Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end joining (NHEJ) pathway required for the repair of DNA double strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. Methods: We evaluated clinicopathological significance of DNA-PKcs protein expression in 1161 tumours and DNA-PKcs mRNA expression in 1950 tumours. We correlated DNA-PKcs to other markers of aggressive phenotypes, DNA repair, apoptosis and cell cycle regulation. Results: Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps<0.05). Absence of BRCA1, low XRCC1/SMUG1/APE1/Polβ were also more likely in low DNA-PKcs expressing tumours (ps<0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer specific survival (BCCS) in univariate and multivariate analysis (ps<0.01). At the mRNA level, low DNA-PKcs was associated with PAM50.Her2 and PAM50.LumA molecular phenotypes (ps<0.01) and poor BCSS. In patients with ER positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Conclusions: Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers

Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Early star-forming galaxies and the reionization of the Universe

Star forming galaxies represent a valuable tracer of cosmic history. Recent observational progress with Hubble Space Telescope has led to the discovery and study of the earliest-known galaxies corresponding to a period when the Universe was only ~800 million years old. Intense ultraviolet radiation from these early galaxies probably induced a major event in cosmic history: the reionization of intergalactic hydrogen. New techniques are being developed to understand the properties of these most distant galaxies and determine their influence on the evolution of the universe.Comment: Review article appearing in Nature. This posting reflects a submitted version of the review formatted by the authors, in accordance with Nature publication policies. For the official, published version of the review, please see http://www.nature.com/nature/archive/index.htm

KRILLBASE: a circumpolar database of Antarctic krill and salp numerical densities, 1926–2016

Antarctic krill (Euphausia superba) and salps are major macroplankton contributors to Southern Ocean food webs and krill are also fished commercially. Managing this fishery sustainably, against a backdrop of rapid regional climate change, requires information on distribution and time trends. Many data on the abundance of both taxa have been obtained from net sampling surveys since 1926, but much of this is stored in national archives, sometimes only in notebooks. In order to make these important data accessible we have collated available abundance data (numerical density, no.

Gravitational Waves from Gravitational Collapse

Gravitational wave emission from the gravitational collapse of massive stars has been studied for more than three decades. Current state of the art numerical investigations of collapse include those that use progenitors with realistic angular momentum profiles, properly treat microphysics issues, account for general relativity, and examine non--axisymmetric effects in three dimensions. Such simulations predict that gravitational waves from various phenomena associated with gravitational collapse could be detectable with advanced ground--based and future space--based interferometric observatories.Comment: 68 pages including 13 figures; revised version accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org

Formation of Supermassive Black Holes

Evidence shows that massive black holes reside in most local galaxies. Studies have also established a number of relations between the MBH mass and properties of the host galaxy such as bulge mass and velocity dispersion. These results suggest that central MBHs, while much less massive than the host (~ 0.1%), are linked to the evolution of galactic structure. In hierarchical cosmologies, a single big galaxy today can be traced back to the stage when it was split up in hundreds of smaller components. Did MBH seeds form with the same efficiency in small proto-galaxies, or did their formation had to await the buildup of substantial galaxies with deeper potential wells? I briefly review here some of the physical processes that are conducive to the evolution of the massive black hole population. I will discuss black hole formation processes for `seed' black holes that are likely to place at early cosmic epochs, and possible observational tests of these scenarios.Comment: To appear in The Astronomy and Astrophysics Review. The final publication is available at http://www.springerlink.co

Krill (Euphausia superba) distribution contracts southward during rapid regional warming

High-latitude ecosystems are among the fastest warming on the planet1. Polar species may be sensitive to warming and ice loss, but data are scarce and evidence is conflicting2,3,4. Here, we show that, within their main population centre in the southwest Atlantic sector, the distribution of Euphausia superba (hereafter, ‘krill’) has contracted southward over the past 90 years. Near their northern limit, numerical densities have declined sharply and the population has become more concentrated towards the Antarctic shelves. A concomitant increase in mean body length reflects reduced recruitment of juvenile krill. We found evidence for environmental controls on recruitment, including a reduced density of juveniles following positive anomalies of the Southern Annular Mode. Such anomalies are associated with warm, windy and cloudy weather and reduced sea ice, all of which may hinder egg production and the survival of larval krill5. However, the total post-larval density has declined less steeply than the density of recruits, suggesting that survival rates of older krill have increased. The changing distribution is already perturbing the krill-centred food web6 and may affect biogeochemical cycling7,8. Rapid climate change, with associated nonlinear adjustments in the roles of keystone species, poses challenges for the management of valuable polar ecosystems3

Recent progress in understanding and projecting regional and global mean sea-level change

