dropped it from his tongs when he'd been startled. "This is important for your education and your duties. Watch closely."
Jim was attentive, asking intelligent questions about how Vendel decided which planes to smooth and which angles to cut. Despite the boy's illusion of youth, Vendel felt confident allowing Jim to cleave the Eye himself.
(Stones always worked best for the one who cleaved them, no matter how well they worked for anyone else.)
When the shaping was done, Jim opened the back of the Amulet to insert the new stone, and Vendel saw another stone already in it. He thought for a moment that Jim had stolen the Umbra Stone already.
"What is that?"
"Uh … Remember when you let me bring a Heartstone piece to Draal? When I got it home, I noticed this tiny piece had chipped off. I didn't think he would miss it. I read in one of Blinky's books about Trollhunters putting stones in the Amulet and wanted to try. It lets me summon a knife." Blatantly trying to distract Vendel, Jim asked, "What do you think the Eye will do?"
"It's impossible to know for sure. Properly cut gemstones work in ways one can never predict – only discover."
"There must be patterns. Mineral type? Crystal lattice structure? Colour, age … nutrition?"
"The trollish classification of stones is rather more complex than the human one," said Vendel. "Minute differences in composition or the environment in which the stone develops can result in vast differences between two crystals of the same size and overall type. It is astronomically rare for stones to be identical."
Jim turned into a human again before he summoned his armour.
"I'm going to train and unlock the potential of the Eye. I will be back for the Umbra Stone."
Vendel watched him go, and slowly opened the book the human whelps had given him.
If they were really that young, no wonder they wanted their parents.
Honestly, it was a wonder their parents hadn't wondered where their whelps were wandering off to and beaten down the market door already.
If Vendel wanted to head off a human invasion, he needed to know who he'd be dealing with.
+=+
Previous Chapter (Heartstone pieces? In the Janus Order base? It’s more likely than you think)
Table of Contents
Next Chapter (Various characters grapple with insecurity for various reasons)
So, how about that latest Tales of Arcadia news, eh? Wizards release date, August 7th? Exciting! I'm not expecting it to change much of what's planned for this fic, but I said that about Season 3 and about 3Below, too.
I do know some stuff expected to come up which I want to know for other stories but also plan to ignore for this one: when exactly the Battle of Killahead Bridge took place, when Deya trapped Gunmar in the Darklands.
In this fic, as Vendel says, that happened 400-odd years before the main storyline, in the late 1500s, shortly before the trolls stowed away on the Mayflower in 1620. (And after Angor Rot got his soul ripped out by Morgana in 1297, because why would he need to protect his people from Gunmar if Gunmar was already trapped in the Darklands, huh, novel spin-offs?!)
This was a number I came up with back when I thought trolls only lived 1500-1600 years, based on tweet from Guillermo del Toro; and that Blinky was around 600 years old, as opposed to just having actively studied humans for that amount of time, based on that line about the human dances he's witnessed; and that Draal, obviously younger than Blinky, was either a whelp during the Battle of Killahead Bridge or not born until afterwards (rather than fighting in the battle) and that was a factor in why Kanjigar didn't want him involved in Trollhunting, because Draal was part of the first generation to grow up 'in peace'; and likewise Bular was a whelp during that battle, which was why he was the only Gumm-Gumm not trapped in the Darklands, or he was born after and sent to the surface by Fetch because he was the only one small enough, and either way he was basically raised by the Janus Order; and that trolls had an approximate 15:1 ratio with humans for age, based on the line about bowel control.
However, I have altered troll aging rates a little, based on the idea of Blinky participating in the Battle of Killahead. If he's 600-ish in 2016, that would make him only 200-ish in the late 1500s/early 1600s – which would also, proportionately, be the same age or younger than the humans are. (16x15=240)
So, how to have Vendel be scandalized at how young Jim is when a troll that age is apparently fit for combat? Shuffle the stages of development.
I decided, in this universe, trolls reach their full size a century or so before they actually become adults. So, a mid-adolescent troll would actually be 120, translating in human terms to be about 8 years old – still a child rather than a 'young adult'.
In other lore, I made up the names for the Aequati Stone and the Umbra Stone, based on mangled Latin for 'balancing' and 'shade' respectively. The Omniscein Stone, and Deya going on a quest to punch Merlin for being cryptic, came from the spin-off comic The Felled. 'Omnisceinstone' was all one word in the comic but that doesn't fit the pattern set up by the Aspectus Stone, the only one named on-screen in the show.
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compneuropapers · 4 years
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Interesting Papers for Week 47, 2020
Ensemble perception and focused attention: Two different modes of visual processing to cope with limited capacity. Baek, J., & Chong, S. C. (2020). Psychonomic Bulletin & Review, 27(4), 602–606.
Brain-optimized extraction of complex sound features that drive continuous auditory perception. Berezutskaya, J., Freudenburg, Z. V., Güçlü, U., van Gerven, M. A. J., & Ramsey, N. F. (2020). PLOS Computational Biology, 16(7), e1007992.
Dopamine role in learning and action inference. Bogacz, R. (2020). eLife, 9, e53262.
Towards optogenetic vision restoration with high resolution. Ferrari, U., Deny, S., Sengupta, A., Caplette, R., Trapani, F., Sahel, J.-A., … Marre, O. (2020). PLOS Computational Biology, 16(7), e1007857.
Self-organization of action hierarchy and compositionality by reinforcement learning with recurrent neural networks. Han, D., Doya, K., & Tani, J. (2020). Neural Networks, 129, 149–162.
