#gck family

[burningcheese-merchant]

Wake up, BurningCheese/GoldenSpice babes, new poorly drawn blorbos just dropped

They look cooler in my head, I swear.

the images didn't show up the first time wtf lol

The kids are finally here, yay. I promised I'd show you them, and I finally stopped being an asshole and followed through. Almost got 200 followers and I'm very grateful for it - really, I'm nobody. I'm just some clown who says dumb stuff and makes dumb memes and writes cringey stories, and yet I convinced almost 200 people to tune in. Thank you all so much, users on here and anons in my inbox alike. As a token of appreciation, you can all endure my rambling about my OCs and witness a person in their early 20s draw like a 12 year old.

The boy is Pepper Jack (or Pepper Jack Cookie). He's the firstborn and older than his sister by a few years. He takes after his mother in a lot of ways, primarily in her appearance (save for nabbing his father's red eyes). He's incredibly bright (and a smartass lol), preferring to think his way out of conflict rather than fight his way out... not that he's above violence at all, if that glaive doesn't give it away lol. He harbors a deep sense of love and loyalty towards his family and his peoples, and carries the weight of his responsibilities and heritage with as much confidence and poise as he can muster. (There are/will be times where he stumbles, of course. He's not perfect. He struggles a lot more than he lets on, really. But he tries his best, for everyone's sake.)

The girl is Matar Paneer (or Matar Paneer Cookie). Again, she's the younger one by a few years. She was all but made in her father's image, save for inheriting her mother's eyes. She's a little firecracker: lively and fun-loving and stubborn as a mule. She doesn't ask "can I have/do this thing", she tells you "I'm going to have/do this thing". Golden is proud as anything to see her daughter be so greedy... until that greed comes into conflict with her and Spice's authority lol. But she's a good kid, despite being such a handful. She has an enormous heart and is not afraid to stand up for others/what's right, and she loves her parents and brother more than anything in the world. She might doubt her own capabilities, she might secretly fear that she's not strong enough to do what she needs to... but she keeps pushing anyway, because she'd honestly choose death over quitting.

Your eyes are not deceiving you, Pepper Jack's wings are blue lol. There's an actual reason for that. And that USO (Unidentified Sitting Object) in Matar Paneer's hair is a lotus (the cheese one in the GCK decor set lol). There's a reason for that, too. I thought it would be cool to give Jack a glaive and swap out the normal blade for that of a khopesh sword (glaives are not Egyptian, they only saw use in Asia and Europe, but I just HAD to give him a glaive), to add that Egyptian touch. Paneer's supposed to be wearing a pattu pavadai, it's a traditional Indian dress for young girls. It's a blouse plus a skirt. She's holding katar, Indian knives (Cilantro Cobra has them, too). And her hair's supposed to be in a low ponytail.

Merchant thinks that if they explain what their terrible drawings are supposed to convey, people will understand their intended vision and the pain will stop

I sat down and did research into both Egyptian and Hindu mythology for the sake of drawing inspiration for them both. I'll explain in detail in another post, but basically: both of them take after one Egyptian god and one Hindu god each. Golden takes after Ra and Spice takes after Shiva, so I figured I'd follow along that line.

Please flood my inbox with questions about them now. I've really been dying to talk about them for ages now. I've drafted extensive character sheets for them both, I even made up in-game descriptions for them lol. They're my little fankid blorbos and I love them :') I hope you all come to love them, too

(Also, I'm sorry they're on lined paper. I'm visiting family rn and that's the only paper my grandmother has in her house. I'd have to drive to a stationery to get printer paper and I'd really rather not drive in this particular country lol (shit roads, even shittier drivers). I'll doodle them on printer paper whenever somebody remembers to bring me some)

[koolkat9]

Fanfiction/Writing Summary 2022

Because I am more of a writer than artist, I decided to do something that showcases my favourite pieces of writing from over the year. If you'd like to do it yourself basically you're going to go through your writing each month, choose a piece you really like and put a sentence or section from said fic.

January

Arthur was sure this had to be a dream now, that or he was seeing his lover’s angel. Basked in the golden light of the sun filtering in, Feliciano was practically glowing with an even brighter smile to match. It was as if the accident had never happened. 

“Amore Mio, why are you crying?” Feliciano asked, voice hoarse from not having used it for almost two months. 

“Wha…” Arthur lifted a hand to his cheek only to find it wet with tears. “Please tell me this isn’t a dream…”

-I Must be Dreaming || AO3 || Tumblr

February

Tossing his bow to the side, the teen picked up the toddler, wiping away the boy’s tears with his cloak. “Shhh,” Dylan hushed as he began rocking the child back and forth, “It’s okay little one.” Dylan turned back towards his siblings. “It’s alright you two, he’s one of us.”

“He?” Niamh asked, being the first to come to Dylan’s side. Dylan turned towards his sister, giving her a better view of the young boy in his arms. Niamh’s eyes lit up at the sight. “Awww look at him! He’s so little.” She placed a hand on top of the toddler’s shaggy blond hair, smoothing it down. The young boy leaned into the touch, releasing a pleased hum. It made Niamh giggle. 

“Indeed,” Dylan agreed. 

Alastair cautiously came over as well, stiff as a board. Luckily, as soon as his eyes landed on the child, all the tension was alleviated. The toddler gave Alastair a wide smile when he noticed him, reaching out with his free hand. Unable to say no, Alastair took the small hand in his own. 

“Looks like we have another brother,” Dylan beamed. But his words fell on deaf ears as his siblings stared in awe at the child in his arms. His smile widened at the endearing sight. 

-Weeping in the Woods || AO3 || Tumblr

March

“Are you nervous?”

The young boy nodded. 

Arthur gave him a tired smile before putting the luggage down and crouching to be at Matthew’s level. “Don’t be. Uncle Allie will be there, and I’m sure you’ll get along swimmingly with your Uncle Dylan. You remind me a lot of him, you know?”

Matthew peeked up from behind his stuffed animal’s head. “Really?”

“Mhm,” Arthur hummed. When he noticed Matthew was still hesitant, he scooped the boy into his arms. “But, if you’re still nervous, you can stay right here with me.” 

“Okay,” Matthew whispered, a shy smile spreading across his face. 

-Meet the Family || AO3 || Tumblr

April

"The tea is–” But Francis was cut off by Arthur swinging around, pressing his arm against the Frenchman’s neck. Francis looked up at him with genuine fear as Arthur’s acidic green eyes burned into him. For a moment, it was as if they were back to their old ways. 

“Angl–gck–Angleterre it’s just me…mon lapin…”

Arthur’s gaze softened, and he lowered his arm as fear subsided. “Oh god…I-I…Francis I genuinely didn’t mean–” Francis silenced him with a kiss.

“It’s okay. I’m sorry to have startled you.” Francis let out a light laugh. “I probably would have done the same.”

“Francis…”

The Frenchman’s hand came to rest against Arthur’s face. “We’ll be okay mon amour. It’s all over now, and we can enjoy our time together.”

-A Very Awkward Anniversary || AO3 || Tumblr

May

 Jan was tense as Matthew began to lead him in a slow waltz. Matthew himself was nervous, but either because of the alcohol or the quietness of the outdoors, he was much more at ease than Jan. “Relax,” he murmured, breath tickling Jan’s neck causing him to shiver. “No one’s watching.”

“And everyone says you’re the shy, awkward, little prince.”

“The alcohol probably has helped in this case,” Matthew laughed. 

Jan let out an amused huff, and it melted Matthew’s heart. Jan didn’t seem to be someone who laughed a lot, and there he was, amused by Matthew. He unconsciously began leaning in. 

-Royal Weddings and Slow Dances || AO3 || Tumblr

June

“Mhm.” Arthur turned his gaze wistfully at the sky. “It’s…It’s nice you know…Not to have to hide as much anymore. To have more public spaces to go to and be able to dance with the man you love. To kiss him and not have to be scared of getting arrested or…even worse…”

Ludwig wrapped a loving arm around his shoulder. “Hey…It’s okay now. Things are changing and I have a feeling it’s going to continue going uphill from here.”

Arthur gave him a sentimental smile. “I never coloured you to be such an optimist darling.”

-Things are Changing || AO3 || Tumblr

July

“Ah…” the man sighed, “So good…So good for me…Ludwig, Ludwig, Ludwig.”

That wasn't right. His master never used his name. Then someone was shaking him, but it wasn’t the man in front of him. It felt…distance almost. “Ludwig…Ludwig come on…you got to get up,” the voice called, though it felt farther than before.

Ludwig opened his eyes slowly, meeting a familiar flash of green. The actor? No. “Arthur?” he rasped.

-Got a Secret, Can You Keep it: Chapter 2 || AO3 || Tumblr

*Warning, this entry is nsft

August

“Shhhh. You’re okay. You’re alright. Shhhhhhh.”

Ludwig let out a choked sob. Now he could add confusion to his list of things being wrong. How could something as small as a loving touch strip him bare and break him like this? It was embarrassing and made the situation even more overwhelming.

“Oh, darling. It’s going to be okay. Shhh.”

“I-I’m sorry,” Ludwig blubbered, “I-I don’t know what’s came over me.”

“Never apologize for this kind of thing,” Arthur murmured against Ludwig’s forehead, “I’ve learned the hard way, it’s not good to push it all down.”

-An Indulgent GerEng Sick Fic || AO3 || Tumblr

September

“That’s good.” Francis let his hand linger in Arthur’s hair, his fingers becoming tangled in the strands.

“Francis?” Arthur spoke softly.

Francis immediately pulled his hand back. “Ah…Desole.”

But the Brit pulled his hand back. “N-No…It’s alright. Just…um…Thank you. For everything. For giving us a place to stay, for watching the boys, watching over me…” Arthur coughed awkwardly. “You’re very good with them. The boys I mean…”

“Oh now I really think you hit your head,” Francis teased.

Arthur shoved him though only half-heartedly. “Shut up!”

-To be Cared for || AO3 || Tumblr

October

“Arthur…”

“If you asked me two decades ago, I would have had a very different answer for you. But I don’t have any comforting words, Ludwig.”

“I’m sorry…” Arthur shook his head, giving Ludwig a lopsided grin.

