Considerable changes in cellular metabolism occur when T cells transition from a resting to an activated state. One side effect of this process is an increase in reactive oxygen species (ROS). These molecules potentiate T cell receptor (TCR) signaling but can also result in detrimental oxidative stress (see the Perspective by Su and Dutta). Yue et al. describe one mechanism by which T cells can resolve this contradiction. Using mice with a T cell-specific deficiency in Schlafen 2 (SLFN2), they found that this protein binds to and protects transfer RNAs from oxidative stress-induced cleavage by the ribonuclease angiogenin. This process is downstream of ROS generation, which allows activated T cells to maintain protein synthesis despite the ROS that would otherwise inhibit translation.
Naïve T cells activated by cognate antigens and costimulation proliferate and differentiate to effector T cells. The shift from a resting to a proliferative state entails profound changes in cellular metabolism, in particular increases in glycolysis, glutaminolysis, and mitochondrial metabolism, to produce high levels of adenosine 5′-triphosphate (ATP). T cells depend on a translational burst to produce the metabolic enzymes that support an increase in metabolism and to produce the protein components of clonal T cell progeny and their cytokines. Paradoxically, the metabolic processes that provide energy for growth and expansion also produce reactive oxygen species (ROS). These are capable of inducing oxidative stress, which leads to the repression of translation. On the other hand, ROS function as second messengers in T cell receptor (TCR) signaling and are essential for proliferation and development of effector function. This suggests that to preserve the signaling activities of ROS, protective mechanisms against oxidative stress may occur at multiple levels beyond simply reducing ROS levels in T cells.
From a mouse-forward genetic screen for mutations affecting immunity, we previously identified a recessive mutation in the Schlafen 2 ( Slfn2 ) gene, which leads to elevated susceptibility to bacterial and viral infections and to diminished numbers of T cells that failed to proliferate in response to infection and diverse proliferative stimuli. Here, we aimed to investigate the molecular function of SLFN2 in T cells by generating mice with a T cell–specific deletion of Slfn2 .
T cell–specific SLFN2-deficient mice displayed compromised humoral and cellular immune responses to immunization with a T cell–dependent antigen and to infection with mouse cytomegalovirus, respectively. These defects stemmed from impaired CD4 + and CD8 + T cell proliferative responses to TCR stimulation, despite normal induction of TCR signaling events in SLFN2-deficient T cells. Interleukin-2 (IL-2) production by SLFN2-deficient T cells was normal after TCR stimulation, but these cells failed to proliferate in response to exogenous IL-2, which suggests that interleukin-2 receptor (IL-2R) signaling was defective. The abrogation of the mitogenic effects of IL-2 was a result of a failure to translationally up-regulate the β and γ chains of the IL-2 receptor. There was a globally dampened translational response to TCR activation in SLFN2-deficient T cells both in vitro and in vivo.
The cellular oxidative stress response includes translation repression by transfer RNA (tRNA) fragments generated by angiogenin (ANG), a stress-induced tRNA-directed ribonuclease (RNase). ANG cleaves tRNAs within their anticodon loops, yielding 30- to 40-nucleotide tRNA fragments (tiRNAs). In response to TCR activation, SLFN2-deficient T cells accumulated tiRNA, which could be reduced by antioxidant treatment or by knockdown or inhibition of ANG. Moreover, global translation rates in activated SLFN2-deficient T cells could be rescued by antioxidant treatment or by ANG knockdown. SLFN2 directly bound to tRNAs, but it exerted no nucleolytic activity toward them, unlike other SLFN proteins. Binding of SLFN2 to tRNAs blocked tRNA cleavage by ANG, thereby averting tiRNA accumulation and tiRNA-mediated translation repression.
We describe a protective mechanism by which SLFN2 shields tRNA from oxidative stress–induced cleavage, thereby preventing the translation inhibitory effects of ROS produced in response to T cell activation. Notably, SLFN2 acts downstream of ROS production itself, leaving ROS functions in T cell metabolism and signaling intact. We identify ANG as a stress-activated RNase whose effects are opposed by SLFN2 in T cells. Our data provide further support for a key role of SLFN family members in the regulation of RNA and translation.
T cell–specific SLFN2 deficiency results in excessive tRNA cleavage mediated by the oxidative stress–activated ribonuclease ANG during the metabolic reprogramming phase of activated T cells. Accumulated tiRNA promotes stress-granule assembly and inhibits translation by displacing eukaryotic initiation factors (eIFs) from mRNA. SLFN2-deficient T cells fail to translationally up-regulate IL-2Rβ and IL-2Rγ. MHC, major histocompatibility complex; APC, antigen-presenting cell; TCA, tricarboxylic acid.