Electrical coupling controls dimensionality and chaotic firing of inferior olive neurons. Hoang, H., Lang, E. J., Hirata, Y., Tokuda, I. T., Aihara, K., Toyama, K., … Schweighofer, N. (2020). PLOS Computational Biology, 16(7), e1008075.
V1 neurons encode the perceptual compensation of false torsion arising from Listing’s law. Khazali, M. F., Ramezanpour, H., & Thier, P. (2020). Proceedings of the National Academy of Sciences of the United States of America, 117(31), 18799–18809.
Sparse Activity of Hippocampal Adult-Born Neurons during REM Sleep Is Necessary for Memory Consolidation. Kumar, D., Koyanagi, I., Carrier-Ruiz, A., Vergara, P., Srinivasan, S., Sugaya, Y., … Sakaguchi, M. (2020). Neuron, 107(3), 552-565.e10.
An electrophysiological marker of arousal level in humans. Lendner, J. D., Helfrich, R. F., Mander, B. A., Romundstad, L., Lin, J. J., Walker, M. P., … Knight, R. T. (2020). eLife, 9, e55092.
Plasticity and Spontaneous Activity Pulses in Disused Human Brain Circuits. Newbold, D. J., Laumann, T. O., Hoyt, C. R., Hampton, J. M., Montez, D. F., Raut, R. V., … Dosenbach, N. U. F. (2020). Neuron, 107(3), 580-589.e6.
Computational principles of neural adaptation for binaural signal integration. Oess, T., Ernst, M. O., & Neumann, H. (2020). PLOS Computational Biology, 16(7), e1008020.
A circuit model of auditory cortex. Park, Y., & Geffen, M. N. (2020). PLOS Computational Biology, 16(7), e1008016.
The interplay between somatic and dendritic inhibition promotes the emergence and stabilization of place fields. Pedrosa, V., & Clopath, C. (2020). PLOS Computational Biology, 16(7), e1007955.
Arousal Modulates Retinal Output. Schröder, S., Steinmetz, N. A., Krumin, M., Pachitariu, M., Rizzi, M., Lagnado, L., … Carandini, M. (2020). Neuron, 107(3), 487-495.e9.
Depth in convolutional neural networks solves scene segmentation. Seijdel, N., Tsakmakidis, N., de Haan, E. H. F., Bohte, S. M., & Scholte, H. S. (2020). PLOS Computational Biology, 16(7), e1008022.
Estimation of neuron parameters from imperfect observations. Taylor, J. D., Winnall, S., & Nogaret, A. (2020). PLOS Computational Biology, 16(7), e1008053.
Signaling models for dopamine-dependent temporal contiguity in striatal synaptic plasticity. Urakubo, H., Yagishita, S., Kasai, H., & Ishii, S. (2020). PLOS Computational Biology, 16(7), e1008078.
Short-Term Plasticity at Hippocampal Mossy Fiber Synapses Is Induced by Natural Activity Patterns and Associated with Vesicle Pool Engram Formation. Vandael, D., Borges-Merjane, C., Zhang, X., & Jonas, P. (2020). Neuron, 107(3), 509-521.e7.
The location of the axon initial segment affects the bandwidth of spike initiation dynamics. Verbist, C., Müller, M. G., Mansvelder, H. D., Legenstein, R., & Giugliano, M. (2020). PLOS Computational Biology, 16(7), e1008087.
The perceived present: What is it, and what is it there for? White, P. A. (2020). Psychonomic Bulletin & Review, 27(4), 583–601.
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dj-funky · 4 years
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Best Dj Speakers Expert Review In 2020
Best Dj Speakers Expert Review In 2020
With the right cartridge the Rega Planar three presents an thrilling, enjoyable sound, whereas additionally looking nice and simply being an entire blast to use. Cygolite publishes claimed lumen counts just for its brightest settings.
In an e mail, Cygolite marketing director Andrew Ibanez explained to us you could infer the brightness of different settings by evaluating the estimated run times.
The newer Light & Motion Vya Switch feels prefer it was made in direct response to some of our nitpicks about the unique. You can now swap it through three modes—high erratic pulse (six-hour battery life), low erratic pulse , and a steady-on mode —and off.
Tomshine 60w Moving Head Lights
best dj lights 2020 It has a multi-function controller included that plays sound and has volume management buttons, too. Each automotive sits at 11-inches lengthy, and it’s made of robust plastic that’s plastered with purple and green Christmasy paint.
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Rega has made turntables for over forty years, and was the primary to develop the light-weight plinth or base that's now seen in most modern turntables. Even at $1,000 the Planar three solely sits in the midst of the company's range,
however it's arguably the best worth. It's also a thing of elegance, with a simple to set up design and the gorgeous (should you're into that sort of thing) RB330 tonearm. If you are a tweaker you possibly can customise almost every part with a big selection of third-get together upgrades.
Our testers additionally contemplate each unit as a worth proposition—whether or not a product justifies its price tag, and the way it compares to competitive merchandise.
All of the fashions we reviewed were purchased by Lifewire; not one of the evaluate units have been furnished by the producer or retailer. The Kiyo is optimized for use with the Streamlabs suite of streaming software and can also be suitable with OBS and XSplit.
The hinge stand lets you mount the webcam on either your pc monitor or on a tripod and allows you to customise your streaming setup. The constructed-in microphone captures your voice for crisp, clear audio during recreation and Discord chat.
Small and lightweight, the BD310 measures 5.1 x 2.four x 0.6 inches and weighs 5.4 ounces, meaning that it could live in your car's glove field. The Pro 5210 scanner’s 2.eight-inch colour screen is bright and its slender and lengthy side ratio means it could possibly squeeze in additional automotive particulars, from fault codes to live information to a pre-inspection examine.
