#nonsense mediated decay

[medicomunicare]

Splicing alternativo dell'RNA: importante per la diversità proteica ma anche per l'espressione genica

Splicing alternativo: un anagramma biologico Lo splicing alternativo è un processo fondamentale nella regolazione dell’espressione genica e della diversità proteica. È un processo post-trascrizionale che consente a un singolo gene di generare più varianti di mRNA e quindi di produrre proteine ​​diverse, attraverso la selezione differenziale di esoni e introni durante il processo di splicing…

[rnomics]

Biomolecules, Vol. 14, Pages 1023: #RNA Surveillance Factor SMG5 Is Essential for Mouse Embryonic Stem Cell Differentiation

Nonsense-mediated #mRNA decay (NMD) is a highly conserved post-transcriptional gene expression regulatory mechanism in eukaryotic cells. NMD eliminates aberrant #mRNAs with premature termination codons to surveil transcriptome integrity. Furthermore, NMD fine-tunes gene expression by destabilizing #RNAs with specific NMD features. Thus, by controlling the quality and quantity of the transcriptome, NMD plays a vital role in mammalian development, stress response, and tumorigenesis. Deficiencies of NMD factors result in early embryonic lethality, while the underlying mechanisms are poorly understood. SMG5 is a key NMD factor. In this study, we generated an Smg5 conditional knockout mouse model and found that Smg5-null results in early embryonic lethality before E13.5. Furthermore, we produced multiple lines of Smg5 knockout mouse embryonic stem cells (mESCs) and found that the deletion of Smg5 in mESCs does not compromise cell viability. Smg5-null delays differentiation of mESCs. Mechanistically, our study reveals that the c-MYC protein, but not c-Myc #mRNA, is upregulated in SMG5-deficient mESCs. The overproduction of c-MYC protein could be caused by enhanced protein synthesis upon SMG5 loss. Furthermore, SMG5-null results in dysregulation of alternative splicing on multiple stem cell differentiation regulators. Overall, our findings underscore the importance of SMG5-NMD in regulating mESC cell-state transition. https://www.mdpi.com/2218-273X/14/8/1023?utm_source=dlvr.it&utm_medium=tumblr

[orderoftheturningeyes]

intro

Hello! my name is Larch🌈

She/her, bi-curious

this is just going to be a little personal blog documenting my wild and unconventional life. I am 23 years old as of writing this. I live with five roommates and we are all part of a small neo pagan religion worshiping a god of our own creation to cope with the nonsense of the world using our own rules. No we are not a cult, we all have different interpretations and ideas, and we write them all down in a big list and have weekly meetings to discuss what ideas we turn into practices. The only constant is our god, Mother Orev, not to be mistaken for human Orev, who lives here too.

Our current practices include:

Mediating under the moonlight by running water

Paying tribute to the mushrooms by composting all our food

Dancing in the rain, the stormier the better

Revering all things bones and decay and forever holding in our hearts that the earth will consume us all one day

Channeling Mother Orev through communion with the birds and the frogs and the moths

Taking baths filled with roses and spice to show our appreciation for life

That's all! I'll mostly be posting about little personal things about my daily life living like this.

PS. Other people in the house might post here too! if they do, I've told them to give a little intro, so you'll know who's talking.

[ribosome-papers]

SMG1:SMG8:SMG9-complex integrity maintains robustness of nonsense-mediated mRNA decay

bioRxiv: http://dlvr.it/T5YgM9

[pasunepipette]

god I wish that were me

(side note: intro molecular bio courses need to start explicitly saying that most premature stop codons will result in nonsense-mediated decay, NOT a truncated protein...this is important and hard to unlearn!)

[daily-dose-of-imagines]

ᴊᴏᴇꜱᴛᴀʀ ꜱʏɴᴅɪᴄᴀᴛᴇ | Yakuza!AU | Head Canons | 19+ [𝕁𝕁𝔹𝔸]

[JOESTARS] [JOBROS i] [JOBROS ii] [JOBROS iii] [JOBROS iv]

Here is the next part to the headcanons~! I’m so happy you guys like this so much! ;; I’m excited to write more for this AU~! After this it’ll be one more Jobros and then the one-shots, drabbles, etc will follow through~!

