Long-term culture captures injury-repair cycles of colonic stem cells

The colonic epithelium can undergo multiple rounds of damage and repair, often in response to excessive inflammation. The responsive stem cell that mediates this process is unclear, in part because of a lack of in vitro models that recapitulate key epithelial changes that occur in vivo during damage and repair. Here, we identify a Hop

Searching for O2_2 in the SMC:Constraints on Oxygen Chemistry at Low Metallicities

We present a 39 h integration with the Odin satellite on the ground-state 118.75 GHz line of O2 towards the region of strongest molecular emission in the Small Magellanic Cloud. Our 3sigma upper limit to the O2 integrated intensity of <0.049 K km/s in a 9'(160 pc) diameter beam corresponds to an upper limit on the O2/H2 abundance ratio of <1.3E-6. Although a factor of 20 above the best limit on the O2 abundance obtained for a Galactic source, our result has interesting implications for understanding oxygen chemistry at sub-solar metal abundances. We compare our abundance limit to a variety of astrochemical models and find that, at low metallicities, the low O2 abundance is most likely produced by the effects of photo-dissociation on molecular cloud structure. Freeze-out of molecules onto dust grains may also be consistent with the observed abundance limit, although such models have not yet been run at sub-solar initial metallicities.Comment: 4 pages, accepted to A&A Letter

Developing the principles of chair based exercise for older people: a modified Delphi study

Background Chair based exercise (CBE) is suggested to engage older people with compromised health and mobility in an accessible form of exercise. A systematic review looking at the benefits of CBE for older people identified a lack of clarity regarding a definition, delivery, purpose and benefits. This study aimed to utilise expert consensus to define CBE for older people and develop a core set of principles to guide practice and future research. Methods The framework for consensus was constructed through a team workshop identifying 42 statements within 7 domains. A four round electronic Delphi study with multi-disciplinary health care experts was undertaken. Statements were rated using a 5 point Likert scale of agreement and free text responses. A threshold of 70% agreement was used to determine consensus. Free text responses were analysed thematically. Between rounds a number of strategies (e.g., amended wording of statements, generation and removal of statements) were used to move towards consensus. Results 16 experts agreed on 46 statements over four rounds of consultation (Round 1: 22 accepted, 3 removed, 5 new and 17 modified; Round 2: 16 accepted, 0 removed, 4 new and 6 modified; Round 3: 4 accepted, 2 removed, 0 new and 4 modified; Round 4: 4 accepted, 0 removed, 0 new, 0 modified). Statements were accepted in all seven domains: the definition of CBE (5), intended users (3), potential benefits (8), structure (12), format (8), risk management (7) and evaluation (3). The agreed definition of CBE had five components: 1. CBE is primarily a seated exercise programme; 2. The purpose of using a chair is to promote stability in both sitting and standing; 3. CBE should be considered as part of a continuum of exercise for frail older people where progression is encouraged; 4. CBE should be used flexibly to respond to the changing needs of frail older people; and 5. Where possible CBE should be used as a starting point to progress to standing programmes. Conclusions Consensus has been reached on a definition and a set of principles governing CBE for older people; this provides clarity for implementation and future research about CBE

Development of the supply chain oriented quality assurance system for aerospace manufacturing SMEs and its implementation perspectives

Aerospace manufacturing SMEs are continuously facing the challenge on managing their supply chain and complying with the aerospace manufacturing quality standard requirement due to their lack of resources and the nature of business. In this paper, the ERP system based approach is presented to quality control and assurance work in light of seamless integration of in-process production data and information internally and therefore managing suppliers more effectively and efficiently. The Aerospace Manufacturing Quality Assurance Standard (BS/EN9100) is one of the most recognised and essential protocols for developing the industry-operated-and-driven quality assurance systems. The research investigates using the ERP based system as an enabler to implement BS/EN9100 quality management system at manufacturing SMEs and the associated implementation and application perspectives. An application case study on a manufacturing SME is presented by using the SAP based implementation, which helps further evaluate and validate the approach and application system development

Effects of conjugated linoleic acid on myogenic and inflammatory responses in a human primary muscle and tumor coculture model

