Adenosine to inosine editing by ADAR2 requires formation of a ternary complex on the GluR-B R/G site

RNA editing by members of the ADAR (adenosine deaminase that acts on RNA) enzyme family involves hydrolytic deamination of adenosine to inosine within the context of a double-stranded pre-mRNA substrate. Editing of the human GluR-B transcript is catalyzed by, the enzyme ADAR2 at the Q/R and R/G sites. We have established a minimal RNA substrate for editing based on the RIG site and have characterized the interaction of ADAR2 with this RNA by gel shift, kinetic, and cross-linking analyses. Gel shift analysis revealed that two complexes are formed on the RNA as protein concentration is increased; the ADAR monomers can be crosslinked to one another in an RNA-dependent fashion. We performed a detailed kinetic study of the editing reaction; the data from this study are consistent with a reaction scheme in which formation of an ADAR2.RNA ternary complex is required for efficient RNA editing and in which formation of this complex is rate determining. These observations suggest that RNA adenosine deaminases function as homodimers on their RNA substrates and may partially explain regulation of RNA editing in these systems

Infant sleep and anxiety disorders in early childhood: Findings from an Australian pregnancy cohort study

Emphasis on continuous infant sleep overnight may be driven by parental concern of risk to child mental health outcomes. The Mercy Pregnancy and Emotional Wellbeing Study (MPEWS) examined whether infant sleep at 6 and 12 months postpartum predicts anxiety disorders at 2–4 years, and whether this is moderated by maternal depression, active physical comforting (APC) or maternal cognitions about infant sleep. Data included 349 women and infants. Infant sleep was measured using the Brief Infant Sleep Questionnaire and child anxiety disorders by the Preschool Age Psychiatric Assessment. The risk of developing generalised anxiety or social phobia disorders at 3–4 years was reduced by 42% (p = 0.001) and 31% (p = 0.001), respectively, for a one standard deviation increase in total sleep at 12 months. No other infant sleep outcomes were associated. Maternal depression, APC and cognitions about infant sleep did not significantly moderate these relationships. Focus may need to be on total infant sleep, rather than when sleep is achieved. Highlights: To assess whether infant sleep outcomes (i.e., frequency of nocturnal wakes; nocturnal wakefulness and total sleep per day) at 6 and 12 months predict early childhood anxiety disorders at 3–4 years of age. Maternally reported infant sleep outcomes were not associated with the risk of developing early childhood anxiety disorders at 3–4 years. It may be total infant sleep, irrespective of when sleep occurs or night waking and, independently, active physical comforting that requires further investigation

Surgical management of ductal carcinoma in situ of the breast: A large retrospective study from a single institution

Background: Management of breast ductal carcinoma in situ (DCIS) has various approaches with distinct institutional specific practice. Here, we review DCIS management in a single institution with emphasise on re-operation rates and outcome. Methods: DCIS cases diagnosed at the Nottingham Breast Institute between 1987 and 2017 were identified (n=1,249). Clinicopathological data was collected. Cases were histologically reviewed, and different factors associated with primary operation selection, re-excision, presence of residual tumour in the re-excision specimens, use of radiotherapy and ipsilateral recurrences were analysed. Results: 34% of DCIS patients were initially treated by mastectomy and were more frequently symptomatic, of high nuclear tumour grade, size >40mm, and associated with comedo necrosis and Paget’s disease of the nipple. Further surgery was due to involved or narrow surgical margins. Residual tumour tissue was detected in 53% of the re-excision specimens. Re-excision rates of patients treated with breast conserving surgery (BCS) were reduced from approximately 70% to 23% and the final mastectomy rates decreased from 60% to 20%. Changes in surgical practice with acceptance of smaller excision margins and more frequent use of local radiotherapy have led to a significant decrease not only in the re-excision rate but also in the final mastectomy rate together with non-significant reduction in 5- and 10-year local recurrence rates. Conclusion: Although BCS is increasingly the preferred primary surgical option for DCIS management, a proportion of low-risk DCIS patients continue to undergo re-excision surgery or completion mastectomy. Despite acceptance of smaller margins, recurrence rate is decreasing

Do Natural Experiments of Changes in Neighborhood Built Environment Impact Physical Activity and Diet? A Systematic Review.

Physical activity and diet are major modifiable risk factors for chronic disease and have been shown to be associated with neighborhood built environment. Systematic review evidence from longitudinal studies on the impact of changing the built environment on physical activity and diet is currently lacking. A systematic review of natural experiments of neighborhood built environment was conducted. The aims of this systematic review were to summarize study characteristics, study quality, and impact of changes in neighborhood built environment on physical activity and diet outcomes among residents. Natural experiments of neighborhood built environment change, exploring longitudinal impacts on physical activity and/or diet in residents, were included. From five electronic databases, 2084 references were identified. A narrative synthesis was conducted, considering results in relation to study quality. Nineteen papers, reporting on 15 different exposures met inclusion criteria. Four studies included a comparison group and 11 were pre-post/longitudinal studies without a comparison group. Studies reported on the impact of redeveloping or introducing cycle and/or walking trails (n = 5), rail stops/lines (n = 4), supermarkets and farmers' markets (n = 4) and park and green space (n = 2). Eight/15 studies reported at least one beneficial change in physical activity, diet or another associated health outcome. Due to limitations in study design and reporting, as well as the wide array of outcome measures reported, drawing conclusions to inform policy was challenging. Future research should consider a consistent approach to measure the same outcomes (e.g., using measurement methods that collect comparable physical activity and diet outcome data), to allow for pooled analyses. Additionally, including comparison groups wherever possible and ensuring high quality reporting is essential