» » Admin Ko

»»————-　♔　————-««

𝕆𝕜𝕦𝕪𝕒𝕤𝕦 ℕ𝕚𝕛𝕚𝕞𝕦𝕣𝕒 [21]

Josuke’s most trusted right hand man. Though many within Josuke’s faction really question whether or not the psychologically unstable male should be the right hand man. With the onslaught of crimes and cynical things the man has done, they’re surprised he isn’t one of the torturers or clean up men. 

Within a week, however, their minds change at how utterly fast the male reacts to a threat made to the Higashikata. From then, no one really questions why Okuyasu is the right hand instead of Koichi. 

Besides being the right-hand, Okuyasu is Josuke’s most trusted bodyguard. All of the Joestar siblings know and recognize this and honestly don’t even try to go against the young male.

One of the most terrifying assassins within the group, and is recognized by Lisa Lisa as a man with potential and power to make his enemies cower.

He honestly feels indifferent about all of Josuke’s siblings and makes decent conversation with most of them. 

Out of all the commanders within the younger Joestar line, he’s well acquainted with practically all of them and has no problems when both he and Josuke visit Giorno or Jolyne.

𝕂𝕠𝕚𝕔𝕙𝕚 ℍ𝕚𝕣𝕠𝕤𝕖 [20]

The literal brains and planner of the Higashikata faction. 

He is literally the most trusted man who keeps connections between Giorno and Josuke.  Every other week he’s usually sent to Italy to update the Don on the happenings at the main base along with any of the commotions that may have occurred that he should keep an open ear for.

Alongside Yukako, the pair make a rather deadly assassin duo. His skill with quick tactical deductions and quick thinking pairs well with her inhumanely quick reflexes and desire for blood as they’ve taken out quite a number of individuals that were planning on trying to overtake the small town of Morioh.

Besides being one of the main assassins, he’s also one of the main interrogators alongside Rohan. He may not seem like it at first, but Koichi takes immense pleasure in seeing the victim mentally break before him. The information that falls out of the victim always being written at great speeds by Rohan. 

ℝ𝕠𝕙𝕒𝕟 𝕂𝕚𝕤𝕙𝕚𝕓𝕖 [25]

A stick in Josuke’s side, but still a crucial person to the Higashikata team.

In all honesty, both he and Josuke are usually at each other’s throats because of the clash of personalities. Though when they work their differences out on rare occasions, they are definitely a force to be reckoned with.

The main source of information and stalker expertise. He had actually traveled to Italy on a couple of occasions and took lessons from both Leone and Bruno in the art of watching and shadowing a target for information. 

Besides being the informant, he absolutely loves to interrogate people. His dislike of getting himself dirty though leaves Koichi with the more heavy duty portion of the job, but always provides the younger with the most amount of information and will do any favors asked without a moment’s hesitation. 

He personally doesn’t consider himself friendly, or to even have friends; but he does consider the Higashikata gang--- really the Duwang gang-- as his home.

𝕐𝕦𝕜𝕒𝕜𝕠 𝕐𝕒𝕞𝕒𝕘𝕚𝕤𝕙𝕚 [21]

Similar to Rohan, she isn’t necessarily on the best of terms with Josuke. Though it was immensely worse when they had first met. Now, they’re on better speaking terms but still there’s an unsettling tension between the two if there’s no one there as a mediator. 

The Duwang gang’s number one assassin. Her shadowing and quick kill skills are rather legendary within the Duwang gang. Whenever she visits the main base she takes lessons with Lisa Lisa, and like Rohan, had visited Italy on more than one occasion to improve her shadowing technique from Bruno and Leone.

Her skills lie mostly in sniping and quick strangulation via fishing line. She once used her own hair and relished in the fact, but found it to be too risky as she didn’t want to leave any evidence behind. 

Out of all the members, she works the best alongside Koichi and gets the most done with him. 

𝔹𝕣𝕦𝕟𝕠 𝔹𝕦𝕔𝕔𝕚𝕒𝕣𝕒𝕥𝕚 [25]

Giorno’s most trusted man. Literally everyone in Passione and the Joestar family trust this man. 

Despite being the main cause of Passione’s previous leader’s downfall. He choose to not take the position of Don. Instead, felt that it would be better if he stood alongside someone with strong ideals and beliefs in their own work and dreams. 

He is the most skilled in assassination with high respect from Lisa Lisa. He does like to teach any of the newer recruits any necessary skills, and is always open to having guest commanders from other factions over to learn from one another. 

Easily one of the most feared men within Passione. 

