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After General Relativity was established in essentially its present form in 1915 it was celebrated as a great success of mathematical physics. But the initial hopes for this theory as a basis for all of physics began to fade in the next several decades, as General Relativity was relegated to the margins of theoretical physics. Its fate began to rise in the 1950's in a revival of interest and research that over time made gravitational physics one of the hottest research topics it is today. One center of this renaissance was Princeton, where two relative newcomers explored new and different approaches to gravitational physics. Robert Dicke showed that gravity is not as inaccessible to experiment as was thought, and John Wheeler propelled it into the mainstream by proposing highly original and imaginative consequences of Einstein's theory. We will concentrate on these ideas that, in his characteristically intriguing style, Wheeler called "Daring Conservatism" -- a term well known to his associates, but one he never mentioned in print. With the aid of unpublished manuscripts and notes we will explore Daring Conservatism's origin and motivation, its successes and failures, and the legacy it left behind.

Kidney epithelia develop from the metanephric mesenchyme after receiving inductive signals from the ureteric bud and from the renal stroma. However, it is not clear how these signals induce the different types of epithelia that make up the nephron. To investigate inductive signaling, we have isolated clusters of epithelial progenitors from the metanephric mesenchyme, thereby separating them from the renal stroma. When the isolated progenitors were treated with the ureteric bud factor LIF, they expressed epithelial proteins (ZO-1, E-cadherin, laminin [alpha.sub.5]) and produced nephrons (36 glomeruli with 58 tubules), indicating that they are the target of inductive signaling from the ureteric bud, and that renal stroma is not absolutely required for epithelial development in vitro. In fact, stroma-depleted epithelial progenitors produced sevenfold more glomeruli than did intact metanephric mesenchyme (5 glomeruli, 127 tubules). Conversely, when epithelial progenitors were treated with both LIF and proteins secreted from a renal stromal cell line, glomerulogenesis was abolished but tubular epithelia were expanded (0 glomeruli, 47 tubules). Hence, by isolating epithelial progenitors from the metanephric mesenchyme, we show that they are targeted by factors from the ureteric bud and from the renal stroma, and that epithelial diversification is stimulated by the ureteric bud and limited by renal stroma. Key Words: epithelia; progenitor; mesenchyme; induction; kidney; stroma.

Background Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available. Methods We conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes. Results Of 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P  = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI},.6–2.4]) or adjusted (HR, 0.8 [95% CI,.5–1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2–8.8]). Conclusions In a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test–based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB. [ABSTRACT FROM AUTHOR]