Genotoxic agents promote the nuclear accumulation of annexin A2: role of annexin A2 in mitigating DNA damage

Annexin A2 is an abundant cellular protein that is mainly localized in the cytoplasm and plasma membrane, however a small population has been found in the nucleus, suggesting a nuclear function for the protein. Annexin A2 possesses a nuclear export sequence (NES) and inhibition of the NES is sufficient to cause nuclear accumulation. Here we show that annexin A2 accumulates in the nucleus in response to genotoxic agents including gamma-radiation, UV radiation, etoposide and chromium VI and that this event is mediated by the nuclear export sequence of annexin A2. Nuclear accumulation of annexin A2 is blocked by the antioxidant agent N-acetyl cysteine (NAC) and stimulated by hydrogen peroxide (H2O2), suggesting that this is a reactive oxygen species dependent event. In response to genotoxic agents, cells depleted of annexin A2 show enhanced phospho-histone H2AX and p53 levels, increased numbers of p53-binding protein 1 nuclear foci and increased levels of nuclear 8-oxo-2'-deoxyguanine, suggesting that annexin A2 plays a role in protecting DNA from damage. This is the first report showing the nuclear translocation of annexin A2 in response to genotoxic agents and its role in mitigating DNA damage.Natural Sciences and Engineering Research Council of Canada (NSERC); European Union [PCOFUND-GA-2009-246542]; Foundation for Science and Technology of Portugal; Beatrice Hunter Cancer Research Institute; Terry Fox Foundationinfo:eu-repo/semantics/publishedVersio

Linear Estimation of Location and Scale Parameters Using Partial Maxima

Consider an i.i.d. sample X^*_1,X^*_2,...,X^*_n from a location-scale family, and assume that the only available observations consist of the partial maxima (or minima)sequence, X^*_{1:1},X^*_{2:2},...,X^*_{n:n}, where X^*_{j:j}=max{X^*_1,...,X^*_j}. This kind of truncation appears in several circumstances, including best performances in athletics events. In the case of partial maxima, the form of the BLUEs (best linear unbiased estimators) is quite similar to the form of the well-known Lloyd's (1952, Least-squares estimation of location and scale parameters using order statistics, Biometrika, vol. 39, pp. 88-95) BLUEs, based on (the sufficient sample of) order statistics, but, in contrast to the classical case, their consistency is no longer obvious. The present paper is mainly concerned with the scale parameter, showing that the variance of the partial maxima BLUE is at most of order O(1/log n), for a wide class of distributions.Comment: This article is devoted to the memory of my six-years-old, little daughter, Dionyssia, who leaved us on August 25, 2010, at Cephalonia isl. (26 pages, to appear in Metrika

Mindfulness-based interventions in epilepsy: a systematic review

Mindfulness based interventions (MBIs) are increasingly used to help patients cope with physical and mental long-term conditions (LTCs). Epilepsy is associated with a range of mental and physical comorbidities that have a detrimental effect on quality of life (QOL), but it is not clear whether MBIs can help. We systematically reviewed the literature to determine the effectiveness of MBIs in people with epilepsy. Medline, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, Allied and Complimentary Medicine Database, and PsychInfo were searched in March 2016. These databases were searched using a combination of subject headings where available and keywords in the title and abstracts. We also searched the reference lists of related reviews. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Three randomised controlled trials (RCTs) with a total of 231 participants were included. The interventions were tested in the USA (n = 171) and China (Hong Kong) (n = 60). Significant improvements were reported in depression symptoms, quality of life, anxiety, and depression knowledge and skills. Two of the included studies were assessed as being at unclear/high risk of bias - with randomisation and allocation procedures, as well as adverse events and reasons for drop-outs poorly reported. There was no reporting on intervention costs/benefits or how they affected health service utilisation. This systematic review found limited evidence for the effectiveness of MBIs in epilepsy, however preliminary evidence suggests it may lead to some improvement in anxiety, depression and quality of life. Further trials with larger sample sizes, active control groups and longer follow-ups are needed before the evidence for MBIs in epilepsy can be conclusively determined

