ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC

A Novel and Cost-Effective Monitoring Approach for Outcomes in an Australian Biodiversity Conservation Incentive Program

We report on the design and implementation of ecological monitoring for an Australian biodiversity conservation incentive scheme - the Environmental Stewardship Program. The Program uses competitive auctions to contract individual land managers for up to 15 years to conserve matters of National Environmental Significance (with an initial priority on nationally threatened ecological communities). The ecological monitoring was explicitly aligned with the Program's policy objective and desired outcomes and was applied to the Program's initial Project which targeted the critically endangered White Box-Yellow Box-Blakely's Red Gum Grassy Woodland and Derived Native Grassland ecological community in south eastern Australia. These woodlands have been reduced to <3% of their original extent and persist mostly as small remnants of variable condition on private farmland. We established monitoring sites on 153 farms located over 172,232 sq km. On each farm we established a monitoring site within the woodland patch funded for management and, wherever possible, a matched control site. The monitoring has entailed gathering data on vegetation condition, reptiles and birds. We also gathered data on the costs of experimental design, site establishment, field survey, and data analysis. The costs of monitoring are approximately 8.5% of the Program's investment in the first four years and hence are in broad accord with the general rule of thumb that 5-10% of a program's funding should be invested in monitoring. Once initial monitoring and site benchmarking are completed we propose to implement a novel rotating sampling approach that will maintain scientific integrity while achieving an annual cost-efficiency of up to 23%. We discuss useful lessons relevant to other monitoring programs where there is a need to provide managers with reliable early evidence of program effectiveness and to demonstrate opportunities for cost-efficiencies.Specialist staff within SEWPaC assisted in the design of the monitoring program to ensure its policy relevance. The funders contributed to development of the monitoring program but this did not prejudice the content of the paper in any way. The funders had no role in data collection, analysis and interpretation of results. The funders read and suggested improvements to the manuscript and agreed to publication

Direct iminization of PEEK

Semi-crystalline poly(ether ketone)s are important high-temperature engineering thermoplastics, but are difficult to characterize at the molecular level because of their insolubility in conventional organic solvents. Here we report that polymers of this type, including PEEK, react cleanly at high temperatures with low-volatility aralkyl amines to afford stable, noncrystalline poly(ether-imine)s, which are readily soluble in solvents such as chloroform, THF and DMF and so characterizable by conventional size-exclusion chromatography

Protostellar collapse: A comparison between SPH and AMR calculations

The development of parallel supercomputers allows today the detailed study of the collapse and the fragmentation of prestellar cores with increasingly accurate numerical simulations. Thanks to the advances in sub-millimeter observations, a wide range of observed initial conditions enable us to study the different modes of low-mass star formation. The challenge for the simulations is to reproduce the observational results. Two main numerical methods, namely AMR and SPH, are widely used to simulate the collapse and the fragmentation of prestellar cores. We compare thoroughly these two methods within their standard framework. We use the AMR code RAMSES and the SPH code DRAGON. Our physical model is as simple as possible and consists of an isothermal sphere rotating around the z-axis. We first study the conservation of angular momentum as a function of the resolution. Then, we explore a wide range of simulation parameters to study the fragmentation of prestellar cores. There seems to be a convergence between the two methods, provided resolution in each case is sufficient. Resolution criteria adapted to our physical cases, in terms of resolution per Jeans mass, for an accurate description of the formation of protostellar cores are deduced from the present study. This convergence is encouraging for future work in simulations of low-mass star formation, providing the aforementioned criteria are fulfilled. Higher resolution figures can be downloaded at http://www-dapnia.cea.fr/Projets/COAST/paper_amrvssph.pdfComment: 16 pages, 16 figures, accepted for publication in A&

What do people do with porn? qualitative research into the consumption, use and experience of pornography and other sexually explicit media

This article reviews qualitative research into the consumption of pornography and other sexually explicit media emerging from a range of subject areas. Taking a critique of quantitative methods and a focus on measuring sexual effects and attitudes as a starting point, it considers the proposition that qualitative work is more suited to an examination of the complex social, cultural and political constructions of sexuality. Examining studies into the way men, women and young people see, experience, and use explicit media texts, the article identifies the key findings that have emerged. Qualitative work shows that sexuality explicit media texts are experienced and understood in a variety of ways and evoke strong and often contradictory reactions, not all of which are represented in public debates about pornography. These texts function in a range of different ways, depending on context; as a source of knowledge, a resource for intimate practices, a site for identity construction, and an occasion for performing gender and sexuality. The article reviews these studies and their findings, identifying what they suggest about directions for future research, both in terms of developing methodology and refining approaches to sexuality and media consumption.</p

Perceptions Of School By Two Teenage Boys With Asperger Syndrome And Their Mothers: A Qualitative Study

This qualitative study aimed to develop an understanding of the challenges faced by teenage boys with Asperger syndrome and their mothers. A case study approach was used to collect data from two 13-year-old boys who have Asperger syndrome and their mothers in Queensland, Australia. Data were collected through the use of semi¬structured interviews. The words of the boys and their mothers provide a valuable insight into the personal experiences and feelings of the par¬ticipants. An inductive approach to data analysis identified four themes: (1) developmental differences; (2) problems associated with the general characteristics of Asperger syndrome (i.e. communication and social difficulties, restricted range of interests, a need for routine); (3) stress; and (4) 'masquerading'. The first three themes relate strongly to the current literature, but the emergence of masquerading is of particular interest in developing a fuller understanding of the experiences of individuals with Asperger syndrome at school

Menu engineering to encourage sustainable food choices when dining out: An online trial of priced-based decoys

Menu-based ‘nudges’ hold promise as effective ways to encourage a shift away from ruminant meat and towards more environmentally friendly plant-based options when dining out. One example of a menu-based nudge is including an inferior ‘decoy’ option to existing items on menus. Decoys have been shown to influence decision-making in other domains (e.g. Lichters, Bengart, Sarstedt, & Vogt, 2017), but have yet to be used to promote sustainable food choices. Two online randomized controlled trials tested whether the addition of higher priced ‘decoy’ vegetarian options to menus influenced the number of diners choosing a ‘target’ vegetarian option. Adjusted Generalized Estimating Equations on data from four menu conditions showed no main effect of intervention group in study 1 (decoy absent vs. decoy present; odds ratio (OR) 1.08 (95% Confidence Interval (CI) 0.45 to 2.57). Replicating the trial in study 2 across seven menu conditions and testing a more expensive decoy also showed no main effect of the intervention (decoy absent vs. decoy present; OR 0.68 (95% CI 0.41 to 1.12). Further analyses revealed that our price-based decoy strategy (a £30% price increase) did not significantly influence the numbers who chose the inferior decoy dish, potentially due to the fact that dish choices were purely hypothetical. Further research is now needed to clarify which attributes of a dish (e.g. taste, portion size, signature ingredients etc.) are optimal candidates for use as decoys and testing these in real world choice contexts

Microtubules in Bacteria: Ancient Tubulins Build a Five-Protofilament Homolog of the Eukaryotic Cytoskeleton

Microtubules play crucial roles in cytokinesis, transport, and motility, and are therefore superb targets for anti-cancer drugs. All tubulins evolved from a common ancestor they share with the distantly related bacterial cell division protein FtsZ, but while eukaryotic tubulins evolved into highly conserved microtubule-forming heterodimers, bacterial FtsZ presumably continued to function as single homopolymeric protofilaments as it does today. Microtubules have not previously been found in bacteria, and we lack insight into their evolution from the tubulin/FtsZ ancestor. Using electron cryomicroscopy, here we show that the tubulin homologs BtubA and BtubB form microtubules in bacteria and suggest these be referred to as “bacterial microtubules” (bMTs). bMTs share important features with their eukaryotic counterparts, such as straight protofilaments and similar protofilament interactions. bMTs are composed of only five protofilaments, however, instead of the 13 typical in eukaryotes. These and other results suggest that rather than being derived from modern eukaryotic tubulin, BtubA and BtubB arose from early tubulin intermediates that formed small microtubules. Since we show that bacterial microtubules can be produced in abundance in vitro without chaperones, they should be useful tools for tubulin research and drug screening

The shifting terrain of sex and power: From the 'sexualisation of culture' to Me Too

In this short article we will aim to do three things. First, we want to use this opportunity to reflect on some of the changes we have seen in the scholarly field of gender, sexuality, and intimacy over this period, and on new emerging directions. Second, we want to discuss the move away from discussions of ‘sexualization’ to a more critical and political register interested in a variety of ways in which sex and power intersect. Thirdly, we will discuss MeToo as an example of this shifted form of engagement, and raise some questions about its possibilities and limitations

Risk stratification of Barrett's oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study

Background Barrett's oesophagus predisposes to adenocarcinoma. However, most patients with Barrett's oesophagus will not progress and endoscopic surveillance is invasive, expensive, and fraught by issues of sampling bias and the subjective assessment of dysplasia. We investigated whether a non-endoscopic device, the Cytosponge, could be coupled with clinical and molecular biomarkers to identify a group of patients with low risk of progression suitable for non-endoscopic follow-up. Methods In this multicentre cohort study (BEST2), patients with Barrett's oesophagus underwent the Cytosponge test before their surveillance endoscopy. We collected clinical and demographic data and tested Cytosponge samples for a molecular biomarker panel including three protein biomarkers (P53, c-Myc, and Aurora kinase A), two methylation markers (MYOD1 and RUNX3), glandular atypia, and TP53 mutation status. We used a multivariable logistic regression model to compute the conditional probability of dysplasia status. We selected a simple model with high classification accuracy and applied it to an independent validation cohort. The BEST2 study is registered with ISRCTN, number 12730505. Findings The discovery cohort consisted of 468 patients with Barrett's oesophagus and intestinal metaplasia. Of these, 376 had no dysplasia and 22 had high-grade dysplasia or intramucosal adenocarcinoma. In the discovery cohort, a model with high classification accuracy consisted of glandular atypia, P53 abnormality, and Aurora kinase A positivity, and the interaction of age, waist-to-hip ratio, and length of the Barrett's oesophagus segment. 162 (35%) of 468 of patients fell into the low-risk category and the probability of being a true non-dysplastic patient was 100% (99% CI 96–100) and the probability of having high-grade dysplasia or intramucosal adenocarcinoma was 0% (0–4). 238 (51%) of participants were classified as of moderate risk; the probability of having high-grade dysplasia was 14% (9–21). 58 (12%) of participants were classified as high-risk; the probability of having non-dysplastic endoscopic biopsies was 13% (5–27), whereas the probability of having high-grade dysplasia or intramucosal adenocarcinoma was 87% (73–95). In the validation cohort (65 patients), 51 were non-dysplastic and 14 had high-grade dysplasia. In this cohort, 25 (38%) of 65 patients were classified as being low-risk, and the probability of being non-dysplastic was 96·0% (99% CI 73·80–99·99). The moderate-risk group comprised 27 non-dysplastic and eight high-grade dysplasia cases, whereas the high-risk group (8% of the cohort) had no non-dysplastic cases and five patients with high-grade dysplasia. Interpretation A combination of biomarker assays from a single Cytosponge sample can be used to determine a group of patients at low risk of progression, for whom endoscopy could be avoided. This strategy could help to avoid overdiagnosis and overtreatment in patients with Barrett's oesophagus. Funding Cancer Research UK