Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution

Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Here we measure allele-specific transcription factor binding occupancy of three liver-specific transcription factors between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor binding variations in mammals. Our results highlight the pre-eminence of cis-acting variants on transcription factor occupancy divergence. Transcription factor binding differences linked to cis-acting variants generally exhibit additive inheritance, while those linked to trans-acting variants are most often dominantly inherited. Cis-acting variants lead to local coordination of transcription factor occupancies that decay with distance; distal coordination is also observed and may be modulated by long-range chromatin contacts. Our results reveal the regulatory mechanisms that interplay to drive transcription factor occupancy, chromatin state, and gene expression in complex mammalian cell states.We thank the CRUK—CI Genomics, BRU, and Bioinformatics Cores for technical assistance and the EMBL-EBI systems team for management of computational resources. This research was supported by the European Molecular Biology Laboratory (E.S.W., D.T., J.C.M., P.F.), Cancer Research UK (B.M.S., T.F.R., F.C., C.F., A.R., D.T.O.), the BOLD ITN (B.M.S.), Darwin Fellowship (A.K.), the Wellcome Trust (WT202878/B/16/Z, WT108749/Z/15/Z) (P.F.), (WT202878/A/16/Z) (D.T.O), (WT095606) (A.C.F.-S) and (WT098051) (P.F., D.T.O.), EMBO Long-term (ALTF1518-2012) and Advanced Fellowships (aALTF1672-2014) (E.S.W.), and by the European Research Council (award 615584) and EMBO Young Investigator Programme (D.T.O.)

Advancing translational research with the Semantic Web

<p>Abstract</p> <p>Background</p> <p>A fundamental goal of the U.S. National Institute of Health (NIH) "Roadmap" is to strengthen <it>Translational Research</it>, defined as the movement of discoveries in basic research to application at the clinical level. A significant barrier to translational research is the lack of uniformly structured data across related biomedical domains. The Semantic Web is an extension of the current Web that enables navigation and meaningful use of digital resources by automatic processes. It is based on common formats that support aggregation and integration of data drawn from diverse sources. A variety of technologies have been built on this foundation that, together, support identifying, representing, and reasoning across a wide range of biomedical data. The Semantic Web Health Care and Life Sciences Interest Group (HCLSIG), set up within the framework of the World Wide Web Consortium, was launched to explore the application of these technologies in a variety of areas. Subgroups focus on making biomedical data available in RDF, working with biomedical ontologies, prototyping clinical decision support systems, working on drug safety and efficacy communication, and supporting disease researchers navigating and annotating the large amount of potentially relevant literature.</p> <p>Results</p> <p>We present a scenario that shows the value of the information environment the Semantic Web can support for aiding neuroscience researchers. We then report on several projects by members of the HCLSIG, in the process illustrating the range of Semantic Web technologies that have applications in areas of biomedicine.</p> <p>Conclusion</p> <p>Semantic Web technologies present both promise and challenges. Current tools and standards are already adequate to implement components of the bench-to-bedside vision. On the other hand, these technologies are young. Gaps in standards and implementations still exist and adoption is limited by typical problems with early technology, such as the need for a critical mass of practitioners and installed base, and growing pains as the technology is scaled up. Still, the potential of interoperable knowledge sources for biomedicine, at the scale of the World Wide Web, merits continued work.</p

From 'event-led' to 'event-themed' regeneration: the 2002 Commonwealth Games Legacy Programme

Hosting large events has long been associated with the physical regeneration of cities. To supplement these ‘hard’ impacts, cities are now attempting to use events to stimulate ‘softer’ social and economic regeneration. This paper evaluates the impacts of a regeneration Programme adopted in conjunction with the 2002 Commonwealth Games held in Manchester, UK. Alongside its emphasis on social and economic regeneration, this Programme was unusual in that the projects were Games-themed, rather than being directly linked to the event. Despite some concerns about the organisational structures employed and the sustainability of impacts, target beneficiaries have received valuable assistance from the Programme. As such there appears to be valuable lessons that other cities can learn from this example of event regeneration

