Cytological mapping of the human glucose-6-phosphate dehydrogenase gene distal to the fragile-X site suggests a high rate of meiotic recombination across this site.

The human gene for glucose-6-phosphate dehydrogenase (G6PD) has been subregionally mapped to band Xq28 by segregation analysis in rodent-human somatic cell hybrids [Pai, G. S., Sprinkel, J. A., Do, T. T., Mareni, C. E. & Migeon, B. R. (1980) Proc. Natl. Acad. Sci. USA 77, 2810-2813]. We have previously reported a common type of X-linked mental retardation associated with an inducible fragile site at Xq27-Xq28 segregates in a close linkage relationship with a G6PD variant, but the relative position of G6PD with respect to the fragile site has not yet been established. This fragile-X syndrome has been shown to be closely linked also to a Taq I restriction fragment length polymorphism detected by a cDNA probe for factor IX, and the latter locus has been mapped to the subtelomeric region Xq26-Xq28 [Camerino, G., Mattei, M. G., Mattei, G. F., Jaye, B. & Mandel, J. L. (1983) Nature (London) 306, 701-704]. The in situ hybridization studies reported here provide strong evidence that G6PD is located on the Xq telomeric fragment distal to the fragile site. These observations and the well-established knowledge that the genes for Deutan and Protan colorblindness are closely linked to G6PD, but segregate independently of factor IX deficiency, suggest that the fragile site associated with this type of X-linked mental retardation occurs in a region prone to high frequency of meiotic recombination.     

The genetics of hepatitis C virus underlie its ability to escape humoral immunity

Hepatitis C virus (HCV) is a leading cause of chronic liver disease, and efforts to develop therapeutic vaccine strategies have been limited by immune escape due to HCV variants that are resistant to current vaccines or HCV variants that rapidly acquire new resistance-conferring mutations. Recently, the crystal structure of the viral envelope protein E2 region was resolved as well as how E2 docks to the host CD81 protein; therefore, antibodies that block this interaction should prevent viral entry into host cells. In this issue of the JCI, Bailey and colleagues show that immune escape of HCV can occur by naturally occurring polymorphisms in E2 that are distinct from those at mapped sites of antibody binding. These data reveal alternative mechanisms of resistance that need to be considered in both natural viral escape as well as in rationale vaccine design against HCV.     

Free energy reconstruction from nonequilibrium single-molecule pulling experiments

Laser tweezers and atomic force microscopes are increasingly used to probe the interactions and mechanical properties of individual molecules. Unfortunately, using such time-dependent perturbations to force rare molecular events also drives the system away from equilibrium. Nevertheless, we show how equilibrium free energy profiles can be extracted rigorously from repeated nonequilibrium force measurements on the basis of an extension of Jarzynski's remarkable identity between free energies and the irreversible work.     

Theory of the energy transfer efficiency and fluorescence lifetime distribution in single-molecule FRET

In single-molecule FRET experiments with pulsed lasers, not only the colors of the photons but also the fluorescence lifetimes can be monitored. Although these quantities appear to be random, they are modulated by conformational dynamics. In order to extract information about such dynamics, we develop the theory of the joint distribution of FRET efficiencies and fluorescence lifetimes determined from bins (or bursts) of photons. Our starting point is a rigorous formal expression for the distribution of the numbers of donor and acceptor photons and donor lifetimes in a bin that treats the influence of conformational dynamics on all timescales. This formula leads to an analytic result for a two-state system interconverting on a timescale slower than the interphoton time and to an efficient simulation algorithm for multistate dynamics. The shape of the joint distribution contains more information about conformational dynamics than the FRET efficiency histogram alone. In favorable cases, the connectivity of the underlying conformational states can be determined directly by simple inspection of the projection of the joint distribution on the efficiency-lifetime plane.     

Declining rates of deceased donor renal transplantation in the United States over successive years of listing

ObjectiveRenal transplantation is the best treatment for end-stage renal disease. However, limited availability of donor organs is a problem. We analyzed the changing trends of transplantation and mortality in subjects listed for deceased donor renal transplantation over successive years.MethodsBy using US Renal Data System data, we identified Medicare patients receiving dialysis who were listed for their first deceased donor renal transplant between January 1996 and December 2005. Subjects were followed to the first occurrence of transplant, death, or September 30, 2007. The effect of the year of listing was analyzed adjusting for age, sex, race, vintage, panel reactive antibody, and cause of end-stage renal disease.ResultsThere were 70,891 subjects (mean age 50.1 ± 14.3 years, 59.9% were men, 54% were white, average duration of dialysis 2 ± 2.2 years). Multivariate analysis revealed that compared with patients listed in 1996, for patients listed in subsequent years the cumulative incidence of death remained within a narrow boundary and the cumulative incidence of transplant progressively declined. For example, for subjects listed in 1998, 2000, 2002, and 2004, the cumulative incidence of death relative to 1996 was 1.02 (95% confidence interval [CI], 1.01-1.03), 1.02 (CI, 1.01-1.03), 0.99 (CI, 0.98-0.99), and 0.94 (CI, 0.93-0.94), respectively, 12 months after listing. However, correspondingly for these subjects at the 12-month follow-up time point, the cumulative incidence of transplant relative to 1996 was 0.85 (CI, 0.84-0.86), 0.73 (CI, 0.71-0.74), 0.63 (CI, 0.62-0.64), and 0.58 (CI, 0.57-0.59), respectively.ConclusionThere is a progressive unfavorable pattern of declining transplantation rates with each successive year of listing in patients listed for deceased donor renal transplantation.