Its LED lights glow purple for a everlasting fault, yellow for an intermittent fault and inexperienced for no issues. Our professional reviewers and editors consider webcams primarily based on design, video quality, performance, and features.
We test their actual-life efficiency in actual use instances, in video chat apps, streaming services, and for dedicated recordings and taking stills.
While they're now not very popular as a result of presence of smartphones, compact digital cameras nonetheless have advantages over smartphones. They provide higher zoom capabilities, with many merchandise featuring superior optical zoom for higher close-up shots.
Having a devoted gadget for taking photos and movies also saves your smartphone’s battery, which is important throughout extended out of doors journeys.
But if you're a kind of who has but to adopt the custom of putting a train under the tree, we have you lined with our list of the highest 10 best Christmas practice sets in 2018. The list above features all kinds of underneath the tree trains in each worth vary, so have a look.
With its padded case, lifetime software program upgrades and one of many longest OBD cables, the NX501 is likely one of the best OBD2 scanners for the money.
Despite its gentle rubber bumpers, the AL539 is pretty compact and lightweight at 6.7 x three.6 x 1.4 inches and 10.6 ounces. It has a unique pull-out leg so the system can stand by itself, as well as a beneficiant fifty eight-inch cable. Its bright, 2.eight-inch colour display has icons for major capabilities and a simple-to-follow, eight-key interface.
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perksofwifi · 5 years
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Want to Help Self-Driving Cars Drive Better? Give ‘Em a Better Feel for Their Tires
The modern automobile is getting pretty clever when it comes to stopping. Far from Fred Flintstone digging his heels into the ground beneath his rock car, today’s braking systems benefit from anti-lock tech that can rapidly pulse the brakes to avoid locking an individual tire and sliding, automated emergency braking that will apply the stoppers for you to prevent a collision, and cruise control systems using GPS data to slow your car to the appropriate speed for an upcoming bend. There is, however, one glaring blind spot all of these tricks share.
All of those fancy braking systems assume the tires are brand-new and delivering maximum grip. Given how your tires are only new once, and briefly, that means for most of the useful life of your tires—and beyond—your vehicle’s electronic safety nets aren’t taking that rubber’s wear into account. That’s okay, for the most part, because you, the human driver, can pick up the slack, sensing through the brake pedal when grip is reduced and driving accordingly, just as you might when driving in snow or other reduced-grip conditions.
Unaccounted-for tire wear becomes a potentially larger issue when it comes to autonomous cars and automated braking systems, such as the emergency auto-braking feature we’ve already mentioned. Theoretically, each time a self-driving car goes for maximum braking power, it’ll rediscover worn tires, since there’s no feedback loop beyond a car’s wheel-speed sensors (the ones that inform anti-lock braking systems and stability control when a tire is locking up or sliding) to reveal grip deficiencies. Put another way, unaware that its tires aren’t new, a self-driving car might misjudge an emergency braking scenario, braking later than it should because it assumes the tires are ready to give their all when in reality, they are half worn.
Bridgestone’s solution to the future self-driving car’s assumed-forever-new tire problem is a small, quarter-size Smart Strain Sensor mounted on the inside of the contact patch of its tires. This widget measures tire strain as a percentage of the tire’s deformation, and Bridgestone claims that, unlike older accelerometer-based measurement of the same deformation, its new sensors work even at speeds below 25 mph and when the vehicle is stationary. (This low-speed performance is critical for autonomous vehicles, many of which are, in the near term, expected to be low-speed urban dwellers.) The sensor’s data is fed into an algorithm that is used to infer tire wear and load, information that’s then sent to the vehicle’s electronic braking systems to adjust their behavior accordingly.
Note that the strain sensor tech is designed to work with traditional pneumatic tires, not the re-treadable airless tires Bridgestone also showcased at the 2020 Consumer Electronics Show. Bridgestone clearly sees our self-driving future automobiles as still relying on current tire tech, at least within the next couple of years. And the Smart Strain Sensors even help human-driven cars—after all, less skilled or tire-aware drivers could also benefit from having their cars’ electronic brains adjusting braking force and such to adapt to worn tires. Another target audience? Cross-country trucking fleets, which could benefit from real-time tire-wear data, both for onboard systems and replacement interval tracking. We’d love to see Smart Strain tech used in some kind of futuristic self-driving-car racing series, where they could help the computer-driven vehicles consistently reach and hang onto their absolute grip limits. Wouldn’t that be something?
The post Want to Help Self-Driving Cars Drive Better? Give ‘Em a Better Feel for Their Tires appeared first on MotorTrend.
https://www.motortrend.com/news/bridgestone-smart-strain-sensor-tire-wear-autonomous/ visto antes em https://www.motortrend.com
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abbkineeu · 6 years
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New Post has been published on Biotech Advisers
New Post has been published on http://www.bioadvisers.com/targeted-neurotechnology-restores-walking-humans-spinal-cord-injury/
Targeted neurotechnology restores walking in humans with spinal cord injury
Content introduction:
TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle
Targeted neurotechnology restores walking in humans with spinal cord injury
DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Shared and distinct transcriptomic cell types across neocortical areas
De novo NAD+ synthesis enhances mitochondrial function and improves health
1. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here Thomas O. Vogler at University of Colorado in Boulder, USA and his colleagues show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which they call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.
Read more, please click https://www.nature.com/articles/s41586-018-0665-2
2. Targeted neurotechnology restores walking in humans with spinal cord injury Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here Fabien B. Wagner at Swiss Federal Institute of Technology (EPFL) in Lausanne, Switzerland and his colleagues introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, they delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.