Crop Updates 2000 - Cereals part 1

This session covers eleven papers from different authors: PLENARY PAPERS 1. New Wheat for a Secure, Sustainable Future, Timothy G. Reeves, Sanjaya Rajaram, Maarten van Ginkel, Richard Trethowan, Hans-Joachim Braun, and Kelly Cassaday, International Maize and Wheat Improvement Centre (CIMMYT) 2. Managing Cereal Rusts - a National Perspective, R.A. McIntosh, University of Sydney Plant Breeding Institute, New South Wales 3. Managing Cereal Rusts in 2000 - a regional imperative, R. Loughman, Agriculture Western Australia 4. Is nutrition the answer to wheat after canola problems?Ross Brennan1, Bill Bowden1, Mike Bolland1, Zed Rengel2 and David Isbister2 1 Agriculture Western Australia 2University of Western Australia 5. Improved Sandplain Cropping Systems by Controlled Traffic, Dr Paul Blackwell, Agriculture Western Australia 6. Raised bed farming for improved cropping of waterlogged soils, Derk Bakker, Greg Hamilton, David Houlbrooke, Cliff Spann and Doug Rowe, Agriculture Western Australia 7. Banded Urea increased wheat yields, Patrick Gethin, Stephen Loss, Frank Boetel, and Tim O’Dea, CSBP futurefarm 8. Flexi N is as effective as Urea on wheat and canola, Frank Boetel, Stephen Loss, Patrick Gethin, and Tim O’Dea CSBP futurefarm 9. Why potassium may reduce cereal leaf disease, Noeleen Edwards, Agriculture Western Australia 10, Trace elements, Wayne Pluske CSBP futurefarm, and Ross BrennanAgriculture Western Australia 11. Historical Nutrient Balance at Paddock and Whole Farm scales for typical wheatbelt farms in the Dowerin - Wongan Hills area, M.T.F. Wong, K. Wittwer and H. Zhang Precision Agriculture Research Group, CSIRO Land and Wate

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Dynamic Contrast-Enhanced MRI Assessment of Hyperemic Fractional Microvascular Blood Plasma Volume in Peripheral Arterial Disease: Initial Findings

OBJECTIVES: The aim of the current study was to describe a method that assesses the hyperemic microvascular blood plasma volume of the calf musculature. The reversibly albumin binding contrast agent gadofosveset was used in dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) to assess the microvascular status in patients with peripheral arterial disease (PAD) and healthy controls. In addition, the reproducibility of this method in healthy controls was determined. MATERIALS AND METHODS: Ten PAD patients with intermittent claudication and 10 healthy control subjects were included. Patients underwent contrast-enhanced MR angiography of the peripheral arteries, followed by one DCE MRI examination of the musculature of the calf. Healthy control subjects were examined twice on different days to determine normative values and the interreader and interscan reproducibility of the technique. The MRI protocol comprised dynamic imaging of contrast agent wash-in under reactive hyperemia conditions of the calf musculature. Using pharmacokinetic modeling the hyperemic fractional microvascular blood plasma volume (V(p), unit: %) of the anterior tibial, gastrocnemius and soleus muscles was calculated. RESULTS: V(p) was significantly lower for all muscle groups in PAD patients (4.3±1.6%, 5.0±3.3% and 6.1±3.6% for anterior tibial, gastrocnemius and soleus muscles, respectively) compared to healthy control subjects (9.1±2.0%, 8.9±1.9% and 9.3±2.1%). Differences in V(p) between muscle groups were not significant. The coefficient of variation of V(p) varied from 10-14% and 11-16% at interscan and interreader level, respectively. CONCLUSIONS: Using DCE MRI after contrast-enhanced MR angiography with gadofosveset enables reproducible assessment of hyperemic fractional microvascular blood plasma volume of the calf musculature. V(p) was lower in PAD patients than in healthy controls, which reflects a promising functional (hemodynamic) biomarker for the microvascular impairment of macrovascular lesions

Distinct Neurobehavioural Effects of Cannabidiol in Transmembrane Domain Neuregulin 1 Mutant Mice

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT2A receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABAA receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT2A binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes

Regional differences in lumbar spinal posture and the influence of low back pain

<p>Abstract</p> <p>Background</p> <p>Spinal posture is commonly a focus in the assessment and clinical management of low back pain (LBP) patients. However, the link between spinal posture and LBP is not fully understood. Recent evidence suggests that considering regional, rather than total lumbar spine posture is important. The purpose of this study was to determine; if there are regional differences in habitual lumbar spine posture and movement, and if these findings are influenced by LBP.</p> <p>Methods</p> <p>One hundred and seventy female undergraduate nursing students, with and without LBP, participated in this cross-sectional study. Lower lumbar (LLx), Upper lumbar (ULx) and total lumbar (TLx) spine angles were measured using an electromagnetic tracking system in static postures and across a range of functional tasks.</p> <p>Results</p> <p>Regional differences in lumbar posture and movement were found. Mean LLx posture did not correlate with ULx posture in sitting (r = 0.036, p = 0.638), but showed a moderate inverse correlation with ULx posture in usual standing (r = -0.505, p < 0.001). Regional differences in range of motion from reference postures in sitting and standing were evident. BMI accounted for regional differences found in all sitting and some standing measures. LBP was not associated with differences in regional lumbar spine angles or range of motion, with the exception of maximal backward bending range of motion (F = 5.18, p = 0.007).</p> <p>Conclusion</p> <p>This study supports the concept of regional differences within the lumbar spine during common postures and movements. Global lumbar spine kinematics do not reflect regional lumbar spine kinematics, which has implications for interpretation of measures of spinal posture, motion and loading. BMI influenced regional lumbar posture and movement, possibly representing adaptation due to load.</p

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers\u27 tissue of origin