𝕃𝕖𝕠𝕟𝕖 𝔸𝕓𝕓𝕒𝕔𝕔𝕙𝕚𝕠 [26]

Similar to Rohan with Josuke, Leone is not on the best terms with Giorno. The only difference is that this is a one-sided relationship as Giorno tries hard to appease everyone within his faction in terms of respect. 

Second to Bruno, he is the most feared member within Passione. Mainly because of his no nonsense attitude and ability to crack a man’s skull open with only three hits. 

He is one of the main assassins that’s sent out to get rid of competing gangs. 

Prefers to work alongside Bruno whenever he can, but doesn’t mind working with the other members. 

𝔾𝕦𝕚𝕕𝕠 𝕄𝕚𝕤𝕥𝕒 [23]

Besides having tetra-phobia, he is one of the best marksman within Passione, falling second to Johnny Joestar. 

Despite being one of the more casual and laid-back member, he is quite the force to be reckoned with out on the field. 

He most definitely leaves an impression on the Joestar family when they first meet him and become absolutely surprised at how well he manages to hold up against Johnny in a marksman competition. 

Besides Leone, Guido is one of the other assassins that helps to not only deal with threats to Passione, but threats to the Joestar family. 

Out of all of the members, he works the best alongside Narancia and Giorno (Though Giorno rarely goes on missions now because of the amount of work he has now.)

ℕ𝕒𝕣𝕒𝕟𝕔𝕚𝕒 𝔾𝕙𝕚𝕣𝕘𝕒 [22]

The most chaotic and one of the most unstable members within Giorno’s chain of command. 

Despite his age and how he looks, Narancia is a seasoned veteran in the field of torture and death. 

Absolutely, positively loves to cause misery and despair to his enemies and will undoubtedly torture them for his own personal pleasure if he has the spare time to do so. 

Besides being one of the assassins, he’s also part of clean-up duty with Trish and helps bring back any bodies that can later be used as autopsy and study material for the forensics analyst. 

ℙ𝕒𝕟𝕟𝕒𝕔𝕠𝕥𝕥𝕒 𝔽𝕦𝕘𝕠 [23]

The second unstable member within Giorno’s chain of command. Unlike Narancia, his bouts of insanity stem mainly from emotional stress. 

He’s the team’s medic, strategist, and interrogator. He most definitely enjoys ripping information out of victims, and has no qualms in using inhumane methods in gathering that information. 

He mainly works alongside Giorno and Trish when it comes to anything pertaining the medical field. 

Besides working within the medical field, Fugo absolutely loves to work with dangerous poisons and bacteria that’ll leave the victim in absolute pain. 

As unlikely as it would seem, he works alongside Cioccolata much more than one would expect. 

𝕋𝕣𝕚𝕤𝕙 𝕌𝕟𝕒 [21]

The clean-up crew. Despite her appearance and no nonsense attitude, Trish loves to learn various ways of getting rid of a corpse as well as how the human body decays with time. 

Her extensive research in the decaying process and experimentation process with...live test subjects help further the connections that can be drawn to Passione and the Joestar family. 

Not only that, but it makes for a very nice item on the market to help smaller ‘businesses’ get rid of any threats they deem worthy of her work. 

She enjoys working alongside Fugo and Narancia whenever she gets the chance to.

Definitely teases and makes fun of Guido when she works alongside him, and won’t hesitate to yell at him if he happens to wreck a potential test subject.

[collapsedsquid]

Good thing I don’t know any russian agents so my hottest new secrets in the field of nonsense-mediated decay in trypanosomes won’t be compromised.  It would be disastrous for US policy if those were compromised

[jobrxiv]

Postdoctoral Position at Washington University - Genotoxic Stress, RNA surveillance and Cancer Washington University in St. Louis, School of Medicine Application Deadline: 2022-12-28 A postdoctoral research associate position is currently available in the laboratory of Dr. Zhongsheng You in the Department of Cell Biology and Physiology at the Washington University School of Medicine (WUSM) in St. Louis, USA. WUSM provides a superb research and training environment and is consistently ranked among the top medical schools in the country. The You lab investigates cellular responses to genotoxic stress with the goal to better understand and treat cancer. A current focus in this area is to investigate an emerging role of intracellular Ca2+ and Ca2+ signaling in the replication stress response and the DNA damage response that are essential for genome protection and tumor suppression (Li et al., Mol Cell 2019; Li et al., under review). Our lab also studies RNA surveillance mechanisms in cancer, focusing on the nonsense-mediated RNA decay (NMD) pathway. A major focus in this direction is to develop innovative tools for NMD analysis, and to explore the interplay between NMD... See the full job description on jobRxiv: https://jobrxiv.org/job/washington-university-in-st-louis-school-of-medicine-27778-associate-professor/?feed_id=23100 #ScienceJobs #hiring #research #ScienceJobs

