Effects of a Community Population Health Initiative on Blood Pressure Control in Latinos.

Background Hypertension remains one of the most important, modifiable cardiovascular risk factors. Yet, the largest minority ethnic group (Hispanics/Latinos) often have different health outcomes and behavior, making hypertension management more difficult. We explored the effects of an American Heart Association-sponsored population health intervention aimed at modifying behavior of Latinos living in Texas. Methods and Results We enrolled 8071 patients, and 5714 (65.7%) completed the 90-day program (58.5 years ±11.7; 59% female) from July 2016 to June 2018. Navigators identified patients with risk factors; initial and final blood pressure ( BP ) readings were performed in the physician\u27s office; and interim home measurements were recorded telephonically. The intervention incorporated home BP monitoring, fitness and nutritional counseling, and regular follow-up. Primary outcomes were change in systolic BP and health-related quality of life. Using a univariate paired-samples pre-post design, we found an average 5.5% (7.6-mm Hg) improvement in systolic BP (139.1 versus 131.5, t=10.32,

Chemogenetic fingerprinting by analysis of cellular growth dynamics

<p>Abstract</p> <p>Background</p> <p>A fundamental goal in chemical biology is the elucidation of on- and off-target effects of drugs and biocides. To this aim chemogenetic screens that quantify drug induced changes in cellular fitness, typically taken as changes in composite growth, is commonly applied.</p> <p>Results</p> <p>Using the model organism <it>Saccharomyces cerevisiae </it>we here report that resolving cellular growth dynamics into its individual components, growth lag, growth rate and growth efficiency, increases the predictive power of chemogenetic screens. Both in terms of drug-drug and gene-drug interactions did the individual growth variables capture distinct and only partially overlapping aspects of cell physiology. In fact, the impact on cellular growth dynamics represented functionally distinct chemical fingerprints.</p> <p>Discussion</p> <p>Our findings suggest that the resolution and quantification of all facets of growth increases the informational and interpretational output of chemogenetic screening. Hence, by facilitating a physiologically more complete analysis of gene-drug and drug-drug interactions the here reported results may simplify the assignment of mode-of-action to orphan bioactive compounds.</p

Modes of Gene Duplication Contribute Differently to Genetic Novelty and Redundancy, but Show Parallels across Divergent Angiosperms

BACKGROUND: Both single gene and whole genome duplications (WGD) have recurred in angiosperm evolution. However, the evolutionary effects of different modes of gene duplication, especially regarding their contributions to genetic novelty or redundancy, have been inadequately explored. RESULTS: In Arabidopsis thaliana and Oryza sativa (rice), species that deeply sample botanical diversity and for which expression data are available from a wide range of tissues and physiological conditions, we have compared expression divergence between genes duplicated by six different mechanisms (WGD, tandem, proximal, DNA based transposed, retrotransposed and dispersed), and between positional orthologs. Both neo-functionalization and genetic redundancy appear to contribute to retention of duplicate genes. Genes resulting from WGD and tandem duplications diverge slowest in both coding sequences and gene expression, and contribute most to genetic redundancy, while other duplication modes contribute more to evolutionary novelty. WGD duplicates may more frequently be retained due to dosage amplification, while inferred transposon mediated gene duplications tend to reduce gene expression levels. The extent of expression divergence between duplicates is discernibly related to duplication modes, different WGD events, amino acid divergence, and putatively neutral divergence (time), but the contribution of each factor is heterogeneous among duplication modes. Gene loss may retard inter-species expression divergence. Members of different gene families may have non-random patterns of origin that are similar in Arabidopsis and rice, suggesting the action of pan-taxon principles of molecular evolution. CONCLUSION: Gene duplication modes differ in contribution to genetic novelty and redundancy, but show some parallels in taxa separated by hundreds of millions of years of evolution

Spontaneous Reaction Silencing in Metabolic Optimization

Metabolic reactions of single-cell organisms are routinely observed to become dispensable or even incapable of carrying activity under certain circumstances. Yet, the mechanisms as well as the range of conditions and phenotypes associated with this behavior remain very poorly understood. Here we predict computationally and analytically that any organism evolving to maximize growth rate, ATP production, or any other linear function of metabolic fluxes tends to significantly reduce the number of active metabolic reactions compared to typical non-optimal states. The reduced number appears to be constant across the microbial species studied and just slightly larger than the minimum number required for the organism to grow at all. We show that this massive spontaneous reaction silencing is triggered by the irreversibility of a large fraction of the metabolic reactions and propagates through the network as a cascade of inactivity. Our results help explain existing experimental data on intracellular flux measurements and the usage of latent pathways, shedding new light on microbial evolution, robustness, and versatility for the execution of specific biochemical tasks. In particular, the identification of optimal reaction activity provides rigorous ground for an intriguing knockout-based method recently proposed for the synthetic recovery of metabolic function.Comment: 34 pages, 6 figure

