Proinflammatory cytokines have a toxic effect on human stem cell-derived beta cells
R. Dettmer, I. Niwolik, I. Mehmeti, E. Gurgul-Convey, O. Naujok;
Institute of Clinical Biochemistry, Hannover, Germany.
Background and aims:Β A potential therapy for type 1 diabetes mellitus is the replacement of beta cells with differentiated human pluripotent stem cells (hPSC). However, it is unclear whether these cells will survive in an environment with persistent autoimmunity after implantation. An encapsulation of stem cell implants could provide protection against the cellular components of the immune system. Soluble substances could, however, overcome this encapsulation barrier. The effect of proinflammatory cytokines on hPSC-derived beta cells has not yet been adequately clarified.
Materials and methods:Β A human hPSC line, with mCherry knock-in in the insulin locus, was differentiated into hPSC-derived beta cells. The cells were then treated with a mix of IFN-g, TNF-a and IL-1B for 24 hours and purified. The viability was then measured using the Caspase 3/7, Caspase 8 and Caspase 9 tests and transcriptional changes were measured using a whole transcriptome microarray and RT-qPCR. An increase of reactive oxygen species (ROS) was determined by detecting oxidation of 2',7'-dichlorofluorescin-diacetate (DCF-DA). Protein expression of the cytokine receptors was determined by Western blot.
Results:Β Within 12 hours caspase8 and caspase 9 activities were increased by 4-fold compared to the control. Within 24 hours, the incubation with cytokines led to an almost 3-fold increase in caspase 3/7 activity compared to the control. DCF measurement revealed an increase of ROS in cytokine treated cells compared to untreated cells. The expression of the cytokine receptors IL1R1, TNFRSF1A and IFNGR1 could be detected. At the gene expression level, activation of the STAT1 and NFkB signaling pathways, induction of inflammation markers and increased expression of cytokines such as IL1-B, TNF-a and IL32 and chemokines such as CCL2, CXCL9 and CXCL10 were measured. In addition, genes of the MHC family were induced.
Conclusion:Β This study shows that IFN-g, TNF-a and IL-1B have a toxic effect on hPSC-derived beta cells. Apoptosis is induced by the intrinsic and extrinsic pathway via caspase 8 and 9 activation. An increase of ROS could also be detected and indicates oxidative stress of cytokine-treated cells. The OMICS analysis indicates that the induced expressio
... keep reading on reddit β‘I don't want to step on anybody's toes here, but the amount of non-dad jokes here in this subreddit really annoys me. First of all, dad jokes CAN be NSFW, it clearly says so in the sub rules. Secondly, it doesn't automatically make it a dad joke if it's from a conversation between you and your child. Most importantly, the jokes that your CHILDREN tell YOU are not dad jokes. The point of a dad joke is that it's so cheesy only a dad who's trying to be funny would make such a joke. That's it. They are stupid plays on words, lame puns and so on. There has to be a clever pun or wordplay for it to be considered a dad joke.
Again, to all the fellow dads, I apologise if I'm sounding too harsh. But I just needed to get it off my chest.
Do your worst!
β Background: A Mediterranean diet is favourable for cardiometabolic risk.
Objective: To examine the residual effect of a green Mediterranean diet, further enriched with green plant-based foods and lower meat intake, on cardiometabolic risk.
Methods: For the DIRECT-PLUS parallel, randomised clinical trial we assigned individuals with abdominal obesity/dyslipidaemia 1:1:1 into three diet groups: healthy dietary guidance (HDG), Mediterranean and green Mediterranean diet, all combined with physical activity. The Mediterranean diets were equally energy restricted and included 28 g/day walnuts. The green Mediterranean diet further included green tea (3-4 cups/day) and a Wolffia globosa (Mankai strain; 100 g/day frozen cubes) plant-based protein shake, which partially substituted animal protein. We examined the effect of the 6-month dietary induction weight loss phase on cardiometabolic state.
Results: Participants (n=294; age 51 years; body mass index 31.3 kg/m2; waist circumference 109.7 cm; 88% men; 10 year Framingham risk score 4.7%) had a 6-month retention rate of 98.3%. Both Mediterranean diets achieved similar weight loss ((green Mediterranean -6.2 kg; Mediterranean -5.4 kg) vs the HDG group -1.5 kg; p<0.001), but the green Mediterranean group had a greater reduction in waist circumference (-8.6 cm) than the Mediterranean (-6.8 cm; p=0.033) and HDG (-4.3 cm; p<0.001) groups. Stratification by gender showed that these differences were significant only among men. Within 6 months the green Mediterranean group achieved greater decrease in low-density lipoprotein cholesterol (LDL-C; green Mediterranean -6.1 mg/dL (-3.7%), -2.3 (-0.8%), HDG -0.2 mg/dL (+1.8%); p=0.012 between extreme groups), diastolic blood pressure (green Mediterranean -7.2 mm Hg, Mediterranean -5.2 mm Hg, HDG -3.4 mm Hg; p=0.005 between extreme groups), and homeostatic model assessment for insulin resistance (green Mediterranean -0.77, Mediterranean -0.46, HDG -0.27; p=0.020 between extreme groups). The LDL-C/high-density lipoprotein cholesterol (HDL-C) ratio decline was greater in the green Mediterranean group (-0.38) than in the Mediterranean (-0.21; p=0.021) and HDG (-0.14; p<0.001) groups. High-sensitivity C-reactive protein reduction was greater in the green Mediterranean group (-0.52 mg/L) than in the Mediterranean (-0.24 mg/L; p=0.023) and HDG (-0.15 mg/L; p=0.044) groups. The green Mediterranean group achieved a better improvement (-3.7% absolute risk reduction) in the 10
... keep reading on reddit β‘I'm surprised it hasn't decade.
For context I'm a Refuse Driver (Garbage man) & today I was on food waste. After I'd tipped I was checking the wagon for any defects when I spotted a lone pea balanced on the lifts.
I said "hey look, an escaPEA"
No one near me but it didn't half make me laugh for a good hour or so!
Edit: I can't believe how much this has blown up. Thank you everyone I've had a blast reading through the replies π
It really does, I swear!
Because she wanted to see the task manager.
Heard they've been doing some shady business.
but then I remembered it was ground this morning.
Edit: Thank you guys for the awards, they're much nicer than the cardboard sleeve I've been using and reassures me that my jokes aren't stale
Edit 2: I have already been made aware that Men In Black 3 has told a version of this joke before. If the joke is not new to you, please enjoy any of the single origin puns in the comments
BamBOO!
Theyβre on standbi
A play on words.
Pilot on me!!
Christopher Walken
Nothing, he was gladiator.
They were cooked in Greece.
Or would that be too forward thinking?
Dad jokes are supposed to be jokes you can tell a kid and they will understand it and find it funny.
This sub is mostly just NSFW puns now.
If it needs a NSFW tag it's not a dad joke. There should just be a NSFW puns subreddit for that.
Edit* I'm not replying any longer and turning off notifications but to all those that say "no one cares", there sure are a lot of you arguing about it. Maybe I'm wrong but you people don't need to be rude about it. If you really don't care, don't comment.
What did 0 say to 8 ?
" Nice Belt "
So What did 3 say to 8 ?
" Hey, you two stop making out "
When I got home, they were still there.
I won't be doing that today!
[Removed]
Where ever you left it π€·ββοΈπ€
This morning, my 4 year old daughter.
Daughter: I'm hungry
Me: nerves building, smile widening
Me: Hi hungry, I'm dad.
She had no idea what was going on but I finally did it.
Thank you all for listening.
