Genomic DNA can be damaged by endogenous or environmental stresses. During repair, these short single-stranded DNAs are continuously generated and may leak out to the cytoplasm, where they are generally drawn back into the nucleus by DNA repair and replication factors (RPA and Rad51). Alongside this, TREX1, a cytoplasmic exonuclease, is anchored on the outer nuclear membrane to degrade leaking DNAs immediately. This prevents activation of the cGAS/STING pathway against self DNA. Inhibition of any of the above-mentioned proteins leads to accumulation of cytoplasmic DNA and subsequent inflammatory cytokine production. During interphase, self DNA, existing as nucleosomes, does not trigger cGAS. However, during mitosis, when the nuclear envelope disassembles, there exists a possibility of self-DNA detection by cGAS, leading to the production of type I IFNs. cGAS binds to nucleosomes with a much higher affinity than to naked DNA, using distinct mechanisms in both cases. Nucleosomes also suppress the cGAMP synthase activity of cGAS, hence, not allowing production/activation of downstream molecules. In this stage of mitosis, nucleosomes competitively interfere with cGAS activation.
However, during mitotic arrest, when cGAS is bound for a prolonged time, it gets activated and serves as a signal for error in the cell cycle. It stimulates mitochondrial relocalisation of IRF3, which, in turn, activates Bax-mediated apoptosis. Apart from cGAS, other exogenous DNA sensors are also known – one of them being IFI16 (interferon-g inducible protein 16). IFI16 is shown (in human keratinocytes) to be required for the cGAMP-induced activation of STING, and its interaction with STING promotes STING phosphorylation and translocation. It can be said that these two cytoplasmic DNA sensors cooperate during DNA sensing, and both are required for the full activation of an innate immune response. They also prevent spurious activation of the type I interferon response by adding another level of regulation. DNA binding to cGAS induces the formation of liquid-like droplets, which function as micro reactors in which the enzyme (activated cGAS) and reactants (ATP, GTP) are concentrated to enhance the production of cGAMP. This mechanism allows cGAS to detect the presence of DNA in the cytoplasm only above a certain threshold. Such a switch-like response is made possible by the multivalent interactions between the DNA binding domains of cGAS and DNA, with the mechanism depending on the DNA length as well as on Zn2+ concentration.
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A Just Society In “The Giver”
Unlike a drop of water which loses its identity when it joins the ocean, man does not lose his being in the society in which he lives. Man’s life is independent. He is born not for the development of the society alone, but for the development of himself. I believe Balance, tradition, and honesty are the most important factors for a just society. In class we have recently read The Giver, “The Lottery”, and “The Children’s Story”. This is what I think is highly important for a just society.
I think having a balance is highly important for a just society. In The Giver everything was chosen for you. I think that is a good choice because everyone makes mistakes but, you will never learn without mistakes. Mistakes are bad but the freedom to make choices for yourself is what everyone needs. In the giver no one had the choice to do what they want, choose who to marry, or even what life to live. In “The Children’s Story”, I think that we need to find the balance between sameness or equality and inequality. If there is one-hundred percent samness then no one will be able to improve or be smart. If everything was the same then nothing would be good or bad. If there is nothing good you dont lose anything but you also don’t win everything. Yes, sameness would be good for unfortainit people, but for the people that are the best they lose everything, money, choice, and even a life.
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I also think tradition is really important for a just society. In the book “The Lottery”, there tradition was a lottery that killed you. There are other traditions like holidays such as Christmas or Easter. There tradition was whoever go called got pelted with rocks until they die for some form of population control. In the giver they had a tradition. You get your job picked for you and they only have one receiver and or giver of memory. There was no change and most importantly no choice. I know some people might say that tradition is a great thing. Sometimes, it is a great thing but sometimes it is horrible.
The third most important factor for a just society in my opinion is honesty. In a just society you need to be able to trust. In the story “A Children’s Story” by James Clavell, the new teacher lied to the kids with things like telling them there dads will come home. She also convinced them to cut up there flag, trust her, and through away the pole. Also, in Lois Lowry’s book the giver the government lied to them about emotion and took it away from them. The government also didn’t let them see things like color or individuality. Some times, Honesty hurt, the truth hurts, but sometimes the truth is all we need to make things clear.