Macrophages exposed continuously to lipopolysaccharide and other agonists that act via toll-like receptors exhibit a sustained and additive activation state

BACKGROUND: Macrophages sense microorganisms through activation of members of the Toll-like receptor family, which initiate signals linked to transcription of many inflammation associated genes. In this paper we examine whether the signal from Toll-like receptors [TLRs] is sustained for as long as the ligand is present, and whether responses to different TLR agonists are additive. RESULTS: RAW264 macrophage cells were doubly-transfected with reporter genes in which the IL-12p40, ELAM or IL-6 promoter controls firefly luciferase, and the human IL-1β promoter drives renilla luciferase. The resultant stable lines provide robust assays of macrophage activation by TLR stimuli including LPS [TLR4], lipopeptide [TLR2], and bacterial DNA [TLR9], with each promoter demonstrating its own intrinsic characteristics. With each of the promoters, luciferase activity was induced over an 8 hr period, and thereafter reached a new steady state. Elevated expression required the continued presence of agonist. Sustained responses to different classes of agonist were perfectly additive. This pattern was confirmed by measuring inducible cytokine production in the same cells. While homodimerization of TLR4 mediates responses to LPS, TLR2 appears to require heterodimerization with another receptor such as TLR6. Transient expression of constitutively active forms of TLR4 or TLR2 plus TLR6 stimulated IL-12 promoter activity. The effect of LPS, a TLR4 agonist, was additive with that of TLR2/6 but not TLR4, whilst that of lipopeptide, a TLR2 agonist, was additive with TLR4 but not TLR2/6. Actions of bacterial DNA were additive with either TLR4 or TLR2/6. CONCLUSIONS: These findings indicate that maximal activation by any one TLR pathway does not preclude further activation by another, suggesting that common downstream regulatory components are not limiting. Upon exposure to a TLR agonist, macrophages enter a state of sustained activation in which they continuously sense the presence of a microbial challenge

Palaeogeographical evolution of the Rattray Volcanic Province, Central North Sea

Funded by Carnegie Trust for the Universities of Scotland PHD060365Peer reviewedPostprin

Challenges of future exploration within the UK Rockall Basin

We would like to acknowledge the two reviewers, Tony Dore and Clayton Grove for their constructive, positive and enthusiastic reviews which substantially improved this manuscript. The editor Matt Allen is thanked for encouragement and support in putting the paper together. We acknowledge a governmental research grant from the Oil and Gas Authority Frontier Basins Research Program and British Government for funding the project “Evaluating the Prospectivity of the Rockall Trough – Towards a Complete View of the Petroleum System West of Britain”. Schofield would like to acknowledge the 8th Petroleum Geology of Northwest Europe Conference for the DG Roberts/Peter Zeigler Best Paper Award. This contribution forms part of the theme “Key Future Geoscience Challenges” held at the 8th Petroleum Geology Conference. We would like to Acknowledge PGS for the donation of datasets in Rockall, and for continued support of research. CDA are acknowledged for providing publically released well and seismic data. Spectrum Geophysical are also thanked for donation of data for research in the Rockall. Interpretation was carried out using IHS Kingdom software. WGM 2012 gravity data courtesy of International Gravimetric Bureau. Maersk are thanked for use of Gravity Maps.Postprin

Instrumental performance and results from testing of the BLAST-TNG receiver, submillimeter optics, and MKID arrays

Polarized thermal emission from interstellar dust grains can be used to map magnetic fields in star forming molecular clouds and the diffuse interstellar medium (ISM). The Balloon-borne Large Aperture Submillimeter Telescope for Polarimetry (BLASTPol) flew from Antarctica in 2010 and 2012 and produced degree-scale polarization maps of several nearby molecular clouds with arcminute resolution. The success of BLASTPol has motivated a next-generation instrument, BLAST-TNG, which will use more than 3000 linear polarization sensitive microwave kinetic inductance detectors (MKIDs) combined with a 2.5m diameter carbon fiber primary mirror to make diffraction-limited observations at 250, 350, and 500 $\mu$m. With 16 times the mapping speed of BLASTPol, sub-arcminute resolution, and a longer flight time, BLAST-TNG will be able to examine nearby molecular clouds and the diffuse galactic dust polarization spectrum in unprecedented detail. The 250 $\mu$m detector array has been integrated into the new cryogenic receiver, and is undergoing testing to establish the optical and polarization characteristics of the instrument. BLAST-TNG will demonstrate the effectiveness of kilo-pixel MKID arrays for applications in submillimeter astronomy. BLAST-TNG is scheduled to fly from Antarctica in December 2017 for 28 days and will be the first balloon-borne telescope to offer a quarter of the flight for "shared risk" observing by the community.Comment: Presented at SPIE Millimeter, Submillimeter, and Far-Infrared Detectors and Instrumentation for Astronomy VIII, June 29th, 201

Developing expertise through experience: Ideas for continuing professional development

Edited by Alan Maley, the book is focusing on the role of experience in teacher training and life-long development, it is an exploration and extension of Prabhu’s concept of ‘the teacher’s sense of plausibility’. Prabhu suggests that whatever forms of training and professional development teachers are exposed to, they will make sense of them in their own way, drawing on their own values, beliefs and experiences and their evolving sense of what will be appropriate for them in their specific context. Twenty practitioners world-wide were invited to reflect on their own career trajectories in the light of Prabhu’s idea. Their responses offer fascinating insights into the way places, publications, ideas and key people have influenced the professional and personal development of the contributors

RESILIENT Part 2: A Randomized, Open-Label Phase III Study of Liposomal Irinotecan Versus Topotecan in Adults With Relapsed Small Cell Lung Cancer

PURPOSE The phase III RESILIENT trial compared second-line liposomal irinotecan with topotecan in patients with small cell lung cancer (SCLC). PATIENTS AND METHODS Patients with SCLC and progression on or after first-line platinum-based chemotherapy were randomly assigned (1:1) to intravenous (IV) liposomal irinotecan (70 mg/m(2) every 2 weeks in a 6-week cycle) or IV topotecan (1.5 mg/m(2) daily for 5 consecutive days, every 3 weeks in a 6-week cycle). The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) and objective response rate (ORR). RESULTS Among 461 randomly assigned patients, 229 received liposomal irinotecan and 232 received topotecan. The median follow-up was 18.4 months. The median OS was 7.9 months with liposomal irinotecan versus 8.3 months with topotecan (hazard ratio [HR], 1.11 [95% CI, 0.90 to 1.37]; P = .31). The median PFS per blinded independent central review (BICR) was 4.0 months with liposomal irinotecan and 3.3 months with topotecan (HR, 0.96 [95% CI, 0.77 to 1.20]; nominal P = .71); ORR per BICR was 44.1% (95% CI, 37.6 to 50.8) and 21.6% (16.4 to 27.4), respectively. Overall, 42.0% and 83.4% of patients receiving liposomal irinotecan and topotecan, respectively, experienced grade >= 3 related treatment-emergent adverse events (TEAEs). The most common grade >= 3 related TEAEs were diarrhea (13.7%), neutropenia (8.0%), and decreased neutrophil count (4.4%) with liposomal irinotecan and neutropenia (51.6%), anemia (30.9%), and leukopenia (29.1%) with topotecan. CONCLUSION Liposomal irinotecan and topotecan demonstrated similar median OS and PFS in patients with relapsed SCLC. Although the primary end point of OS was not met, liposomal irinotecan demonstrated a higher ORR than topotecan. The safety profile of liposomal irinotecan was consistent with its known safety profile; no new safety concerns emerged

500 activities for the primary classroom: Intermediate ideas and solutions

London320 p.: bibl., index; 24 c

700 classroom activities: Instant lessons for busy teachers

London155 p.: index; 24 c