The Speed of Adaptation in Large Asexual Populations

In large asexual populations, beneficial mutations have to compete with each other for fixation. Here, I derive explicit analytic expressions for the rate of substitution and the mean beneficial effect of fixed mutations, under the assumptions that the population size N is large, that the mean effect of new beneficial mutations is smaller than the mean effect of new deleterious mutations, and that new beneficial mutations are exponentially distributed. As N increases, the rate of substitution approaches a constant, which is equal to the mean effect of new beneficial mutations. The mean effect of fixed mutations continues to grow logarithmically with N. The speed of adaptation, measured as the change of log fitness over time, also grows logarithmically with N for moderately large N, and it grows double-logarithmically for extremely large N. Moreover, I derive a simple formula that determines whether at given N beneficial mutations are expected to compete with each other or go to fixation independently. Finally, I verify all results with numerical simulations.Comment: 33 pages, 6 figures. Minor changes in discussion. To appear in Genetic

Methotrexate and Cardiovascular Protection: Current Evidence and Future Directions

Patients with autoimmune rheumatic conditions, particularly rheumatoid arthritis, have an increased cardiovascular risk when compared with the general population. Methotrexate is a relatively old, yet effective, immunomodulatory drug for the management of autoimmune and chronic inflammatory disorders, such as rheumatoid arthritis, particularly in terms of symptom control, quality of life, and disease progression. Recent meta-analyses have also shown that methotrexate treatment is associated with a lower risk of cardiovascular events when compared with other disease-modifying antirheumatic drugs. This suggests that methotrexate might exert specific protective effects against atherosclerosis and thrombosis. This mini-review discusses the mechanisms associated with the increased cardiovascular risk in rheumatoid arthritis, the pharmacokinetics and pharmacodynamics of methotrexate, the available evidence on the in vitro and in vivo effects of methotrexate on modifiable cardiovascular risk factors, and suggestions for future research directions