“Don’t be. You’ve got a far better head on your shoulders than I did at your age. I was always itching for a fight, and I didn’t care who I hurt, but you…You’re…You’re full of surprises. It’s a good sign. It gives me hope. As does this.” He gestured to the football game in front of him.

“Humans are something,” Ludwig hummed.

“That they are.” Arthur smiled genuinely. “It’s beautiful.”

-Christmas with the "Enemy" || AO3 || Tumblr

November

Arthur let out a long sigh. “Even if you were the Holy Roman Empire, you’re Germany now. That hasn’t changed. You’ll always be Germany. You’ll always be Ludwig. Stubborn, strong, hard-working Ludwig who overworks himself. Who loves dogs, baking, vinyl records, and morning jogs at sunrise. You’re still you with just a little extra tacked on.” He squeezed Ludwig’s hand, guiding him by the chin to look at him. “Your supposed past shouldn’t dictate your future, and don’t let anyone else make you think it should.”

Ludwig let out a shuttered breath, wiping at his eyes, trying to keep his tears at bay. He had felt so heavy, but at Arthur’s words, it was as if some of that weight had been taken from him, the Brit helping him shoulder it.

“Shhhh, it’s alright Lud. It’s going to be alright.”

OR

Feliciano looked up at him with glassy eyes. “I should have seen this coming,” Feliciano said with a wet laugh, “I…I-I should have never accepted your confession. I was…He was finally home and I just…I had been waiting for you–him–for so long that I jumped on the chance not thinking you were different now.” The tears were streaming now and they punched Ludwig in the stomach. “I wasn’t thinking that maybe all of this had put you in a confused, vulnerable state, twisting what you really wanted. It’s complicated…Gilbert tried to explain that to me. But whatever this means for you…It’s clear your heart doesn’t belong to me and I’m sorry for feeling entitled to it because of the past.”

-Ludwig || AO3 || Tumblr

December

“Thank you,” Matthew rasped, “It gets lonely in the winter.”

“What?”

“The cold…Scares everyone away…Those who stay shut themselves in and hope they’ll all make it to spring.”

“Mattie…”

“Papa didn’t know how to deal with it. He tried to take me to France, but that made it worse, he left me with doctors, but…” Matthew sniffled. “But…”

“Now, now Matthew,” Father said gravely, striding into the room, “We needn’t get wrapped up in the past. We must embrace the present. Speaking of present…” He presented two neatly wrapped heaps to the boys. “An early Christmas present to liven all of our spirits.”

-A Little Christmas Magic || AO3 || Tumblr

This was a lot harder than I thought. Anyway, I wrote 137 fics this year woooo!

[cheesecakemermaid1048]

Tell your friends, family, even your pets.

Please vote for Burnt Cheese Cookie 🙏

We need the GCK to get a W

ㅤ

[goldenclosetkook]

I wanna post my face too ☺☺ uwu

[nuadox]

Study: How to protect neurons and stimulate their growth

- By University of California San Diego -

By inhibiting a particular family of enzymes, it may be possible to develop new therapies for treating neurodegenerative diseases from glaucoma to Alzheimer’s.

Many neurodegenerative conditions, from glaucoma to Alzheimer’s disease, are characterized by injury to axons — the long, slender projections that conduct electrical impulses from one nerve cell to another, facilitating cellular communications. Injury to axons often leads to neuronal impairment and cell death.

Researchers know that inhibiting an enzyme called dual leucine zipper kinase (DLK) appears to robustly protect neurons in a wide range of neurodegenerative diseases models, but DLK also inhibits axonal regeneration. Until now, there have been no effective methods to modify genes to improve both the long-term survival of neurons and promote regeneration.

In a paper published December 14, 2020 in PNAS, a multi-university team led by researchers at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health identified another family of enzymes called germinal cell kinase four kinases (GCK-IV kinases) whose inhibition is robustly neuroprotective, while also permitting axon regeneration, making it an attractive therapeutic approach for treating at some neurodegenerative diseases.

“We basically figured out that there are a set of genes that, when inhibited, allow optic nerve cells to survive and regenerate,” said senior author Derek Welsbie, MD, PhD, associate professor of ophthalmology in the Viterbi Family Department of Ophthalmology at Shiley Eye Institute.  

“Prior to this work, the field knew how to get these cells to survive, but not regenerate. Conversely, there are ways to promote regeneration, but then the survival was rather modest. Of course, for a successful strategy of vision restoration, you need both and this is a step in that direction.”

The researchers conducted a series of screens after first creating retinal ganglion cells (RGC) from human stem cells. RGCs are a type of neuron located near the inner surface of the retina of the eye. They receive visual information from photoreceptors and collectively help transmit that information to the brain.

Image: Example of retinal ganglion cells with axons and dendrites in the retina of a healthy eye. Credit: UC San Diego Health Sciences.

The first screen involved testing a group of well-studied chemicals to assess their ability to increase the survival of RGCs; the second to measure the ability of chemicals to promote regeneration.

“We then used a machine-learning technique to understand why certain compounds were active while others were not and it identified these key genes,” said Welsbie.

The discovery that these genes improved RGC survival was not surprising, he said. “However, you would have predicted that they (like DLK) would have blocked regeneration when inhibited, not promote regeneration. That was definitely a surprise. It highlights one of the advantages of discovery-based science using high-throughput screening: By testing many agents at once, we can find identify overlooked genes that might not have been thought to play a role.”

Welsbie and colleagues focused their work on RGCs because they are interested in optic neuropathies, such as glaucoma. “Most people think only about glaucoma in terms of ‘eye pressure,’” Welsbie said. But eye pressure is only part of the problem. At its core, glaucoma is a neurodegenerative disease characterized by progressive loss of RGCs and their axons, leading to measurable structural and functional damage to the optic nerve, visual impairment and blindness.

The U.S. Centers for Disease Control and Prevention estimate 3 million Americans have glaucoma. It is the second leading cause of blindness worldwide.

Welsbie cautioned that it’s not yet known whether these findings extend to other neuron types, but he noted that the work suggests strong therapeutic possibilities.

Co-authors include: Amit K. Patel, Risa M. Broyer, Cassidy D. Lee, Tianlun Lu, Mai T. Vu, Karl J. Wahlin and Robert N. Weinreb, all at UC San Diego; Mikaela J. Louie, Anna La Torre and Yang Hu, UC Davis; Hassan Al-Ali, John L. Bixby and Vance P. Lemmon, University of Miami; Katherine L. Mitchell and Vinod Jaskula-Ranga and Donald J. Zack, Johns Hopkins University; Xin Duan, UC San Francisco; Santiago Vilar, Truvitech, Miami.

Funding for this research came, in part, from the National Institutes of Health (grant 1RO1EY029342), Research to Prevent Blindness, E. Matilda Ziegler Foundation, Brightfocus Foundation, Fight for Sight Foundation, the Glaucoma Research Foundation Catalyst for the Cure and the Tushinsky family.

--

Source: University of California San Diego

Full study: “Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons”, Proceedings of the National Academy of Sciences (PNAS).

https://doi.org/10.1073/pnas.2004683117

Read Also

Biomarker suggesting neurodegeneration identified in the eye

[lynenspray]

there’s something in the water

(seulrene gp!seulgi gp!irene frotting)

joohyun isn't a big fan of water, so when her girlfriend suggests they take a trip out to the beach, she's set on only laying back and maybe getting a tan. seulgi, however, has other ideas.

---

joohyun was not a big fan of water. or swimming. or any other water-related activities.

so when her girlfriend suggested they take a trip out to the beach, joohyun was set on only laying back and maybe getting a tan.

beside her, seulgi clicked the sunblock bottle closed. “are you sure you don’t want to take a dip in with me?”

joohyun looked out at the view of the beach. the resort they’d booked at was on the exclusive--and expensive--side, so there were a lot fewer people out here than any other regular beach. the only other people besides them were a few kids being watched over by their parents, not even a lifeguard in sight because of the clear, shallow water.

joohyun shook her head and laid back on the lounger, putting on her sunglasses. “I’m good, babe. you go ahead.”

seulgi stood up from her own lounger beside her and stretched her arms up, warming up her muscles for the cool water that was about to hit her skin.

joohyun watched her from the corner of her eye. seulgi’s gaze was focused out at the scene of the beach and the perfect weather, but joohyun’s attention was on her girlfriend. seulgi was, like joohyun, wearing board shorts to the beach--it was the best way to hide their packages, since a bikini bottom was an outright no and leggings and swimsuits of the like were a little tight and weird.

seulgi was so beautiful, her golden skin on display, especially after she’d taken off the kimono shirt that was half covering her up. the older woman bit her lip when she saw the shadow of seulgi’s dick beneath her pale yellow board shorts, the same color her bikini top was if only a bit obviously easier to see through. seulgi was teasing her for sure, but joohyun couldn’t resist; a quick look at her own shorts showed her own bulge, cock beginning to wake up thanks to the way joohyun’s thoughts were heading.

she almost jumped when seulgi swiftly delivered a kiss upon her lips. “you look like you’ve got a problem there,” she teased, leaning in closer and kissing joohyun’s cheeks until her lips met the shell of the older woman’s ear. joohyun watched her dick stand up at attention, a little resigned, but she couldn’t blame herself, not when seulgi was inches away, and especially not when she was this half naked. “need some help?”

joohyun closed her eyes, unable to resist imagining removing her shorts and spreading her legs wide open for seulgi to go down on her, bobbing her head along her length with the beach behind her, making for a beautiful view. she felt herself throb even harder in her shorts. fuck. no way. get it together.

“I am not going to let you touch me, even on a private beach like this.”

seulgi chuckled and leaned back up before throwing a leg over joohyun, gently sitting on top of her at the perfect angle, joohyun gasping at the feeling of their dicks meeting. she was rock hard now.

“why not? no one’s here.” seulgi had a point. the family that was here earlier were gone now, and the entire stretch of beach was theirs.

joohyun shifted nonetheless. “because I don’t want a scandal.”

seulgi laughed and rocked a bit, inconspicuous, but it made joohyun grunt anyway, the friction of their dicks and the materials of their shorts against each other a little too good. “scandal? unnie, we’re not celebrities. no one’s going to care. maybe fifteen minutes of fame for a porn site--but that’s it.”

the older woman bit her lip and looked away, but seulgi’s movement forced her eyes back. the taller woman dragged a hand down her own stomach and slipped a thumb between her navel and the waistband of her swimming shorts, pulling them down until joohyun got a peek of seulgi’s member. then she raised her hips as the garter cupped around her balls and half erect cock, rubbing it with a sunblock-soaked hand, smirking down at joohyun who felt her own swimming shorts get tighter and tighter.