Read more, please click https://www.nature.com/articles/s41586-018-0649-2
3. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, Yizhou Joseph He at Harvard Medical School in Boston, USA and his colleagues identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, they infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.
Read more, please click https://www.nature.com/articles/s41586-018-0670-5 4. Shared and distinct transcriptomic cell types across neocortical areas The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here Bosiljka Tasic at Allen Institute for Brain Science in Seattle, USA and his colleagues analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. They define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, they match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Their study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.
Read more, please click https://www.nature.com/articles/s41586-018-0654-5
5. De novo NAD+ synthesis enhances mitochondrial function and improves health Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here Elena Katsyuba at École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland and his colleagues show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. They also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, they identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.
Read more, please click https://www.nature.com/articles/s41586-018-0645-6
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bioadvisers · 6 years
Text
Bioadvisers shared on Biotech Advisers
Targeted neurotechnology restores walking in humans with spinal cord injury
Content introduction:
TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle
Targeted neurotechnology restores walking in humans with spinal cord injury
DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Shared and distinct transcriptomic cell types across neocortical areas
De novo NAD+ synthesis enhances mitochondrial function and improves health
1. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here Thomas O. Vogler at University of Colorado in Boulder, USA and his colleagues show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which they call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.
Read more, please click https://www.nature.com/articles/s41586-018-0665-2
2. Targeted neurotechnology restores walking in humans with spinal cord injury Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here Fabien B. Wagner at Swiss Federal Institute of Technology (EPFL) in Lausanne, Switzerland and his colleagues introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, they delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.
Read more, please click https://www.nature.com/articles/s41586-018-0649-2
3. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, Yizhou Joseph He at Harvard Medical School in Boston, USA and his colleagues identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, they infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.
Read more, please click https://www.nature.com/articles/s41586-018-0670-5 4. Shared and distinct transcriptomic cell types across neocortical areas The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here Bosiljka Tasic at Allen Institute for Brain Science in Seattle, USA and his colleagues analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. They define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, they match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Their study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.
Read more, please click https://www.nature.com/articles/s41586-018-0654-5
5. De novo NAD+ synthesis enhances mitochondrial function and improves health Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here Elena Katsyuba at École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland and his colleagues show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. They also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, they identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.
Read more, please click https://www.nature.com/articles/s41586-018-0645-6
0 notes
abbkine · 6 years
Text
BioAdvisers said on Biotech Advisers
Targeted neurotechnology restores walking in humans with spinal cord injury
Content introduction:
TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle
Targeted neurotechnology restores walking in humans with spinal cord injury
DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Shared and distinct transcriptomic cell types across neocortical areas
De novo NAD+ synthesis enhances mitochondrial function and improves health
1. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here Thomas O. Vogler at University of Colorado in Boulder, USA and his colleagues show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which they call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.
Read more, please click https://www.nature.com/articles/s41586-018-0665-2
2. Targeted neurotechnology restores walking in humans with spinal cord injury Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here Fabien B. Wagner at Swiss Federal Institute of Technology (EPFL) in Lausanne, Switzerland and his colleagues introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, they delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.
Read more, please click https://www.nature.com/articles/s41586-018-0649-2
3. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, Yizhou Joseph He at Harvard Medical School in Boston, USA and his colleagues identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, they infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.
Read more, please click https://www.nature.com/articles/s41586-018-0670-5 4. Shared and distinct transcriptomic cell types across neocortical areas The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here Bosiljka Tasic at Allen Institute for Brain Science in Seattle, USA and his colleagues analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. They define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, they match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Their study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.
Read more, please click https://www.nature.com/articles/s41586-018-0654-5
5. De novo NAD+ synthesis enhances mitochondrial function and improves health Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here Elena Katsyuba at École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland and his colleagues show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. They also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, they identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.
Read more, please click https://www.nature.com/articles/s41586-018-0645-6
0 notes
symphonysouth-blog · 6 years
Text
School of Symphony: Music School In Delhi,Learn Guitar In Lajpat Nagar
Music School In Delhi Guitar, apart from being such a fascinating musical instrument, shows a path which when followed can lead to an ocean of benefits in the process of learning to play it. Some of these benefits which makes the guitar one of the best musical instrument are:
1.       The Release of Stress: Embedded with a series of responsibilities, the brain is always engaged and needs some relaxation. The music itself gives a great relief to the human brain but, the sound of the strings of the guitar has a soothing effect of some different level on the mind.
 2.       A way to a Healthy Heart: It has been evident from several studies that while playing the guitar, human heart rate is equivalent to that of jogging. Also, the guitar can be practised for some prolonged hours but can jogging can’t be done continuously. It is also the result of the stress levels, as they lower down, the pulse rate and the blood pressure stabilize.
 3.       A Perfect Hobby: It proves to be a perfect hobby for life. In addition to being your hobby, it does make you look cool and have a positive impact on others. So, it’s a hobby that doesn’t require much arrangement, just you and the guitar making a perfect combination.
 4.       A feel of Happiness: The sound imparted by the guitar has a soothing effect on our minds. As the brain is stress-free, it results in the release of happy hormones in the body. By the time, one learns the art, he/she becomes a changed and happier person.
 5.       Mental Fitness:
It has been inferred from several studies that performing together results in connecting with people as the events lead to the synchronization of the brainwave. As we learn new songs, actually new neurons are being developed which helps in making the person mentally fit.
 6.       A feel of a Superstar:
One loves to grab all the attention at a party or a function with the acquired knowledge of playing the guitar. A platform to showcase the talent acquired definitely makes you feel like a superstar.
