The Werner's Syndrome protein collaborates with REV1 to promote replication fork progression on damaged DNA

AbstractDNA damage tolerance pathways facilitate the bypass of DNA lesions encountered during replication. These pathways can be mechanistically divided into recombinational damage avoidance and translesion synthesis, in which the lesion is directly bypassed by specialised DNA polymerases. We have recently shown distinct genetic dependencies for lesion bypass at and behind the replication fork in the avian cell line DT40, bypass at the fork requiring REV1 and bypass at post-replicative gaps requiring PCNA ubiquitination by RAD18. The WRN helicase/exonuclease, which is mutated in the progeroid and cancer predisposition disorder Werner's Syndrome, has previously been implicated in a RAD18-dependent DNA damage tolerance pathway. However, WRN has also been shown to be required to maintain normal replication fork progression on a damaged DNA template, a defect reminiscent of REV1-deficient cells. Here we use the avian cell line DT40 to demonstrate that WRN assists REV1-dependent translesion synthesis at the replication fork and that PCNA ubiquitination-dependent post-replicative lesion bypass provides an important backup mechanism for damage tolerance in the absence of WRN protein

Is There Still Room for Warm/Hot Gas? Simulating the X-ray Background Spectrum

At low redshifts, a census of the baryons in all known reservoirs falls a factor of two to four below the total baryon density predicted from Big Bang nucleosynthesis arguments and observed light element ratios. Recent cosmological hydrodynamic simulations suggest that a significant fraction of these missing baryons could be in the form of warm/hot gas in the filaments and halos within which most field galaxies are embedded. With the release of source count results from Chandra and recent detections of this gas in O VI quasar absorption lines, it becomes interesting to examine the predictions and limits placed on this component of the X-ray background (XRB). We have used new hydrodynamical simulations to predict the total X-ray spectrum from the gas in the 100 eV to 10 keV range. We find that, when uncertainties in the normalization of the observed XRB and the value of Omega_b are taken into account, our results are consistent with current observational limits placed on the contribution of emission from gas to the XRB. In the 0.5-2 keV range, we expect the contribution from this component to be 0.63 10^{-12} erg s^-1 cm^-2 deg^-2 or between 6% and 18% of the extragalactic surface brightness. The peak fraction occurs in the 0.5-1 keV range where the predicted line emission mirrors a spectral bump seen in the latest ASCA/ROSAT XRB data.Comment: 5 pages with 1 figure; submitted to ApJ Letter

Proper Motions in Compact Symmetric Objects

We discuss recent measurements of proper motions of the hotspots of Compact Symmetric Objects. Source expansion has been detected in ten CSOs so far and all these objects are very young (<3000 years). In a few sources ages have also been estimated from energy supply and spectral ageing arguments and these estimates are comparable. This argues that these sources are close to equipartition and that standard spectral ageing models apply. Proper motions studies are now constraining hotspot accelerations, side-to-side motions and differences in hotspot advance speeds between the two hotspots within sources. Although most CSOs are young sources their evolution is unclear. There is increasing evidence that in some objects the CSO structure represents a new phase of activity within a recurrent source.Comment: 10 pages, 3 figures, Accepted by Publications of the Astronomical Society of Australia (Vol. 20), as part of the proceedings of the 3rd GPS/CSS workshop, eds. T. Tzioumis, W. de Vries, I. Snellen, A. Koekemoe

On the Identification of High Mass Star Forming Regions using IRAS: Contamination by Low-Mass Protostars