Synergies for Improving Oil Palm Production and Forest Conservation in Floodplain Landscapes

Lowland tropical forests are increasingly threatened with conversion to oil palm as global demand and high profit drives crop expansion throughout the world’s tropical regions. Yet, landscapes are not homogeneous and regional constraints dictate land suitability for this crop. We conducted a regional study to investigate spatial and economic components of forest conversion to oil palm within a tropical floodplain in the Lower Kinabatangan, Sabah, Malaysian Borneo. The Kinabatangan ecosystem harbours significant biodiversity with globally threatened species but has suffered forest loss and fragmentation. We mapped the oil palm and forested landscapes (using object-based-image analysis, classification and regression tree analysis and on-screen digitising of high-resolution imagery) and undertook economic modelling. Within the study region (520,269 ha), 250,617 ha is cultivated with oil palm with 77% having high Net-Present-Value (NPV) estimates ($413/ha?yr–$637/ha?yr); but 20.5% is under-producing. In fact 6.3% (15,810 ha) of oil palm is commercially redundant (with negative NPV of $-299/ha?yr-$-65/ha?yr) due to palm mortality from flood inundation. These areas would have been important riparian or flooded forest types. Moreover, 30,173 ha of unprotected forest remain and despite its value for connectivity and biodiversity 64% is allocated for future oil palm. However, we estimate that at minimum 54% of these forests are unsuitable for this crop due to inundation events. If conversion to oil palm occurs, we predict a further 16,207 ha will become commercially redundant. This means that over 32,000 ha of forest within the floodplain would have been converted for little or no financial gain yet with significant cost to the ecosystem. Our findings have globally relevant implications for similar floodplain landscapes undergoing forest transformation to agriculture such as oil palm. Understanding landscape level constraints to this crop, and transferring these into policy and practice, may provide conservation and economic opportunities within these seemingly high opportunity cost landscapes

Dark Matter Annihilation around Intermediate Mass Black Holes: an update

The formation and evolution of Black Holes inevitably affects the distribution of dark and baryonic matter in the neighborhood of the Black Hole. These effects may be particularly relevant around Supermassive and Intermediate Mass Black Holes (IMBHs), the formation of which can lead to large Dark Matter overdensities, called {\em spikes} and {\em mini-spikes} respectively. Despite being larger and more dense, spikes evolve at the very centers of galactic halos, in regions where numerous dynamical effects tend to destroy them. Mini-spikes may be more likely to survive, and they have been proposed as worthwhile targets for indirect Dark Matter searches. We review here the formation scenarios and the prospects for detection of mini-spikes, and we present new estimates for the abundances of mini-spikes to illustrate the sensitivity of such predictions to cosmological parameters and uncertainties regarding the astrophysics of Black Hole formation at high redshift. We also connect the IMBHs scenario to the recent measurements of cosmic-ray electron and positron spectra by the PAMELA, ATIC, H.E.S.S., and Fermi collaborations.Comment: 12 pages, 7 figures. Invited contribution to NJP Focus Issue on "Dark Matter and Particle Physics

The clinical significance of oestrogen receptor expression in breast ductal carcinoma in situ

Background: Oestrogen receptor (ER) in invasive breast cancer (BC) predicts response to endocrine therapy (ET) and provides prognostic value. In this study, we investigated the value of ER expression in ductal carcinoma in situ (DCIS) in terms of outcome and the impact on ET decision.Methods: 643 pure DCIS, diagnosed at Nottingham University Hospitals, were assessed for ER. Clinicopathological data were correlated against ER status together with assessment of recurrence rate.Results: ER-positivity was observed in 74% (475/643) of cases. ER positivity was associated with clinicopathological variables of good prognosis; however, outcome analysis revealed that ER status was not associated with local recurrence. In the intermediate and high-grade ER-positive DCIS, 58% (11/19) and 63% (15/24) of the recurrences were invasive, respectively, comprising 7% and 6% of all ER-positive DCIS, respectively. Invasive recurrence in low-grade DCIS was infrequent (2%) and none of these patients died of BC. The ER status of the recurrent invasive tumours matched the primary DCIS ER status (94% in ipsilateral and 90% of contralateral recurrence).Conclusion: The strong correlation between DCIS and invasive recurrences ER status and the clinical impact of ET justify discussion of the use of ET in ER-positive DCIS treated by breast conserving surgery. The excellent outcome of low-grade DCIS, which was almost always ER- positive, does not, in the opinion of authors, justify the use of risk reducing ET. Therefore, the decision on ET for DCIS should be personalised and consider grade, ER status and other characteristics

Verbal working memory and functional large-scale networks in schizophrenia

The aim of this study was to test whether bilinear and nonlinear effective connectivity (EC) measures of working memory fMRI data can differentiate between patients with schizophrenia (SZ) and healthy controls (HC). We applied bilinear and nonlinear Dynamic Causal Modeling (DCM) for the analysis of verbal working memory in 16 SZ and 21 HC. The connection strengths with nonlinear modulation between the dorsolateral prefrontal cortex (DLPFC) and the ventral tegmental area/substantia nigra (VTA/SN) were evaluated. We used Bayesian Model Selection at the group and family levels to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging was used to assess the connection strengths with nonlinear modulation. The DCM analyses revealed that SZ and HC used different bilinear networks despite comparable behavioral performance. In addition, the connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area showed differences between SZ and HC. The adoption of different functional networks in SZ and HC indicated neurobiological alterations underlying working memory performance, including different connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area. These novel findings may increase our understanding of connectivity in working memory in schizophrenia