All these benefits definitely make the guitar as the best musical instrument. So, to learn this art One might search for different Guitar classes and schools. In South Delhi and that too at the Lajpat Nagar, there is an abundance of Guitar Classes In Delhi. One can easily get registered and learn all the required basics and master the art. With flexible timings and only a few weekday classes make the mall the more relevant for the people really interested to learn to play the guitar. Vocals Classes In South Delhi
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naivelocus · 8 years
Text
Expanding the structural biology toolbox with single-molecule holography [Applied Physical Sciences]
Expanding the structural biology toolbox with single-molecule holography
The discovery of the double-helical structure of DNA is generally considered to be the milestone discovery that led to the birth of molecular biology. Since then, the impact of structural studies on all aspects of biology, from the understanding of basic cellular processes to the development of drugs and vaccines, can hardly be overestimated (1).
Classically, the methodological pillars of structural biology have been crystallography, NMR, and electron microscopy. In crystallography, the X-ray diffraction patterns generated by single crystals are used to obtain electron densities that are interpreted to locate the atomic positions in 3D space (2) (Fig. 1A). Synchrotron radiation coupled to the ever-improving detector instrumentation has been a major transforming technology that now makes it possible to determine the atomic structures of multi-megadalton complexes (3). The implementation of X-ray free-electron lasers that generate very bright X-ray pulses is moving the experiments toward time-resolved structural studies with submicrometer crystals and ultra-short exposures (4). Nevertheless, crystallization remains a challenge because it can sometimes be extremely difficult, if not impossible, given the intrinsically flexible nature and limited stability of biological macromolecules. NMR spectroscopy bypasses this hurdle by interrogating the sample in solution. Here, the macromolecular spectral properties are used to infer sets of restraints that are used to computationally derive atomic models that best fit the data. Thus, NMR does not really “see” the macromolecule under investigation. Rather, it provides the information to reconstitute its atomic structure. With the advent of high-frequency magnets and powerful computational methods, it has become viable to solve macromolecular structures of up to 100 kDa (5). The big plus of NMR stems from its capacity to probe the dynamics of the macromolecule in solution, a feature that is truly characteristic of the method (6). Electron microscopy is a relatively old technique that has classically been …
↵1To whom correspondence may be addressed. Email: federico.forneris{at}unipv.it or andrea.mattevi{at}unipv.it.
— PNAS
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Text
Focusing light with a flame lens
Focusing light with a flame lens The lens is a well understood optical component used for focusing light, but is mont blanc pens almost exclusively made in the solid state form and, thus, suffers from optical damage at high powers. Attempts to overcome this through the use of non solid graded index media for lensing, for example, heated gasses, have found limited application owing to their long focal lengths. Here we describe the first flame lens, which produces a sharp focus with very little stray light and has a fourfold increase in focal power per unit length over previous gas lenses. Such gas devices remain topical due to their inherent ability to deliver high power laser beams: our flame lens has a 'damage' threshold that is several orders of magnitude higher than that of most conventional lenses and is immediately repaired after damage for reuse, and thus will be of use in focusing high irradiance laser beams. Gas lenses using air to focus light were invented several decades ago1, 2, 3, 4 and later applied in a range of demonstrations, including laser drilling5, the generation of plasmas6 and telescopy7. All gas lenses rely on the production of a refractive index gradient to focus or defocus natural or laser light propagating through the lens, usually along some axis of symmetry. The gradient can be generated either by heating the walls of a long tube1, 2 or by colliding shock waves in air8. Further control and stabilization of the gradient can be maintained by rotation, as in the spinning pipe gas lens5, 9. Unfortunately, such devices have suffered from intrinsic aperture limitations; they are cumbersome and they require complex power supplies or moving parts, and have been optically weak owing to their low refractive index gradients. There has also been interest in the optics of flames10, where the passive optical properties of flames have long been used in spectroscopy10, 11, 12, 13, and flames have been used to line focus laser light14, 15, 16. Optical devices based on gases and flames have the advantage of a high damage threshold. Although conventional lenses are susceptible to optical damage, a known limitation in advancement of high power laser systems in the petawatt regimes and beyond, gases and plasmas have very high breakdown thresholds17 of the order of 1013Wcm2 and 1017Wcm2, respectively, and thus flames offer several orders of magnitude increase in damage threshold over conventional solid state optical components, which damages at levels of 109Wcm2 for coated elements and 1012Wcm2 for polished substrates18, 19. To date, no studies have taken this concept further to create high damage threshold lens. In this study we outline the concept of a flame lens, demonstrate it experimentally and perform a full computational fluid dynamics (CFDs) model to validate the concept theoretically. We demonstrate the efficacy of the lens in two proof of principle experiments: the first verifying the ability to image a highly chromatic object and the second illustrating the focal quality of the lens in creating circular holes laser drilled in plastic targets. We show that our flame lens produces a sharp focus by gas lens standards and is four times stronger per lens unit length than a conventional gas lens. Unlike previous gas lens devices, the flame lens has no moving parts or electrical circuits, nor does it suffer from aperture restrictions. The composite flame lensOur composite flame lens (Fig. 1) consists of a short (5cm) tubular gas lens (Fig. 1a) with an aperture of 10mm, followed by a spiral flame lens (Fig 1b) of length 2.5cm. The stainless steel of both lenses is heated to 400C (almost 'red hot'). The drawn air tubular lens is a conventional hot air lens, which works by aspiring cold atmospheric air down the tube. It is known5 that such lenses must have an aperture of less than 7mm, a radial temperature difference of less than 100C and a length between 30cm and 1m. A short, large aperture lens only refracts the outer rays to produce a ring focus; so this drawn air lens would not point focus on its own. We introduce a second lens, the spiral flame lens, which acts mainly on the inner rays to form the composite lens (Fig. 1b). In the spiral or vortex flame lens, a single oxyacetylene