Fe65 Is Phosphorylated on Ser289 after UV-Induced DNA Damage

Fe65 undergoes a phosphatase-sensitive gel mobility shift after DNA damage, consistent with protein phosphorylation. A recent study identified Ser228 as a specific site of phosphorylation, targeted by the ATM and ATR protein kinases, with phosphorylation inhibiting the Fe65-dependent transcriptional activity of the amyloid precursor protein (APP). The direct binding of Fe65 to APP not only regulates target gene expression, but also contributes to secretase-mediated processing of APP, producing cytoactive proteolytic fragments including the APP intracellular domain (AICD) and cytotoxic amyloid β (Aβ) peptides. Given that the accumulation of Aβ peptides in neural plaques is a pathological feature of Alzheimer’s disease (AD), it is essential to understand the mechanisms controlling Aβ production. This will aid in the development of potential therapeutic agents that act to limit the deleterious production of Aβ peptides. The Fe65-APP complex has transcriptional activity and the complex is regulated by multiple post-translational modifications and other protein binding partners. In the present study, we have identified Ser289 as a novel site of UV-induced phosphorylation. Interestingly, this phosphorylation was mediated by ATM, rather than ATR, and occurred independently of APP. Neither phosphorylation nor mutation of Ser289 affected the Fe65-APP interaction, though this was markedly decreased after UV treatment, with a concomitant decrease in the protein levels of APP in cells. Using mutagenesis, we demonstrated that Fe65 Ser289 phosphorylation did not affect the transcriptional activity of the Fe65-APP complex, in contrast to the previously described Ser228 site

Pasts and pagan practices: moving beyond Stonehenge

Theorizing the past is not restricted to archaeology and interpretations of 'past' both influence and are themselves constituted within politicized understandings of self, community and in certain instances, spirituality. 'The past in the imagination of the present' is appropriated, variously, to give meaning to the present or to justify actions and interpret experiences. Summer solstice at Stonehenge, with an estimated 21,000 celebrants in 2005, is only the most publicized appropriation (by pagans and other adherents of alternative spirituality and partying) of a 'sacred site'; and conflicts and negotiations occurring throughout Britain are represented in popular and academic presentations of this 'icon of Britishness'. This paper presents work from the Sacred Sites, Contested Rites/Rights Project (http://www.sacredsites.org.uk) project, a collaboration of archaeology and anthropology informed by pagan and alternative approaches and standpoints investigating and theorizing discourse and practice of heritage management and pagan site users. Whether in negotiations around the Stonehenge solstice access or in dealing with numerous other sites, boundaries between groups or discourses are not clearly drawn - discursive communities merge and re-emerge. But clearly 'past' and 'site' are increasingly important within today's Britain, even as television archaeology increases its following, and pagan numbers continue to grow.</p

Checkpoint kinase 1 is activated and promotes cell survival after exposure to sulphur mustard

Sulphur mustard (SM) is a vesicating agent that has been used several times as a weapon during military conflict and continues to pose a threat as an agent of warfare/terrorism. After exposure, SM exerts both acute and delayed long-term toxic effects principally to the skin, eyes and respiratory system. These effects are thought to be mediated, at least in part, by direct interaction of SM with DNA, forming a myriad of DNA lesions and initiating effects on cell cycle and cell death pathways. Previous studies have demonstrated that a complex network of cellular DNA damage response pathways are utilised in cells exposed to SM, consistent with SM causing multiple forms of DNA damage. The present study focused on the role of Checkpoint kinase 1 (CHK1), a protein with putative roles in homologous recombination repair, p53 activation and the initiation of cell cycle checkpoints after certain forms of DNA damage. The data showed that SM caused robust activation of CHK1, monitored by multi-site phosphorylation analysis and that this activation was dependent on the ataxia telangiectasia and Rad3-related (ATR) protein kinase. Furthermore, specific inhibition of CHK1 increased SM toxicity in multiple human cell lines, with concomitant increases in markers of apoptosis, DNA damage and mitosis. Finally, the effect of CHK1 inhibition on SM toxicity was much more marked in cells with non-functional p53

The 60-μm extragalactic background radiation intensity, dust-enshrouded active galactic nuclei and the assembly of groups and clusters of galaxies

Submillimetre- (submm-) wave observations have revealed a cosmologically significant population of high-redshift dust-enshrouded galaxies. The form of evolution inferred for this population can be reconciled easily with COBE FIRAS and DIRBE measurements of the cosmic background radiation (CBR) intensity at wavelengths longer than ~100 μm. At shorter wavelengths, however, the 60-μm CBR intensity reported by Finkbeiner, Davis & Schlegel is less easily accounted for. Lagache et al. have proposed that this excess CBR emission is a warm Galactic component, and the detection of the highest-energy γ-rays from blazars limits the CBR intensity at these wavelengths, but here we investigate possible sources of this excess CBR emission, assuming that it has a genuine extragalactic origin. We propose and test three explanations, each involving additional populations of luminous, evolving galaxies not readily detected in existing submm-wave surveys. First, an additional population of dust-enshrouded galaxies with hot dust temperatures, perhaps dust-enshrouded, Compton-thick active galactic nuclei (AGN) as suggested by recent deep Chandra surveys. Secondly, a population of dusty galaxies with temperatures more typical of the existing submm-selected galaxies, but at relatively low redshifts. These could plausibly be associated with the assembly of groups and clusters of galaxies. Thirdly, a population of low-luminosity, cool, quiescent spiral galaxies. Hot AGN sources and the assembly of galaxy groups can account for the excess 60-μm background. There are significant problems with the cluster assembly scenario, in which too many bright 60-μm IRAS sources are predicted. Spiral galaxies have the wrong spectral energy distributions to account for the excess. Future wide-field far-infrared (IR) surveys at wavelengths of 70 and 250 μm using the SIRTF and Herschel space missions will sample representative volumes of the distant Universe, allowing any hot population of dusty AGNs and forming groups to be detected