The antiproliferative and anti-inflammatory properties of conjugated linoleic acid (CLA) make it a potentially novel treatment in chronic inflammatory muscle wasting disease, particularly cancer cachexia. Human primary muscle cells were grown in coculture with MIA PaCa-2 pancreatic tumor cells and exposed to varying concentrations of c9,t11 and t10,c12 CLA. Expression of myogenic (Myf5, MyoD, myogenin, and myostatin) and inflammatory genes (CCL-2, COX-2, IL-8, and TNF-) were measured by real-time PCR. The t10,c12 CLA isomer, but not the c9,t11 isomer, significantly decreased MIA PaCa-2 proliferation by between 15% and 19%. There was a marked decrease in muscle MyoD and myogenin expression (78% and 62%, respectively), but no change in either Myf5 or myostatin, in myotubes grown in coculture with MIA PaCa-2 cells. CLA had limited influence on these responses. A similar pattern of myogenic gene expression changes was observed in myotubes treated with TNF- alone. Several-fold significant increases in CCL-2, COX-2, IL-8, and TNF- expression in myotubes were observed with MIA PaCa-2 coculture. The c9,t11 CLA isomer significantly decreased basal expression of TNF- in myotubes and could ameliorate its tumor-induced rise. The study provides insight into the anti-inflammatory and antiproliferative actions of CLA and its application as a therapeutic agent in inflammatory disease states.<br /

The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.

The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome

Caenorhabditis elegans SMA-10/LRIG Is a Conserved Transmembrane Protein that Enhances Bone Morphogenetic Protein Signaling

Bone morphogenetic protein (BMP) pathways control an array of developmental and homeostatic events, and must themselves be exquisitely controlled. Here, we identify Caenorhabditis elegans SMA-10 as a positive extracellular regulator of BMP–like receptor signaling. SMA-10 acts genetically in a BMP–like (Sma/Mab) pathway between the ligand DBL-1 and its receptors SMA-6 and DAF-4. We cloned sma-10 and show that it has fifteen leucine-rich repeats and three immunoglobulin-like domains, hallmarks of an LRIG subfamily of transmembrane proteins. SMA-10 is required in the hypodermis, where the core Sma/Mab signaling components function. We demonstrate functional conservation of LRIGs by rescuing sma-10(lf) animals with the Drosophila ortholog lambik, showing that SMA-10 physically binds the DBL-1 receptors SMA-6 and DAF-4 and enhances signaling in vitro. This interaction is evolutionarily conserved, evidenced by LRIG1 binding to vertebrate receptors. We propose a new role for LRIG family members: the positive regulation of BMP signaling by binding both Type I and Type II receptors

The United States' next generation of atmospheric composition and coastal ecosystem measurements : NASA's Geostationary Coastal and Air Pollution Events (GEO-CAPE) Mission

Author Posting. © American Meteorological Society, 2012. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 93 (2012): 1547–1566, doi:10.1175/BAMS-D-11-00201.1.The Geostationary Coastal and Air Pollution Events (GEO-CAPE) mission was recommended by the National Research Council's (NRC's) Earth Science Decadal Survey to measure tropospheric trace gases and aerosols and coastal ocean phytoplankton, water quality, and biogeochemistry from geostationary orbit, providing continuous observations within the field of view. To fulfill the mandate and address the challenge put forth by the NRC, two GEO-CAPE Science Working Groups (SWGs), representing the atmospheric composition and ocean color disciplines, have developed realistic science objectives using input drawn from several community workshops. The GEO-CAPE mission will take advantage of this revolutionary advance in temporal frequency for both of these disciplines. Multiple observations per day are required to explore the physical, chemical, and dynamical processes that determine tropospheric composition and air quality over spatial scales ranging from urban to continental, and over temporal scales ranging from diurnal to seasonal. Likewise, high-frequency satellite observations are critical to studying and quantifying biological, chemical, and physical processes within the coastal ocean. These observations are to be achieved from a vantage point near 95°–100°W, providing a complete view of North America as well as the adjacent oceans. The SWGs have also endorsed the concept of phased implementation using commercial satellites to reduce mission risk and cost. GEO-CAPE will join the global constellation of geostationary atmospheric chemistry and coastal ocean color sensors planned to be in orbit in the 2020 time frame.Funding for GEO-CAPE definition activities is provided by the Earth Science Division of the National Aeronautics and Space Administration.2013-04-0

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20–25 mg m−2 intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m−2 and escalated in an accelerated titration design to 25 mg m−2. Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m−2. The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10–73) ml h−1 m−2 in cycle 1 to 18 (3–37) ml h−1 m−2 with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m−2 in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent