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

Cockayne syndrome group B protein has novel strand annealing and exchange activities

Cockayne syndrome (CS) is a rare inherited human genetic disorder characterized by UV sensitivity, severe neurological abnormalities and prageroid symptoms. The CS complementation group B (CSB) protein is involved in UV-induced transcription coupled repair (TCR), base excision repair and general transcription. CSB also has a DNA-dependent ATPase activity that may play a role in remodeling chromatin in vivo. This study reports the novel finding that CSB catalyzes the annealing of complementary single-stranded DNA (ssDNA) molecules with high efficiency, and has strand exchange activity. The rate of CSB-catalyzed annealing of complementary ssDNA is 25-fold faster than the rate of spontaneous ssDNA annealing under identical in vitro conditions and the reaction occurs with a high specificity in the presence of excess non-homologous ssDNA. The specificity and intrinsic nature of the reaction is also confirmed by the observation that it is stimulated by dephosphorylation of CSB, which occurs after UV-induced DNA damage, and is inhibited in the presence of ATPγS. Potential roles of CSB in cooperation with strand annealing and exchange activities for TCR and homologous recombination are discussed

A protective role for BRCA2 at stalled replication forks

The hereditary breast and ovarian cancer predisposition genes BRCA1 and BRCA2 account for the lion's share of heritable breast cancer risk in the human population. Loss of function of either gene results in defective homologous recombination (HR) and triggers genomic instability, accelerating breast tumorigenesis. A long-standing hypothesis proposes that BRCA1 and BRCA2 mediate HR following attempted replication across damaged DNA, ensuring error-free processing of the stalled replication fork. A recent paper describes a new replication fork protective function of BRCA2, which appears to collaborate with its HR function to suppress genomic instability

The Effect of Auditory Distraction on the Useful Field of View in Hearing Impaired Individuals and its implications for driving

This study assessed whether the increased demand of listening in hearing impaired individuals exacerbates the detrimental impact of auditory distraction on a visual task (useful field of view test), relative to normally hearing listeners. Auditory distraction negatively affects this visual task, which is linked with various driving performance outcomes. Hearing impaired and normally hearing participants performed useful field of view testing with and without a simultaneous listening task. They also undertook a cognitive test battery. For all participants, performing the visual and auditory tasks together reduced performance on each respective test. For a number of subtests, hearing impaired participants showed poorer visual task performance, though not to a statistically significant extent. Hearing impaired participants were significantly poorer at a reading span task than normally hearing participants and tended to score lower on the most visually complex subtest of the visual task in the absence of auditory task engagement. Useful field of view performance is negatively affected by auditory distraction, and hearing loss may present further problems, given the reductions in visual and cognitive task performance suggested in this study. Suggestions are made for future work to extend this study, given the practical importance of the findings

The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA

Individuals with BRCA2 mutations are predisposed to breast cancers owing to genome instability. To determine the functions of BRCA 2, the human protein was purified. It was found to bind selectively to single-stranded DNA (ssDNA), and to ssDNA in tailed duplexes and replication fork structures. Monomeric and dimeric forms of BRCA 2 were observed by EM. BRCA 2 directed the binding of RA D51 recombinase to ssDNA, reduced the binding of RA D51 to duplex DNA and stimulated RA D51-mediated DNA strand exchange. These observations provide a molecular basis for the role of BRCA 2 in the maintenance of genome stability

A rationally designed peptide enhances homologous recombination in vitro and resistance to DNA damaging agents in vivo

The RecA family of proteins is essential in homologous recombination, a critical step in DNA repair. Here, we report that a rationally-designed small peptide based on the crystal structure of Escherichia coli RecA–DNA complex can promote homologous recombination through the enhancement of both RecA-mediated strand assimilation and three-strand exchange activity. Among 17 peptides tested, peptide #3 with the amino acid sequence of IRFLTARRR has the most potent activity in promoting the RecA-mediated D-loop formation by ∼7.2-fold at 37°C. Other peptides such as IRFLTAKKK and IRLLTARRR also have similar, albeit lower, activities. Therefore, hydrophobicity and poly-positive charges, and the space between them in those small peptides are crucial features for such activities. The enhancement of recombination by these peptides appears to be a general phenomenon as similar results were seen by using different plasmids. Remarkably, peptide #3 alone without RecA can also promote the D-loop formation at elevated temperature. Cell viability assays showed that the peptide elevates mammalian cell resistance to two cytotoxic DNA drugs, cisplatin and doxorubicin. The rescue of viability may result from increased DNA repair efficiency. Such peptides may find future biological applications

Integrated acoustic immunoaffinity-capture (IAI) platform for detection of PSA from whole blood samples.

On-chip detection of low abundant protein biomarkers is of interest to enable point-of-care diagnostics. Using a simple form of integration, we have realized an integrated microfluidic platform for the detection of prostate specific antigen (PSA), directly in anti-coagulated whole blood. We combine acoustophoresis-based separation of plasma from undiluted whole blood with a miniaturized immunoassay system in a polymer manifold, demonstrating improved assay speed on our Integrated Acoustic Immunoaffinity-capture (IAI) platform. The IAI platform separates plasma from undiluted whole blood by means of acoustophoresis and provides cell free plasma of clinical quality at a rate of 10 uL/min for an online immunoaffinity-capture of PSA on a porous silicon antibody microarray. The whole blood input (hematocrit 38-40%) rate was 50 μl min(-1) giving a plasma volume fraction yield of ≈33%. PSA was immunoaffinity-captured directly from spiked female whole blood samples at clinically significant levels of 1.7-100 ng ml(-1) within 15 min and was subsequently detected via fluorescence readout, showing a linear response over the entire range with a coefficient of variation of 13%

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

The Epistatic Relationship between BRCA2 and the Other RAD51 Mediators in Homologous Recombination

RAD51 recombinase polymerizes at the site of double-strand breaks (DSBs) where it performs DSB repair. The loss of RAD51 causes extensive chromosomal breaks, leading to apoptosis. The polymerization of RAD51 is regulated by a number of RAD51 mediators, such as BRCA1, BRCA2, RAD52, SFR1, SWS1, and the five RAD51 paralogs, including XRCC3. We here show that brca2-null mutant cells were able to proliferate, indicating that RAD51 can perform DSB repair in the absence of BRCA2. We disrupted the BRCA1, RAD52, SFR1, SWS1, and XRCC3 genes in the brca2-null cells. All the resulting double-mutant cells displayed a phenotype that was very similar to that of the brca2-null cells. We suggest that BRCA2 might thus serve as a platform to recruit various RAD51 mediators at the appropriate position at the DNA–damage site

Does transition from an unstable labour market position to permanent employment protect mental health? Results from a 14-year follow-up of school-leavers

<p>Abstract</p> <p>Background</p> <p>Having secure employment, in contrast to being unemployed, is regarded as an important determinant of health. Research and theories about the negative health consequences of unemployment indicated that transition from unemployment to a paid job could lead to improved health. The objective of this study was to test the hypothesis that obtaining permanent employment after being in an unstable labour market position protects mental health.</p> <p>Methods</p> <p>A 14-year follow-up of all graduates from compulsory school in an industrial town in northern Sweden was performed at ages 16, 18, 21 and 30 years. Complete data on the cohort were collected for 1044 individuals with the aid of a comprehensive questionnaire. The response rate was 96.4%. The health measurement used in this study was the psychological symptoms analysed by multivariate logistic regression. Those who obtained permanent employment were the focus of the analysis. This group consisted of people who were in an unstable labour market position for a year or more between the ages of 25 and 29, and who had acquired a permanent job one year before and at the time of the investigation.</p> <p>Results</p> <p>After controlling for gender as well as for an indicator of health-related selection, possible confounders and mediators, an association was found between the lower probability of psychological symptoms and obtaining permanent employment (OR = 0.35, 95% CI 0.19–0.63) as well as having permanent employment (OR = 0.22, 95% CI 0.10–0.51).</p> <p>Conclusion</p> <p>Our findings suggest that transition from an unstable labour market position to permanent employment could be health-promoting, even after controlling for possible confounders and mediators, as well as for an indicator of health-related selection. However, as there are few studies in the field, there is a need for more longitudinal studies in order to further analyse the relationship and to examine possible explanations. The policy implication of our study is that the transformation of unstable labour market positions into permanent employment could contribute to better public health.</p