[sundayswiththeilluminati]

BG Sultai Guide

Faction Name: No internal name. Outsiders have yet to agree on whether this faction should be considered a kingdom or a single growing, slithering being. It’s called variously “the Beast,” “Silumgar’s Hold,” “the Rotted Lands,” or simply “the Mire.”

Dragonlord: Silumgar, the Creeping Death, the Great Beast

Dragonlord’s Seat: The Palace Animate, sited in the oldest part of the Rotted Lands and the first region the dragonlord claimed, given the name “Weeping Heart” by the Sultai who watched in confusion at its transformation before it claimed them too. Silumgar’s body rests within the throne chamber on a great couch of jade, surrounded by heaps of treasure overgrown with vines and rot. His mind and will, however, are manifest everywhere within the Rotted Lands, and he is aware of everything that occurs within. Wherever an emissary of the Mire goes, Silumgar’s desires go also.

Brood Magic: Silumgar’s will creeps and corrupts, ensnaring the thoughts until his target realizes too late that their mind is no longer their own. Dragons of Silumgar’s brood have this power of mental contagion and dominance. Their breath weapon is a corrosive mist. They are masters of necromancy, curses, and poisons. The most powerful of the brood can shapeshift. Non-dragons are often imbued with temporary magic to perform various tasks, but their power is severely limited. The rakshasa groups that failed to leave in time are kept under Silumgar’s direct control and allowed to continue practicing their own demonic magic, so long as they do so in firm accordance with their dragonlord’s will.

Faction Species: Primarily human, orc, naga, vampire, and demon. Most rakshasa abandoned the Sultai before they could be subsumed, but Silumgar managed to seize a few weaker clans, Pockets of every species on Tarkir - even dragons of other broods - can be found among those ensnared by Silumgar’s will. Sibsig (zombies) are common. A number of elementals have also arisen within the Rotted Lands.

Faction Structure: The new BG Silumgar are bad news. Trust me, you don’t want to get involved. The corrupt, decadent hierarchy of the Sultai crossed with the swarm nature of the Golgari yields a bizarre half-hivemind half-dictatorship that no one enjoys except the few on top. It’s a bit like the Zerg in that individuals are subservient to a collective mind, but there are levels of control similar to a military hierarchy. Factions exist within the swarm that battle for resources and control; indeed, this competition is encouraged, as it improves the collective survival by culling the weak and forcing evolution. Imagine the ferment and constant decay/growth of a tropical rainforest, the eternal pressure of competing organisms with no concept of morality or restraint. The collective acts like The Thing from the John Carpenter movie: it has no awareness of a difference between living and dead biomass, no understanding or interest in the pre-existing organisms - it sees only resources to be utilized.

Individuals being mentally subsumed into the hive don’t appear changed at first, and even close companions may not notice the infection in their thoughts. Subtle alterations in vocal patterns, sleep habits, and eating habits are the first outward signs. Once the mental contamination has taken hold, the individual voluntarily submits to physical incorporation into the swarm, mediated by the implantation of tendrils similar to vines or roots that grow through the individual’s existing nervous system to allow direct physical control should the collective will deem it necessary to override local thought processes. When swarm individuals interact, these tendrils will emerge from their bodies and join together into a larger network for the swift exchange of nutrients, pheromone signaling, and sensory information. Later stages of incorporation, depending on the needs of the collective, may make it necessary to alter the individual, break it down entirely for parts or resources, or combine it with others to create a tool suitable for the given purpose.

Silumgar grants a select few individuals a degree of physical and mental autonomy in order to preserve useful skills. Those rakshasa who failed to leave the Sultai in time and fell under his influence are allowed physical autonomy and permitted to keep some control of their own minds so they can continue to practice the powerful demonic magic they shared with the Sultai. Wary of that power, Silumgar monitors them directly and does not hesitate to cull any who show the slightest rebellious tendency. The few subsumed dragons of the Mire also retain some level of their original thoughts and skills, but have been imbued with utter loyalty to their new dragonlord.

No member of the collective is permitted a truly individual identity; the only name ever spoken in the Rotted Lands is that of Silumgar.

Faction Goals: Live. Grow. Take. Change. Kill. Eat. Grow. Live.

Faction History: Nothing distinct remains of the Sultai’s culture, history, or most of the population. Palaces and wealthy estates have been abandoned except for the occasional expedition to extract a needed resources. Many of the original settlements remain as twisted echoes of their former selves, farms and fisheries still worked by the remnants of the inhabitants in great drone swarms. Any unnecessary items or information - scrolls or tapestries of history, for instance - were ignored by the collective and have long since crumbled back into the jungle.

Silumgar himself didn’t conquer the Sultai directly. He didn’t need to. He is called the “Creeping Death” for the nature of his own will, which spreads and corrupts those he seeks to control. Newly-born, Silumgar found the riot of growth and decay and violent symbiosis exemplified by the deep jungle greatly to his liking. He selected an area then uninhabited by the Sultai due to its unpleasant climate and tenacious jungle life, and settled himself in the heart of it, fixing his will on seizing it as his territory alone. This patch of rainforest soon began to exhibit unsettling changes: Sultai travelers and scouts reported previously-unseen beings that seemed part plant and part animal, creatures that should have been mortal enemies working together in eerie, silent harmony, and the rapid spread of unknown plant life out from the area. Sultai rulers dismissed these accounts, however, interpreting the odd behavior as some new elemental magic in the region and receiving reassurances from the rakshasa that it certainly posed no threat to them. Soon the travelers and scouts stopped reporting back at all. 

The corruption in the heart of the jungle grew, and whole estates began to disappear into its shadow as Silumgar consumed, killed, created, and grew more and more. Some Sultai, especially those farthest away from the corrupted zone now called Weeping Heart, tried to raise the alarm. But the usual indolence and callousness of the Sultai elite masked the transformation in their thoughts long enough for Silumgar to take hold. By the time anyone thought to take action, the dragonlord already controlled the bulk of Sultai territory and resources, including its combination labor force and army of undead sibsig, and any sparks of true resistance that could not be converted by thought were simply crushed by force. The entire population unlucky enough to be present in Sultai territory at that time ended up dead, subsumed into the collective, or both.

Upon realizing what was happening to him, Tasigur, khan of the Sultai at the time of the takeover, sought out the dragonlord within Weeping Heart and threw himself at Silumgar’s feet. He claimed he would order his people to submit to their new master in exchange for keeping his own mind - which Silumgar granted. Unfortunately, Tasigur forgot to ask for his own body, too. He survives - in a manner of speaking - to this day; he retains full possession of his thoughts and memories, unclouded by the dragonlord’s influence, but his body is quite firmly controlled by Silumgar’s magic and serves as his favorite emissary. For the first hundred years or so it amused the dragonlord to permit Tasigur to keep his own voice as well, and the khan’s screams and insane raving were a common sound in Weeping Heart; but Silumgar eventually grew bored and removed Tasigur’s vocal chords, leaving him mouthing silent nonsense and endless pleas for death even as his body goes about its dragonlord’s errands.

Faction Relations: The Rotted Lands might be the only thing on Tarkir the other factions can all agree on: they’d rather leave it alone. Silumgar’s influence expands as the Rotted Lands grow, and those who cross too close to his territory can’t let themselves linger long for fear that the dragonlord’s whispers will take root in their hearts and lead them to walk into the jungle of their own volition. The Undying Kingdoms chew at its edges with axes and blasts of dry, withering desert heat; the Ojutai slip in to steal threads of knowledge from the collective memory; Atarka’s clans purify what they can and try to save those seized by the tangle; the Glorious Horde swings its blades and calls down the lightning; but all these efforts never matter. The jungle only grows back stronger. The beast endures, and its territory creeps ever outward.

Other Changes: So why venture into the Rotted Lands? Because Silumgar’s territory contains the ruins of immensely wealthy Sultai palaces and pleasure gardens, and his Palace Animate holds the greatest horde of all. Despite only rarely awakening in his own body, the dragonlord seems to enjoy treasure and directs his minions to pile it around his slumbering form in great heaps. Rumors of staggering wealth left to the jungle’s hold entice those with bad judgement and nothing to lose. Most never return, but once in a very great while one of these explorers stumbles back with fistfuls of gold - and unspeakable terror in their eyes.

Faction Mechanic: For the BG Sultai I wanted a mechanic that involved possession and taking control of opponent’s creatures. I’m not sure that would ever work out right since it kinda relies on your opponent playing a certain way, but anyway. The best I came up with was “Possess,” which was an ability on creatures. You paid the Possess cost and sacrificed the creature in order to manifest a card from any graveyard. Manifesting the card instead of putting it into play meant you still had to pay the full CMC to flip the creature up; otherwise it’d be insanely broken.

[rnomics]

IJMS, Vol. 25, Pages 3420: MaSMG7-Mediated Degradation of MaERF12 Facilitates Fusarium oxysporum f. sp. cubense Tropical Race 4 Infection in Musa acuminata

Modern plant breeding relies heavily on the deployment of susceptibility and resistance genes to defend crops against diseases. The expression of these genes is usually regulated by transcription factors including members of the AP2/ERF family. While these factors are a vital component of the plant immune response, little is known of their specific roles in defense against Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) in banana plants. In this study, we discovered that MaERF12, a pathogen-induced ERF in bananas, acts as a resistance gene against Foc TR4. The yeast two-hybrid assays and protein-protein docking analyses verified the interaction between this gene and MaSMG7, which plays a role in nonsense-mediated #RNA decay. The transient expression of MaERF12 in Nicotiana benthamiana was found to induce strong cell death, which could be inhibited by MaSMG7 during co-expression. Furthermore, the immunoblot analyses have revealed the potential degradation of MaERF12 by MaSMG7 through the 26S proteasome pathway. These findings demonstrate that MaSMG7 acts as a susceptibility factor and interferes with MaERF12 to facilitate Foc TR4 infection in banana plants. Our study provides novel insights into the biological functions of the MaERF12 as a resistance gene and MaSMG7 as a susceptibility gene in banana plants. Furthermore, the first discovery of interactions between MaERF12 and MaSMG7 could facilitate future research on disease resistance or susceptibility genes for the genetic improvement of bananas. https://www.mdpi.com/1422-0067/25/6/3420?utm_source=dlvr.it&utm_medium=tumblr

[ribosome-papers]

Four-dimensional omics data reveals ribosome heterogeneity, regulation of translation efficacy, and nonsense-mediated decay in the differentiation of spermatocyte to round spermatid.

bioRxiv: http://dlvr.it/Ss8jD2

[lupine-publishers-lojpcr]

Lupine Publishers | A De Novo Mutation in TSC2 Gene is Associated with Tuberous Sclerosis Complex (TSC): A Case Report

Lupine Publishers | LOJ Pharmacology & Clinical Research

 Abstract

Tuberous sclerosis, also known as tuberous sclerosis complex (TSC), is an autosomal dominant multisystem disorder characterized by hamartomas in multiple organ systems including brain, skin, heart, kidneys, and lung. These changes can result in epilepsy, learning difficulties, behavioral problems, renal failure, and other complications [1,2]. The affected genes are TSC1 and TSC2, encoding hamartin and tuberin respectively. The hamartin tuberin complex inhibits the mammalian target of rapamycin (mTOR) pathway, which controls cell growth and proliferation [2]. In this case, we report a 21-year-old Chinese female patient with TSC due to a de-nove mutation c.1806C>G (p. Tyr602Ter) in TSC2 gene [3]. This is likely to be the first report of this mutation in Chinese population. This mutation was evaluated as a pathogenic mutation based on the standards and guidelines of ACMG (American College of Medical Genetics and Genomics).

Keywords: Chinese; Epilepsy; Tuberous sclerosis complex (TSC); Tuberous sclerosis-1 (TSC1); Tuberous sclerosis-2 (TSC2); de novo mutation; ACMG

Introduction

TSC (tuberous sclerosis complex) is an autosomal dominant multi system disorder characterized by hamartomas in multiple organ systems. The genes which are related to TSC include two tumor-suppressor genes called TSC1 and TSC2. The TSC1 and TSC2 encoding hamartin and tuberin respectively. The hamartin tuberin complex inhibits the mammalian target of rapamycin (mTOR) pathway, which controls cell growth and proliferation [2]. Approximately 10 to 30% of cases of TSC are due to mutations in the TSC1 gene, the frequency of cases due to mutations in the TSC2 gene is consistently higher. TSC2 mutations are associated with more severe diseases [1]. The mutation of the gene TSC2 (c.1806C>G; p. Tyr602Ter) we detected does not exist in either Chinese population or any other populations. It has been identified as a pathogenic mutation in Clinvar database based on the hypotheses [4]. However, as of today, no detailed clinical study data or published research articles are found to support these hypotheses. It is likely to be the first clinical report of this mutation in the Chinese population.