Considerable progress has been made in understanding the present and future regional and global sea level in the 2 years since the publication of the Fifth Assessment Report (AR5) of the Intergovernmental Panel on Climate Change. Here, we evaluate how the new results affect the AR5’s assessment of (i) historical sea level rise, including attribution of that rise and implications for the sea level budget, (ii) projections of the components and of total global mean sea level (GMSL), and (iii) projections of regional variability and emergence of the anthropogenic signal. In each of these cases, new work largely provides additional evidence in support of the AR5 assessment, providing greater confidence in those findings. Recent analyses confirm the twentieth century sea level rise, with some analyses showing a slightly smaller rate before 1990 and some a slightly larger value than reported in the AR5. There is now more evidence of an acceleration in the rate of rise. Ongoing ocean heat uptake and associated thermal expansion have continued since 2000, and are consistent with ocean thermal expansion reported in the AR5. A significant amount of heat is being stored deeper in the water column, with a larger rate of heat uptake since 2000 compared to the previous decades and with the largest storage in the Southern Ocean. The first formal detection studies for ocean thermal expansion and glacier mass loss since the AR5 have confirmed the AR5 finding of a significant anthropogenic contribution to sea level rise over the last 50 years. New projections of glacier loss from two regions suggest smaller contributions to GMSL rise from these regions than in studies assessed by the AR5; additional regional studies are required to further assess whether there are broader implications of these results. Mass loss from the Greenland Ice Sheet, primarily as a result of increased surface melting, and from the Antarctic Ice Sheet, primarily as a result of increased ice discharge, has accelerated. The largest estimates of acceleration in mass loss from the two ice sheets for 2003–2013 equal or exceed the acceleration of GMSL rise calculated from the satellite altimeter sea level record over the longer period of 1993–2014. However, when increased mass gain in land water storage and parts of East Antarctica, and decreased mass loss from glaciers in Alaska and some other regions are taken into account, the net acceleration in the ocean mass gain is consistent with the satellite altimeter record. New studies suggest that a marine ice sheet instability (MISI) may have been initiated in parts of the West Antarctic Ice Sheet (WAIS), but that it will affect only a limited number of ice streams in the twenty-first century. New projections of mass loss from the Greenland and Antarctic Ice Sheets by 2100, including a contribution from parts of WAIS undergoing unstable retreat, suggest a contribution that falls largely within the likely range (i.e., two thirds probability) of the AR5. These new results increase confidence in the AR5 likely range, indicating that there is a greater probability that sea level rise by 2100 will lie in this range with a corresponding decrease in the likelihood of an additional contribution of several tens of centimeters above the likely range. In view of the comparatively limited state of knowledge and understanding of rapid ice sheet dynamics, we continue to think that it is not yet possible to make reliable quantitative estimates of future GMSL rise outside the likely range. Projections of twenty-first century GMSL rise published since the AR5 depend on results from expert elicitation, but we have low confidence in conclusions based on these approaches. New work on regional projections and emergence of the anthropogenic signal suggests that the two commonly predicted features of future regional sea level change (the increasing tilt across the Antarctic Circumpolar Current and the dipole in the North Atlantic) are related to regional changes in wind stress and surface heat flux. Moreover, it is expected that sea level change in response to anthropogenic forcing, particularly in regions of relatively low unforced variability such as the low-latitude Atlantic, will be detectable over most of the ocean by 2040. The east-west contrast of sea level trends in the Pacific observed since the early 1990s cannot be satisfactorily accounted for by climate models, nor yet definitively attributed either to unforced variability or forced climate change

Keeping an eye on noisy movements: On different approaches to perceptual-motor skill research and training

Contemporary theorising on the complementary nature of perception and action in expert performance has led to the emergence of different emphases in studying movement coordination and gaze behaviour. On the one hand, coordination research has examined the role that variability plays in movement control, evidencing that variability facilitates individualised adaptations during both learning and performance. On the other hand, and at odds with this principle, the majority of gaze behaviour studies have tended to average data over participants and trials, proposing the importance of universal 'optimal' gaze patterns in a given task, for all performers, irrespective of stage of learning. In this article, new lines of inquiry are considered with the aim of reconciling these two distinct approaches. The role that inter- and intra-individual variability may play in gaze behaviours is considered, before suggesting directions for future research

"Closing-in" phenomenon in Alzheimer's disease and subcortical vascular dementia

BACKGROUND: The 'closing-in' phenomenon is defined as a tendency to close in on a model while copying it. This is one of several constructional apraxia observed in dementia, particularly in Alzheimer's disease (AD). The aim of this study was to investigate the usefulness of it in the differential diagnosis of AD and subcortical vascular dementia (SVD) and to clarify the factors associated with it. METHODS: We operationally defined and classified it into three types, namely overlap, adherent, and near type. We analyzed the incidence of it in patients with AD (n = 98) and SVD (n = 48). RESULTS: AD patients exhibited a significantly higher occurrence of it as compared to SVD patients. Among the different types of it, the overlap and adherent types occurred almost exclusively in AD patients. A discriminant analysis in AD subjects revealed that the scores obtained from the MMSE, CDR, Barthel index, and the Rey-Osterrieth complex figure test were correlated significantly with the occurrence of it. There was no statistical difference between the Q-EEG parameters of patients that exhibited the closing-in phenomenon and those that did not. CONCLUSIONS: This study suggests that the closing-in phenomenon is phase- and AD-specific and might be a useful tool for the differential diagnosis of AD and SVD