Reactive oxygen species (ROS) increase in activated T cells because of metabolic activity induced to support T cell proliferation and differentiation. We show that these ROS trigger an oxidative stress response that leads to translation repression. This response is countered by Schlafen 2 (SLFN2), which directly binds transfer RNAs (tRNAs) to protect them from cleavage by the ribonuclease angiogenin. T cell–specific SLFN2 deficiency results in the accumulation of tRNA fragments, which inhibit translation and promote stress-granule formation. Interleukin-2 receptor β (IL-2Rβ) and IL-2Rγ fail to be translationally up-regulated after T cell receptor stimulation, rendering SLFN2-deficient T cells insensitive to interleukin-2's mitogenic effects. SLFN2 confers resistance against the ROS-mediated translation-inhibitory effects of oxidative stress normally induced by T cell activation, permitting the robust protein synthesis necessary for T cell expansion and immunity.
By Tao Yue , Xiaoming Zhan , Duanwu Zhang , Ruchi Jain , Kuan-wen Wang , Jin Huk Choi , Takuma Misawa , Lijing Su , Jiexia Quan , Sara Hildebrand , Darui Xu , Xiaohong Li , Emre Turer , Lei Sun , Eva Marie Y. Moresco , Bruce Beutler
Is This a COVID-19 ‘Smoking Gun,’ or Is it a Damp Squib? – Reason.com
Science journalist Nicholas Wade recently argued that circumstantial evidence suggests the COVID-19 pandemic began with a lab leak at the Wuhan Institute of Virology. As I noted here yesterday, one of his biggest pieces of evidence is the virus's supposedly anomalous furin cleavage site—a specific protein that it uses to enter human cells.
Wade claims that "no known SARS-related beta-coronavirus, the class to which [the novel coronavirus] belongs, possesses a furin cleavage site." To back this up, Wade quotes the Nobel-winning biologist David Baltimore: "When I first saw the furin cleavage site in the viral sequence, with its arginine codons, I said to my wife it was the smoking gun for the origin of the virus. These features make a powerful challenge to the idea of a natural origin for" the COVID-19 virus, SARS-CoV-2.
While acknowledging that researchers don't know for sure how the virus acquired its furin cleavage site, Andersen then reviews four natural ways the COVID-19 virus could have done so. He concludes that "Baltimore's first point—that the FCS found in SARS-CoV-2 is somehow unusual—is simply incorrect. FCSs are found in a multitude of different coronaviruses."
Anderson moves on to Baltimore's claim that the codons associated with the FCS are anomalous. Codons are specific sequences of three consecutive nucleotides in the genetic code; they specify particular amino acids for constructing proteins. While somewhat rare, Andersen points out that all sorts of coronaviruses naturally contain the codons that Baltimore suggests is evidence of lab manipulation.
"So Baltimore's second point is also false," concludes Andersen. "Baltimore does not provide any evidence to support his hypothesis and the data support a natural origin."
Does this disprove a lab leak? No. However, it disproves there being a "smoking gun" in the FCS and lends further evidence to natural emergence—but it also does not *prove* that scenario. To this day, we have yet to see any scientific evidence supporting a lab leak.
Emmerdale viewers distracted by Tracy's insane cleavage in sexy Christening dress - Daily Star
Not only was the character dressed up to the nines for her baby daughter Frankie's big Christening day, in a stunning fuschia dress, but it was also an incredibly revealing outfit.
Tracy's signature platinum blonde locks were styled into loose waves, and the character paired her frock with a smart white blazer.
Another exclaimed: "Blimey!! Stay well clear of Tracey's cleavage because if you fall in you may never be found again #Emmerdale."
Another fan commented on the character's cleavage being dangerously close to spilling out, as they joked: "Tracey, don't lean forward ok! LMAO!! #Emmerdale."
Viewers were also concerned over why Tracy's sister and fan-favourite character Vanessa Woodfield (Michelle Hardwick) hadn't returned to the village for such an important family occasion.
But after extended maternity leave, Vanessa will finally be back in the Dales in upcoming episodes, and fans are excited to see her reunite with Charity. Will the couple get things back on track?
De-stressing the T cells in need | Science
Scarlett Moffatt was comforted by Caroline Flack after being trolled while on Love Island:
Scarlett Moffatt has revealed she was comforted by Caroline Flack after vile trolls attacked her looks when she appeared on an episode of Love Island : Aftersun.
Writing for metro.co.uk , Scarlett admitted she vowed never to eat again and threw out the dress she wore after receiving the horrific messages.
She wrote: 'When I was asked to go on I remember thinking that if ever there was a show where I can wear something that shows a bit of cleavage, it's Love Island.
'After all, it was a programme where women weren't penalised for showing a bit of flesh, it was actually encouraged. But of course I soon discovered that you're not allowed to show cleavage if you're fat.