Case Report

A 21-year-old female patient who was born with no family history of seizures or other types of neurological disease has experienced Tuberous sclerosis complex (TSC) since she was 13-year-old. The patient experienced seizures seven to eight times per month. Most of the seizures occurred during the daytime and were presented as tonic-clonic seizures which lasted approximately 2 minutes in length. There was no obvious symptom prior to the seizures. But whenever the seizures occurred, the patient would experience severe fatigue over the whole body. Besides seizures, there were several other clinical features including mental retardation, a sebaceous adenoma and a brown-pigment patch on her forehead, many depigmentation spots of different sizes on her neck, chest, back and limbs. The clinical diagnosis of her seizures was epilepsy, but the exact cause of her seizures was not found. However, according to MRI scan which showed a nodular sclerosis at the parenchyma of her brain and various other diagnoses, tuberous sclerosis complex (TSC) was highly likely to be the cause of her epilepsy. As displayed in Figure 1A, the patient’s Electroencephalography (EEG) showed frequent slow complex waves in the left anterior temporal area and the middle temporal area. Antiepileptic drugs of Carbamazepine, Zolosamide, and Everolimus were prescribed, and the improvement of the syndromes of the patient was observed after one year, as the patient experienced less seizures (Figure 1B).

 In order to identify the causes of her disease, we conducted a Whole Exome Sequencing (WES) based on Next-generation sequencing. A heterozygous nonsense mutation c.1806C>G (p. Tyr602Ter) in TSC2 gene (reference transcript, NM_000548) was discovered in the patient. This mutation rarely occurs among either Chinese or any other ethnic groups, as it was not reported in mutation frequency databases including 1000 Genomes Database and genome AD database. This variant was further confirmed by Sanger Sequencing and was not detected in either of her healthy parents or her healthy younger brother, which indicated that this variant was a de novo mutation (Figure 2). This variant was evaluated as pathogenic mutation based on the standards and guidelines of ACMG. So far, this has been the first report of the mutation in Chinese population.

(red rectangles).

 Discussion

In this case, we evaluated WES data from 253 Chinese patients with epilepsy and identified a de-nove heterozygous nonsense mutation in TSC2 gene (c.1806C>G (p. Tyr602Ter) in a 21-yearold female patient with Tuberous sclerosis complex (TSC). Sanger Sequencing further confirmed that it is a de novo mutation since no mutations were detected in either of her healthy parents or younger brother. This variant was evaluated as pathogenic mutation based on the standards and guidelines of ACMG. The mutation of the gene TSC2 we detected (c.1806C>G (p. Tyr602Ter) has been identified as a pathogenic mutation in Clinvar database based on the following two hypotheses. First, the Y602X variant is not observed in large population cohorts. Second, the mutation causes the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay pathway [4]. However, as of today, no detailed clinical study data or published research articles are found to support these hypotheses. Our study provided some evidence for the cause of TSC from a genetic level, and it is likely to be the first report of this mutation (p. Tyr602Ter) in Chinese population. Furthermore, our identification of this denove mutation in TSC2 gene might be helpful for advancing our understanding the role of TSC2 in TSC. The TSC2 mutations are usually detected in random cases with a frequency ranging from 75% to 80%. About 15% to 20% patients do not have identifiable mutations, which may due to mosaicism [1,2].

Conclusion

A novel nonsense mutation in TSC2 gene (c.1806C>G (p. Tyr602Ter) was identified in a 21-year-old Chinese female patient with Tuberous sclerosis complex (TSC). This is the first report in Chinese population, which may enrich the understanding of the causes of TSC.

 https://lupinepublishers.com/pharmacology-clinical-research-journal/pdf/LOJPCR.MS.ID.000130.pdf

https://lupinepublishers.com/pharmacology-clinical-research-journal/fulltext/a-de-novo-mutation-in-tsc2-gene-is-associated-with-tuberous-sclerosis-complex-(tsc)-a-case-report.ID.000130.php

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[jobrxiv]