“come on out in the water with me, unnie. we’ll have a good time.”

"I don't swim."

"the only thing that will be swimming is your sperm. and mine."

joohyun looked up at seulgi, seulgi and her teasing grin, seulgi and her golden tan, seulgi and the future joohyun could see with her. she was never an adventurous person, but seulgi could edge a bit of it out of her now and again, and to joohyun it meant the world.

she’d follow seulgi wherever she went, because the younger girl always made sure joohyun was happy, if a bit out of her comfort zone, but always better in the end. this was probably one of those times, and joohyun couldn’t resist. not with seulgi’s dick against hers.

“fine.”

seulgi grinned and hid her cock in again, happily tugging her along as they weaved through the clear, cold water. it was probably one of the best beaches joohyun would ever be in--she could see all the way down to her toes in the white sand. the price was definitely worth it.

joohyun could swim, it was just that she'd really rather not, in all possible occasions. and so as soon as the water was her chest level, she climbed onto seulgi's back and wrapped her legs around the taller woman's waist and placed her arms atop her wide shoulders.

"is this it? you want me to fuck you in the water?" the older woman asked, raising a brow as seulgi laughed and waved her hands around.

"no! that doesn't sound very appealing. at least not in seawater."

so does that mean seulgi would be willing if it was a private pool? a bath?

the bathtub in the room they'd booked?

joohyun blinked as seulgi pushed her away and turned around so that they were now face to face.

with a quick kiss onto her lips and hands sneaking between joohyun's back and the waistband of her coral pink shorts, seulgi tugged at them, helped slip them off joohyun's pale legs until her bottom was completely naked.

and then joohyun watched seulgi heave in a deep breath before suddenly diving into the water. "seulg--gck!" joohyun choked as she felt seulgi's hands cup her ass cheeks and mouth wrap around her dick. joohyun's legs opened wider in reflex, her hands going down to curl around seulgi's bobbing head. seulgi held her up and rocked her hips back and forth for her, cock buried in the cavern seulgi provided.

joohyun moaned, long and low, and leaned back, surrendering to the addicting feeling of seulgi's hot hole juxtaposed to the cold temperature of the ocean around them. if joohyun looked down she knew she'd be able to see seulgi's head swallowing down her shaft, pumping her with her lips and tongue, but for now, this was enough.

it took several long seconds before seulgi resurfaced with a gasp, and even joohyun felt breathless when she watched seulgi catch her breath, skin wet and glistening in the afternoon sun. she was so beautiful, gasping for breath after trying something new with joohyun, always making sure whatever shenanigans she'd push joohyun into that was outside her comfort zone were going to be fun, and they were going to be worth it.

even their relationship made joohyun wary--wouldn't they be better off fucking pussy instead of flinging their swords around at each other all the time?--but seulgi pushed, gently, carefully, and now joohyun was addicted. she would never imagine being with anyone else. would never imagine getting an underwater blowjob from anyone else, either. seulgi was a keeper.

"I love you," joohyun said when she swam closer, wrapping her arms and legs around her girlfriend as seulgi laughed. "I love you so much."

"I," seulgi swallowed and wrapped her own arms around the smaller woman. "I love you too, unnie. was it that good?" she teased.

joohyun kissed her shoulder. "it was perfect."

"do you want me to do it again?"

the older woman held onto her tighter. "no," she answered honestly, because she really didn't want seulgi to drown while giving her a blowjob. "I just want to bury this cock in your tight little ass."

seulgi caressed her bare back. "I want to try something else first, is that okay?"

"as long as you won't risk drowning."

seulgi laughed before sneaking a hand between them and shifting, joohyun feeling the younger woman pull her own waistband down and fish her cock out. joohyun moved so their dicks were aligned and against each other, held in the palm of seulgi's hand, and they both moaned as soon as she pumped.

"you feel so good, unnie."

joohyun groaned in response as she looked down, seulgi's hand and long fingers caressing them both. she was fully erect now, thanks to seulgi's mouth. while the younger wasn't quite where joohyun was at yet, this was the only time their dicks were the same size. joohyun was nothing to scoff at, but seulgi was bigger, meatier, and joohyun loved the fact that seulgi would rather bottom for her every time.

the older woman kept one hand on seulgi's shoulder and brought the other one down to roughly rub against the tips of their dicks while they were still level, seulgi whimpering the same time joohyun grunted, the younger's dick stiffening up in the cold water.

when she was past joohyun's length and an inch longer, the smaller woman (in both senses) brought both hands down and rubbed their crowns as seulgi pumped their shafts and fondled their balls.

seulgi was humping her in the water now, closing her eyes in bliss as joohyun hit her favorite spot, roughly chafing the pads of her fingers against the lining of her cockhead as it met the rest of her length.

"unnie," seulgi whined, head tilted skyward. joohyun watched the ocean water drip down her cheek, watched her brow furrow. seulgi's nails dug into joohyun's back. she was close now, and so was joohyun.

"I know, baby," the older woman whispered breathlessly as she felt seulgi's pace increase, rutting against her and splashing the water around them. joohyun let go and pulled seulgi closer, hugging her tight as seulgi have one last pump before she came. joohyun was right behind her, squeezing their dicks between their stomachs, bucking her hips to stimulate them and keep them going. she felt seulgi hug her closer as they came together, dicks throbbing and twitching together, cum mixing in between them, sullying the clear ocean water.

seulgi gasped when they finished, trying to catch her breath again, while joohyun only melted into their embrace.

the taller landed a kiss onto the side of joohyun's head, the older woman now exhausted from the activity and merely floating as seulgi held onto her. she'd not only had seulgi grinding down against her on the lounger earlier, but also got a blowjob, and only now came as their dicks rubbed against each other.

"oh no," seulgi chuckled when joohyun showed no signs of moving. "is grandma too tired to move n--OW!" she yelped when joohyun bit at her neck, more of surprised than hurt because joohyun obviously wouldn't do that much damage.

"you are such a brat. when will you grow up?" joohyun grumbled jokingly as seulgi slipped her shorts back on for her and tucked her softened dick back inside after one last rub against her tip. tsk. naughty kid.

"never," seulgi caressed her back and held her close. "I'm never, ever, ever, ever going to grow up." seulgi delivered each word with a kiss. "not by your standards, anyway, because you're always gonna be older than me, unnie. happy birthday."

joohyun hummed and nuzzled into seulgi's neck, content to just float around with seulgi's arms around her.

"as soon as you want to go back to shore, we can head to our room so you can fuck me for real. I packed a lot of lube knowing that would happen, so just tell me--"

joohyun pushed off of her before tugging her towards the shoreline, hearing seulgi's surprised giggles ring in the clear beach air.

"come on, then. we might as well be made of money from the price they made us pay for that suite. I want to get my money's worth out of that bed."

---

*part 2 found here

[theblueskyphoenix]

Grid Ghost Chapter 2: Down and Out

Obake was doing his best to keep himself from falling over. He only had another block or so to go before he reached his destination. He could taste copper in his mouth.

Never a good sign.

His steps were staggering, his vision flickering but he kept pushing till he was finally through a set of doors. Soon as he passed through, he let himself fall to the floor, his eyes sliding shut.

Before he blacked out entirely, he could hear people coming towards him. Their voices had a slight panic to them yet they were mostly calm.

The last thing he could hear clearly was someone shouting:

“Get him on a stretcher and have an OR on standby!”

I’ll leave the rest to you, now.

Please, don’t kill me.

oooooo

Dr. Shaylin Sky was used to crazy.

When you sign up to be a doctor, it was a given that anything could possibly go wrong and anything could possibly happen during a shift at a hospital and you just had to learn to roll with it and not question things.

Though sometimes she wished nights could be quieter. Especially when she was about to head home.

It had been a long day of appointments and assisting surgeons in surgery and trying to get the hospital back in proper working order after everything went to heck with concerns of the city being destroyed by a star that seemed to come out of nowhere.

And now… she had an unconscious man she was rushing to an OR after exams had revealed he was suffering massive amounts of internal bleeding in the abdominal region.

Along with something else that was definitely not normal but I don’t got time for that. Treat and stabilize now, ask questions later.

As soon as the man was in the OR she quickly scrubbed in before joining in on the procedure.

“Shouldn’t you be heading home?” The surgeon asked as he started to make incisions into the affected areas. “And is a blood transfusion on the way?”

“I would be, Leon, but I had a man pass out on the floor in front of me and you know I don’t like dropping a patient and running, even if I’m supposed to be gone by now and yes, I got the boys looking through our O- stash as we speak.

"Devoted as ever and good, because he’s losing a lot and fast.” Leon narrowed his eyes. “What the heck did he do to himself? Throw himself off a building?”

“Doubt it, considering the only broken bones I saw in the scans were a couple of ribs. If he had been thrown off a building there would be a lot more broken. Though with the bruises he’s got on him he certainly had something rough happen be it a landing or a fight. Just not sure what.”

“Questions we can ask him once he’s stable and awake. Clamps, please.”

Shaylin handed Leon on the tool in question.

“Oh, trust me, I got a LOT of questions for this guy once he’s conscious and lucid.”

“That’s an omen.” Leon looked to Shaylin with some concern. “See something of interest in your exam?”

“Nothing harmful… I think but it was… definitely of interest.”

“Wanna enlighten me?”

“Drain blood and fix injuries first, then I’ll tell you.”

“Very well.” Leon eyed the man’s face before getting back to work. “Though, gotta say, it’s a miracle he made it here on his own. You said he stumbled on in?”

“Yeah. Again, not sure what the story is but I’m sure we’ll find out soon.”

And I get the feeling it’s going to be a weird one.

oooooo

For Obake, it had only been a few minutes between when he had blacked out to when he was waking up again. He knew it had certainly been longer than a few minutes he just wasn’t sure how much longer.

As he opened his eyes, he could hear the faint sounds of a heart monitor beeping and the dripping of an IV bag.

Those are sounds that bring back memories…

“Just a little longer, Bob. You’re almost done.”

“Just a few more drops then we can go home and watch Teenage Mutant Ninja Turtles together like you promised, Daddy! You can do it!”

For a moment, he was back in that treatment bed again, his daughter holding his hand while his wife monitored his vitals. He could see a young Trina smiling at him, hopefulness in her light blue eyes as she helped keep him comfortable.

It all quickly faded as a voice broke the illusion, revealing he was in an ICU room with a woman he didn’t recognize.

The woman appeared to be of latina descent with tan skin and light brown hair that was pulled into a loose ponytail. She had a look of concern in her deep blue eyes. Judging from the lab coat and ID tag she had hanging around her neck, she was most likely a doctor.

He squinted his eyes to read the name on the ID tag.

“Dr. Shaylin Sky”

“With me?” she asked.

“More or less.” He said, practically whispered. He cringed, bringing a hand to his abdomen. “What happened…?”

“You collapsed in our ER bay. You were rushed in for emergency surgery after some quick tests. You had a couple of broken ribs and massive internal bleeding in the abdominal region due to damage done to various organs. All of it was treated and you’re stable now and are on strict bed rest till further notice.”

“I see… perfect.” Obake sighed, looking up at the ceiling. “Anything else I need to know about in regards to injuries?”

“No… More so I need to know about something.”

Obake looked to Shaylin, raising an eyebrow.

“What do you mean?”

Shaylin crossed her arms.

“You got an interesting looking implant on the left side of your skull… and a pretty nicely sized tumor to boot. I doubt those are things you don’t know about. Care to explain?”

Obake glanced to the side.

“… I have to ask a question before I can answer anything in regards to those two things. Are you associated with Sycorax or Liv Amara?”

Shaylin gave a disgusted look.

“The day I associate with that woman or her company is the day I resign from being a doctor. No offense to her and her work but I don’t like her attitude. She’s just…. condescending and sometimes has no regards for morality… It's… a long story. Either way, no, I am not associated with her, nor is this particular hospital. They’re not rich enough for her. Who wants to know?”

Obake let out another sigh.

“Bob Aken wants to know, that’s who.”

Shaylin’s eyes widened at this, though kept her composure.

“Go on.”

Obake closed his eyes.

“I’ve had this tumor in my head since I was 15 years old that manifested due to a rather unfortunate accident with an experiment. It was managed with chemo treatments for the longest time till around last year when someone came in, claiming they could help me. This someone being Liv Amara.” Obake opened his eyes, his implant letting off a glow for a second. “This implant was supposed to cure me… when it all it did was make things worse.” His eyes narrowed. “She took everything from me that day I entered her operating room doors… all with a simple series of shocks.”

“Your family is none of your concern anymore, Obake. Your concern is making your mark on San Fransokyo. To be remembered as a legend.”

Obake was panting, grabbing at the table as electricity pulsed through his mind.

“Ngh! No! Kim… Trina… I… Gck! I need to…”

“Shhhh…” Liv brought a hand to his cheek again, stroking it with her thumb. “They’re not here anymore… It’s just you, Obake. You’re alone. And there’s nothing wrong with that. Think of all you can do. No limits whatsoever. You can be the genius you longed to be. You can make great accomplishments. You can make Grace regret ever abandoning you in your time of need. You can make her wish she had never given up on you.”

“I… I….” Obake’s pupils dilated. “I could be… remembered by all…”

“That’s right.” Liv smiled. “You just have to do exactly as I tell you. There’s no Bob Aken anymore. There is only Obake. A ghost. But soon to be remembered and revered by all.”

“Remembered… and revered by all.”

Obake grabbed at the blankets of his bed, lowering his head.

“I haven’t been in my right mind for awhile now… and I want it to stop. And I only know one person I could trust with my head.” Obake looked at Shaylin. “Do you know Dr. Kim Aken?”

Shaylin nodded.

“I do. She’s a dear friend of mine… who has been dearly missing her husband who disappeared around last year.” Shaylin’s look turned gentle. “And it seems he’s finally been found.”

Obake nodded.

“Can you get me to her? And do you have my things? There’s some important equipment in that backpack I came in with along with the USB I had around my neck.”

“Yes and yes. I have your possessions in my office for safekeeping and I can contact Kim’s hospital right away and have you transferred.”

“Thank you… Where is she at, by the way?”

“Saga Regional Hospital.”

Home…

“Good… I want to get away from this city for a bit.” Obake leaned back into his pillow. “Too much crime and too much noise.”

Shaylin chuckled.

“Kim said the same thing.” She gave a small smile. “You know, she never stopped looking for you. Even came here for a bit with her daughter in hopes they’d find you. They’re going to be so happy when they see you.”

“Maybe… though I’m expecting irritation considering my current state.”

And telling them what I’ve been doing for the past year. That’s going to be fun.

“Possibly. Kim’s more level headed than I am. If you were my husband you would’ve gotten a slight pow pow.”

“And a sandal?”

“That’s la chancla to you, mister.”

“Nuance.”

Shaylin rolled her eyes, getting up from her chair.

“I’ll go make some calls then. Can I get you anything?”

Obake gave a small smirk.

“I have a blueberry scone in a tupperware in that backpack of mine. I’d like to eat it now, please.”

Shaylin smirked, shaking her head.

“You’re not gonna be able to enjoy it as you are so, patience on that one.”

“Oh, come now, I know how to eat slow.”

“Eat it when you don’t have a tumor the size of a ping pong ball suppressing your right from wrong junction.”

Shaylin left without another word.

Obake gave a flat look, plopping his head into his pillow.

It’s called the temporo-parietal junction, plebeian.

… And it’s not the size of a ping pong ball!

[jainarepellista]

Tower of God S2ch315 Rough Translations

W.. what the?! Who are those guys?

(There are.. So many!!)

That symbol on the suspendiships, does that mean they’re regulars sponsored by families?

*To maintain fairness with the 10 Families and the natives, regulars team up and get sponsorship from the families to obtain resources. However, side effects have emerged such as the families taking advantage of the regulars to do their dirty work.

..I think I’ve seen that skull pattern before. // “Always Asking” Levi

They’re one of the few regulars who are supported by Zahard.

Why are those guys flocking to this place?

Well..

Maybe they’re headed to the same destination as us.

You mean the last station?

Why the heck would they go to the end of the Train?

How would I know // It’s just a hunch.

I think we need to find out more.

43F Hell Train - The Three Commands - 07

Suspendiship Shelter (Docks)

3rd Dock

So tired.

That was a long flight.

The schedule was too tight.

If our captain says this is an order from our sponsor, this must be a real killer. [zumi: difficult might as well be ded]

(Haha!)

It can’t be helped. They’re responsible for our lives.

Well, that is true.

This is the Third Dock. The ningen on board are descending. [T/N: Vespa uses ningen to refer to humans.]

Well- looking at them, their skills seem to be on par with children // They look like a bunch of beggars who got sponsored by a family to climb the Tower.

Their mark is a red-bearded human. // It’s ugly.

(Dis--gusting--)

Alright, keep on watching.

And let us know if you find out why they’re heading to the last station.

Uh.. okay. // You got me honey so I’ll help.

5th Dock

Verdi-ahjumma. How’s it going on your end?

Hehee~ This is Verdi~

Verdi the Special Correspondent!

(Ta-da!)

(Long time no see, everyone!)

Ahjumma.. Just tell us what’s happening..

The regulars here have also alighted! // Oh my~ they’re all different ethnicities!

Looks like the crew* is multi-ethnic too~

*Refers to an alliance of teams

Their mark seems to be an ear on a green background? // I’m not a lightbearer so it’s difficult to search, but it’s probably a pretty huge crew?

Maybe their ace is su.per. strong? Hehehee!! [zumi: dots intentional]

And that is all from special correspondent, Verdi~!

Yeah.. Sure~ I got it. Verdi-ssi.

(Why is our team like this…)

Hmm.. It looks like Benny’s crew did not stop at the shelter. // Should we wait until they leak information.. No..

Ergh?! Where are you going Hatsu?

I’m going to ask them where they’re going.

Wait a sec, Hatsu! Let’s wait for them to leak out information!!

It’s faster to ask with my sword.

It’ll be trouble if you get out of control..

You’re so noisy.

?!

W.. what the!! You!!

Why did you break in!!

My name is Hatsu. // Excuse me for breaking in-

But if you don’t answer my questions

Prepare to die [lit. I will cut you down. But the urge to meme….]

Koon-ssi..

A month ago

Huh?!

You think there’s a way for Koon-ssi to wake up again?!

That’s right.

H.. how will you do it?!

I have almost finished my analysis on his current state. // According to the data, it’s a rare ability that manifests in some direct-line descendants.

There are cases where a person who is competent in dealing with ice can break out of that state by themselves. // But his power awakened in a moment of crisis so he won’t be able to do that.

However, in the ancient chronicles, there was a record of somebody waking up again by the Yeon Family’s flame.

!!

The Yeon Family, which means..!!

Flamethrower turtle!!

We can ask Yihwa-ssi!!

But it’s not as easy as it sounds. // The person recorded is a very famous ranker, “Yeon Un”.

It’s highly impossible for a mere regular’s power, and that lady in your group is still far down in the lower parts to arrive here.

That’s why! I’m going to introduce you to that ranker “Yeon Un”!

That person is actually affiliated with Wolhaiksong now. // She’ll do it if I ask for it. [zumi: assumed female; text is neutral]

Really?!

Yeah. Of course it’s best to see her in person. // I will let you meet “Yeon Un”.

Turtle!!

This is great, Rak-ssi!!

(Haha…)

Yeah!! Not that I want him to wake up or anything!!

Please wait for a bit.

Koon-ssi.

You’ll wake up again for sure-

Ah- I feel alive now!

What sort of Train is this that it reflects the seasons thoroughly.

It’s so hot now that it’s summer..

I’m glad we found a big bathroom.

That last battle left a bad taste in my mouth. // Rachel escaped

And it seems White also disappeared together with her..

He’s definitely not the type to run away.. // so I don’t understand why he suddenly disappeared.

Hwa Ryun, you went down first. // Don’t you know anything?

None at all. // Why, do you doubt me?

Isn’t that natural? You both belong to FUG!!

Speak up. You’re hiding something, aren’t you?

….White was already gone when I went down. // I don’t know anything.

This person..

(Super suspicious..)

I never trusted her ever since I first met her..

What about Miseng?

She’s training by herself. // She wants to become stronger to avenge her companions..

Hmm- she’s doing well then. I actually gave her some good stuff.

Good stuff?

Yeah~ Something real good. [zumi: androssi don’t give drugs to kids reee]

Princess Androssi!!

Oi!! I told you not to come out because I’m washing up!!

(Beta)

T-that’s not important!! Right now!!

White’s final clone disappeared!!

...What..?!

Train God of Guardian’s Residence

God of Guardians-nim.

You have come today too.

Yes.

You keep coming even though you’re already strong enough to not need my training.. // Are you sure you’re okay?

Yes. It’s fine.

I cannot get the second thorn out yet. // I want to accomplish that before I leave the Train.

Hmm.. There’s nothing I can do.

I’ll take you on today!

Yes!

Rachel..

Maybe what you said is true. // Maybe you’re just an ordinary person

Who thinks I’m a monster.

But I.. do not care.

No matter what anybody calls me // And whatever the fate I was born with is

I will get stronger-

To protect those people precious to me.

Boro, what kind of place is the last station?

The last station?

Mhm. I’m curious.

Hmm- It’s a nice place, I guess? // Don’t worry about it. There’s nothing dangerous with arriving at the station.

The last station is divided into two sections // Unlike the other stations, non-ticket holders can go to the circular portion.

And all the regulars who cleared the Train stay at first-class hotels // and are given the best treatment.

By the way, the person ruling the station // Li Xiaong, is a quite skillful regular. // He lost his legs while in the Train and decided to settle down at the station afterwards.

Now, it looks like control of the station is divided between his adopted son and his daughter.

His daughter is especially cute and she runs a huge bar. // The beer there is delicious.

You shouldn’t drink too much, Boro. // It’s not good for your health.

Have you thought about what you’re going to do once we leave the Train, Hockney?

Ah well.. I’ll go with Baam for now // I need to find the piece of my painting.

I see-

Well- That was a wild ride // that I never would have imagined I would experience.

It would be nice if things will just be uneventful until we reach the end.

You crazy guy!!

Die!!

(Demonic Fishwheel Dance-)

(Single Annihilation-!!)

Kaagh!!

Aaaaaack!!

!!

Answer me. // Why are you heading to the last station?

T-that’s..!

If you don’t answer, you will die.

W-We received the order from our sponsor!! // To subdue the ticket holders in the Hell Train!!

It looked like those people in the Train broke some major rule!

What..?

I heard that they allied with FUG and took over the Train // and that they’re moving the Train as they please

(And then the signal to subdue them came..!)

The rankers from Zahard’s army are already gathering to confront FUG’s affiliates // and looks like we’re the ones who are going to handle the regulars..!

Everyone in the Hell Train is going to die!!

Somewhere in the Tower

Zahard Army’s High Speed Suspendiship

Gck!!

Initiating eye recognition-

Kgu..keuk..!!

Identity confirmed.

Keuk..

Would you like to set the route?

At top speed-

To the last station of the Hell Train.

Understood-!

Kallaban’s symbol..

This will not be easy.

52F of the Tower

Zahard Army’s 4th Unit Kallaban’s Carrier

This “rhapsody”..

4th Unit Army Commander Kallaban

It’s a good song for this war.

[thevaloroushearts]

"Alyx, look, the rays...! Do you see them...?"

"Mm'yep, sure do, sis... sure do..."

Cloudy skies, lowering temperature, gentle chills blowing across the cityfolk of Altiel... the cooler seasons were arriving, meaning many citizens were bundling up and readying themselves for the holidays. Shopping, staying warm, making memories with photoshoots, families walking together... no matter the lowering temperature, there was still a sense of warmth bustling about...

"I'm not certain why, but seeing rays of light breaking through winter clouds... it's such a gentle yet inspiring sight..." the normally sheepish Gardevoir commented with a tender tint of excitement, ears lifting as she felt her artist fingers twitch her finger across an open page in her sketchbook.

“Yeah, it’s kinda pretty I guess...” Meanwhile, the pale Gallade just looked on towards the sea, his gaze seeming... disinterested...? This didn't go by Oriel unnoticed, of course...

"Brother?"

"... Yeah?"

"... Pardon me for saying so, but you seem distant... is everything alright? You've grown passive as of late..."

"Eh, well... it's just, we've been working here for a while, doing all these fights and whatnot, raising money to make our ends meet..."

"Yes...?"

"... I guess I've just been wondering..." Alyx just rubbed the back of his head as a pessimistic sigh left his lips, "Don't get me wrong, Oriel, I'm thankful we've gone this far, it's just... As psyched as I am, I was just wondering if we ever will... , or at least, if we did go to see them, if something would make things take a turn for--"

"Heeey li'l bro, hey li'l sis! What're YOU two doing out without your li'l jackets, hm? Heehee~!"

Well that was a pleasant change of pace. The twins ears shot up as they caught the wind of a very familiar doting sisterly voice, with Oriel being first to turn her neck and see their adoptive sibling Lixue hopping over ever-so-cheerfully, sipping a cold beverage.

"Ah, Lixue! Hello again!"

"Hiya hiya! Have you two been standing here this whole time? C'mon, we live in Altiel! Go walk around the city! See the sights! What's gotten my lively li'l bro Alyx and inspired li'l sis Oriel staying put like this? It's not like ya!"

"Ah! W-well, erm, we're just--"

"Catching our breath and taking in the sights for once. Day off and all, sometimes all we just need is fresh air, y'know?"

Lixue could only giggle. "I could believe Oriel saying that, but YOU needing a break, Alyx? Heehee, you have the stamina of a Mudsdale! That's just silly!"

"Erm, Lixue... where is Masou...?"

"Hm? Oh!" She stuck her tongue out as she took a sip of her lemonade before  giving a little sigh. "He's just back at the League, thinking to himself as usual."

"The guy's gotta get out more... can't go isolating himself all the time, y'know? Hasn't he beaten himself up enough yet...?"

Way back at the ABL, the Hellfire Hoodlum himself was perched upon the ceiling of their fighting organization workplace, looming over the city. His own version of sight-seeing, perhaps? Akin to what a nightwatcher would do, at least. The reptile let out a steamy hiss as a whispy trail left his nostrils, gazing down at the cityfolk while allowing himself to be lost in his own thoughts.

<< Mmh... this view of the city...>> he thought to himself, tail idly swishing about as he hissed behind his collar, <<... perhaps one day I'll allow myself to actually enjoy it, once my debt is repaid... >> A disgruntled yet brooding exhale left his mouth, wanting to uncover his head to welcome the breeze, but he held himself back, as if fighting temptation, or perhaps refusing for another reason...

As his eyes wandered, he noticed far off in the distance that the vacant block of space far away from the more lively part of the city had but a few souls attending to it... an area that gave a chillingly silent vibe.

---

"..."

A somber wind howled lightly around the tall dark knight as he glanced down at his subject, as a sigh echoed within his mask and helmet.

"Two years..." he muttered to himself, "... nearly two years now... how time flies..."

Zarathos remained still, unmoving not unlike a statue, as his thoughts continued to escape him...

" ... To think, had I not allowed something so... primal... so arrogant..."

The rest of those would-be words died in his throat, replacing the remnants with harsh mumbles. At a loss for what else to say, Zarathos pledged a hand powerfully to his chest, letting out an adamant snarl.

" ... rest well, soldier..."

Unbeknownst to the Bisharp, at least yet, there were two other Altiel citizens that happened to walk by the entry to this somber field, looking on at the terrifyingly tall warrior from a safe  distance.

"... Erm, how long do you think he's been there...?" a soft, concerned male Bisharp's voice uttered to the other.

"Ah, that I cannot say, mein Freund..." retorted the girl, holding a hand up to her mouth. "I... try to avoid areas such as these, yet seeing him here all by myself makes me wonder..."

"I agree, it's a somber place, but the fact that the Champion is all the way from the Battle League, here, all alone...?"

"Pardon me, but what are you two unlikely onlookers doing?"

"GCK--!" "ACK--!"

Takeshi and Eira nearly leaped at the sound of being addressed from behind, the Medicham behind the both of them merely chuckling in amusement. Adjusting his glasses, he continued to prod.

"Are the two of you here to spy our notorious battle-reigning brood? My my, how unusually rude of you two! Even the champion can't get a moment of peace during such glum displays of consciousness. I highly doubt you two came to merely stare at the dead from a long distance?"

"O-oh! I was just, er, fetching supplies for the Kirikuisine! Food supplies!"

"And I was, er, making my way to the Blue Moon Cafe!"

"The Blue Moon Cafe is not this many blocks away from the ABL, madame. And why come here when the food supermarket provides superior ingredients in the other direction for your quaint little foodshop?"

Just before the two could answer, they felt a burning glare pierce them from the distance.

" ... How long have you been there?" snarled the champion at his unwelcome 'audience.'

Needless to say, Takeshi and Eira were quick to make their ways away, but not before awkwardly waving to Zarathos and then each other.

"T-to the food market with me! Ahaha, farewell!"

"Oh of course! Take care, Takeshi!"

The Medicham just rolled his eyes and shook his head, raising a hand peaceably at the dark champion before walking off. <<Very well, leaving him to his charmingly depressing payment of respects is fair enough I suppose... my curiosity would only be squandered in a place such as this.>>

---

" ... I'm sure he'll be alright~!" Lixue remarked before sidling up to her adoptive siblings, tilting her head with a cute smile. "C'mon, cheer up Alyx! Masou does enough frowning for the rest of us, you don't have to stay so quiet! C'mon, let's see a smile," insisted the icy Lucaritales before hugging her adoptive Gallade brother.

"Nnh, Li, please--"

And then Alyx's blood sister joined, smiling up at the bladed brawler in hopes he would listen to the words of Lixue. Al could only sigh and give off an awkward grin.

"C-c'mon Oriel, Lixue, you're embarrassing me out here..."

"Heehee, you're beyond embarrassment at this age, Alyx!"

"There's that smile..." Oriel chimed with a little giggle. “How ironic, is it not? You’re usually the one who consoles me...”

"Hah, alright alright, ya win. I've just been thinking a lot that's all, but I guess I'll spend more time seein' sights as usual.”

"Yee~! There we go! Great idea! Let's walk around Altiel together!"

"I-If you're alright with that, Alyx...?"

"... Heh... sure, why not."

---

(( The Valorous Hearts is back! This is a soft boot; a continuation from the older archive blog, with some tweaks to designs, stories, motives and other details! Most relationships, unless desired otherwise, will remain canon, but some have been redone/adjusted! Some questions can be re-asked, feel free to ask which ones! ))

[lettersfrombasement]

Many neurodegenerative conditions, from glaucoma to Alzheimer’s disease, are characterized by injury to axons — the long, slender projections that conduct electrical impulses from one nerve cell to another, facilitating cellular communications. Injury to axons often leads to neuronal impairment and cell death.

Researchers know that inhibiting an enzyme called dual leucine zipper kinase (DLK) appears to robustly protect neurons in a wide range of neurodegenerative diseases models, but DLK also inhibits axonal regeneration. Until now, there have been no effective methods to modify genes to improve both the long-term survival of neurons and promote regeneration.

In a paper published on December 14, 2020, in Proceedings of the National Academy of Sciences (PNAS), a multi-university team led by researchers at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health identified another family of enzymes called germinal cell kinase four kinases (GCK-IV kinases) whose inhibition is robustly neuroprotective, while also permitting axon regeneration, making it an attractive therapeutic approach for treating at some neurodegenerative diseases.

[doe-clotureofyellow]

Chapter 3, Section 1–The Gathering of Allies; Scene 9

Clôture of Yellow (VG), page 223-227

♠  Germaine, ~the Kingdom of Lucifenia, “Bar”~

.

It was the same bar as always.

I hadn't had any alcohol.

The bar was far more crowded than it was usually.

Two men opened the door and came inside. They were the mercenaries from earlier, named Yarera and Zusco, or something like that. Like before they were making vulgar chuckles, heading to sit at their spot like they owned the place.

"Heh heh, we've come again….What's this, it's awfully packed today. Well, nevermind. Hey Zusco, let's have a drink."

"Sure, big brother…Oi, woman! Bring us some wine!"

The two sat at a table far in, and the barmaid flusteredly brought them their drinks.

After a short time, they began to cause a stir, clearly in a good mood; probably out of being drunk.

Zusco touched the woman who had carried over the wine.

"Hey sweetheart, you've got a nice ass. It's a little big, but that's how I like it."

"P-please stop…"

The woman had started trembling pitifully.

"You don't mean 'Please stop', do you? You mean 'Please harass me some more'! Gya ha ha!"

She withered more and more under Yarera's loud voice.

Just as Zusco began to move his hand towards the woman's breast,

"That's far enough,"

York, who was nearby, seized his arm.

"Wha--what's that, you ass?...Gck!"

York kicked Zusco with all his might, sending him flying towards the wall.

"Y-you asshole!"

I threw a nearby wine bottle at Yarera as he stood.

Magnificently, the bottle hit him right between the eyes.

I drew closer to the fallen Yarera and stomped on his stomach as hard as I could.

"Ugh! Y-you'll be sorry having done this, you bitch…"

Bam!

I knelt to straddle him, ignoring his words and bringing my fist down on his face several times.

Yarera, face having completely swollen up, began to whine, "P-please stop…"

"You don't mean 'Please stop', do you? You mean 'Please harass me some more'!"

Bam! Bam! Bam!

I continued striking him even more.

"You--you bitch! Get off my brother!"

At some point Zusco had run out of the bar, and returned bringing back some of his allies. Six people, including Zusco. They were likely all mercenaries.

"I refuse."

I continued to hit Yarera without paying them any mind.

"D-dumbass! It's six against two! You won't win!" Zusco cried.

I stood and murmured, glaring at the mercenaries, "We aren't just two."

My voice acting as a signal, all the people in the bar stood and surrounded the mercenaries.

"Wh-what's goin on…?"

"You're up against all of the people here."

 .

Many people had gathered in Milanais Square outside the bar. The people inside all headed outside to join them.

"What should we do with this lot?" Marc asked, pointing at the tied up mercenaries.

"Wrap them up and toss them in the river."

I stood before the assembled people and raised my sword to the sky.

They began to cheer.

“Everyone! The time has come!”

When I raised my voice, the cheering grew even louder.

“This entire time we have continued to be made to suffer! By the nobles! By that abominable princess! But that all ends today! Today is the end of everything, and the beginning! Everyone! Do you all have the courage to fight!?”

“YEE--AAAH!”

"Your shields, what are they for!?"

"To protect our beloved families!"

"Your armor, what is it for!?"

"To protect true peace in this country!"

“Your swords, what are they for!?”

“For defeating the Daughter of Evil!”

"Let's go! My comrades! The time for revolution has come!"

“YEEEEE--AAAH!”

The cheers got noticeably louder. And then…

The revolution had begun.

<<prev------directory------next>>

[bookboleynreads]

“A Hurt So Sweet is like a drug, you want the next dose, and it will never (be) enough for you. It plays a cruel game with your mind.” - GCK's Book Review Blog A Hurt So Sweet by Betti Rosewood is now LIVE!! Are you ready for your first dose of beautiful darkness? Dexter is waiting for you. US 🇺🇸 https://amzn.to/2O2LqZp UK 🇬🇧 https://www.amazon.com/dp/B07TJVHBTH AU 🇦🇺 https://www.amazon.com.au/dp/B07TJVHBTH CA 🇨🇦 https://www.amazon.ca/dp/B07TJVHBTH #KindleUnlimited 🅑🅛🅤🅡🅑 ⬇️ If you can't beat the rich boys... F*ck them. Lily Anna Oakes and I share everything. We have the same billion-dollar name, the same designer clothes, and the same messed up problems. But Lily Anna and I will never meet. She died years ago. This town broke her. I’ll burn it to the ground before I let that happen to me. In Eden Falls, I’m forced to attend a school for the elite. The Firstborns own this place and they think they own me, too. It’s not long before Dexter, Caspian, Lai, and Julian become the bane of my existence. There are only two people I’m afraid of – my strict father, and my malevolent fiancé. Unfortunately for me, my husband-to-be is one of the Firstborns ruining my life. Dexter Booth and I will marry on my birthday to secure our families’ bond. Every woman in this damn town wants to be Dexter’s toy. Except me. Dex and his Eden Falls Prep cronies have forced me to give up my body. I know my betrothed wants my mind next. I play along… But soon, I’ll leave the beautiful jerk behind without the thing he wants most from me. His heir.

[cadcnce-archived]

@dissimulxte || because

Wylan has always been frustrated that he’s never been able to break into Mari’s home. Leave it to a career thief such as her to have anti-tampering locks and windows that tell one to fuck off should similar methods be applied. It’s a notable departure from his usual relations with those he meets, a flirtatious friendship marked without sudden appearances, usually involving chilling on the couch or partaking of food or going through lingerie. It was an invite only sort of club, and while the invites came easily and frequently from the purple thief it was still invited. He wishes he appreciated those invites more, appreciated Mari more in general.

Maybe then he wouldn’t be locked on the outside of her vault.

The fault is readily taken on himself, making the first retreat when emotions started to bubble and fester between the pair. Things that were meant to be mutual fun became more... impacting. He panicked, more at himself than Mari, though when he disappeared suddenly one night the damage was still done regardless of what his reasons were. A change of scenery, a new employ with new contracts to handle. The cure all to bad decisions, right?

Except he couldn’t get her out of his head.

She had tried to call him one time. Just once (she wouldn’t try twice). He knows because in a continued fit of empty stupidity he checked the records of the phone he had deactivated and saw her number. Stared at it for awhile for good measure. One of the many things that triggered the surge of regret and disgust he felt within himself for what he had done. Instead of talking. Instead of.... trying something. He just skipped town. The string of reminders (including finding a collar in his things of all the...) culminates in an angered breakdown, leaving a broken apartment in its wake that takes days to clean and put back to normal, including dealing with the complaints from neighbors.

The vault comparison comes when he does inevitably return to see her. She answers the door, sees him, and turns him away with a smile before the door closes again. The entire exchange takes roughly 10 seconds, but the pacing of Wylan’s chest makes it feel like an hour. The way her face takes the shape of a smile, the way it looks at him like he’s no longer anything to her.

So he stands at her door for another minute. The realization taking even longer to set in as he stares at the door. He’d been smiling when he saw her, a pained thing full of regrets and doubts and hope. She was as beautiful and incredible as ever, and perhaps that’s where it started. By comparison Wylan’s hair was out of whack, the shadow on his jaw and chin darker than the one cast by the building as it loomed over him as he stands in the street.

It doesn’t work like in the movies. The set scene in no way compliments what is happening to him. There’s no pouring rain, drops of water beating on his skull and mixing with tears as they shed to the slick concrete. On the contrary it was probably one of the most beautiful days of summer. The birds are singing outside the breezeway and there’s families out for walks in the sun. They’re happy, and completely ignorant of the man around the corner who can barely hold himself together any longer. It doesn’t work like in the movies. Just like last time he thought he could do this. Sorry doesn’t always work. Give me another chance. Goodbye, Wylan.

He’d seen inside her heart, while invited into the vault that was her life, she had dared to open an even deeper treasure to him. And he got scared. He fucking ran. His vision swims and spins as he still stands at her door. He feels his lungs tighten and his body go numb but he doesn’t leave. There wasn’t a plan B here. Then again, Plan A never even got a start before Mari closed him out of the vault again.

Fuck.

His lips quiver and move against each other, opening and closing as silence escapes and his ears ring. Even if he said something he can’t even hear it at first. A shaking hand reaches for the bell, but falls short and brushes off the handle of the door. Fingers curl up to his head, wrenching at brown locks as he tries to keep from yelling.

“No... no no no...” It’s a whine, barely discernible from his breathing as he grips at his head, feeble attempts to keep what little composure he has left. It was always going to be a robbery, but he never expected just how much it was going to be turned on its head. And just how much he was going to lose because of the woman named Mari Lovelace.

I should have killed her.