or propane pencil flame is injected into an 11 mm diameter cylinder, so that it spirals along the 2.5 cm long flame tube (Fig. 1c), generating a visible luminous cylindrical sheath (Fig 1d). This sheath establishes the required refractive index gradient for lensing. Evidently, the very high temperature of the flame creates a much steeper temperature and refractive index gradient than in a conventional gas lens. However, as will be shown later, there is significant stray light around the focal spot as well as a ring of non refracted peripheral light. By adding the tubular lens to the spiral flame lens so that the two fit tightly together (Fig. 1b), it is possible to eliminate both the stray light and the unfocused ring. , where r is the thickness of the warm air sheath and leff is the effective length of the lens, which is a parameter of order half the actual length and which depends on the air flow (in conventional gas lenses the effective length is the actual length reduced by the distance needed to establish a gradient21, 22). For our experimental conditions (Tw400C, r3mm and leff2.5cm), the divergence of the rays is 1mrad. For rays starting at r=4mm, the radial displacement after 2.5m is 3mm. We thus see that the flame lens need hardly refract these rays for them to arrive nonetheless in the focal region. This general behaviour of the drawn air tubular lens has been confirmed by running a preheated flame lens on pure oxygen and no flame. For the spiral flame lens we make the following assumptions. First, the temperature coefficient (TwT0)/Tw0.8, as the wall temperature is now the flame temperature and is very high (Tw1300K). Second, from simulations and experiments we know that the effective tube radius is reduced to about 3.5mm to take the existence of the non refracting peripheral flame into account (see, for example, the dark core of the flame lens in Fig. 1d). And lastly, the effective length is half of the 2.5 cm real length, because the pitch of the flame spiral is at 45, reducing its refractive effects. With these assumptions we find f2m, a four times increase in focal power per unit length over conventional gas lenses. Computational modelA CFD model of the lens was developed to allow predictions of the density and temperature of the air in the flame lens as a function of axial and radial position, and time. We modelled a stainless steel lens housing of length 75mm (50mm for the tubular lens component and 25mm for the flame lens component), and with inner and outer diameters cheap jordan shoes of 10mm and 11mm, respectively. The model consisted of two phases: a fluid phase (air represented with 274,682 computational cells) and a solid http://www.partydressuk.com phase (carbon steel represented with 79,323 computational cells). The pressure and density of the air were allowed to change in accordance with the ideal gas law, and the temperature of the steel was allowed to change through the process of conjugate heat transfer. The calculated density, temperature and gas velocity distributions are shown in Fig. 2 for four cross sectional positions in the flame lens. The physical structure of the lens is shown as a light grey outline. Near the centre of the lens, the density and temperature (and, hence, refractive index) variation is approximately symmetric, but changes over the length of the lens due to the nature of the vortex flame. In Fig. 3 we show the density, temperature and gas velocity a few seconds after the flame is injected in the lens. The temperature cross section along the length of the flame lens shows that near the exit of the pipe the temperature distribution is rather complicated and not symmetric about the beam axis, which is parallel to the pipe walls. This accounts for the majority of the aberrations introduced to the laser beam. Although the phase profile shown in Fig. 4a have higher order aberrations, the predominant contribution is defocused, giving rise to the approximately parabolic refractive index profile as shown in Fig. 4b. Flame lens performanceExperimental results confirm the concept and theoretical analysis. A Helium Neon laser beam was transmitted through the flame lens and it formed a visual point focus at a distance of about 2.5m, in good agreement with the predicted value of 2m. The focal spot had a central peak of radius w=0.460.06mm only a few times diffraction limited (Fig. 4d). A movie of the changing focal spot due to imperfections in the entry angle of the flame is shown in Supplementary Movie 1. The measured phase of the laser beam on exiting the flame lens was used to compute the cumulative phase change due to the lens (Fig. 4c) and the experimentally inferred refractive index gradient (Fig. 4b). The refractive index profiles of the CFD and experimental data match well, with parabolic coefficients (from equation (3)) given by 2=3.6 10 6mm 2 and by 2=3.2 10 6mm 2, respectively. From the experimental data, the focal length of the lens was inferred (equation (5)) to be f=2.40.5m, corroborating the aforementioned analysis, whereas the focal length as calculated from the CFD data was found to be f=2.2m. There is good quantitative agreement between the CFD model predictions and the experimental data; it is expected that the agreement would improve if the initial conditions of the flame were known more precisely, for example, the precise injection angle, velocity and temperature of the flame. Two high power focusing experiments were performed to demonstrate the ability of the lens to withstand high peak powers. In the first experiment, a pulsed Nd:YAG laser was used to successfully drill a hole in a plastic target (Fig. 5). cheap jordans With the flame turned off, the laser beam makes a barely perceptible sound as each unfocused pulse illuminates the plastic. The moment the flame is ignited loud 'cracks' are audible and a bright plasma plume appears. Varying the flame intensity and its entry level into the lens changes its strength. Such varifocal behaviour may be useful in, for example, maintaining a focus on a moving target or machining high aspect ratio materials. In the second experiment, a high irradiance Ti:Sapphire laser pulse was focused using the flame lens. The initial expanded spot entering the lens had a peak irradiance of 1010Wcm2 and could be increased to 1016Wcm2 by prior focusing. An important aspect of the flame lens is its ability to withstand high laser intensities. The laser spot was focused into the flame lens and the breakdown threshold recorded both for the air and the flame regions. Breakdown was observed for values of the order of 1013Wcm2 for both; when the same spot was focused into the hottest and most intense part of the flame, no breakdown was observed even at significantly higher peak intensities. Finally, a proof of principle experiment demonstrated the imaging properties of the flame lens. We present here the first image by a flame lens. Figure 6a shows the illumination due to some seventy light emitting diodes (LEDs) forming a blurry image of Africa through the switched off flame lens. When the lens was ignited, an in focus picture of the object was formed (Fig 6b). A notable point is that all the LEDs are focused in the same degree, corresponding to a field of view of some 70 mrad, or over 3. Another way