Smc5/6: a link between DNA repair and unidirectional replication?

Of the three structural maintenance of chromosome (SMC) complexes, two directly regulate chromosome dynamics. The third, Smc5/6, functions mainly in homologous recombination and in completing DNA replication. The literature suggests that Smc5/6 coordinates DNA repair, in part through post-translational modification of uncharacterized target proteins that can dictate their subcellular localization, and that Smc5/6 also functions to establish DNA-damage-dependent cohesion. A nucleolar-specific Smc5/6 function has been proposed because Smc5/6 yeast mutants display penetrant phenotypes of ribosomal DNA (rDNA) instability. rDNA repeats are replicated unidirectionally. Here, we propose that unidirectional replication, combined with global Smc5/6 functions, can explain the apparent rDNA specificity

Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph

Evaluating the effects of catch-and-release angling on Cape stumpnose Rhabdosargus holubi in a South African estuary

Fisheries managers are increasingly promoting catch and release (C&R) as a means to manage recreational fish stocks. Several commonly used output regulations, including bag and size limits, require the mandatory release of captured fishes by anglers. In addition to mandatory C&R, conservation-conscious anglers have adopted voluntary C&R behaviour as a result of the noticeable declines in the populations of many fishery species and this behaviour is becoming increasingly popular among recreational anglers (Cooke et al. 2013a). The combination of mandatory and voluntary C&R behaviour is substantial, as Raby et al. (2014) estimated that 60% of fish captured in global recreational fisheries are released. In South Africa, Cowley et al. (2013) found that a large proportion (mean 74% [SD 7.3]) of the five most-dominant fishery species captured in the Sundays Estuary recreational fishery were released

Age and growth of Cape stumpnose Rhabdosargus holubi (Pisces: Sparidae) in the Eastern Cape, South Africa

Rhabdosargus holubi (Steindachner, 1881) is a small (maximum size = 450 mm total length; Heemstra and Heemstra 2004) sparid that is distributed along the south-east coast of Africa from St Helena Bay, South Africa, to Maputo, Mozambique (Götz and Cowley 2013). Spawning occurs in the nearshore marine environment primarily during winter, specifically May–August in KwaZulu-Natal (KZN) (Wallace 1975) and July–February in the South-Eastern Cape (Whitfield 1998). Individuals reach 50% sexual maturity at approximately 150 mm standard length (SL) in the Eastern Cape (Whitfield 1998). The early life stages are transported by the south-westward-flowing Agulhas Current, and recruit as post-flexion larvae and early juveniles into estuaries during late winter and early summer (Blaber 1974). The warm temperatures and high nutrient levels in estuaries favour fast growth (Blaber 1973a), and fish spend their first year of life in these environments, migrating back out to sea after reaching approximately 120 mm SL. Some individuals remain trapped in closed estuaries, where they may reach sizes greater than 200 mm SL (James et al. 2007a). Rhabdosargus holubi is the dominant estuarine-dependent marine teleost species recorded in permanently open and temporarily open/closed estuaries in the warm-temperate region, which spans the south, south-east and east coast of South Africa (Harrison 2005). The species is also an important component of the linefishery in many SouthAfrican estuaries (10–15.6% by number) (Pradervand and Baird 2002), particularly in Eastern Cape estuaries (Cowley et al. 2003). These figures underestimate the presence of R. holubi, as most individuals making use of estuaries are young, feeding predominately on filamentous macroalgae and diatom flora, and are generally too small to be caught with hook and line (De Wet and Marais 1990). James et al. (2007b) showed that R. holubi made up 34–92% of the annual seine-net catch in the East Kleinemonde Estuary. Rhabdosargus holubi is also important in the KZN shorebased linefishery, representing 4.6% of the total landed catch (Dunlop and Mann 2012)

Promising outcomes of a national programme for the prevention of mother-to-child HIV transmission in Addis Ababa: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Prevention of Mother-to-Child HIV Transmission (PMTCT) is still the most effective intervention in combating new HIV infections. In 2008, revised national PMTCT guidelines that incorporated new policies on HIV counselling and testing, antiretroviral prophylaxis regimen and infant HIV diagnosis came into effect in Ethiopia. In the present study we have examined trends in PMTCT service utilization and assessed the rate of MTCT in relation to policy changes in the national PMTCT programme.</p> <p>Methods</p> <p>Reports from February 2004 to August 2009 were reviewed in 10 sub-cities in Addis Ababa, Ethiopia. The data was collected from May to October 2009.</p> <p>Results</p> <p>The proportion of women who received HIV counselling and testing among new antenatal care attendees increased from 50.7% (95% CI 50.2-51.2) in 2007 to 84.5% (95% CI 84.1-84.9) in 2009 following the shift to routine opt-out testing. Nevertheless, in 2009 only 53.7% of the positive women and 40.7% of their infants received antiretroviral prophylaxis. The HIV prevalence among antenatal attendees decreased significantly from 10.5% in 2004 to 4.6% in 2009 in parallel to the increased number of women being tested. The HIV positive women were over 18 times (RR 18.5, p < 0.0001) more likely to be referred for treatment, care and support in 2009 than in 2004. The proportion of partners tested for HIV decreased by 14% in 2009 compared to 2004, although the absolute number was increasing year by year. Only 10.6% (95% CI 9.9-11.2) of the HIV positive women completed their follow up to infant HIV testing. The cumulative probability of HIV infection among babies on single dose nevirapine regimen who were tested at >=18 months was 15.0% (95% CI 9.8-22.1) in 2007, whereas it was 8.2% (95% CI 5.55-11.97) among babies on Zidovudine regimen who were tested at >=45 days in 2009.</p> <p>Conclusion</p> <p>The paper demonstrates trends in PMTCT service utilization in relation to changing policy. There is marked improvement in HIV counselling and testing service utilization, especially after the policy shift to routine opt-out testing. However, despite policy changes, the ARV prophylaxis uptake, the loss to follow up and the partner testing have remained unchanged across the years. This should be a matter of immediate concern and a topic for further research.</p