Phosphorylation of MCPH1 isoforms during mitosis followed by isoform‐specific degradation by APC/C‐CDH1

Microcephalin‐1 (MCPH1) exists as 2 isoforms that regulate cyclin‐dependent kinase‐1 activation and chromosome condensation during mitosis, with MCPH1 mutations causing primary microcephaly. MCPH1 is also a tumor suppressor protein, with roles in DNA damage repair/checkpoints. Despite these important roles, there is little information on the cellular regulation of MCPH1. We show that both MCPH1 isoforms are phosphorylated in a cyclin‐dependent kinase‐1–dependent manner in mitosis and identify several novel phosphorylation sites. Upon mitotic exit, MCPH1 isoforms were degraded by the anaphase‐promoting complex/cyclosome–CDH1 E3 ligase complex. Anaphase‐promoting complex/cyclosome–CDH1 target proteins generally have D‐Box or KEN‐Box degron sequences. We found that MCPH1 isoforms are degraded independently, with the long isoform degradation being D‐Box dependent, whereas the short isoform was KEN‐Box dependent. Our research identifies several novel mechanisms regulating MCPH1 and also highlights important issues with several commercial MCPH1 antibodies, with potential relevance to previously published data.—Meyer, S. K., Dunn, M., Vidler, D. S., Porter, A., Blain, P. G., Jowsey, P. A. Phosphorylation of MCPH1 isoforms during mitosis followed by isoform‐specific degradation by APC/C‐CDH1. FASEB J. 33, 2796–2808 (2019). www.fasebj.or

Lensing-Induced Structure of Submillimeter Sources: Implications for the Microwave Background

We consider the effect of lensing by galaxy clusters on the angular distribution of submillimeter wavelength objects. While lensing does not change the total flux and number counts of submillimeter sources, it can affect the number counts and fluxes of flux-limited samples. Therefore imposing a flux cut on point sources not only reduces the overall Poisson noise, but imprints the correlations between lensing clusters on the unresolved flux distribution. Using a simple model, we quantify the lensing anisotropy induced in flux-limited samples and compare this to Poisson noise. We find that while the level of induced anisotropies on the scale of the cluster angular correlation length is comparable to Poisson noise for a slowly evolving cluster model, it is negligible for more realistic models of cluster evolution. Thus the removal of point sources is not expected to induce measurable structure in the microwave or far-infrared backgrounds.Comment: 22 pages, 9 figures, accepted to Astrophysical Journa

Deoxyribonucleic acid damage in Iranian veterans 25 years after wartime exposure to sulfur mustard

• Background: More than 100,000 Iranian veterans and civilians still suffer from various long-term complications due to their exposure to sulfur mustard (SM) during the Iran–Iraq war in 1983–88. The aim of the study was to investigate DNA damage of SM in veterans who were exposed to SM, 23–27 years prior to this study. • Materials and Methods: Blood samples were obtained from the veterans and healthy volunteers as negative controls. Lymphocytes were isolated from blood samples and DNA breaks were measured using single-cell microgel electrophoresis technique under alkaline conditions (comet assay). Single cells were analyzed with “Tri Tek Comet Score version 1.5” software and DNA break was measured based on the percentage of tail DNA alone, or in the presence of H2O2 (25 μM) as a positive control. • Results: A total of 25 SM exposed male veterans and 25 male healthy volunteers with similar ages (44.66 ± 6.2 and 42.12 ± 5.75 years, respectively) were studied. Percentage of the lymphocyte DNA damage was significantly (p < 0.01) higher in the SM-exposed individuals than in the controls (6.47 ± 0.52 and 1.31 ± 0.35, respectively). Percentages of DNA damage in the different age groups of 35–39, 40–44, 45–49, and 50–54 years in SM-exposed veterans (5.48 ± 0.17, 6.7 3 ± 1.58, 6.42 ± 0.22, and 7.27 ± 0.38, respectively) were all significantly (p < 0.05) higher than the controls (1.18 ± 0.25, 1.53 ± 0.22, 1.27 ± 0.20, and 1.42 ± 0.10, respectively). The lymphocytes incubated with H2O2 had much higher DNA damage as expected. The average of tail DNA is 42.12 ± 2.75% for control cells + H2O2 and 18.48 ± 2.14% for patients cells + H2O2; P < 0.001. • Conclusion: SM exposure of the veterans revealed DNA damage as judged by the comet assay

Índice padronizado de precipitação aplicado às condições de seca no Estado do Espírito Santo.

O Índice Padronizado de Precipitação (SPI) é um dos métodos mais utilizados para quantificação da seca. A fim de verificar a possibilidade de utilização do SPI no monitoramento das deficiências e excessos de precipitação na escala mensal, no Estado do Espírito Santo objetivou-se, neste trabalho, verificar o ajuste das séries temporais dessa variável meteorológica à distribuição gama em cinco localidades do Estado. Por meio dos testes de aderência Kolmogorov-Smirnov e qui-quadrado, as séries mensais de precipitação pluvial das localidades sob análise podem ser consideradas oriundas de uma população com distribuição gama incompleta, permitindo o uso do SPI no monitoramento das condições de seca meteorológica. Através de análises de autocorrelação e correlação-cruzada, observou-se que a principal característica das séries do SPI é sua grande variabilidade espaço-temporal, a qual indica que em uma mesma região meses extremamente secos podem ser precedidos e/ou seguidos de meses úmidos ou normais, e que distintos casos de seca podem ocorrer de forma aleatória, entre as localidades e em um mesmo período