We present the results of a survey of a small sample (14) of low-mass protostars (L_IR < 10^3 Lsun) for 6.7 GHz methanol maser emission performed using the ATNF Parkes radio telescope. No new masers were discovered. We find that the lower luminosity limit for maser emission is near 10^3 Lsun, by comparison of the sources in our sample with previously detected methanol maser sources. We examine the IRAS properties of our sample and compare them with sources previously observed for methanol maser emission, almost all of which satisfy the Wood & Churchwell criterion for selecting candidate UCHII regions. We find that about half of our sample satisfy this criterion, and in addition almost all of this subgroup have integrated fluxes between 25 and 60 microns that are similar to sources with detectable methanol maser emission. By identifying a number of low-mass protostars in this work and from the literature that satisfy the Wood & Churchwell criterion for candidate UCHII regions, we show conclusively for the first time that the fainter flux end of their sample is contaminated by lower-mass non-ionizing sources, confirming the suggestion by van der Walt and Ramesh & Sridharan.Comment: 8 pages with 2 figures. Accepted by Ap

HRM practices used to promote pro-environmental behavior: a UK survey

To date, the extent to which UK organizations use human resource management (HRM) practices to promote pro-environmental behavior through workplace HRM policies and initiatives is under-researched within the literature. Therefore, this paper presents results of a survey investigating current HRM practices used to promote pro-environmental behavior in a sample of 214 UK organizations representing different sizes and industry sectors. Overall, findings indicated that HRM practices are not used to a great extent to encourage employees to become more pro-environmental. The most prevalent practices used within organizations incorporated elements of management involvement supporting the idea that managers are the gatekeepers to environmental performance. Although organizations indicated that some HRM practices were more effective than others at encouraging pro-environmental behavior in their staff, only a very small percentage of organizations actually conducted any form of evaluation; organizations consequently lack clear evidence as to whether their HRM practices actually result in employee behavior change. Practical implications and future research directions are discussed

How Mistimed and Unwanted Pregnancies Affect Timing of Antenatal Care Initiation in three Districts in Tanzania

Early antenatal care (ANC) initiation is a doorway to early detection and management of potential complications associated with pregnancy. Although the literature reports various factors associated with ANC initiation such as parity and age, pregnancy intentions is yet to be recognized as a possible predictor of timing of ANC initiation. Data originate from a cross-sectional household survey on health behaviour and service utilization patterns. The survey was conducted in 2011 in Rufiji, Kilombero and Ulanga districts in Tanzania on 910 women of reproductive age who had given birth in the past two years. ANC initiation was considered to be early only if it occurred in the first trimester of pregnancy gestation. A recently completed pregnancy was defined as mistimed if a woman wanted it later, and if she did not want it at all the pregnancy was termed as unwanted. Chisquare was used to test for associations and multinomial logistic regression was conducted to examine how mistimed and unwanted pregnancies affect timing of ANC initiation. Although 49.3% of the women intended to become pregnant, 50.7% (34.9% mistimed and 15.8% unwanted) became pregnant unintentionally. While ANC initiation in the 1st trimester was 18.5%, so was 71.7% and 9.9% in the 2nd and 3rd trimesters respectively. Multivariate analysis revealed that ANC initiation in the 2nd trimester was 1.68 (95% CI 1.10‒2.58) and 2.00 (95% CI 1.05‒3.82) times more likely for mistimed and unwanted pregnancies respectively compared to intended pregnancies. These estimates rose to 2.81 (95% CI 1.41‒5.59) and 4.10 (95% CI 1.68‒10.00) respectively in the 3rd trimester. We controlled for gravidity, age, education, household wealth, marital status, religion, district of residence and travel time to a health facility. Late ANC initiation is a significant maternal and child health consequence of mistimed and unwanted pregnancies in Tanzania. Women should be empowered to delay or avoid pregnancies whenever they need to do so. Appropriate counseling to women, especially those who happen to conceive unintentionally is needed to minimize the possibility of delaying ANC initiation.\u

The International Olympic Committee framework on fairness, inclusion and nondiscrimination on the basis of gender identity and sex variations does not protect fairness for female athletes