“Fuck! No!” He spits out, the invasive thought ringing like black in his stricken mind. “Goddamnit. God fucking damnit. FFfffffuck!” His voice is rising now as the panic continues to set in and as the adrenaline from first knocking on the door when he arrived fades out of his bloodstream. He feels the crash, he feels the wetness and the familiar empty and all the shit in his head crashing around him.

“Mari.” It’s still quiet, spoken just a hair away from the door. “Please. Mari.” The more he talks the weaker his composure, every word untying another lace around what he’s managed to build up. “Mari... Mari...” He rests against the door, pressing his ear against the wood, listening for something. Waiting for something. But nothing comes. There may as well have been nobody there. He may as well be talking to himself.

“Please.” It’s been ten minutes since he began conversing with a wooden door. Begging for it to open and give him another chance. The door is as unmoved as Mari was by his return, and still shows no further signs of moving. There’s no sound from inside either, and it could mean Mari left some other way or chooses to ignore him. “I don’t want to leave. I really don’t want to fucking leave.”

Perhaps against his better judgement (not that he has any good judgement left at this point) he tries to pick her lock. With shaking hands he slips in the steel and filed hex that he prefers. The first failure comes quickly, the anti-tampering clamping down. Twice. Three times. It’s impossible at this point for him to be successful, he should know, the steel slip so bent and crooked from the tumblers that they can’t even reach all the way to the back.

“Fuck. No. No no no. God damnit come on.” He’s crying then, throwing a fist at the door out of the rising frustration and tumultuous emotions. Slumping the rest of the way to the ground his forehead thumps against the surface, his hand placed on the panel next. “I’m sorry. Please. I... I swear... I won’t... ff.. gck.” His throat squeezes shut and the tears burst forth in one violent sob. Still nothing changes. The only reaction his emotions getting coming from the odd passerby that looks in, appears concerned, then leaves when they see his face. He’s only left to wonder why he’s trying.

This is hopeless.

[goldenclosetkook]

I'll jump on the bandwagon too I guess (this is love anon).

[luna-reverie]

Gilbert/Jin Parent/Child Supports (C-A)

Jin: Son, do you have a moment? I've been hearing some things…

Gilbert: Yes, of course, father. What sort of things?

J: Well... how do I say this... you seem to keep people at a distance. I'm a bit concerned to be honest.

G: ... G: Ah. I…

J: Sorry to bring this up so abruptly, I don't mean to put you off guard. But I want to know if there's a certain reason for this? Any way I can help?

G: It's just... the... the other kids don't seem to mesh well with my... personality.

J: ...Personality? (Why do I have trouble believing that?)

G: Er--Yes. I'm sorry for an unsatisfactory answer.

J: Well if it counts for anything, I think your personality is amazing. So come on... please tell me.

G: (He saw right through me...) It's, erm. Rather embarrassing for me to admit. Do you remember how when I was young, I always cried when I got angry? G: *sigh* I… still do that. Urgh, I hate to admit it…

J: … J: ...gck… c’mon…

G: Father…? Are you alright?

J: I need... to show you... men can cry too… *sigh* Nothing is coming out… Where's your mother?

G: Mother? Wh-Why? What does she have to do with this--

J: I trust she'll help me cry so I can set a good example for you. Where can she be…

Jin: (Hmm... nothing has been working so far. I guess I'm just too tough to cry on my own. I need someone else to push me into it.) J: (There's Gilbert now! Quick, quick...) You! Soldier man! You're a commoner! W-wait... no... Come back...!

Gilbert: Father? What are you doing?

J: *sigh* Hello, son. I'm just trying to pick another fi- I mean, uh... start a conversation with the commoners.

G: Pick another... fight? Why are you trying to start fights? That's not like you, father. (Most of the time anyways.)

J: Ah ha, I suppose not... I guess… Well, out loud it sounds odd, but I guess I just want to cry for you.

G: You--You don't have to do that! (It was bad enough when you tried to get mom to yell at you...)

J: Don't I? It's probably my fault you're ashamed of your feelings... I need to set a good male role model! It’s... It’s bad enough I wasn't there for your childhood…

G: N-No, it's not you! …Father… I just... *sniff* I just…

J: Gilbert… you're finally… I'm so sorry. It's ok to let it all out, I'm here now.

G: *sniff* I-I want to be someone y-you can be proud of! *sob* I'm a prince, I c-can't... shouldn't cry this easily! *sob* G: What i-if I get so angry during a meeting th-that I start crying!? I'd n-never live it down!

J: I understand that fear all too well, it's something us royals seem to be cursed with… J: But I'll tell you this. It's nothing to be ashamed of. Surprisingly, your followers will look to you as an even more dependable leader that they can trust as a fellow human. J: *sniff* Crying means you're passionate, and that's something we need in great leaders like you. I'm so proud of you every day, you have no idea...

G: …!! R-Really? I won’t be seen as weak? *sniff* Father… th-thank you. I n-needed to hear that.

J: You are a strong warrior, who will become a great leader one day. I would never see you as weak, and I'm glad I could help. I love you, son.

Gilbert: Father? Are you in here?

Jin: Hm? I'm here, what can I do for you, son?

G: I just wanted to say thank you for trying so hard for me.

J: You're welcome. Honestly though, I'm happy you were able to open up and tell me what was bothering you. I just wish my original plan had worked…

G: Th-That's okay. There's something I've been meaning to tell you since the other day, actually…

J: Oh? What would that be?

G: You... you have been a good role model, father. I really look up to you. And I admire your relationship with mother, how in love you still are despite years apart.

J: I love your mother so much, I don't think any amount of time apart could separate us… J: But thank you, that's actually really reassuring to hear… I want to do everything for my family… You, Rhyne and your mother… and to know that I'm doing a good job... *sniffle*

G: And... I never blamed you for not being with me my whole childhood. I know the war has taken up all your time. Actually, it spurred me to start training, so when the time was right I could come help... and then I'd be with you and mother.

J: Gilbert... oh gods, I'm finally crying... but I'm just so happy you understand... You're such a strong soldier now, I couldn't be any prouder of you.

G: Haha, dad stop, you'll set me off too!

J: Ah ha... my apologies, but I'm just so happy!! I love you so much, Gilbert. Look! We can finally cry together, like a father and son should.

G: I love you too, dad.

[juniperpublishers-endocrinology]

Clinical Feature and Mutation Analysis of Glutamate Dehydrogenase (GLUD1) in Three Chinese Patients with Congenital Hyperinsulinism- Juniper Publishers

Abstract

Aim: To summarize the clinical feature and analyze the gene mutation for three pediatric patients with congenital hyperinsulinism (CHI) and hyperammonemia (HA).

Methods: Three Chinese pedigree of CHI-HA in Peking Union Medical College Hospital from 2009 to 2012 was analyzed for the clinical features and laboratory data. DNA sequencing was performed to identify mutation in ATP binding cassette subfamily C member 8 (ABCC8), potassium voltage-gated channel subfamily J member 11 (KCNJ11), glutamate dehydrogenase 1 (GLUD1), glucokinase (GCK) and INS gene in the pedigree.

Results: Besides CHI-HA, all patients suffered various degree of neurodevelopment disorders, with mean birth weight of 3.15kg and delay onset of 6.0 months at average. Two patients presented mutation of c.1493 C>T (p. S498L) in exon 11 and one patients confirmed mutation of c.968 G>A (p.S269H) in exon 7 in GLUD1 gene. We did not detect any mutation inABCC8, KCNJ11, GCK, and INS genes. Leucine limited dietary therapy and diazoxide were responsive for all patients.

Conclusion: GLUD1 mutation was one common cause of CHI-HA and early molecular diagnosis was of great importance.

Keywords: Congenital hyperinsulinism; Hyperammonemia; DNA mutation analysis; Glutamate dehydrogenase

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Introduction

Congenital hyperinsulinism (CHI), or persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a genetically heterogenous disease with mutation of eleven genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF1A, HNF4A, SLC16A1, UCP2, HK1, PGM1) [1,2]. Gain of function mutation of GLUD1 is the second commonly seen genetic defect for CHI, characterized by hyperinsulinemia-hyperammonemia (HIHA) syndrome [3]. GLUD1 mutation can be sporadic de novo mutation or inherited in autosomal dominant pattern. Phenotype of GLUD1 includes relative mild symptomatic hypoglycemia and leucine sensitive insulin secretion as well as asymptomatic hyperammonemia [3].

GLUD1 encodes the intramitochondrial enzyme glutamate hydrogenase (GDH), of which the common mutation locus includes allosteric GTP binding domain (exon 11 and 12), catalytic domain (exon 6 and 7) and antenna-like structure (exon 10) [4]. GDH is involved in glucose-stimulating insulin secretion by catalyzing glutamate to α-ketoglutarate and ammonia, finally generating ATP to trigger insulin release in pancreas β cells. GDH can be activated by ADP and leucine and inhibited by GTP and ATP at normal physiological condition. Gain of function mutation results in excessive secretion of insulin by activating GDH via decreasing the sensitivity for GTP. Also, lack of a glucagon response was found in alpha cells in impaired counter-regulation of hyperinsulinism via mitochondrial GTP signal pathway generated by GDH in β cells, contributing to symptomatic hypoglycemia [5].

Thus, children with GLUD1 mutation often have recurrent symptomatic hypoglycemia and persistent asymptomatic hyperammonemia. The phenotype is usually associated with normal birth weight, delayed age of presentation and higher risk of seizure compared to other subtypes of CH [4,6]. Excessive release of ammonia can also be detected in patients with GDH mutation, which usually elevated 3~8 times than upper limit of normal [7]. Fortunately, most of patients were responsive to diazoxide and could alleviate by protein-limit diet [4].

In recent years, some articles reported mutation analysis for GLUD1-HIHA, which focused on mutation in exon 6,7,10,11 and 12 [8-11]. Our aim was to analyze clinical character and genome mutation for three pediatric patients with HIHA and provide more evidence for genetic diagnosis and treatment in the future.

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Materials And Methods

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of Peking Union Medical College Hospital. Informed written consent was obtained from all patients before their enrollment in the study.

