An RNA interference screen for identifying downstream effectors of the p53 and pRB tumour suppressor pathways involved in senescence

Background: Cellular senescence is an irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress and acts as an important tumour suppressor mechanism.Results: To identify the downstream effectors of the p53-p21 and p16-pRB tumour suppressor pathways crucial for mediating entry into senescence, we have carried out a loss-of-function RNA interference screen in conditionally immortalised human fibroblasts that can be induced to rapidly undergo senescence, whereas in primary cultures senescence is stochastic and occurs asynchronously. These cells are immortal but undergo a rapid irreversible arrest upon activation of the p53-p21 and p16-pRB pathways that can be readily bypassed upon their inactivation. The primary screen identified 112 known genes including p53 and another 29 shRNAmirs targetting as yet unidentified loci. Comparison of these known targets with genes known to be up-regulated upon senescence in these cells, by micro-array expression profiling, identified 4 common genes TMEM9B, ATXN10, LAYN and LTBP2/3. Direct silencing of these common genes, using lentiviral shRNAmirs, bypassed senescence in the conditionally immortalised cells.Conclusion: The senescence bypass screen identified TMEM9B, ATXN10, LAYN and LTBP2/3 as novel downstream effectors of the p53-p21 and p16-pRB tumour suppressor pathways. Although none of them has previously been linked to cellular senescence, TMEM9B has been suggested to be an upstream activator of NF-kappa B signalling which has been found to have a causal role in promoting senescence. Future studies will focus on determining on how many of the other primary hits also have a casual role in senescence and what is the mechanism of action

The rise and restraint of the preventive state

Security has always been a core function of the modern state. Yet the rise of the Preventive State captures an intensification of that role as threats to security and demands for public protection increase, prompting states to prioritize new practices of preventive criminalization, policing, and punishment. The rise of the Preventive State may promise greater security, but the costs of ever more coercive preventive laws and measures are burdensome and pose a threat to civil liberties. This review considers the drivers, multiple manifestations, and direct and collateral consequences of preventive endeavors that assess and manage risk, target hazards, and restrain or detain those deemed dangerous. It also explores their ramifications for criminology and criminal justice. It concludes by considering the potential of criminology to join cross-disciplinary efforts to articulate a new jurisprudence of security and to elaborate principles of preventive justice with which to restrain the excesses of the Preventive State

The transition to adulthood for autistic young people with additional learning needs: the views and experiences of education professionals in special schools

Education professionals (n = 41) in special schools were interviewed about supporting their autistic pupils transitioning to adulthood following the introduction of the Children and Families Act 2014. Our participants explained how they lacked the time to fully implement knowledge gained from training, leading to growing reliance on experiential expertise. While our participants reported employing a variety of methods to elicit the voices of pupils, they were uncertain how effective and ethical these were. Further, a lack of available opportunities meant that participants felt they could not always support young people in achieving their goals. Based on these findings, we recommend greater investment in the implementation of staff training, more flexibility for schools to be able to meaningfully elicit and act on pupils' voices, and better vocational opportunities for autistic young people with additional learning needs. This would enable the principles of the Act, which have been widely lauded, to become a closer reality

Toward a simulation approach for alkene ring-closing metathesis : scope and limitations of a model for RCM

A published model for revealing solvent effects on the ring-closing metathesis (RCM) reaction of di-Et diallylmalonate 7 has been evaluated over a wider range of conditions, to assess its suitability for new applications. Unfortunately, the model is too flexible and the published rate consts. do not agree with exptl. studies in the literature. However, by fixing the values of important rate consts. and restricting the concn. ranges studied, useful conclusions can be drawn about the relative rates of RCM of different substrates, precatalyst concn. can be simulated accurately and the effect of precatalyst loading can be anticipated. Progress has also been made toward applying the model to precatalyst evaluation, but further modifications to the model are necessary to achieve much broader aims

Chandra Detection of the Forward and Reverse Shocks in Cassiopeia-A

We report the localization of the forward and reversed shock fronts in the young supernova remnant Cas-A using X-ray data obtained with the Chandra Observatory. High resolution X-ray maps resolve a previously unseen X-ray feature encompassing the extremity of the remnant. This feature consists of thin, tangential wisps of emission bordering the outer edge of the thermal X-ray and radio remnant, forming a circular rim, approx. 2.7 in radius. Radio images show a sharp rise in brightness at this X-ray rim, along with a large jump in the synchrotron polarization angle. These characteristics suggest that these wisps are the previously unresolved signature of the forward, or outer, shock. Similarly, we identify the sharp rise in emissivity of the bright shell for both the radio and X-ray line emission associated with the reverse shock. The derived ratio of the averaged forward and reverse shock radii of approx. 3:2 constrains the remnant to have swept up roughly the same amount of mass as was ejected; this suggests that Cas-A is just entering the Sedov phase. Comparison of the X-ray spectra from the two shock regions shows that the equivalent widths of prominent emission lines are significantly lower exterior to the bright shell, as expected if they are respectively identified with the shocked circumstellar material and shocked ejecta. Furthermore, the spectrum of the outer rim itself is dominated by power-law emission, likely the counterpart of the non-thermal component previously seen at energies above 10 keV.Comment: 7 pages with 5 figures, LaTex, emulateapj.sty. To appear in the Astrophysical Journal Letter

Influence of Pyrolysis Temperature and Production Conditions on Switchgrass Biochar for Use as a Soil Amendment

