Effects of X-ray irradiation on human spermatogenesis

Direct cell kill and inhibition of mitosis have been suggested as mechanisms to explain the occurrence of absolute sterility following the irradiation of the testes. In order to obtain information on the existence and dose dependency of the mechanisms for man, a controlled study was initiated. Sixty-four men received a single midorgan dose to both of their testes ranging from 7.5 to 400r (f = .95). It was deduced from resulting pre-sterile period and sterile period data that both cell kill and mitosis halting mechanisms were operating. The maximum observed sterile period was 501 days with eventual recovery observed in each individual where the follow-up was complete. Thus man appears to be highly radiosensitive in regard to temporary sterility but quite radioresistant in regard to permanent sterility

Trends in absolute socioeconomic inequalities in mortality in Sweden and New Zealand. A 20-year gender perspective

BACKGROUND: Both trends in socioeconomic inequalities in mortality, and cross-country comparisons, may give more information about the causes of health inequalities. We analysed trends in socioeconomic differentials by mortality from early 1980s to late 1990s, comparing Sweden with New Zealand. METHODS: The New Zealand Census Mortality Study (NZCMS) consisting of over 2 million individuals and the Swedish Survey of Living Conditions (ULF) comprising over 100, 000 individuals were used for analyses. Education and household income were used as measures of socioeconomic position (SEP). The slope index of inequality (SII) was calculated to estimate absolute inequalities in mortality. Analyses were based on 3–5 year follow-up and limited to individuals aged 25–77 years. Age standardised mortality rates were calculated using the European population standard. RESULTS: Absolute inequalities in mortality on average over the 1980s and 1990s for both men and women by education were similar in Sweden and New Zealand, but by income were greater in Sweden. Comparing trends in absolute inequalities over the 1980s and 1990s, men's absolute inequalities by education decreased by 66% in Sweden and by 17% in New Zealand (p for trend <0.01 in both countries). Women's absolute inequalities by education decreased by 19% in Sweden (p = 0.03) and by 8% in New Zealand (p = 0.53). Men's absolute inequalities by income decreased by 51% in Sweden (p for trend = 0.06), but increased by 16% in New Zealand (p = 0.13). Women's absolute inequalities by income increased in both countries: 12% in Sweden (p = 0.03) and 21% in New Zealand (p = 0.04). CONCLUSION: Trends in socioeconomic inequalities in mortality were clearly most favourable for men in Sweden. Trends also seemed to be more favourable for men than women in New Zealand. Assuming the trends in male inequalities in Sweden were not a statistical chance finding, it is not clear what the substantive reason(s) was for the pronounced decrease. Further gender comparisons are required

Structural and Functional Analyses of Five Conserved Positively Charged Residues in the L1 and N-Terminal DNA Binding Motifs of Archaeal RadA Protein

RecA family proteins engage in an ATP-dependent DNA strand exchange reaction that includes a ssDNA nucleoprotein helical filament and a homologous dsDNA sequence. In spite of more than 20 years of efforts, the molecular mechanism of homology pairing and strand exchange is still not fully understood. Here we report a crystal structure of Sulfolobus solfataricus RadA overwound right-handed filament with three monomers per helical pitch. This structure reveals conformational details of the first ssDNA binding disordered loop (denoted L1 motif) and the dsDNA binding N-terminal domain (NTD). L1 and NTD together form an outwardly open palm structure on the outer surface of the helical filament. Inside this palm structure, five conserved basic amino acid residues (K27, K60, R117, R223 and R229) surround a 25 Å pocket that is wide enough to accommodate anionic ssDNA, dsDNA or both. Biochemical analyses demonstrate that these five positively charged residues are essential for DNA binding and for RadA-catalyzed D-loop formation. We suggest that the overwound right-handed RadA filament represents a functional conformation in the homology search and pairing reaction. A new structural model is proposed for the homologous interactions between a RadA-ssDNA nucleoprotein filament and its dsDNA target

Plasticity of BRCA2 Function in Homologous Recombination: Genetic Interactions of the PALB2 and DNA Binding Domains

The breast cancer suppressor BRCA2 is essential for the maintenance of genomic integrity in mammalian cells through its role in DNA repair by homologous recombination (HR). Human BRCA2 is 3,418 amino acids and is comprised of multiple domains that interact with the RAD51 recombinase and other proteins as well as with DNA. To gain insight into the cellular function of BRCA2 in HR, we created fusions consisting of various BRCA2 domains and also introduced mutations into these domains to disrupt specific protein and DNA interactions. We find that a BRCA2 fusion peptide deleted for the DNA binding domain and active in HR is completely dependent on interaction with the PALB2 tumor suppressor for activity. Conversely, a BRCA2 fusion peptide deleted for the PALB2 binding domain is dependent on an intact DNA binding domain, providing a role for this conserved domain in vivo; mutagenesis suggests that both single-stranded and double-stranded DNA binding activities in the DNA binding domain are required for its activity. Given that PALB2 itself binds DNA, these results suggest alternative mechanisms to deliver RAD51 to DNA. In addition, the BRCA2 C terminus contains both RAD51-dependent and -independent activities which are essential to HR in some contexts. Finally, binding the small peptide DSS1 is essential for activity when its binding domain is present, but not when it is absent. Our results reveal functional redundancy within the BRCA2 protein and emphasize the plasticity of this large protein built for optimal HR function in mammalian cells. The occurrence of disease-causing mutations throughout BRCA2 suggests sub-optimal HR from a variety of domain modulations