Advantages of doubly polished thin sections for the study of microfossils in volcanic rock

Doubly polished thin sections, originally prepared for fluid inclusion studies, present great advantages in the study of microfossils in volcanic rocks. Better visibility and light conditions, variation in thickness of the thin sections and the possibility to combine fluid inclusion studies with microfossil studies lead to a wide range of advantages over ordinary thin sections. This includes the study of morphology, internal microstructures, colonies, association with the substrate that microfossils are attached to and geological and environmental context in which the microfossil once lived. When meeting the criteria of microfossil recognition the advantages of doubly polished thin sections are substantial and can be crucial in distinguishing between biogenic microfossils and abiotically formed abiomorphs

Identification of histone modifications in biomedical text for supporting epigenomic research

Corinna K, Klinger R, Hofmann-Apitius M. Identification of Histone Modifications in Biomedical Text for Supporting Epigenomic Research. BMC Bioinformatics. 2009;10(Suppl 1):S28

Male mice with deleted Wolframin (Wfs1) gene have reduced fertility

Background: Wolfram Syndrome (WS) is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO) male mice have reduced fertility and, if so, to examine possible causes. Methods: Wfs1KO mice were generated by homologous recombination. Both Wfs1KO and wild type (wt) male mice were mated with wt female mice. The number of litters and the number of pups were counted and pregnancy rates calculated. The motility and morphology of the sperm and the histology of testes were analysed. Serum testosterone and FSH concentrations were also measured. Results: The pregnancy rate in wt females mated with Wfs1KO males was significantly lower than in the control group (15% vs. 32%; p < 0.05), but there was no significant difference in litter size. Analysis of male fertility showed that, in the Wfs1KO group, eight males out of 13 had pups whereas in the control group all 13 males had at least one litter. Sperm motility was not affected in Wfs1KO mice, but Wfs1KO males had less proximal bent tails (14.4 +/- 1.2% vs. 21.5 +/- 1.3 p < 0.05) and less abnormal sperm heads (22.8 +/- 1.8 vs. 31.5 +/- 3.5, p < 0.05) than wt males. Testes histology revealed significantly reduced number of spermatogonia (23.9 +/- 4.9 vs. 38.1 +/- 2.8; p < 0.05) and Sertoli cells (6.4 +/- 0.5 vs. 9.2 +/- 1.0; p < 0.05) in Wfs1KO mice. Serum testosterone and FSH concentrations did not differ between the two groups. Conclusion: The impaired fertility of Wfs1KO male mice is most likely due to changes in sperm morphology and reduced number of spermatogenic cells. The exact mechanism through which the Wfs1 gene influences sperm morphology needs to be clarified in further studies

Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease

Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials

Profiles of Human Serum Antibody Responses Elicited by Three Leading HIV Vaccines Focusing on the Induction of Env-Specific Antibodies

In the current report, we compared the specificities of antibody responses in sera from volunteers enrolled in three US NIH-supported HIV vaccine trials using different immunization regimens. HIV-1 Env-specific binding antibody, neutralizing antibody, antibody-dependent cell-mediated cytotoxicity (ADCC), and profiles of antibody specificity were analyzed for human immune sera collected from vaccinees enrolled in the NIH HIV Vaccine Trial Network (HVTN) Study #041 (recombinant protein alone), HVTN Study #203 (poxviral vector prime-protein boost), and the DP6-001 study (DNA prime-protein boost). Vaccinees from HVTN Study #041 had the highest neutralizing antibody activities against the sensitive virus along with the highest binding antibody responses, particularly those directed toward the V3 loop. DP6-001 sera showed a higher frequency of positive neutralizing antibody activities against more resistant viral isolate with a significantly higher CD4 binding site (CD4bs) antibody response compared to both HVTN studies #041 and #203. No differences were found in CD4-induced (CD4i) antibody responses, ADCC activity, or complement activation by Env-specific antibody among these sera. Given recent renewed interest in realizing the importance of antibody responses for next generation HIV vaccine development, different antibody profiles shown in the current report, based on the analysis of a wide range of antibody parameters, provide critical biomarker information for the selection of HIV vaccines for more advanced human studies and, in particular, those that can elicit antibodies targeting conformational-sensitive and functionally conserved epitopes

