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The age of the democratic revolution
For the Western world, the period from 1760 to 1800 was the great revolutionary era in which the outlines of the modern democratic state came into being. Here for the first time in one volume is R. R. Palmer's magisterial account of this incendiary age. Palmer argues that the American, French, and Polish revolutions-and the movements for political change in Britain, Ireland, Holland, and elsewhere-were manifestations of similar political ideas, needs, and conflicts. Palmer traces the clash between an older form of society, marked by legalized social rank and hereditary or self-perpetuating elites, and a new form of society that placed a greater value on social mobility and legal equality.
Featuring a new foreword by David Armitage, this Princeton Classics edition ofThe Age of the Democratic Revolutionintroduces a new generation of readers to this enduring work of political history.
eBook
OptM: estimating the optimal number of migration edges on population trees using Treemix
Abstract
The software Treemix has become extensively used to estimate the number of migration events, or edges (m), on population trees from genome-wide allele frequency data. However, the appropriate number of edges to include remains unclear. Here, I show that an optimal value of m can be inferred from the second-order rate of change in likelihood (Δm) across incremental values of m. Repurposed from its original use to estimate the number of population clusters in the software Structure (ΔK), I show using simulated populations that Δm performs equally as well as current recommendations for Treemix. A demonstration of an empirical dataset from domestic dogs indicates that this method may be preferable in large, complex population histories and can prioritize migration events for subsequent investigation. The method has been implemented in a freely available R package called “OptM” and as a web application (https://rfitak.shinyapps.io/OptM/) to interface directly with the output files of Treemix.
Journal Article
Branched-chain amino acids and muscle protein synthesis in humans: myth or reality?
The branched chain amino acids (BCAAs) are leucine, valine and isoleucine. A multi-million dollar industry of nutritional supplements has grown around the concept that dietary supplements of BCAAs alone produce an anabolic response in humans driven by a stimulation of muscle protein synthesis. In this brief review the theoretical and empirical bases for that claim are discussed. Theoretically, the maximal stimulation of muscle protein synthesis in the post-absorptive state in response to BCAAs alone is the difference between muscle protein breakdown and muscle protein synthesis (about 30% greater than synthesis), because the other EAAs required for synthesis of new protein can only be derived from muscle protein breakdown. Realistically, a maximal increase in muscle protein synthesis of 30% is an over-estimate because the obligatory oxidation of EAAs can never be completely suppressed. An extensive search of the literature has revealed no studies in human subjects in which the response of muscle protein synthesis to orally-ingested BCAAs alone was quantified, and only two studies in which the effect of intravenously infused BCAAs alone was assessed. Both of these intravenous infusion studies found that BCAAs decreased muscle protein synthesis as well as protein breakdown, meaning a decrease in muscle protein turnover. The catabolic state in which the rate of muscle protein breakdown exceeded the rate of muscle protein synthesis persisted during BCAA infusion. We conclude that the claim that consumption of dietary BCAAs stimulates muscle protein synthesis or produces an anabolic response in human subjects is unwarranted.
Journal Article
Optimization algorithms on matrix manifolds
Many problems in the sciences and engineering can be rephrased as optimization problems on matrix search spaces endowed with a so-called manifold structure. This book shows how to exploit the special structure of such problems to develop efficient numerical algorithms. It places careful emphasis on both the numerical formulation of the algorithm and its differential geometric abstraction--illustrating how good algorithms draw equally from the insights of differential geometry, optimization, and numerical analysis. Two more theoretical chapters provide readers with the background in differential geometry necessary to algorithmic development. In the other chapters, several well-known optimization methods such as steepest descent and conjugate gradients are generalized to abstract manifolds. The book provides a generic development of each of these methods, building upon the material of the geometric chapters. It then guides readers through the calculations that turn these geometrically formulated methods into concrete numerical algorithms. The state-of-the-art algorithms given as examples are competitive with the best existing algorithms for a selection of eigenspace problems in numerical linear algebra.
eBook
Role of the intestinal microbiome and microbial-derived metabolites in immune checkpoint blockade immunotherapy of cancer
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block immune inhibitory pathways. Administration of ICIs augments T cell-mediated immune responses against tumor, resulting in improved overall survival in cancer patients. It has emerged that the intestinal microbiome can modulate responses to ICIs via the host immune system and that the use of antibiotics can lead to reduced efficacy of ICIs. Recently, reports that fecal microbiota transplantation can lead to ICI therapy responses in patients previously refractory to therapy suggest that targeting the microbiome may be a viable strategy to reprogram the tumor microenvironment and augment ICI therapy. Intestinal microbial metabolites may also be linked to response rates to ICIs. In addition to response rates, certain toxicities that can arise during ICI therapy have also been found to be associated with the intestinal microbiome, including in particular colitis. A key mechanistic question is how certain microbes can enhance anti-tumor responses or, alternatively, predispose to ICI-associated colitis. Evidence has emerged that the intestinal microbiome can modulate outcomes to ICI therapies via two major mechanisms, including those that are antigen-specific and those that are antigen-independent. Antigen-specific mechanisms occur when epitopes are shared between microbial and tumor antigens that could enhance, or, alternatively, reduce anti-tumor immune responses via cross-reactive adaptive immune cells. Antigen-independent mechanisms include modulation of responses to ICIs by engaging innate and/or adaptive immune cells. To establish microbiome-based biomarkers of outcomes and specifically modulate the intestinal microbiome to enhance efficacy of ICIs in cancer immunotherapy, further prospective interventional studies will be required.
Journal Article