A Metabolic Dependency for Host Isoprenoids in the Obligate Intracellular Pathogen Rickettsia parkeri Underlies a Sensitivity to the Statin Class of Host-Targeted Therapeutics.

Gram-negative bacteria in the order Rickettsiales have an obligate intracellular growth requirement, and some species cause human diseases such as typhus and spotted fever. The bacteria have evolved a dependence on essential nutrients and metabolites from the host cell as a consequence of extensive genome reduction. However, it remains largely unknown which nutrients they acquire and whether their metabolic dependency can be exploited therapeutically. Here, we describe a genetic rewiring of bacterial isoprenoid biosynthetic pathways in the Rickettsiales that has resulted from reductive genome evolution. Furthermore, we investigated whether the spotted fever group Rickettsia species Rickettsia parkeri scavenges isoprenoid precursors directly from the host. Using targeted mass spectrometry, we found that infection caused decreases in host isoprenoid products and concomitant increases in bacterial isoprenoid metabolites. Additionally, we report that treatment of infected cells with statins, which inhibit host isoprenoid synthesis, prohibited bacterial growth. We show that growth inhibition correlates with changes in bacterial size and shape that mimic those caused by antibiotics that inhibit peptidoglycan biosynthesis, suggesting that statins lead to an inhibition of cell wall synthesis. Altogether, our results describe a potential Achilles' heel of obligate intracellular pathogens that can potentially be exploited with host-targeted therapeutics that interfere with metabolic pathways required for bacterial growth.IMPORTANCE Obligate intracellular pathogens, which include viruses as well as certain bacteria and eukaryotes, are a subset of infectious microbes that are metabolically dependent on and unable to grow outside an infected host cell because they have lost or lack essential biosynthetic pathways. In this study, we describe a metabolic dependency of the bacterial pathogen Rickettsia parkeri on host isoprenoid molecules that are used in the biosynthesis of downstream products, including cholesterol, steroid hormones, and heme. Bacteria make products from isoprenoids, such as an essential lipid carrier for making the bacterial cell wall. We show that bacterial metabolic dependency can represent a potential Achilles' heel and that inhibiting host isoprenoid biosynthesis with the FDA-approved statin class of drugs inhibits bacterial growth by interfering with the integrity of the cell wall. This work supports the potential to treat infections by obligate intracellular pathogens through inhibition of host biosynthetic pathways that are susceptible to parasitism

Camptothecin Analogs and Methods of Preparation Thereof

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Camptothecin Analogs and Methods of Preparation Thereof

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Camptothecin Intermediates and Prodrugs and Methods of Preparation Thereof

The present invention relates to novel intermediates and prodrugs of camptothecin and related analogs

Highly Lipophilic Camptothecin Intermediates and Prodrugs and Methods of Preparation Thereof

The present invention relates to novel, highly lipophilic silatecan intermediates and prodrugs of DB-67 and other silatecans

Localised plumes in three-dimensional compressible magnetoconvection

Within the umbrae of sunspots, convection is generally inhibited by the presence of strong vertical magnetic fields. However, convection is not completely suppressed in these regions: bright features, known as umbral dots, are probably associated with weak, isolated convective plumes. Motivated by observations of umbral dots, we carry out numerical simulations of three-dimensional, compressible magnetoconvection. By following solution branches into the subcritical parameter regime (a region of parameter space in which the static solution is linearly stable to convective perturbations), we find that it is possible to generate a solution which is characterised by a single, isolated convective plume. This solution is analogous to the steady magnetohydrodynamic convectons that have previously been found in two-dimensional calculations. These results can be related, in a qualitative sense, to observations of umbral dots.Comment: submitted to MNRA

Genetic instrumental variable regression: Explaining socioeconomic and health outcomes in nonexperimental data

Identifying causal effects in nonexperimental data is an enduring challenge. One proposed solution that recently gained popularity is the idea to use genes as instrumental variables [i.e., Mendelian randomization (MR)]. However, this approach is problematic because many variables of interest are genetically correlated, which implies the possibility that many genes could affect both the exposure and the outcome directly or via unobserved confounding factors. Thus, pleiotropic effects of genes are themselves a source of bias in nonexperimental data that would also undermine the ability of MR to correct for endogeneity bias from nongenetic sources. Here, we propose an alternative approach, genetic instrumental variable (GIV) regression, that provides estimates for the effect of an exposure on an outcome in the presence of pleiotropy. As a valuable byproduct, GIV regression also provides accurate estimates of the chip heritability of the outcome variable. GIV regression uses polygenic scores (PGSs) for the outcome of interest which can be constructed from genome-wide association study (GWAS) results. By splitting the GWAS sample for the outcome into nonoverlapping subsamples, we obtain multiple indicators of the outcome PGSs that can be used as instruments for each other and, in combination with other methods such as sibling fixed effects, can address endogeneity bias from both pleiotropy and the environment. In two empirical applications, we demonstrate that our approach produces reasonable estimates of the chip heritability of educational attainment (EA) and show that standard regression and MR provide upwardly biased estimates of the effect of body height on EA

Relevance of the slowly-varying electron gas to atoms, molecules, and solids

Under a certain scaling, the electron densities of finite systems become both large and slowly-varying, so that the gradient expansions of the density functionals for the Kohn-Sham kinetic and exchange energies become asymptotically exact to order $\nabla^2$. Neutral atoms of large $Z$ scale similarly, but a cusp correction at the nucleus requires generalizing the gradient expansion for exchange, producing the wrong gradient coefficient in the slowly-varying limit. Meta-generalized gradient approximations (meta-GGA's) recover both the slowly-varying and large-$Z$ limits. GGA correlation energies of large-Z atoms are found to be accurate.Comment: 5 pages, 4 figures, submitted at PR