Fibroblast-derived HGF drives acinar lung cancer cell polarization through integrin-dependent RhoA-ROCK1 inhibition

The formation of lumens in epithelial tissues requires apical-basal polarization of cells, and the co-ordination of this individual polarity collectively around a contiguous lumen. Signals from the Extracellular Matrix (ECM) instruct epithelia as to the orientation of where basal, and thus consequently apical, surfaces should be formed. We report that this pathway is normally absent in Calu-3 human lung adenocarcinoma cells in 3-Dimensional culture, but that paracrine signals from MRC5 lung fibroblasts can induce correct orientation of polarity and acinar morphogenesis. We identify HGF, acting through the c-Met receptor, as the key polarity-inducing morphogen, which acts to activate β1-integrin-dependent adhesion. HGF and ECM-derived integrin signals co-operate via a c-Src-dependent inhibition of the RhoA-ROCK1 signalling pathway via p190A RhoGAP. This occurred via controlling localization of these signalling pathways to the ECM-abutting surface of cells in 3-Dimensional culture. Thus, stromal derived signals can influence morphogenesis in epithelial cells by controlling activation and localization of cell polarity pathways

Comparison of novel mechanical cervical dislocation and a modified captive bolt for on-farm killing of poultry on behavioural reflex responses and anatomical pathology

An alternative emergency method for killing poultry on-farm is required following European legislation changes (EU 1099/2009), which heavily restricts the use of manual cervical dislocation. This study investigated the kill efficacy of two mechanical methods that conform to the new legislation: (i) a novel mechanical cervical dislocation device; and (ii) a modified captive-bolt device (Rabbit Zinger™) and manual cervical dislocation (the control). Killing treatments were applied to broilers and layers at two stages of production (broilers: 2–3 and 5 weeks of age; layers: 12–13 and 58–62 weeks), with a total of 180 birds. Latency to abolition of cranial and behavioural reflexes, as well as post mortem analysis of the physiological damage produced, were used to estimate time to unconsciousness and assess kill efficacy. The novel mechanical cervical dislocation device was reliable and a practical method for killing poultry on-farm (100% kill success), with the majority of cranial reflexes showing no significant differences between interval mean durations across killing methods (eg nictitating membrane [mean = 0.7–3.3 s], and rhythmic breathing [mean = 0.0–0.3 s]), however for jaw tone and pupillary reflex, the modified Rabbit Zinger™ had significantly shorter interval mean durations compared to the control and mechanical cervical dislocation device (mean differences: jaw tone = ∼8 s; pupillary = ∼38 s). The novel mechanical cervical dislocation device resulted in consistent anatomical damage to the birds (eg high dislocation of the neck and severing of the spinal cord) compared to the manual method, despite both having 100% success rate, while the modified Rabbit Zinger™ was difficult to operate and resulted in varied anatomical damage. The novel mechanical cervical dislocation device showed promise as a replacement kill method on-farm for poultry

An early Harvard 'Memorandum' on anti-depression policies

[Introductory Note by David Laidler (University of Western Ontario) and Roger Sandilands (University of Strathclyde) ...] The Memorandum which this note introduces was completed by three young members of the Harvard economics department sometime in January 1932 Two of them, Lauchlin Currie and Harry Dexter White were soon to play key roles on the American, indeed the world-wide, policy scene. Both of them would go to Washington in 1934 as founding members of Jacob Viner’s 'Freshman Brains Trust'. In due course, first at the Federal Reserve Board, and later at the Treasury and the White House, Currie would become a highly visible and leading advocate of expansionary fiscal policy, while White, at the Treasury, was to be a co-architect, with Keynes, of the Bretton Woods system. Both would fall victim to anti-communist witch-hunts in the late 1940s, in White’s case perhaps at the cost of his life, since he died of a heart attack in 1948 three days after a strenuous hearing before the House Committee on Unamerican Activities (HUAC). The third author, P. T. Ellsworth, later a Professor of Economics at the University of Wisconsin, is perhaps best remembered nowadays as the author of a leading textbook in International Economics, though it is worth noting that he was also a very early (late 1936) but hitherto unrecognised discoverer of what came to be called the IS-LM model as a means of elucidating issues raised by Keynes' 'General Theory'. It is not known how widely this Memorandum was circulated, but the fact that it is a piece of policy advocacy, combined with its relatively polished style, makes it inconceivable that it was meant for the eyes and files of its authors alone. As readers will see, it sketches out an explanation of the then rapidly developing Great Contraction, as well as a comprehensive and radical policy programme for dealing with it. In keeping with its authors’ explanation of the Contraction as a consequence of a collapsing money supply, the main domestic components of that programme were to be vigorously expansionary open-market operations and substantial deficit spending that, particularly in its early stages, was to be financed by money creation; its international dimension involved a return to free trade and serious efforts to resolve the problems of international indebtedness that had originated in the Great War and in the Treaty of Versailles which had brought it to an uneasy end in 1919. [...

