Machiavelli and Tocqueville on War and Armies

In the Democracy in America’s chapters on war and armies in the transition from the aristocratic to the democratic social state (état social), Tocqueville briefly draws on Machiavelli regarding the conquest of a country with or without intermediary powers between political leadership and the people by which he primarily understands the existence of local nobilities. In this reference, Tocqueville is quick to express skepticism about the overstated importance of Machiavelli in the history of political philosophy. In different places of his work though a more mitigated stance is documented. A comparative approach of Machiavelli and Tocqueville on war may seem odd, even inappropriate. In this paper I argue that the “brief encounter,” in Melvin Richter’s terms, of Tocqueville with Machiavelli can be fruitfully explored in order to make sense of the key importance for modern warfare of the collapse of nobility in Europe. Concomitantly, Machiavelli ‘s intuitions about conquering an absolutist state without intermediary powers compared to a state endowed with “prince” and “barons” can be further elaborated to better grasp its impact on wars including civil strife. In this paper I first explore Machiavelli’s perception of the intermediary powers in conquest and broadly in warfare paying due attention to the importance for the preservation of liberty of latent or open civil discord between social powers or classes; then I turn to Tocqueville’s rich analysis of the transformation of modern warfare due to democratic centralization and obsession with private welfare. Democratic armies constantly challenge democratic liberty and they can sometimes successfully albeit perversely integrate democratic ambition and turn it against democracy. I conclude with some reflections on the connection between war and politics regarding latent civil conflicts in democracies

A Novel Flow Cytometric HTS Assay Reveals Functional Modulators of ATP Binding Cassette Transporter ABCB6

ABCB6 is a member of the adenosine triphosphate (ATP)-binding cassette family of transporter proteins that is increasingly recognized as a relevant physiological and therapeutic target. Evaluation of modulators of ABCB6 activity would pave the way toward a more complete understanding of the significance of this transport process in tumor cell growth, proliferation and therapy-related drug resistance. In addition, this effort would improve our understanding of the function of ABCB6 in normal physiology with respect to heme biosynthesis, and cellular adaptation to metabolic demand and stress responses. To search for modulators of ABCB6, we developed a novel cell-based approach that, in combination with flow cytometric high-throughput screening (HTS), can be used to identify functional modulators of ABCB6. Accumulation of protoporphyrin, a fluorescent molecule, in wild-type ABCB6 expressing K562 cells, forms the basis of the HTS assay. Screening the Prestwick Chemical Library employing the HTS assay identified four compounds, benzethonium chloride, verteporfin, tomatine hydrochloride and piperlongumine, that reduced ABCB6 mediated cellular porphyrin levels. Validation of the identified compounds employing the hemin-agarose affinity chromatography and mitochondrial transport assays demonstrated that three out of the four compounds were capable of inhibiting ABCB6 mediated hemin transport into isolated mitochondria. However, only verteporfin and tomatine hydrochloride inhibited ABCB6’s ability to compete with hemin as an ABCB6 substrate. This assay is therefore sensitive, robust, and suitable for automation in a high-throughput environment as demonstrated by our identification of selective functional modulators of ABCB6. Application of this assay to other libraries of synthetic compounds and natural products is expected to identify novel modulators of ABCB6 activity

Application of fluorescent dye substrates for functional characterization of ABC multidrug transporters at a single cell level

ABC multidrug transporters are key players in cancer multidrug resistance and in determining the ADME-Tox properties of drugs and xenobiotics. The most sensitive and specific detection of these transporters is based on functional assays. Assessment of the transporter-dependent reduction of cellular uptake of the fluorescent dyes, such as Hoechst 33342 (Ho) and more recently DyeCycle Violet (DCV), have been widely advocated for the characterization of both ABCB1 and ABCG2 multidrug transporters. Detailed comparison of these supravital DNA-binding dyes revealed that DCV is less toxic to ABCG2- and ABCB1-expressing cells than Ho. ATPase measurements imply that DCV and Ho are similarly handled by ABCB1, whereas ABCG2 seems to transport DVC more effectively. In addition, we have developed an image-based high content microscopy screening method for simultaneous in situ measurement of the cellular activity and expression of the ABCG2 multidrug transporter. We demonstrated the applicability of this method for identifying ABCG2-positive cells in heterogeneous cell population by a single dye uptake measurement. These results may promote multidrug transporter studies at a single cell level and allow the quantitative detection of clinically important drug-resistant sub-populations. (c) 2016 International Society for Advancement of Cytometry

Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria

Background: Traditional antibiotics are increasingly suffering from the emergence of multidrug resistance amongst pathogenic bacteria leading to a range of novel approaches to control microbial infections being investigated as potential alternative treatments. One plausible antimicrobial alternative could be the combination of conventional antimicrobial agents/antibiotics with small molecules which block multidrug efflux systems known as efflux pump inhibitors. Bioassay-driven purification and structural determination of compounds from plant sources have yielded a number of pump inhibitors which acted against gram positive bacteria. Methodology/Principal Findings: In this study we report the identification and characterization of 4′,5′-O-dicaffeoylquinic acid (4′,5′-ODCQA) from Artemisia absinthium as a pump inhibitor with a potential of targeting efflux systems in a wide panel of Gram-positive human pathogenic bacteria. Separation and identification of phenolic compounds (chlorogenic acid, 3′,5′-ODCQA, 4′,5′-ODCQA) was based on hyphenated chromatographic techniques such as liquid chromatography with post column solid-phase extraction coupled with nuclear magnetic resonance spectroscopy and mass spectroscopy. Microbial susceptibility testing and potentiation of well know pump substrates revealed at least two active compounds; chlorogenic acid with weak antimicrobial activity and 4′,5′-ODCQA with pump inhibitory activity whereas 3′,5′-ODCQA was ineffective. These intitial findings were further validated with checkerboard, berberine accumulation efflux assays using efflux-related phenotypes and clinical isolates as well as molecular modeling methodology. Conclusions/Significance: These techniques facilitated the direct analysis of the active components from plant extracts, as well as dramatically reduced the time needed to analyze the compounds, without the need for prior isolation. The calculated energetics of the docking poses supported the biological information for the inhibitory capabilities of 4′,5′-ODCQA and furthermore contributed evidence that CQAs show a preferential binding to Major Facilitator Super family efflux systems, a key multidrug resistance determinant in gram-positive bacteria.National Institutes of Health (U.S.) (grant R01GM59903)National Institutes of Health (U.S.) (grant R01AI050875)Netherlands Organization for Scientific Research (VICI grant 700.56.442)Massachusetts Technology Transfer Center (MTTC)National Institutes of Health (U.S.) (grant 5U54MH084690-02

Machiavelli and Tocqueville on War and Armies

In the Democracy in America’s chapters on war and armies in the transition from the aristocratic to the democratic social state (état social), Tocqueville briefly draws on Machiavelli regarding the conquest of a country with or without intermediary powers between political leadership and the people by which he primarily understands the existence of local nobilities. In this reference, Tocqueville is quick to express skepticism about the overstated importance of Machiavelli in the history of political philosophy. In different places of his work though a more mitigated stance is documented. A comparative approach of Machiavelli and Tocqueville on war may seem odd, even inappropriate. In this paper I argue that the “brief encounter,” in Melvin Richter’s terms, of Tocqueville with Machiavelli can be fruitfully explored in order to make sense of the key importance for modern warfare of the collapse of nobility in Europe. Concomitantly, Machiavelli ‘s intuitions about conquering an absolutist state without intermediary powers compared to a state endowed with “prince” and “barons” can be further elaborated to better grasp its impact on wars including civil strife. In this paper I first explore Machiavelli’s perception of the intermediary powers in conquest and broadly in warfare paying due attention to the importance for the preservation of liberty of latent or open civil discord between social powers or classes; then I turn to Tocqueville’s rich analysis of the transformation of modern warfare due to democratic centralization and obsession with private welfare. Democratic armies constantly challenge democratic liberty and they can sometimes successfully albeit perversely integrate democratic ambition and turn it against democracy. I conclude with some reflections on the connection between war and politics regarding latent civil conflicts in democracies

Effect of Virulence Factors on the Photodynamic Inactivation of Cryptococcus neoformans

Opportunistic fungal pathogens may cause an array of superficial infections or serious invasive infections, especially in immunocompromised patients. Cryptococcus neoformans is a pathogen causing cryptococcosis in HIV/AIDS patients, but treatment is limited due to the relative lack of potent antifungal agents. Photodynamic inactivation (PDI) uses the combination of non-toxic dyes called photosensitizers and harmless visible light, which produces singlet oxygen and other reactive oxygen species that produce cell inactivation and death. We report the use of five structurally unrelated photosensitizers (methylene blue, Rose Bengal, selenium derivative of a Nile blue dye, a cationic fullerene and a conjugate between poly-L-lysine and chlorin(e6)) combined with appropriate wavelengths of light to inactivate C. neoformans. Mutants lacking capsule and laccase, and culture conditions that favoured melanin production were used to probe the mechanisms of PDI and the effect of virulence factors. The presence of cell wall, laccase and melanin tended to protect against PDI, but the choice of the appropriate photosensitizers and dosimetry was able to overcome this resistance.Fundação de Amparo à Pesquisa do Estado de São Paulo (2010/13313–9

Transtendinous course of the infrapatellar branch of saphenous nerve. A contribution to the aetiology of entrapment neuropathy and modification of the existing classification

Background: The course of the infrapatellar branch of saphenous nerve (IPBSN) in relation to the Sartorius muscle has been classified into presartorial, transsartorial and retrosartorial types. Mechanical compression of the IPBSN within the Sartorius tendon has been surgically recognised as a cause of entrapment neuropathy. Purpose of the present study was to differentiate the IPBSNs penetrating the Sartorius tendon from those penetrating the Sartorius muscle, from an anatomical and clinical point of views and thus modifying the existing classification. Materials and methods: The IPBSN was bilaterally dissected in 27 cadavers. The cases of the IPBSNs penetrating the Sartorius tendon were recorded separately from those penetrating the Sartorius muscle belly. Results: In 11 out of 54 limbs (20.4%) the IPBSN ran through the Sartorius muscle belly. In 3 out of 54 (5.6%) limbs, the IPBSN penetrated the Sartorius tendon. Conclusions: The penetrating type of IPBSN includes two distinct subtypes: the muscle-penetrating type and the tendon-penetrating type. These subtypes are also distinct from a clinical point of view, since only the tendon-penetrating type has been associated with the IPBSN entrapment neuropathy. According to these findings we suggest a modification of the current classification. Further clinical studies are necessary to fully demonstrate whether the tendon-penetrating type should be considered as a predisposing factor for the IPBSN entrapment neuropathy. Distinguishing the two subtypes might be helpful for that purpose