Deleterious mutations are of fundamental importance to all aspects of organismal biology. Evolutionary geneticists have expended tremendous effort to estimate the genome-wide rate of mutation and the effects of new mutations on fitness, but the degree to which genomic mutational properties vary within and between taxa is largely unknown, particularly in multicellular organisms. Beginning with two highly inbred strains from each of three species in the nematode family Rhabditidae (Caenorhabditis briggsae, Caenorhabditis elegans, and Oscheius myriophila), we allowed mutations to accumulate in the relative absence of natural selection for 200 generations. We document significant variation in the rate of decay of fitness because of new mutations between strains and between species. Estimates of the per-generation mutational decay of fitness were very consistent within strains between assays 100 generations apart. Rate of mutational decay in fitness was positively associated with genomic mutation rate and negatively associated with average mutational effect. These results provide unambiguous experimental evidence for substantial variation in genome-wide properties of mutation both within and between species and reinforce conclusions from previous experiments that the cumulative effects on fitness of new mutations can differ markedly among related taxa.Caenorhabditis briggsae ͉ Caenorhabditis elegans ͉ deleterious mutation ͉ mutation accumulation ͉ Oscheius myriophila F ew topics in evolutionary biology have generated as much controversy in recent years as spontaneous mutation, considered at the level of the entire genome (1-4). It is widely accepted that the great majority of new mutations are either neutral or deleterious (refs. 1 and 5-7; also see refs. 3 and 8-13), and the importance of deleterious mutations to a wide variety of biological processes and phenomena is well appreciated (7). The source of the controversy stems from uncertainty in the rate at which new mutations accrue in the genome and the distribution of effects of those mutations on fitness.Beginning in the early 1960s, Mukai, Ohnishi, and their colleagues (14-18) conducted several large mutation accumulation (MA) experiments with Drosophila melanogaster that were designed to estimate the rate and average effect of new mutations on fitness. By the early 1970s, the results seemed clear: averaged over experiments, egg-to-adult viability declined rapidly, on the order of 1% per genome per generation, with the implication that the diploid genomic mutation rate (U) was on the order of 0.6 per generation or greater and the average homozygous effect on fitness of a new mutation (2a ) was Ϸ0.05 or less. The typical newborn fly was thus expected to harbor one new mutation that could be expected to reduce its viability by Ϸ5% when homozygous.Several additional lines of evidence supported the results from the early f ly MA experiments. First, the considerable inbreeding depression in Drosophila implied either a high rate of deleterious mutation or considerable...
Summary Myeloid‐derived suppressor cells (MDSC) are important to the tumour microenvironment as they actively suppress the immune system and promote tumour progression and metastasis. These cells block T‐cell activation in the tumour microenvironment, preventing anti‐tumour immune activity. The ability of a treatment to alter the suppressive function of these cells and promote an immune response is essential to enhancing overall therapeutic efficacy. Interleukin‐12 (IL‐12) has the potential not only to promote anti‐tumour immune responses but also to block the activity of cells capable of immune suppression. This paper identifies a novel role for IL‐12 as a modulator of MDSC activity, with implications for IL‐12 as a therapeutic agent. Treatment with IL‐12 was found to alter the suppressive function of MDSC by fundamentally altering the cells. Interleukin‐12‐treated MDSC exhibited up‐regulation of surface markers indicative of mature cells as well as decreases in nitric oxide synthase and interferon‐γ mRNA both in vitro and in vivo. Treatment with IL‐12 was also found to have significant therapeutic benefit by decreasing the percentage of MDSC in the tumour microenvironment and increasing the percentage of active CD8+ T cells. Treatment with IL‐12 resulted in an increase in overall survival accompanied by a reduction in metastasis. The findings in this paper identify IL‐12 as a modulator of immune suppression with significant potential as a therapeutic agent for metastatic breast cancer.
Telomeres serve the dual function of protecting chromosomes from genomic instability as well as protecting the ends of chromosomes from DNA damage machinery. The enzyme responsible for telomere maintenance is telomerase, an enzyme capable of reverse transcription. Telomerase activity is typically limited to specific cell types. However, telomerase activation in somatic cells serves as a key step toward cell immortalization and cancer. Targeting telomerase serves as a potential cancer treatment with significant therapeutic benefits. Beyond targeting cancers by inhibiting telomerase, manipulating the regulation of telomerase may also provide therapeutic benefit to other ailments, such as those related to aging. This review will introduce human telomeres and telomerase and discuss pharmacological regulation of telomerase, including telomerase inhibitors and activators, and their use in human diseases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.