The relationship between oxidative stress and longevity is a matter of concern in various organisms. We isolated mutants resistant to paraquat from nematode Caenorhabditis elegans. One mutant named mev-4 was longlived and showed cross-resistance to heat and Dyf phenotype (defective in dye filling). Genetic and sequence analysis revealed that mev-4 had a nonsense mutation on the che-11 gene, homologues of which are involved in formation of cilia and flagella in other organisms. The paraquat resistance was commonly observed in various Dyf mutants and did not depend on the daf-16 gene, whereas the extension of life span did depend on it. Expression of antioxidant enzyme genes seemed normal. These results suggest that chemosensory neurons are a target of oxidative stress and influence longevity dependent on the daf-16 signaling in C. elegans.The life spans of animals are determined by both environmental and genetic parameters. Accumulating evidence in model organisms demonstrates the importance of genetic approaches with the findings that single gene mutations affect the life span in nematode Caenorhabditis elegans, fruit fly Drosophila melanogaster, and laboratory mice. The key to understanding longevity seems to lie in the network of cell maintenance systems that reduce accumulation of deleterious stresses. The life span of nematodes is controlled by the insulin-like signals from the nervous system (1-3). Such signals also seem to control life span of the fruit fly and mice (4 -7). These results suggest that neuroendocrine pathways in the neurons constitute an important determinant of life span across phylogeny (8 -11).Various lines of evidence show that oxidative stress is a major damaging factor accelerating aging (12, 13). It is invoked by reactive oxygen species (ROS) 1 generated as chemical byproducts of normal cellular metabolisms. Caloric restriction is shown to be beneficial in decreasing the production of ROS in metabolic pathways such as the mitochondrial electron transport system (13). Animals have evolved defense mechanisms against ROS; antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase work to eradicate ROS as a first aid (14). However, much remains to be understood as regards the defense mechanisms in diverse tissues of vertebrates. To facilitate understanding of the mechanisms, C. elegans and D. melanogaster are frequently used as a multi-cellular model organism because powerful genetic analysis is possible.In C. elegans, longevity is affected by particular genes involved in dauer larvae formation (15-17), stress resistance (18 -24), mitochondrial function (25-28), caloric restriction (29), reproduction (30 -32), sensory perception (33), neurosecretory function (34), and chromatin silencing (35). Although multiple factors seem to be involved in the longevity, there exist a positive relationship between the capacity to resist oxidative stress and the longevity (12). Nonetheless, the target of oxidative stress is yet to be understood even in this model organis...

Hematopoietic stem cells (HSCs) are the source of all blood cells over an individual’s lifetime. Diseased HSCs can be replaced with gene-engineered or healthy HSCs through HSC transplantation (HSCT). However, current protocols carry major side effects and have limited access. We developed CD117/LNP–messenger RNA (mRNA), a lipid nanoparticle (LNP) that encapsulates mRNA and is targeted to the stem cell factor receptor (CD117) on HSCs. Delivery of the anti–human CD117/LNP–based editing system yielded near-complete correction of hematopoietic sickle cells. Furthermore, in vivo delivery of pro-apoptotic PUMA (p53 up-regulated modulator of apoptosis) mRNA with CD117/LNP affected HSC function and permitted nongenotoxic conditioning for HSCT. The ability to target HSCs in vivo offers a nongenotoxic conditioning regimen for HSCT, and this platform could be the basis of in vivo genome editing to cure genetic disorders, which would abrogate the need for HSCT.

The entire and partial gag regions of human immunodeficiency virus type 1 (HIV-1) were overproduced in Escherichia coli and used for epitope mapping of antibodies against p17. We found that a mouse monoclonal antibody to p17, V17 recognizes the mature p17 but not the unprocessed Gag proteins containing the entire p17 moiety. Further analysis revealed that V 17 recognizes the C-terminal 12-amino-acid region of p17 having free C-terminus. This monoclonal antibody may be useful for monitoring the maturation of virus particles.

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