Assessment of the likely sensitivity to climate change for the key marine species in the southern Benguela system

Climate change is altering many environmental parameters of coastal waters and open oceans, leading to substantial present-day and projected changes in the distribution, abundance and phenology of marine species. Attempts to assess how each species might respond to climate change can be data-, resource- and time-intensive. Moreover, in many regions of the world, including South Africa, species may be of vital socioeconomic or ecological importance though critical gaps may exist in our basic biological or ecological knowledge of the species. Here, we adapt and apply a trait-based sensitivity assessment for the key marine species in the southern Benguela system to estimate their potential relative sensitivity to the impacts of climate change. For our analysis, 40 priority species were selected based on their socioeconomic, ecological and/or recreational importance in the system. An extensive literature review and consultation with experts was undertaken concerning each species to gather information on their life history, habitat use and potential stressors. Fourteen attributes were used to estimate the selected species’ sensitivity and capacity to respond to climate change. A score ranging from low to high sensitivity was given for each attribute, based on the available information. Similarly, a score was assigned to the type and quality of information used to score each particular attribute, allowing an assessment of data-quality inputs for each species. The analysis identified the white steenbras Lithognathus lithognathus, soupfin shark Galeorhinus galeus, St Joseph Callorhinchus capensis and abalone Haliotis midae as potentially the most sensitive species to climate-change impacts in the southern Benguela system. There were data gaps for larval dispersal and settlement and metamorphosis cues for most of the evaluated species. Our results can be used by resource managers to determine the type of monitoring, intervention and planning that may be required to best respond to climate change, given the limited resources and significant knowledge gaps in many cases

Extended Interferon-Alpha Therapy Accelerates Telomere Length Loss in Human Peripheral Blood T Lymphocytes

BACKGROUND: Type I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes. METHODS/PRINCIPAL FINDINGS: Using a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFNalpha group for an additional 3.5 years. Significant telomere loss in naive T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8(+)CD45RA(+)CD57(+) memory T cells and an inverse correlation of alanine aminotransferase levels with naive CD8(+) T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index. CONCLUSIONS/SIGNIFICANCE: Sustained interferon-alpha treatment increased telomere loss in naive T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined

Serum Proteome and Cytokine Analysis in a Longitudinal Cohort of Adults with Primary Dengue Infection Reveals Predictive Markers of DHF

10.1371/journal.pntd.0001887PLoS Neglected Tropical Diseases611

Rad21-Cohesin Haploinsufficiency Impedes DNA Repair and Enhances Gastrointestinal Radiosensitivity in Mice

Approximately half of cancer-affected patients receive radiotherapy (RT). The doses delivered have been determined upon empirical experience based upon average radiation responses. Ideally higher curative radiation doses might be employed in patients with genuinely normal radiation responses and importantly radiation hypersensitive patients would be spared the consequences of excessive tissue damage if they were indentified before treatment. Rad21 is an integral subunit of the cohesin complex, which regulates chromosome segregation and DNA damage responses in eukaryotes. We show here, by targeted inactivation of this key cohesin component in mice, that Rad21 is a DNA-damage response gene that markedly affects animal and cell survival. Biallelic deletion of Rad21 results in early embryonic death. Rad21 heterozygous mutant cells are defective in homologous recombination (HR)-mediated gene targeting and sister chromatid exchanges. Rad21+/− animals exhibited sensitivity considerably greater than control littermates when challenged with whole body irradiation (WBI). Importantly, Rad21+/− animals are significantly more sensitive to WBI than Atm heterozygous mutant mice. Since supralethal WBI of mammals most typically leads to death via damage to the gastrointestinal tract (GIT) or the haematopoietic system, we determined the functional status of these organs in the irradiated animals. We found evidence for GIT hypersensitivity of the Rad21 mutants and impaired bone marrow stem cell clonogenic regeneration. These data indicate that Rad21 gene dosage is critical for the ionising radiation (IR) response. Rad21 mutant mice thus represent a new mammalian model for understanding the molecular basis of irradiation effects on normal tissues and have important implications in the understanding of acute radiation toxicity in normal tissues

Electrophysiological Characterization of The Cerebellum in the Arterially Perfused Hindbrain and Upper Body of The Rat

In the present study, a non-pulsatile arterially perfused hindbrain and upper body rat preparation is described which is an extension of the brainstem preparation reported by Potts et al., (Brain Res Bull 53(1):59–67), 1. The modified in situ preparation allows study of cerebellar function whilst preserving the integrity of many of its interconnections with the brainstem, upper spinal cord and the peripheral nervous system of the head and forelimbs. Evoked mossy fibre, climbing fibre and parallel fibre field potentials and EMG activity elicited in forelimb biceps muscle by interpositus stimulation provided evidence that both cerebellar inputs and outputs remain operational in this preparation. Similarly, the spontaneous and evoked single unit activity of Purkinje cells, putative Golgi cells, molecular interneurones and cerebellar nuclear neurones was similar to activity patterns reported in vivo. The advantages of the preparation include the ability to record, without the complications of anaesthesia, stabile single unit activity for extended periods (3 h or more), from regions of the rat cerebellum that are difficult to access in vivo. The preparation should therefore be a useful adjunct to in vitro and in vivo studies of neural circuits underlying cerebellar contributions to movement control and motor learning