Summary
A multi‐armed bandit problem is investigated in which rewards obtained from pulls of any arm depend on the states of the other arms, as well as on the state of the arm pulled. A Dynamic Allocation Index is defined for this class of problems, and it is shown that this leads to optimal policies.
The solution in discrete time of the problem of maximizing the flow in a network with time-varying are capacities and storage at the nodes is a straightforward extension of the static case. In this paper the problem is formulated and solved in continuous time. A continuous version of the Ford-Fulkerson theorem is proved, and an analogue of the labelling algorithm developed. An example is given to clarify some of the ideas of the paper and the duality theory for this problem is discussed.
Mitochondria host key metabolic processes vital for cellular energy provision and are central to cell fate decisions. They are subjected to unique genetic control by both nuclear DNA and their own multi-copy genome - mitochondrial DNA (mtDNA). Mutations in mtDNA often lead to clinically heterogeneous, maternally inherited diseases that display different organ-specific presentation at any stage of life. For a long time, genetic manipulation of mammalian mtDNA has posed a major challenge, impeding our ability to understand the basic mitochondrial biology and mechanisms underpinning mitochondrial disease. However, an important new tool for mtDNA mutagenesis has emerged recently, namely double-stranded DNA deaminase (DddA)-derived cytosine base editor (DdCBE). Here, we test this emerging tool for in vivo use, by delivering DdCBEs into mouse heart using adeno-associated virus (AAV) vectors and show that it can install desired mtDNA edits in adult and neonatal mice. This work provides proof-of-concept for use of DdCBEs to mutagenize mtDNA in vivo in post-mitotic tissues and provides crucial insights into potential translation to human somatic gene correction therapies to treat primary mitochondrial disease phenotypes.
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