Her parents called her to check if she was alright, with the Gogglebox star admitting she didn't want to get her flight back home from Palma Nova in Mallorca.
Scarlett recalled how she cried in the company of the late Caroline Flack, who told her to ignore the heartless trolls.
The media personality said she grabbed her skin and wanted to rip the fat off her body, vowing to never eat again.
SARS-CoV-2 origins | 2021-05-13 | BioWorld
The articles in this collection are from BioWorld's ongoing coverage of the COVID-19 coronavirus outbreak. Note that we have added three critical tables which are...
Emma Corin Wore a Bode Boxing Felt Shirt Jacket | InStyle
Welcome to the new Look of the Day , where we comb through every celebrity outfit from the past 24 hours and feature the single most conversation-worthy ensemble. Love it, leave it, or shop the whole thing below.
People outside of the industry tend to think of Fashion as tight leather pants, cleavage, and towering heels, but actually Fashion is a jacket your grandmother made out of old tablecloths, cheap jewelry you wore in middle school , and the the most hideous sneakers an algorithm could imagine. At least, that's what it is in 2021.
Bleomycin Sulfate Market Research Report by Manufacturers, Region, Type and Application, Forecast
Bleomycin sulfate is the sulfate salt of a complex natural product antibiotic. This compound approximates metals such as Fe(II) which then coordinate dioxygen to generate the active species. This Bleomycin-metal-dioxygen species is capable of inducing oxidative cleavage of the DNA backbone, leading to apoptosis. The species also degrades RNA, and has been reported to display selectivity for RNA over DNA.
The Bleomycin Sulfate market revenue was xx.xx Million USD in 2019, and will reach xx.xx Million USD in 2025, with a CAGR of x.x% during 2020-2025.
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The key regions covered in the Bleomycin Sulfate market report are: North America, Europe, Asia Pacific, Latin America, Middle East and Africa.
It also covers key regions (countries) , viz, U.S., Canada, Germany, France, U.K., Italy, Russia, China, Japan, South Korea, India, Australia, Taiwan, Indonesia, Thailand, Malaysia, Philippines, Vietnam, Mexico, Brazil, Turkey, Saudi Arabia, U.A.E, etc.
1.It provides valuable insights into the Global Bleomycin Sulfate Market.
2.Provides information for the years 2021-2025. Important factors related to the market are mentioned.
3.Technological advancements, government regulations, and recent developments are highlighted.
4.Advertising and marketing strategies, market trends, and analysis are studied in this report.
5.Growth analysis and predictions until the year 2025.
6.Statistical analysis of the key players in the market is highlighted.
7.Extensively researched market overview.
Understand the influence of COVID-19 on the Bleomycin Sulfate Market with our analysts monitoring the situation across the globe. Impact of COVID on supply/demand scenario, trade landscape & supply chain. How Bleomycin Sulfate market participants are preparing/strategizing to combat the impact? and How does the short-term & long-term scenario for the Bleomycin Sulfate Market looks like?
The report is specially designed to analyse and discuss the latest developments in the Global Bleomycin Sulfate market. The study's objective includes:
1.Presenting the current products being sold regionally.
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4.Studying how close the industry is responding to the new products in the Global Bleomycin Sulfate market.
1.What was the market size from 2015-2021?
2.What will be the market forecast till 2025 and what will be the market forecast in the current year?
3.Which segment or region will drive the market growth and why?
4.What are the key sustainable strategies adopted by the market players?
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This Neon Mini Dress Might Be The Shortest Thing Beyonce Has Worn, Like, EVER - SHEfinds
Beyoncé is the epitome of a multi-hyphenate star. She's not only an epic musician, but also an incredible businesswoman and artist—and completely embodies her nickname of Queen Bey.
She also happens to be one of the most stunning women in the world, and when we saw her in this ultra-short dress, we were completely in awe.
“Neon Dream” could be the title of her next album if this dress is any inspiration! Beyoncé absolutely slayed in this highlighter-neon mini dress she posed in and shared with her fans on the gram.
Her long-sleeved mini dress hugs her in all the right places and shows off her cleavage and legs-for-days. We’re also loving her matching bag and…anklet?! We wouldn’t be surprised if she brings back the anklet trend. We’re here for it.
She explained, “My kids and I came up with Fashion Fridays. Every Friday, we would dress up in my clothes or make clothes together and take each other’s pictures. It became a ritual for us and an opportunity to handle this crazy year together. The newest Ivy Park collection was inspired by this new tradition.” As the world starts to open up, we’re sure Bey’s fashion Fridays will only get more and more glam , and extend to the other days of the week as well. And…We. Cannot. Wait.
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