Patients

We enrolled three patients diagnosed with glutamate dehydrogenase congenital hyperinsulinism in department of endocrinology, Peking Union Medical College Hospital (PUMCH) from December 2007 to December, 2012. The diagnostic criteria included detectable concentration of insulin and/or C peptide in serum when blood glucose is lower than 3mmol/L, with inappropriately low concentration of free fatty acids and ketone bodies [6,12]. After diagnosis of CHI was made, patients were treated with protein-limited diet at first. Two patients treated with diazoxide and protein-limited diet. One patient was treated by leucine limited diet alone. Peripheral blood samples (3ml, EDTA-anticoagulant tube) were collected from each patient.

Genomic DNA was extracted from peripheral leukocytes using whole blood genome DNA Rapid Extraction Kit (Biomed Co. Ltd, Beijing, China) according to the manufacturer's instructions. Mutation analysis was conducted using polymerase chain reaction (PCR), and PCR products were sent to Sino Gene Max Co. Ltd, Chinese National Human Genome Center (Beijing, China) for direct DNA sequence analysis. Sequencing reactions were analyzed on the Applied Biosystems 3730x lDNA Analyzer and compared with published sequences using online database of University of California, Santa Crus (http://genome.ucsc.edu/ cgi-bin/hgBlat).

The primers to amplify the ABCC8, KCNJ11, GLUD1, GCK, and INS gene sequences were designed by the Primer 5.0 software. The sequence of the primers is listed in Supplementary Tables. The patients were screened for mutations in the 39 exons of ABCC8 gene; the untranslated regions and the exon of the KCNJ11 gene; the 6, 7, 8,10, 11, 12 exons of GLUD1gene; 10 exons of the GCK gene; and the 1,2 exons of INS gene. The primer sequence for PCR referred to Supplement Table 1. We searched for single nucleotide polymorphism (SNP) in database of dbSNP137, 1000 Genomes and human Exome Aggregation consortium (ExAC). We also searched for reported mutation in human genome mutation database (HGMD). The effect of amino acid substitution on protein function was predicted using Mutation Taster (http:// www.mutationtaster.org/), SIFT

(http://sift.jcvi.org/www/SIFT_BLink_submit.html) and Polyphen-2 (http://genetics.bwh.harvard.edu/pph2/) bioinformatic tools. All gene mutational analyses were performed for participants.

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Results

Patient demographics

Basic information for three eligible participants was shown in Table 1. All three patients were Han Chinese. Patient 1 and 2 came from northern China while Patient 3 was from the southern. All patients suffered from protein-sensitive hypoglycemia and asymptomatic hyperammonemia. Patient 1 and 3 presented convulsion and cyanotic lip. Patient 1 developed frequent unconscious and extremity convulsion, who was later confirmed partial epilepsy by electroencephalogram (EEG). Patient 1 presented delay development with mental retardation and speechless at the age of two years. Patient 2 presented muscular fasciculation at extremities and declined attention at one-year old and then developed mental retardation five years later. Patient 3 had recurrent convulsion and cyanotic lips for one weeks and fortunately received protein-limited diet and diazoxide treatment in hospital. Patient 3 was additional exanimated mild communicating hydrocephalus and right frontal subdural effusion by cranial computed tomography. EEG was conducted for patient 2 and 3, and revealed normal results. Parents of all three patients were healthy, denying family history of hypoglycemia. Grandfather and great-grandmother of patient 2 suffered from diabetes at the age of fifty. Pedigrees of three patients were shown in Figure 1(Supplement Table 1).

F: female; M: male; Blood insulin and ammonia concentration were determined at the presence of hypoglycemia respectively. Nt (nucleotide) and AA (amino acid) change indicated nucleotide codon position numbering.

After CHI-GD diagnosis was made, one patients alleviated by leucine-limited diet and two patients was treated with diazoxide 5mg/kg^d'1. The leucine limited diet was design by experienced nutritionist in PUMCH. Both patient 1 and 3 were responsive to diazoxide. For patient 1, his fasting blood glucose level ranged 4.0 to 5.0mmol/L, and postprandial blood glucose ranged 4.4 to 5.5mmol/L after 50mg diazoxide administration twice a day in combination of leucine limitation diet. And the fasting blood glucose was 4.4mmol/L after 5mg diazoxide administration once a day for patient 3. For patient 2, we designed several leucine limitation diets and found the diet with leucine 16mg (sugar free yogurt 125ml, beef 5g, carbohydrate 50g, 212kcal in total) resulting in proper postprandial blood glucose (3.4 mmol/L).

Mutation analysis

As shown in Table 1 & Figure 2, S498L mutation was detected in Patient 1 and 3. Missense mutation of R269H was detected in Patient 2. For patient 1, genotype of parents was normal indicating that the S498L mutation was de novo. As for Patient 2, blood sample of mother was not available and we collected samples for father and grandmother. They had normal genotype, which suggested the mutation inherited from mother or was de novo. Blood samples of parents of Patient 3 were not available thus it was difficult to determine the origin of mutation. Mutations in S498L and R269H was reported in previous studies [9,10] and protein function prediction suggested highly conserved and pathogenesis mutation, indicating functional significant residues.

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Discussion

In our research, clinical manifestation was heterogenous in regard of age of onset and severity. The mean presentation age was 6.0 months and mean birth weight was 3.15kg without macrosomia. They also presented asymptomatic hyperammonemia. Except for persistent HIHA, three patients had common clinical manifestation of convulsion and neurodevelopmental damage. Mutation analysis revealed amino acid position mutation of S498L in patient 1 and 3 while R269H was found in patient 2.

In recent years, some articles reported mutation in exon of GLUD1 in GDH-CHI children, of which the amino acid position includes S217C, H262Y, R269H, H315Y, Y319H, N410I, N410D, R443W, I444M, S445L, D451V, N463Y, S498L, A500T, H507Y [4,7-11,13-15] etc. Among more than ten kinds of mutation location, R269H in exon 7 was the most commonly seen and was highly conserved among species, indicating functional important residue. In Chinese population, ABCC8 and KCNJ11 are the most common mutation genes in CHI [16]. Relatively fewer cases of GLUD1 mutation was reported in Chinese population. During past decades, less than 10 cases reported GLUD1 mutation in Chinese children [8,10,13,17,18]. In our study, patient 2 had arginine to histidine substitution at position 269 within the catalytic domain of exon 7, which was one of common mutation site of GLUD1. We detected mutation of adenosine to thymine at position 1493 resulting amino acid change of serine to leucine at position 498 within GTP binding domain in exon 11 of patient 1 and 3. From our point of view, it was suggested mild hypoglycemia at the early stage might lead to delay diagnosis of GDH-CHI as well as the development of mental retardation later. Therefore, it is of great importance for early recognition and gene analysis and in CHI patients. In addition, oral leucine tolerance test is helpful for diagnosis.

It was noteworthy that higher frequency of neuro developmental disorder, especially seizure and learning disability, was reported in GLUD1 mutation than other genes [2,4,19]. Pyramidal signs and dystonia were also reported in some patients [19]. To be more specifically, recent studies reported mutation in exon 6 and 7 increased the risk of childhood onset epilepsy [10]. Some researcher explained that overactivity of GDH disturbed the balance of two neurotransmitters (glutamine andgamma-aminobutyric acid) levels in cerebral spinal fluid, which played major roles in brain development [19]. What's more, hyperammonemia and hypoglycemia might also be involved in neurological impairment. Recent research reported sirtuin 4 (SIRT4) inhibited GDH in mitochondrial of glia cell, resulting in down regulation of gliogenesis [20]. It might be part of pathological mechanism for neurodevelopmental disorder in GDH-CHI patients, but further study remained in need to explore the detailed neurological phenotype and genotype relation. For patient 1 and 2, due to delayed diagnosis of HIHA, they had neurodevelopmental disorder several years later during infancy. Patient 2 presented convulsion but dynamic EEG revealed normal, with R269H substitution at exon 7, suggesting significant necessity for follow-up of epilepsy Defect of brain development was found in patient 3 but presence of HIHA was as short as one week. In our view, GLUD1 mutation might not sufficient to explain the severity of brain damages, including communicating hydrocephalus and right frontal subdural effusion. Further examination should be done to differentiated other possibility for severe brain damage for him. Some research reported neurodevelopment disorder could relieve as they grew up with well-controlled diet and blood glucose [21-23]. Thus, neurodevelopmental symptoms should be focused and monitor during long-term follow-up.

Treatment for CHI can be divided into two parts: elevation of blood glucose level and decrease serum insulin. For hypoglycemia, intravenous glucose therapy was usually required to maintain plasma glucose in a normal range, especially when acute severe hypoglycemia episodes occurred. Dietary therapy consisting of low leucine and high carbohydrate is helpful to reduce both the frequency of hypoglycemic episodes and requirement for intravenous glucose. For patients with mild disease, appropriate diet could be enough for glucose control. What's more, fortification of human milk with adequate protein is needed for growth for infants aged 0 to 12 months [24]. For reduction of serum insulin, typical pharmacological therapies included diazoxide, octreotide and glucagon. Diazoxide, a K-ATP channel agonist inhibiting release of insulin from pancreas, is the first-line agent for CHI patients. Inspiringly, most patients with GLUD1 mutation were responsive to diazoxide both in Chinese population and other ethnic groups without K-ATP channel mutations [2,16,17]. In our research, for patient 1 and 2, we decided dose gradient leucine diet to determine appropriate ratio of protein and carbohydrate, which also indicating dose dependent effect for leucine induced insulin secretion. For patient 1 and 3, diazoxide was also used and dosage was monitored based on blood glucose. Blood glucose was under control and frequency for convulsion decreased for all three patients. Thus, we suggested protein-limited diet to be initial treatment for GDH-CHI patients and diazoxide could start for better glucose control. Pharmacologic and dietary therapy are often successful for glucose control for GDH-CHI patient. Follow- up study for these three patients are undergoing to evaluate the treatment outcome in Chinese population.

In conclusion, we detected GLUD1 mutation in three CHI patients, which improved the genotype-phenotype knowledge for better prognosis and treatment for Chinese population. Overall, early diagnosis, evaluation and appropriate management are essential to avoid the neurodevelopmental consequences including epilepsy and learning disabilities for GDH-CHI children. Genetic analysis and counsel should be conducted early for both affected and suspected patients as well as their pedigree.

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Acknowledgement

The authors thank all colleagues of the department of endocrinology for meticulous diagnosis and care for three patients. The authors also thank the patients and their families participated in the study for their continuous support.

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