Cellular Radiosensitivity: How much better do we understand it?

Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies. Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation

Three-dimensional structure of a viral genome-delivery portal vertex.

DNA viruses such as bacteriophages and herpesviruses deliver their genome into and out of the capsid through large proteinaceous assemblies, known as portal proteins. Here, we report two snapshots of the dodecameric portal protein of bacteriophage P22. The 3.25-Å-resolution structure of the portal-protein core bound to 12 copies of gene product 4 (gp4) reveals a ~1.1-MDa assembly formed by 24 proteins. Unexpectedly, a lower-resolution structure of the full-length portal protein unveils the unique topology of the C-terminal domain, which forms a ~200-Å-long α-helical barrel. This domain inserts deeply into the virion and is highly conserved in the Podoviridae family. We propose that the barrel domain facilitates genome spooling onto the interior surface of the capsid during genome packaging and, in analogy to a rifle barrel, increases the accuracy of genome ejection into the host cell

Dynamic light diffusion, Anderson localization and lasing in disordered inverted opals: 3D ab-initio Maxwell-Bloch computation

We report on 3D time-domain parallel simulations of Anderson localization of light in inverted disordered opals displaying a complete photonic band-gap. We investigate dynamic diffusion processes induced by femtosecond laser excitations, calculate the diffusion constant and the decay-time distribution versus the strength of the disorder. We report evidence of the transition from delocalized Bloch oscillations to strongly localized resonances in self-starting laser processes.Comment: 4 pages, 5 figure

A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

The recognition of peptide in the context of MHC by T lymphocytes is a critical step in the initiation of an adaptive immune response. However, the molecular nature of the interaction between peptide and MHC and how it influences T cell responsiveness is not fully understood.We analyzed the immunological consequences of the interaction of MHC class II (I-Au) restricted 11-mer peptides of myelin basic protein with amino acid substitutions at position 4. These mutant peptides differ in MHC binding affinity, CD4+ T cell priming, and alter the severity of peptide-induced experimental allergic encephalomyelitis. Using molecular dynamics, a computational method of quantifying intrinsic movements of proteins at high resolution, we investigated conformational changes in MHC upon peptide binding. We found that irrespective of peptide binding affinity, MHC deformation appears to influence costimulation, which then leads to effective T cell priming and disease induction. Although this study compares in vivo and molecular dynamics results for three altered peptide ligands, further investigation with similar complexes is essential to determine whether spatial rearrangement of peptide-MHC and costimulatory complexes is an additional level of T cell regulation

Transplacental Passage of Interleukins 4 and 13?

The mechanisms by which prenatal events affect development of adult disease are incompletely characterized. Based on findings in a murine model of maternal transmission of asthma risk, we sought to test the role of the pro-asthmatic cytokines interleukin IL-4 and -13. To assess transplacental passage of functional cytokines, we assayed phosphorylation of STAT-6, a marker of IL-4 and -13 signaling via heterodimeric receptor complexes which require an IL-4 receptor alpha subunit. IL-4 receptor alpha−/− females were mated to wild-type males, and pregnant females were injected with supraphysiologic doses of IL-4 or 13. One hour after injection, the receptor heterozygotic embryos were harvested and tissue nuclear proteins extracts assayed for phosphorylation of STAT-6 by Western blot. While direct injection of embryos produced a robust positive control, no phosphorylation was seen after maternal injection with either IL-4 or -13, indicating that neither crossed the placenta in detectable amounts. The data demonstrate a useful approach to assay for transplacental passage of functional maternal molecules, and indicate that molecules other than IL-4 and IL-13 may mediate transplacental effects in maternal transmission of asthma risk

Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder characterized by (i) pruritus with onset in the second or third trimester of pregnancy, (ii) elevated serum aminotransferases and bile acid levels, and (iii) spontaneous relief of signs and symptoms within two to three weeks after delivery. ICP is observed in 0.4–1% of pregnancies in most areas of Central and Western Europe and North America, while in Chile and Bolivia as well as Scandinavia and the Baltic states roughly 5–15% and 1–2%, respectively, of pregnancies are associated with ICP. Genetic and hormonal factors, but also environmental factors may contribute to the pathogenesis of ICP. Intrahepatic cholestasis of pregnancy increases the risk of preterm delivery (19–60%), meconium staining of amniotic fluid (27%), fetal bradycardia (14%), fetal distress (22–41%), and fetal loss (0.4–4.1%), particularly when associated with fasting serum bile acid levels > 40 μmol/L. The hydrophilic bile acid ursodeoxycholic acid (10–20 mg/kg/d) is today regarded as the first line treatment for intrahepatic cholestasis of pregnancy. Delivery has been recommended in the 38th week when lung maturity has been established

Incipient Balancing Selection through Adaptive Loss of Aquaporins in Natural Saccharomyces cerevisiae Populations

A major goal in evolutionary biology is to understand how adaptive evolution has influenced natural variation, but identifying loci subject to positive selection has been a challenge. Here we present the adaptive loss of a pair of paralogous genes in specific Saccharomyces cerevisiae subpopulations. We mapped natural variation in freeze-thaw tolerance to two water transporters, AQY1 and AQY2, previously implicated in freeze-thaw survival. However, whereas freeze-thaw–tolerant strains harbor functional aquaporin genes, the set of sensitive strains lost aquaporin function at least 6 independent times. Several genomic signatures at AQY1 and/or AQY2 reveal low variation surrounding these loci within strains of the same haplotype, but high variation between strain groups. This is consistent with recent adaptive loss of aquaporins in subgroups of strains, leading to incipient balancing selection. We show that, although aquaporins are critical for surviving freeze-thaw stress, loss of both genes provides a major fitness advantage on high-sugar substrates common to many strains' natural niche. Strikingly, strains with non-functional alleles have also lost the ancestral requirement for aquaporins during spore formation. Thus, the antagonistic effect of aquaporin function—providing an advantage in freeze-thaw tolerance but a fitness defect for growth in high-sugar environments—contributes to the maintenance of both functional and nonfunctional alleles in S. cerevisiae. This work also shows that gene loss through multiple missense and nonsense mutations, hallmarks of pseudogenization presumed to emerge after loss of constraint, can arise through positive selection

Goal Priming in Dieters: Recent Insights and Applications

What are the psychological mechanisms that make dieting so challenging in our food-rich living environment? Social psychological research on goal priming provides a useful framework for answering this question, as well as implications for how to enhance dieting success. This review presents and discusses recent research which shows that attractive food cues prime the hedonic eating goal in dieters, and thus facilitate overeating. However, external cues priming the goal of weight control can be used to offset these effects and thus to facilitate dieting success, as is demonstrated in both field and laboratory experiments. In addition, recent strategies to prevent hedonic effects of attractive food, such as mindful attention, can facilitate self-regulation. These recent advances in our understanding of dieting behavior have theoretical and practical implications for how successful dieting can be facilitated, both by means of individual strategies, as well as by environmental changes

The dynamic stator stalk of rotary ATPases

Rotary ATPases couple ATP hydrolysis/synthesis with proton translocation across biological membranes and so are central components of the biological energy conversion machinery. Their peripheral stalks are essential components that counteract torque generated by rotation of the central stalk during ATP synthesis or hydrolysis. Here we present a 2.25-Å resolution crystal structure of the peripheral stalk from Thermus thermophilus A-type ATPase/synthase. We identify bending and twisting motions inherent within the structure that accommodate and complement a radial wobbling of the ATPase headgroup as it progresses through its catalytic cycles, while still retaining azimuthal stiffness necessary to counteract rotation of the central stalk. The conformational freedom of the peripheral stalk is dictated by its unusual right-handed coiled-coil architecture, which is in principle conserved across all rotary ATPases. In context of the intact enzyme, the dynamics of the peripheral stalks provides a potential mechanism for cooperativity between distant parts of rotary ATPases