of explaining why the combination flame lens is a considerable improvement on either a hot drawn air lens or a spiral flame lens comes from comparison with other gas and flame experiments. The important point is that the central part of any flame is a poor refractor. Previous experiments16 in which pencil beams were made to traverse a flat flame showed that the strongest refraction occurs at the flame front, followed by weakening refraction, as the pencil beam moves out of the flame's luminous sheath. This explains mold components why only the light traversing the central regions of the spiral flame lens is refracted and not the peripheral. The second way of explaining the spiral flame's behaviour is to consider the spiral flame as a curved version of the flat flames. The gradually decreasing refraction with increasing distance from the flame (that is, decreasing flame lens radius) focuses laser light exactly as in a converging solid state lens. An interesting experimental observation is that the composite lens also works well at strong inclination, for example, at 45. Once heated, one may even dispense with the flame: convection currents maintain the focusing for several minutes until the metal cools. This is because a heated inclined tube (with no gas injection) generates the same funnel as found in the horizontal version. One of the key motivations for considering such lenses is their high damage threshold. Our results are consistent with reported values of gas and plasma breakdown, which indicate that the flame lens would have a damage threshold approximately three orders of magnitude higher than conventional coated optics17. Indeed, a proposal to circumvent optical damage in high irradiance amplifying systems has recently been mooted: to replace metre scale beams with millimetre diameter plasmas through Raman amplification23. Laser damage in solid state optics is of course permanent, and in many cases when the optics are not damaged the time frame for the cooling of the optics can run into hours. In contrast, should the damage threshold in the flame lens be exceeded, the lens recovers from this in microsecond time scales virtually instantaneously in the context of most high power laser experiments. A present disadvantage of the flame lens is the relatively high aberrations, as noted from the distorted focused beam in Fig. 4d and quantified in Fig. 7. The CFD model predicts cones of cold, as well as exiting plumes of hot air from the flame lens. The cones are obvious focusing elements albeit imperfect as they are far from parabolic, whereas the plumes account for further aberration (described in Fig. 7 as Zernike aberrations). This suggests a route to improving the optical performance of the lens, through aerodynamically engineering the lens structure to minimize the impact of the exit plume on the propagating light, for example, by diverting the flume away from the optical path. In conclusion, we have demonstrated a novel method of employing flames to make a virtually damage free lens for high power laser applications. It is possible to progress from this first proof of concept flame lens to larger http://www.upsmould.com aperture or shorter focal length devices of higher optical quality, for example, by increasing the length and operating at higher pressures. Petawatt lasers are demonstrating potential applications in, for example, medicine and fast ignition of fusion targets, but on a single pulse basis. Repetitively, pulsed petawatt lasers will present damage challenges for conventional optics, but not for a flame lens. The flame lens has none of the aforementioned disadvantages of conventional optics, is inexpensive and is a major improvement on all previous gas lens designs it has no moving parts, no electrical contacts and shows a fourfold performance improvement. This bodes well for the flame lens as a future technology if the present prototype is carefully re engineered for optical quality. Laser experimentsA Helium Neon laser (Thor Labs) was used for the low power experiments and the focal spot recorded with a CCD camera (Spiricon Inc.). The drilling experiment was performed with a Q switched Nd:YAG laser (Spectra Physics) and was operated at 300mJ per pulse, with a pulse length (full width at half maximum) of 20ns. The high irradiance damage and focusing test was done with a mode locked Ti:Sapphire laser (Clark MXR), amplified to pulse energies of up to 1mJ at a repetition rate of 1,000Hz, with a pulse width (full width at half maximum) of 150fs at a wavelength of 775nm. Aberration measurementWe used the Zernike basis for describing optical aberrations, in which a set of Zernike polynomials is defined on a unit circle, with the magnitude of the weighting coefficients signifying how much each aberration contributes to the overall wavefront variance24, 25. We made use of the laser beam quality factor, M2, as our measurable, as it is invariant for propagation through an aberration free system, but increases with optical aberrations other than piston, tilt and defocus26. This allowed us to separate the lensing action from the impact of aberrations. In our experiments a beam from a Helium Neon laser was expanded to a 3.28mm 1/e2 radius beam, attenuated through neutral density filters, and then steered into the flame lens. The wavefront of the exit beam was measured with a Shack Hartmann wavefront sensor (Wavefront Sciences, model CLAS 2D), with a 69 69 lenslet array, placed 91cm from the exit face of the tube to protect the sensor from heat damage. A reference wavefront (with no flame lensing) was subtracted from all further wavefront measurements. The experiment was repeated 24 times to gather lensing statistics and to test repeatability. A Zernike aperture radius of 3.41mm was applied throughout the experiment. Numerical simulationsThe flame lens was modelled using commercial CFD code (StarCCM+) to solve the Reynolds averaged Navier Stokes equations numerically, using a finite volume approach. This approach required the generation of a mesh representing the physical domain to enable the conversion of the partial differential Navier Stokes equations to a set of algebraic equations. The mesh consisted predominantly of hexahedral elements, although a limited number of polyhedral cells were used to ensure that the physical domain was accurately represented. Local grid refinement was done in areas where high gradient in the flow variables were expected, for example, near the tube and directly above it. We modelled a lens of length 75mm and with inner and outer diameters of 10mm and 11mm, respectively. The model consisted of two phases: a fluid phase (air represented with 274,682 computational cells) and a solid phase (carbon steel represented with 79,323 computational cells). The pressure and density of the air were allowed to change in accordance with the ideal gas law and the temperature of the steel was allowed to change through the process of conjugate heat transfer. Initially, the air was at rest at STP conditions. It was assumed that the injected flame had an initial temperature of 2,696C and a velocity of 330ms 1. Turbulence was modelled using the k epsilon turbulence model with wall functions. The steel was initially at 400C. The simulations modelled a total period of 5s.