Biochars form recalcitrant carbon and increase water and nutrient retention in soils; however, the magnitude is contingent upon production conditions and thermo-chemical conversion processes. Herein we aim at (i) characterizing switchgrass (Panicum virgatum L.)-biochar morphology, (ii) estimating water-holding capacity under increasing ratios of char: soil; and, (iii) determining nutrient profile variation as a function of pyrolysis conversion methodologies (i.e. continuous, auger pyrolysis system versus batch pyrolysis systems) for terminal use as a soil amendment. Auger system chars produced at 600 °C had the greatest lignin portion by weight among the biochars produced from the continuous system. On the other hand, a batch pyrolysis system (400 °C – 3h) yielded biochar with 73.10% lignin (12 fold increases), indicating higher recalcitrance, whereas lower production temperatures (400 °C) yielded greater hemicellulose (i.e. greater mineralization promoting substrate). Under both pyrolysis methods, increasing biochar soil application rates resulted in linear decreases in bulk density (g cm-3). Increases in auger-char (400 °C) applications increased soil water-holding capacities; however, application rates of \u3e2 Mt ha-1 are required. Pyrolysis batch chars did not influence water-holding abilities (P\u3e0.05). Biochar macro and micronutrients increased, as the pyrolysis temperature increased in the auger system from 400 to 600 °C, and the residence time increased in the batch pyrolysis system from 1 to 3 h. Conversely, nitrogen levels tended to decrease under the two previously mentioned conditions. Consequently, not all chars are inherently equal, in that varying operation systems, residence times, and production conditions greatly affect uses as a soil amendment and overall rate of efficacy

Incidence of community-acquired lower respiratory tract infections and pneumonia among older adults in the United Kingdom: a population-based study.

Community-acquired lower respiratory tract infections (LRTI) and pneumonia (CAP) are common causes of morbidity and mortality among those aged ≥65 years; a growing population in many countries. Detailed incidence estimates for these infections among older adults in the United Kingdom (UK) are lacking. We used electronic general practice records from the Clinical Practice Research Data link, linked to Hospital Episode Statistics inpatient data, to estimate incidence of community-acquired LRTI and CAP among UK older adults between April 1997-March 2011, by age, sex, region and deprivation quintile. Levels of antibiotic prescribing were also assessed. LRTI incidence increased with fluctuations over time, was higher in men than women aged ≥70 and increased with age from 92.21 episodes/1000 person-years (65-69 years) to 187.91/1000 (85-89 years). CAP incidence increased more markedly with age, from 2.81 to 21.81 episodes/1000 person-years respectively, and was higher among men. For both infection groups, increases over time were attenuated after age-standardisation, indicating that these rises were largely due to population aging. Rates among those in the most deprived quintile were around 70% higher than the least deprived and were generally higher in the North of England. GP antibiotic prescribing rates were high for LRTI but lower for CAP (mostly due to immediate hospitalisation). This is the first study to provide long-term detailed incidence estimates of community-acquired LRTI and CAP in UK older individuals, taking person-time at risk into account. The summary incidence commonly presented for the ≥65 age group considerably underestimates LRTI/CAP rates, particularly among older individuals within this group. Our methodology and findings are likely to be highly relevant to health planners and researchers in other countries with aging populations

The search for common anthropogenic impacts on biodiversity : a global network

We introduce an initiative to assess and compare landscape changes related to human activities on a global scale, using a single group of invertebrates. The GLOBENET programme uses common field methodology (pitfall trapping), to appraise assemblages of ground beetles (Coleoptera, Carabidae) in visually-similar land-mosaics (urban-rural gradients). Carabids were selected as the focal taxon as they are sufficiently varied (both taxonomically and ecologically), abundant and sensitive to the environment. However, work on other taxa is comparable with the GLOBENET framework. The continuum of decreasing human pressure from city centres into the surrounding countryside was selected to represent human-caused disturbance for this initial stage of GLOBENET because these gradients can be found virtually all over the world. Through the broad-scale assessment envisioned in the GLOBENET programme, we seek to separate general, repeated effects on biodiversity from those that depend on local environments or particular biotic assemblages. Based on this understanding we aim to develop simple tools and protocols for assessing ecological effects of human-caused landscape changes, which could help to sustainably manage landscapes for biodiversity and for human requirements. For instance, the response of different functional groups of carabids to these landscape changes may help guide management practices. Further GLOBENET developments and information are available at our website: http://www.helsinki.fi/science/globenet

Nitrogen Fixation and Seeding Rates of Common vs. Hairy Vetch for Interseeding Into Established Switchgrass Stands

Interest in alternatives to synthetic nitrogen (N) fertilizer sources for switchgrass (Panicum virgatum L.) production, such as interseeding with N- fixing legumes continues to increase. Common vetch (Vicia sativa) is a N-fixing legume that occurs naturally throughout the U.S. and has less hard seed than hairy vetch (Vicia villosa), making it potentially less invasive, and it may fix N at similar rates to that of hairy vetch. However, little data exist to substantiate this. In this study, N-fixation rates via the N-difference method were determined to be 59.3 and 43.3 kg N ha-1 for common and hairy vetch, respectively, when seeded at 6.7 kg ha-1. At these rates, neither common nor hairy vetch significantly affected switchgrass yields. Based on the N-fixation rates and vetch plant masses, we estimate that minimum seeding rates of 7.6 and 10.4 kg PLS ha-1 of common and hairy vetch, respectively are required to obtain plant stands needed to fix the current recommended rate of N for switchgrass biomass production