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Discovery of antibiotics acting against Gram-negative species is uniquely challenging due to their restrictive penetration barrier. BamA, which inserts proteins into the outer membrane, is an attractive target due to its surface location. Darobactins produced by Photorhabdus , a nematode gut microbiome symbiont, target BamA. We reasoned that a computational search for genes only distantly related to the darobactin operon may lead to novel compounds. Following this clue, we identified dynobactin A, a novel peptide antibiotic from Photorhabdus australis containing two unlinked rings. Dynobactin is structurally unrelated to darobactins, but also targets BamA. Based on a BamA-dynobactin co-crystal structure and a BAM-complex-dynobactin cryo-EM structure, we show that dynobactin binds to the BamA lateral gate, uniquely protruding into its β-barrel lumen. Dynobactin showed efficacy in a mouse systemic Escherichia coli infection. This study demonstrates the utility of computational approaches to antibiotic discovery and suggests that dynobactin is a promising lead for drug development. Computational search identifies dynobactin A which is a systemically active, natural-product peptide antibiotic that kills Gram-negative bacteria.

A major factor in the resilience of Listeria monocytogenes is the alternative sigma factor B (σB). Type II Toxin/Antitoxin (TA) systems are also known to have a role in the bacterial stress response upon activation via the ClpP or Lon proteases. Directly upstream of the σB operon in L. monocytogenes is the TA system mazEF, which can cleave mRNA at UACMU sites. In this study, we showed that the mazEF TA locus does not affect the level of persister formation during treatment with antibiotics in lethal doses, but exerts different effects according to the sub-inhibitory stress added. Growth of a ΔmazEF mutant was enhanced relative to the wildtype in the presence of sub-inhibitory norfloxacin and at 42 °C, but was decreased when challenged with ampicillin and gentamicin. In contrast to studies in Staphylococcus aureus, we found that the mazEF locus did not affect transcription of genes within the σB operon, but MazEF effected the expression of the σB-dependent genes opuCA and lmo0880, with a 0.22 and 0.05 fold change, respectively, compared to the wildtype under sub-inhibitory norfloxacin conditions. How exactly this system operates remains an open question, however, our data indicates it is not analogous to the system of S. aureus, suggesting a novel mode of action for MazEF in L. monocytogenes.

Why did the colonies of North America rebel against England in 1775? More than ideas of political freedom were at stake. It is unlikely that the colonists would have demanded independence if powerful land speculators, merchants, and urban artisans had not joined forces to protect their economic interests. England had levied taxes on the colonies, and the colonists had successfully overturned those measures. Taxation was a superficial problem. But in 1773, when England imposed a commercial monopoly on tea sales, and in 1774, when it cut off settlement in western lands, the colonists saw no choice but to rebel and create their own nation. George Washington, Thomas Jefferson, Patrick Henry, George Mason, Richard Henry Lee, and other wealthy Virginians who led the American Revolution stood to lose their huge investment in potential land sales if England maintained control of the colonies.

Why did the colonies of N orth A merica rebel against E ngland in 1775? More than ideas of political freedom were at stake. It is unlikely that the colonists would have demanded independence if powerful land speculators, merchants, and urban artisans had not joined forces to protect their economic interests. E ngland had levied taxes on the colonies, and the colonists had successfully overturned those measures. Taxation was a superficial problem. But in 1773, when England imposed a commercial monopoly on tea sales, and in 1774, when it cut off settlement in western lands, the colonists saw no choice but to rebel and create their own nation. G eorge W ashington, T homas J efferson, P atrick H enry, G eorge M ason, R ichard H enry L ee, and other wealthy V irginians who led the A merican R evolution stood to lose their huge investment in potential land sales if E ngland maintained control of the colonies.

M. Weber's concept of the Protestant Ethic is often misunderstood because the PROTESTANT ETHIC AND THE SPIRIT OF CAPITALISM is only a small part of Weber's total work in the fields of econ history, the development of the world's religions, & the growth of diff econ systems. Any criticism of his thesis based solely on this work takes into account only a portion of Weber's life-long study of motivational forces underlying the rise & development of capitalistic org's. The 2nd area of confusion is the linking of the ethic to a particular dogma, usually to Calvinist dogma, & from this linkage it is concluded that Weber created a monocausal theory of capitalistic development, which is applicable only to a limited historical period. However, Weber speaks of an 'elective affinity' between particular types of religious beliefs & the ethics & work habits of the econ actor. Thus it is evident that his thesis is a universal concept which is applicable to almost any situation where a metaphysical orientation influences econ behavior. On the basis of these views, it can be seen that the development of the Protestant Ethic & craft guilds gave a stimulus to the Industr Revolution. The ethic provides the ideological motivation for sustained ED within a specific framework of cultural instit's. The relationship between the ethic & the instit's is that of an elective affinity which contributes to the process of SE change. Weber concludes that the late medieval period was the cumulation of the process of rational capitalism & can best be understood as a part of the development of rationalism as a whole. The rise of medieval cities in the northern part of Europe was one of the major contributors to this evolution of Occidental rationalism. These cities evolved craft guilds, which, with their use of day laborers & rational org of apprenticeship, factor markets, commodity markets, & legal structures, became part of the process of change toward a capitalistic system based upon econ activity. Thus the northern European craft guilds were not major barriers to the Industr Revolution, but can be looked upon as an integral part of the evolutionary process of capitalism. Modified AA.

Almost every study investigating the rate of return from investment in human capital contains some weakness. Errors are likely to be found in data bases methodology, and interpretation of results. This study attempts to modify the work of Hirschleifer by comparing and contrasting a utility optimum with a productivity optimum for human capital investment decisions. The data base used in measuring the returns to human capital investment consists of 3 levels. The differences in each level's characteristics often lead to variations in the estimated rates of return to graduate education. A determination of the returns to human capital of investment in education usually involves differentiating between nominal returns and real returns. Numerous factors have to be considered in defining the proper income streams to use. Proper data sample periods must be chosen, and the rate of return results must be justified.