The International Olympic Committee (IOC) recently published a framework on fairness, inclusion, and nondiscrimination on the basis of gender identity and sex variations. Although we appreciate the IOC's recognition of the role of sports science and medicine in policy development, we disagree with the assertion that the IOC framework is consistent with existing scientific and medical evidence and question its recommendations for implementation. Testosterone exposure during male development results in physical differences between male and female bodies; this process underpins male athletic advantage in muscle mass, strength and power, and endurance and aerobic capacity. The IOC's “no presumption of advantage” principle disregards this reality. Studies show that transgender women (male-born individuals who identify as women) with suppressed testosterone retain muscle mass, strength, and other physical advantages compared to females; male performance advantage cannot be eliminated with testosterone suppression. The IOC's concept of “meaningful competition” is flawed because fairness of category does not hinge on closely matched performances. The female category ensures fair competition for female athletes by excluding male advantages. Case-by-case testing for transgender women may lead to stigmatization and cannot be robustly managed in practice. We argue that eligibility criteria for female competition must consider male development rather than relying on current testosterone levels. Female athletes should be recognized as the key stakeholders in the consultation and decision-making processes. We urge the IOC to reevaluate the recommendations of their Framework to include a comprehensive understanding of the biological advantages of male development to ensure fairness and safety in female sports

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

FANCJ coordinates two pathways that maintain epigenetic stability at G-quadruplex DNA

We have previously reported that DT40 cells deficient in the Y-family polymerase REV1 are defective in replicating G-quadruplex DNA. In vivo this leads to uncoupling of DNA synthesis from redeposition of histones displaced ahead of the replication fork, which in turn leads to loss of transcriptional repression due to failure to recycle pre-existing repressive histone post-translational modifications. Here we report that a similar process can also affect transcriptionally active genes, leading to their deactivation. We use this finding to develop an assay based on loss of expression of a cell surface marker to monitor epigenetic instability at the level of single cells. This assay allows us to demonstrate G4 DNA motif-associated epigenetic instability in mutants of three helicases previously implicated in the unwinding of G-quadruplex structures, FANCJ, WRN and BLM. Transcriptional profiling of DT40 mutants reveals that FANCJ coordinates two independent mechanisms to maintain epigenetic stability near G4 DNA motifs that are dependent on either REV1 or on the WRN and BLM helicases, suggesting a model in which efficient in vivo replication of G-quadruplexes often requires the established 5′–3′-helicase activity of FANCJ acting in concert with either a specialized polymerase or helicase operating in the opposite polarity

Long-Term Costs and Health Impact of Continued Global Fund Support for Antiretroviral Therapy

Background: By the end of 2011 Global Fund investments will be supporting 3.5 million people on antiretroviral therapy (ART) in 104 low- and middle-income countries. We estimated the cost and health impact of continuing treatment for these patients through 2020. Methods and Findings: Survival on first-line and second-line ART regimens is estimated based on annual retention rates reported by national AIDS programs. Costs per patient-year were calculated from country-reported ARV procurement prices, and expenditures on laboratory tests, health care utilization and end-of-life care from in-depth costing studies. Of the 3.5 million ART patients in 2011, 2.3 million will still need treatment in 2020. The annual cost of maintaining ART falls from $1.9 billion in 2011 to$1.7 billion in 2020, as a result of a declining number of surviving patients partially offset by increasing costs as more patients migrate to second-line therapy. The Global Fund is expected to continue being a major contributor to meeting this financial need, alongside other international funders and domestic resources. Costs would be $150 million less in 2020 with an annual 5$150-370 million less with a 5%-12% annual decline in second-line prices, but $200 million higher in 2020 with phase out of stavudine (d4T), or$200 million higher with increased migration to second-line regimens expected if all countries routinely adopted viral load monitoring. Deaths postponed by ART correspond to 830,000 life-years saved in 2011, increasing to around 2.3 million life-years every year between 2015 and 2020. Conclusions: Annual patient-level direct costs of supporting a patient cohort remain fairly stable over 2011-2020, if current antiretroviral prices and delivery costs are maintained. Second-line antiretroviral prices are a major cost driver, underscoring the importance of investing in treatment quality to improve retention on first-line regimens