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abbkineeu · 6 years
Text
New Post has been published on Biotech Advisers
New Post has been published on http://www.bioadvisers.com/targeted-neurotechnology-restores-walking-humans-spinal-cord-injury/
Targeted neurotechnology restores walking in humans with spinal cord injury
Content introduction:
TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle
Targeted neurotechnology restores walking in humans with spinal cord injury
DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Shared and distinct transcriptomic cell types across neocortical areas
De novo NAD+ synthesis enhances mitochondrial function and improves health
1. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here Thomas O. Vogler at University of Colorado in Boulder, USA and his colleagues show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which they call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.
Read more, please click https://www.nature.com/articles/s41586-018-0665-2
2. Targeted neurotechnology restores walking in humans with spinal cord injury Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here Fabien B. Wagner at Swiss Federal Institute of Technology (EPFL) in Lausanne, Switzerland and his colleagues introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, they delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.
Read more, please click https://www.nature.com/articles/s41586-018-0649-2
3. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, Yizhou Joseph He at Harvard Medical School in Boston, USA and his colleagues identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, they infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.
Read more, please click https://www.nature.com/articles/s41586-018-0670-5 4. Shared and distinct transcriptomic cell types across neocortical areas The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here Bosiljka Tasic at Allen Institute for Brain Science in Seattle, USA and his colleagues analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. They define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, they match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Their study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.
Read more, please click https://www.nature.com/articles/s41586-018-0654-5
5. De novo NAD+ synthesis enhances mitochondrial function and improves health Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here Elena Katsyuba at École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland and his colleagues show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. They also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, they identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.
Read more, please click https://www.nature.com/articles/s41586-018-0645-6
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bioadvisers · 6 years
Text
Bioadvisers shared on Biotech Advisers
Targeted neurotechnology restores walking in humans with spinal cord injury
Content introduction:
TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle
Targeted neurotechnology restores walking in humans with spinal cord injury
DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Shared and distinct transcriptomic cell types across neocortical areas
De novo NAD+ synthesis enhances mitochondrial function and improves health
1. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here Thomas O. Vogler at University of Colorado in Boulder, USA and his colleagues show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which they call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.
Read more, please click https://www.nature.com/articles/s41586-018-0665-2
2. Targeted neurotechnology restores walking in humans with spinal cord injury Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here Fabien B. Wagner at Swiss Federal Institute of Technology (EPFL) in Lausanne, Switzerland and his colleagues introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, they delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.
Read more, please click https://www.nature.com/articles/s41586-018-0649-2
3. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, Yizhou Joseph He at Harvard Medical School in Boston, USA and his colleagues identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, they infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.
Read more, please click https://www.nature.com/articles/s41586-018-0670-5 4. Shared and distinct transcriptomic cell types across neocortical areas The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here Bosiljka Tasic at Allen Institute for Brain Science in Seattle, USA and his colleagues analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. They define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, they match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Their study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.
Read more, please click https://www.nature.com/articles/s41586-018-0654-5
5. De novo NAD+ synthesis enhances mitochondrial function and improves health Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here Elena Katsyuba at École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland and his colleagues show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. They also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, they identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.
Read more, please click https://www.nature.com/articles/s41586-018-0645-6
0 notes
bioadvisers · 6 years
Text
Bioadvisers shared on Biotech Advisers
Targeted neurotechnology restores walking in humans with spinal cord injury
Content introduction:
TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle
Targeted neurotechnology restores walking in humans with spinal cord injury
DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Shared and distinct transcriptomic cell types across neocortical areas
De novo NAD+ synthesis enhances mitochondrial function and improves health
1. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here Thomas O. Vogler at University of Colorado in Boulder, USA and his colleagues show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which they call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.
Read more, please click https://www.nature.com/articles/s41586-018-0665-2
2. Targeted neurotechnology restores walking in humans with spinal cord injury Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here Fabien B. Wagner at Swiss Federal Institute of Technology (EPFL) in Lausanne, Switzerland and his colleagues introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, they delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.
Read more, please click https://www.nature.com/articles/s41586-018-0649-2
3. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, Yizhou Joseph He at Harvard Medical School in Boston, USA and his colleagues identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, they infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.
Read more, please click https://www.nature.com/articles/s41586-018-0670-5 4. Shared and distinct transcriptomic cell types across neocortical areas The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here Bosiljka Tasic at Allen Institute for Brain Science in Seattle, USA and his colleagues analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. They define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, they match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Their study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.
Read more, please click https://www.nature.com/articles/s41586-018-0654-5
5. De novo NAD+ synthesis enhances mitochondrial function and improves health Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here Elena Katsyuba at École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland and his colleagues show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. They also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, they identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.
Read more, please click https://www.nature.com/articles/s41586-018-0645-6
0 notes