Loss of Genetic Redundancy in Reductive Genome Evolution

Biological systems evolved to be functionally robust in uncertain environments, but also highly adaptable. Such robustness is partly achieved by genetic redundancy, where the failure of a specific component through mutation or environmental challenge can be compensated by duplicate components capable of performing, to a limited extent, the same function. Highly variable environments require very robust systems. Conversely, predictable environments should not place a high selective value on robustness. Here we test this hypothesis by investigating the evolutionary dynamics of genetic redundancy in extremely reduced genomes, found mostly in intracellular parasites and endosymbionts. By combining data analysis with simulations of genome evolution we show that in the extensive gene loss suffered by reduced genomes there is a selective drive to keep the diversity of protein families while sacrificing paralogy. We show that this is not a by-product of the known drivers of genome reduction and that there is very limited convergence to a common core of families, indicating that the repertoire of protein families in reduced genomes is the result of historical contingency and niche-specific adaptations. We propose that our observations reflect a loss of genetic redundancy due to a decreased selection for robustness in a predictable environment

Duplication and Retention Biases of Essential and Non-Essential Genes Revealed by Systematic Knockdown Analyses

When a duplicate gene has no apparent loss-of-function phenotype, it is commonly considered that the phenotype has been masked as a result of functional redundancy with the remaining paralog. This is supported by indirect evidence showing that multi-copy genes show loss-of-function phenotypes less often than single-copy genes and by direct tests of phenotype masking using select gene sets. Here we take a systematic genome-wide RNA interference approach to assess phenotype masking in paralog pairs in the Caenorhabditis elegans genome. Remarkably, in contrast to expectations, we find that phenotype masking makes only a minor contribution to the low knockdown phenotype rate for duplicate genes. Instead, we find that non-essential genes are highly over-represented among duplicates, leading to a low observed loss-of-function phenotype rate. We further find that duplicate pairs derived from essential and non-essential genes have contrasting evolutionary dynamics: whereas non-essential genes are both more often successfully duplicated (fixed) and lost, essential genes are less often duplicated but upon successful duplication are maintained over longer periods. We expect the fundamental evolutionary duplication dynamics presented here to be broadly applicableclose9

Shaftesbury, Locke, and Their Revolutionary Letter?

A corrigendum for this article was published in vol. 18 of Locke Studies available here. Scholars are kindly asked to reference the corrigendum only and not this version of the article. Late in 1675, the anonymous Letter from a Person of Quality, to His Friend in the Country was condemned in the House of Lords as a ‘dangerous Book’, indeed a ‘lying, scandalous, and seditious Book’. The Peers ordered it to be burned by the public hangman, and opened an investigation designed to discover its author, printer, and publisher. About this search and its success in tracking the author(s) down, very little is known. But as J. R. Milton and Philip Milton, who included the pamphlet in their Clarendon edition of John Locke’s Essay Concerning Toleration and his Other Writings on Law and Politics, 1667–1683, have pointed out, ‘no one has ever doubted that it was written by someone in Shaftesbury’s circle and for Shaftesbury’s purposes. John Locke, Shaftesbury’s secretary at the time, has long been a suspected collaborator in its production

Shaftesbury, Locke, and Their Revolutionary Letter? [Corrigendum]

A correction of an article originally published in vol 17 (2017). In 1675, the anonymous Letter to a Person of Quality was condemned in the House of Lords and ordered to be burned by the public hangman.&nbsp; A propagandistic work that has long been attributed to Anthony Ashley Cooper, 1st Earl of Shaftesbury, and less certainly to his secretary John Locke, it traduced hard-line Anglican legislation considered in Parliament that year—namely the Test Bill, proposing that office-holders and MPs swear off political militancy and indeed any efforts to reform the Church and State.&nbsp; Careful examination of the text of the Letter, and that of one of its sources in the Reasons against the Bill for the Test, also circulated in 1675, reveals the presence of highly seditious passages of covert historical allegory.&nbsp; Hitherto un-noted by modern scholars, this allegory compared King Charles II to the weak and intermittently mad Henry VI, while agitating for armed revolt against a government made prey to popish and French captors.&nbsp; The discovery compels modification, through chronological revision and also re-assessment of the probability of Locke’s authorship of the Letter, of Richard Ashcraft’s picture of Shaftesbury and Locke as first-time revolutionaries for the cause of religious tolerance in the early 1680s.&nbsp; Even more significantly, it lends support to Ashcraft’s view of the nature and intent of duplicitous published writings from the Shaftesbury circle, whose members included Robert Ferguson, ‘the Plotter’ and pamphleteer at home in the world of skilled biblical hermeneutics.&nbsp; Cultivated for stealthy revolutionary purposes, these writings came with designs of engaging discrete reading networks within England’s culture of Protestant dissent

THE PHYSIOLOGICAL DISPOSITION OF AEROSOLIZED 4-[(3-(4-ACETYL-3-HYDROXY-2- PROPYLPHENOXY)PROPYL)SULFONYL]-y-OXOBENZENEBUTANOATE (L-648,05 1) IN

&apos; C-labeIed 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)