Acclimatization of the crustose coralline alga Porolithon onkodes to variable pCO2

Ocean acidification (OA) has important implications for the persistence of coral reef ecosystems, due to potentially negative effects on biomineralization. Many coral reefs are dynamic with respect to carbonate chemistry, and experience fluctuations in pCO2 that exceed OA projections for the near future. To understand the influence of dynamic pCO2 on an important reef calcifier, we tested the response of the crustose coralline alga Porolithon onkodes to oscillating pCO2. Individuals were exposed to ambient (400 ??atm), high (660 ??atm), or variable pCO2 (oscillating between 400/660 ??atm) treatments for 14 days. To explore the potential for coralline acclimatization, we collected individuals from low and high pCO2 variability sites (upstream and downstream respectively) on a back reef characterized by unidirectional water flow in Moorea, French Polynesia. We quantified the effects of treatment on algal calcification by measuring the change in buoyant weight, and on algal metabolism by conducting sealed incubations to measure rates of photosynthesis and respiration. Net photosynthesis was higher in the ambient treatment than the variable treatment, regardless of habitat origin, and there was no effect on respiration or gross photosynthesis. Exposure to high pCO2 decreased P. onkodes calcification by >70%, regardless of the original habitat. In the variable treatment, corallines from the high variability habitat calcified 42% more than corallines from the low variability habitat. The significance of the original habitat for the coralline calcification response to variable, high pCO2 indicates that individuals existing in dynamic pCO2 habitats may be acclimatized to OA within the scope of in situ variability. These results highlight the importance of accounting for natural pCO2 variability in OA manipulations, and provide insight into the potential for plasticity in habitat and species-specific responses to changing ocean chemistry.Funding was provided by grants from the National Science Foundation (OCE-0417412, OCE-10-26852, OCE-1041270) and gifts from the Gordon and Betty Moore Foundation. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Identification of a novel Drosophila gene, beltless, using injectable embryonic and adult RNA interference (RNAi)

BACKGROUND: RNA interference (RNAi) is a process triggered by a double-stranded RNA that leads to targeted down-regulation/silencing of gene expression and can be used for functional genomics; i.e. loss-of-function studies. Here we report on the use of RNAi in the identification of a developmentally important novel Drosophila (fruit fly) gene (corresponding to a putative gene CG5652/GM06434), that we named beltless based on an embryonic loss-of-function phenotype. RESULTS: Beltless mRNA is expressed in all developmental stages except in 0–6 h embryos. In situ RT-PCR localized beltless mRNA in the ventral cord and brain of late stage embryos and in the nervous system, ovaries, and the accessory glands of adult flies. RNAi was induced by injection of short (22 bp) beltless double-stranded RNAs into embryos or into adult flies. Embryonic RNAi altered cuticular phenotypes ranging from partially-formed to missing denticle belts (thus beltless) of the abdominal segments A2–A4. Embryonic beltless RNAi was lethal. Adult RNAi resulted in the shrinkage of the ovaries by half and reduced the number of eggs laid. We also examined Df(1)RK4 flies in which deletion removes 16 genes, including beltless. In some embryos, we observed cuticular abnormalities similar to our findings with beltless RNAi. After differentiating Df(1)RK4 embryos into those with visible denticle belts and those missing denticle belts, we assayed the presence of beltless mRNA; no beltless mRNA was detectable in embryos with missing denticle belts. CONCLUSIONS: We have identified a developmentally important novel Drosophila gene, beltless, which has been characterized in loss-of-function studies using RNA interference. The putative beltless protein shares homologies with the C. elegans nose resistant to fluoxetine (NRF) NRF-6 gene, as well as with several uncharacterized C. elegans and Drosophila melanogaster genes, some with prominent acyltransferase domains. Future studies should elucidate the role and mechanism of action of beltless during Drosophila development and in adults, including in the adult nervous system