Postdoctoral Position at Washington University - Genotoxic Stress, RNA surveillance and Cancer Washington University in St. Louis, School of Medicine Application Deadline: 2022-12-28 A postdoctoral research associate position is currently available in the laboratory of Dr. Zhongsheng You in the Department of Cell Biology and Physiology at the Washington University School of Medicine (WUSM) in St. Louis, USA. WUSM provides a superb research and training environment and is consistently ranked among the top medical schools in the country. The You lab investigates cellular responses to genotoxic stress with the goal to better understand and treat cancer. A current focus in this area is to investigate an emerging role of intracellular Ca2+ and Ca2+ signaling in the replication stress response and the DNA damage response that are essential for genome protection and tumor suppression (Li et al., Mol Cell 2019; Li et al., under review). Our lab also studies RNA surveillance mechanisms in cancer, focusing on the nonsense-mediated RNA decay (NMD) pathway. A major focus in this direction is to develop innovative tools for NMD analysis, and to explore the interplay between NMD... See the full job description on jobRxiv: https://jobrxiv.org/job/washington-university-in-st-louis-school-of-medicine-27778-associate-professor/?feed_id=19280 #ScienceJobs #hiring #research #ScienceJobs

[rnomics]

Pervasive translation of Xrn1-sensitive unstable long non-coding RNAs in yeast [Article]

Despite being predicted to lack coding potential, cytoplasmic long non-coding (lnc)RNAs can associate with ribosomes. However, the landscape and biological relevance of lncRNAs translation remains poorly studied. In yeast, cytoplasmic Xrn1-sensitive lncRNAs (XUTs) are targeted by the Nonsense-Mediated mRNA Decay (NMD), suggesting a translation-dependent degradation process. Here, we report that XUTs are pervasively translated, which impacts their decay. We show that XUTs globally accumulate upon translation elongation inhibition, but not when initial ribosome loading is impaired. Ribo-Seq confirmed ribosomes binding to XUTs and identified actively translated 5’-proximal small ORFs. Mechanistically, the NMD-sensitivity of XUTs mainly depends on the 3’-untranslated region length. Finally, we show that the peptide resulting from the translation of an NMD-sensitive XUT reporter exists in NMD-competent cells. Our work highlights the role of translation in the post-transcriptional metabolism of XUTs. We propose that XUT-derived peptides could be exposed to the natural selection, while NMD restricts XUTs levels. http://rnajournal.cshlp.org/cgi/content/short/rna.079903.123v1?rss=1&utm_source=dlvr.it&utm_medium=tumblr

[naivelocus]

Inhibition of nonsense-mediated RNA decay by ER stress [ARTICLE]

Nonsense-mediated RNA decay (NMD) selectively degrades mutated and aberrantly processed transcripts that contain premature termination codons (PTC). Cellular NMD activity is typically assessed using exogenous PTC-containing reporters. We overcame some inherently problematic aspects of assaying endogenous targets and developed a broadly applicable strategy to reliably and easily monitor changes in cellular NMD activity. Our new method was genetically validated for distinguishing NMD regulation from transcriptional control and alternative splicing regulation, and unexpectedly disclosed a different sensitivity of NMD targets to NMD inhibition. Applying this robust method for screening, we identified NMD-inhibiting stressors but also found that NMD inactivation was not universal to cellular stresses. The high sensitivity and broad dynamic range of our method revealed a strong correlation between NMD inhibition, endoplasmic reticulum (ER) stress, and polysome disassembly upon thapsigargin treatment in a temporal and dose-dependent manner. We found little evidence of calcium signaling mediating thapsigargin-induced NMD inhibition. Instead, we discovered that of the three unfolded protein response (UPR) pathways activated by thapsigargin, mainly protein kinase RNA-like endoplasmic reticulum kinase (PERK) was required for NMD inhibition. Finally, we showed that ER stress compounded TDP-43 depletion in the up-regulation of NMD isoforms that had been implicated in the pathogenic mechanisms of amyotrophic lateral sclerosis and frontotemporal dementia, and that the additive effect of ER stress was completely blocked by PERK deficiency.

— RNA

[geneexpressions]

// 26-02-17 // 

Alternative splicing and nonsense mediated decay in mRNA 

So for this class I’ve decided to both write notes by hand and on my laptop. Most focus will be the hand written ones, like bigger processes and mechanisms and such (and the laptop notes will be just short explanations of less important stuff). In other words, the more likely it is that the thing will be on the exam - write them by hand.

Let’s see if I can be bothered to start the X chromosome inactivation notes or if I’ll just watch call the midwife instead...