Operationalising “Double-Loop” Learning in Service Organisations: A Systems Approach for Creating Knowledge

Learning organisation literature has widely discussed the connections between “double-loop” learning and its significance to organisational performance, but paying little attention to tools and systems that can operationalise “double-loop” learning in organisations. This paper investigates the impact of applying a systems approach for service operations design, expressed as the Vanguard Method (Seddon, Freedom from command and control: a better way to make the work work, 2003), in order to activate “double-loop” learning in service organisations. Two case studies were conducted in the banking mortgage operations and adults’ social care services in the UK, using the dimensions of the learning organisation questionnaire (DLOQ), semi-structured interviews, observations, and documents. The findings of the cross-case analysis support the link of applying the Vanguard Method with operationalising “double-loop” learning through three main factors, namely systematic-operations improvement, organisational capacity development, and outside-in mode of work; that are all embedded into the seven dimensions of the DLOQ. The value of this paper is the introduction of a service operations design tool that can activate “double-loop” learning performance in the fast changing knowledge era. It also provides an impetus for service organisations to creatively influence employees’ competencies to effectively improve internal systems.     

Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3

The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC₃, MC₄, and MC₅ receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r?/? mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC₃ PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases.     

Cilioplasm is a cellular compartment for calcium signaling in response to mechanical and chemical stimuli

Primary cilia with a diameter of ~200 nm have been implicated in development and disease. Calcium signaling within a primary cilium has never been directly visualized and has therefore remained a speculation. Fluid-shear stress and dopamine receptor type-5 (DR5) agonist are among the few stimuli that require cilia for intracellular calcium signal transduction. However, it is not known if these stimuli initiate calcium signaling within the cilium or if the calcium signal originates in the cytoplasm. Using an integrated single-cell imaging technique, we demonstrate for the first time that calcium signaling triggered by fluid-shear stress initiates in the primary cilium and can be distinguished from the subsequent cytosolic calcium response through the ryanodine receptor. Importantly, this flow-induced calcium signaling depends on the ciliary polycystin-2 calcium channel. While DR5-specific agonist induces calcium signaling mainly in the cilioplasm via ciliary CaV1.2, thrombin specifically induces cytosolic calcium signaling through the IP₃ receptor. Furthermore, a non-specific calcium ionophore triggers both ciliary and cytosolic calcium responses. We suggest that cilia not only act as sensory organelles but also function as calcium signaling compartments. Cilium-dependent signaling can spread to the cytoplasm or be contained within the cilioplasm. Our study thus provides the first model to understand signaling within the cilioplasm of a living cell.     

Human heart disease: lessons from human pluripotent stem cell-derived cardiomyocytes

Technical advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to understand human heart disease and discover therapeutic targets that may lead to new compounds for clinical use. Current literature clearly shows that hPSC-CMs recapitulate many molecular, cellular, and functional aspects of human heart pathophysiology and their responses to cardioactive drugs. Here, we provide a comprehensive overview of hPSC-CMs models that have been described to date and highlight their most recent and remarkable contributions to research on cardiovascular diseases and disorders with cardiac traits. We conclude discussing immediate challenges, limitations, and emerging solutions.     

Enhanced performance of nano-sized SiC reinforced Al metal matrix nanocomposites synthesized through microwave sintering and hot extrusion techniques

In the present study, nano-sized SiC (0, 0.3, 0.5, 1.0 and 1.5 vol%) reinforced aluminum (Al) metal matrix composites were fabricated by microwave sintering and hot extrusion techniques. The structural (XRD, SEM), mechanical (nanoindentation, compression, tensile) and thermal properties (co-efficient of thermal expansion- CTE) of the developed Al-SiC nanocomposites were studied. The SEM/EDS mapping images show a homogeneous distribution of SiC nanoparticles into the Al matrix. A significant increase in the strength (compressive and tensile) of the Al-SiC nanocomposites with the addition of SiC content is observed. However, it is noticed that the ductility of Al-SiC nanocomposites decreases with increasing volume fraction of SiC. The thermal analysis indicates that CTE of Al-SiC nanocomposites decreases with the progressive addition of hard SiC nanoparticles. Overall, hot extruded Al 1.5 vol% SiC nanocomposites exhibited the best mechanical and thermal performance as compared to the other developed Al-SiC nanocomposites.     

From the endoplasmic reticulum to the plasma membrane: mechanisms of CFTR folding and trafficking

CFTR biogenesis starts with its co-translational insertion into the membrane of endoplasmic reticulum and folding of the cytosolic domains, towards the acquisition of a fully folded compact native structure. Efficiency of this process is assessed by the ER quality control system that allows the exit of folded proteins but targets unfolded/misfolded CFTR to degradation. If allowed to leave the ER, CFTR is modified at the Golgi and reaches the post-Golgi compartments to be delivered to the plasma membrane where it functions as a cAMP- and phosphorylation-regulated chloride/bicarbonate channel. CFTR residence at the membrane is a balance of membrane delivery, endocytosis, and recycling. Several adaptors, motor, and scaffold proteins contribute to the regulation of CFTR stability and are involved in continuously assessing its structure through peripheral quality control systems. Regulation of CFTR biogenesis and traffic (and its dysregulation by mutations, such as the most common F508del) determine its overall activity and thus contribute to the fine modulation of chloride secretion and hydration of epithelial surfaces. This review covers old and recent knowledge on CFTR folding and trafficking from its synthesis to the regulation of its stability at the plasma membrane and highlights how several of these steps can be modulated to promote the rescue of mutant CFTR.     

On the narrative form of simulations

Understanding complex physical systems through the use of simulations often takes on a narrative character. That is, scientists using simulations seek an understanding of processes occurring in time by generating them from a dynamic model, thereby producing something like a historical narrative. This paper focuses on simulations of the Diels-Alder reaction, which is widely used in organic chemistry. It calls on several well-known works on historical narrative to draw out the ways in which use of these simulations mirrors aspects of narrative understanding: Gallie for “followability” and “contingency”; Mink for “synoptic judgment”; Ricoeur for “temporal dialectic”; and Hawthorn for a related dialectic of the “actual and the possible”. Through these reflections on narrative, the paper aims for a better grasp of the role that temporal development sometimes plays in understanding physical processes and of how considerations of possibility enhance that understanding.     

Duncan F. Gregory,William Walton and the development of British algebra: ‘algebraical geometry’, ‘geometrical algebra’, abstraction

This paper provides a detailed account of the period of the complex history of British algebra and geometry between the publication of George Peacock's Treatise on Algebra in 1830 and William Rowan Hamilton's paper on quaternions of 1843. During these years, Duncan Farquharson Gregory and William Walton published several contributions on ‘algebraical geometry’ and ‘geometrical algebra’ in the Cambridge Mathematical Journal. These contributions enabled them not only to generalize Peacock's symbolical algebra on the basis of geometrical considerations, but also to initiate the attempts to question the status of Euclidean space as the arbiter of valid geometrical interpretations. At the same time, Gregory and Walton were bound by the limits of symbolical algebra that they themselves made explicit; their work was not and could not be the ‘abstract algebra’ and ‘abstract geometry’ of figures such as Hamilton and Cayley. The central argument of the paper is that an understanding of the contributions to ‘algebraical geometry’ and ‘geometrical algebra’ of the second generation of ‘scientific’ symbolical algebraists is essential for a satisfactory explanation of the radical transition from symbolical to abstract algebra that took place in British mathematics in the 1830s–1840s.