Fabrication and Characterization of Topological Insulator Bi2_2Se3_3 Nanocrystals

In the recently discovered class of materials known as topological insulators, the presence of strong spin-orbit coupling causes certain topological invariants in the bulk to differ from their values in vacuum. The sudden change of invariants at the interface results in metallic, time reversal invariant surface states whose properties are useful for applications in spintronics and quantum computation. However, a key challenge is to fabricate these materials on the nanoscale appropriate for devices and probing the surface. To this end we have produced 2 nm thick nanocrystals of the topological insulator Bi$_2$Se$_3$ via mechanical exfoliation. For crystals thinner than 10 nm we observe the emergence of an additional mode in the Raman spectrum. The emergent mode intensity together with the other results presented here provide a recipe for production and thickness characterization of Bi$_2$Se$_3$ nanocrystals.Comment: 4 pages, 3 figures (accepted for publication in Applied Physics Letters

Welfare Risks of Repeated Application of On-Farm Killing Methods for Poultry

Council Regulation (EC) no. 1099/2009 on the protection of animals at the time of killing restricts the use of manual cervical dislocation in poultry on farms in the European Union (EU) to birds weighing up to 3 kg and 70 birds per person per day. However, few studies have examined whether repeated application of manual cervical dislocation has welfare implications and whether these are dependent on individual operator skill or susceptibility to fatigue. We investigated the effects of repeated application (100 birds at a fixed killing rate of 1 bird per 2 min) and multiple operators on two methods of killing of broilers, laying hens, and turkeys in commercial settings. We compared the efficacy and welfare impact of repeated application of cervical dislocation and a percussive killer (Cash Poultry Killer, CPK), using 12 male stockworkers on three farms (one farm per bird type). Both methods achieved over 96% kill success at the first attempt. The killing methods were equally effective for each bird type and there was no evidence of reduced performance with time and/or bird number. Both methods of killing caused a rapid loss of reflexes, indicating loss of brain function. There was more variation in reflex durations and post-mortem damage in birds killed by cervical dislocation than that found using CPK. High neck dislocation was associated with improved kill success and more rapid loss of reflexes. The CPK caused damage to multiple brain areas with little variation. Overall, the CPK was associated with faster abolition of reflexes, with fewer birds exhibiting them at all, suggestive of better welfare outcomes. However, technical difficulties with the CPK highlighted the advantages of cervical dislocation, which can be performed immediately with no equipment. At the killing rates tested, we did not find evidence to justify the current EU limit on the number of birds that one operator can kill on–farm by manual cervical dislocation

Animal Counting Toolkit : a practical guide to small-boat surveys for estimating abundance of coastal marine mammals

The authors thank Synchronicity Earth, Marisla Foundation, and the US Marine Mammal Commission for seed funding for this program.Small cetaceans (dolphins and porpoises) face serious anthropogenic threats in coastal habitats. These include bycatch in fisheries; exposure to noise, plastic and chemical pollution; disturbance from boaters; and climate change. Generating reliable abundance estimates is essential to assess sustainability of bycatch in fishing gear or any other form of anthropogenic removals and to design conservation and recovery plans for endangered species. Cetacean abundance estimates are lacking from many coastal waters of many developing countries. Lack of funding and training opportunities makes it difficult to fill in data gaps. Even if international funding were found for surveys in developing countries, building local capacity would be necessary to sustain efforts over time to detect trends and monitor biodiversity loss. Large-scale, shipboard surveys can cost tens of thousands of US dollars each day. We focus on methods to generate preliminary abundance estimates from low-cost, small-boat surveys that embrace a ‘training-while-doing’ approach to fill in data gaps while simultaneously building regional capacity for data collection. Our toolkit offers practical guidance on simple design and field data collection protocols that work with small boats and small budgets, but expect analysis to involve collaboration with a quantitative ecologist or statistician. Our audience includes independent scientists, government conservation agencies, NGOs and indigenous coastal communities, with a primary focus on fisheries bycatch. We apply our Animal Counting Toolkit to a small-boat survey in Canada’s Pacific coastal waters to illustrate the key steps in collecting line transect survey data used to estimate and monitor marine mammal abundance.Publisher PDFPeer reviewe

Optical evidence of surface state suppression in Bi based topological insulators

A key challenge in condensed matter research is the optimization of topological insulator (TI) compounds for the study and future application of their unique surface states. Truly insulating bulk states would allow the exploitation of predicted surface state properties, such as protection from backscattering, dissipationless spin-polarized currents, and the emergence of novel particles. Towards this end, major progress was recently made with the introduction of highly resistive Bi$_2$Te$_2$Se, in which surface state conductance and quantum oscillations are observed at low temperatures. Nevertheless, an unresolved and pivotal question remains: while room temperature ARPES studies reveal clear evidence of TI surface states, their observation in transport experiments is limited to low temperatures. A better understanding of this surface state suppression at elevated temperatures is of fundamental interest, and crucial for pushing the boundary of device applications towards room-temperature operation. In this work, we simultaneously measure TI bulk and surface states via temperature dependent optical spectroscopy, in conjunction with transport and ARPES measurements. We find evidence of coherent surface state transport at low temperatures, and propose that phonon mediated coupling between bulk and surface states suppresses surface conductance as temperature rises.Comment: 13 pages, 10 figure

New evidence on Allyn Young's style and influence as a teacher

This paper publishes the hitherto unpublished correspondence between Allyn Abbott Young's biographer Charles Blitch and 17 of Young's former students or associates. Together with related biographical and archival material, the paper shows the way in which this adds to our knowledge of Young's considerable influence as a teacher upon some of the twentieth century's greatest economists. The correspondents are as follows: James W Angell, Colin Clark, Arthur H Cole, Lauchlin Currie, Melvin G de Chazeau, Eleanor Lansing Dulles, Howard S Ellis, Frank W Fetter, Earl J Hamilton, Seymour S Harris, Richard S Howey, Nicholas Kaldor, Melvin M Knight, Bertil Ohlin, Geoffrey Shepherd, Overton H Taylor, and Gilbert Walker

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours