A novel missense variant in ATP11CATP11C is associated with reduced red blood cell phosphatidylserine flippase activity and mild hereditary hemolytic anemia

Adenosine Triphosphatase (ATPase) Phospholipid Transporting 11C gene (ATP11C) encodes the major phosphatidylserine (PS) flippase in human red blood cells (RBCs). Flippases actively transport phospholipids (e.g., PS) from the outer to the inner leaflet to establish and maintain phospholipid asymmetry of the lipid bilayer of cell membranes. This asymmetry is crucial for survival since externalized PS triggers phagocytosis by splenic macrophages. Here we report on pathophysiological consequences of decreased flippase activity, prompted by a patient with hemolytic anemia and hemizygosity for a novel c.2365C > T p.(Leu789Phe) missense variant in ATP11C. ATP11C protein expression was strongly reduced by 58% in patient‐derived RBC ghosts. Furthermore, functional characterization showed only 26% PS flippase activity. These results were confirmed by recombinant mutant ATP11C protein expression in HEK293T cells, which was decreased to 27% compared to wild type, whereas PS‐stimulated ATPase activity was decreased by 57%. Patient RBCs showed a mild increase in PS surface exposure when compared to control RBCs, which further increased in the most dense RBCs after RBC storage stress. The increase in PS was not due to higher global membrane content of PS or other phospholipids. In contrast, membrane lipid lateral distribution showed increased abundance of cholesterol‐enriched domains in RBC low curvature areas. Finally, more dense RBCs and subtle changes in RBC morphology under flow hint toward alterations in flow behavior of ATP11C‐deficient RBCs. Altogether, ATP11C deficiency is the likely cause of hemolytic anemia in our patient, thereby underlining the physiological role and relevance of this flippase in human RBCs

Value-Chain Wide Food Waste Management: A Systematic Literature Review

© 2019, Springer Nature Switzerland AG. The agriculture value chain, from farm to fork, has received enormous attention because of its key role in achieving United Nations Global Challenges Goals. Food waste occurs in many different forms and at all stages of the food value chain, it has become a worldwide issue that requires urgent actions. However, the management of food waste has been traditionally segmented and in an isolated manner. This paper reviews existing work that has been done on food waste management in literature by taking a holistic approach, in order to identify the causes of food waste, food waste prevention strategies, and elicit recommendations for future work. A five step systematic literature review has been adopted for a thorough examination of the existing research on the topic and new insights have been obtained. The findings suggest that the main sources of food waste include food overproduction and surplus, food waste caused by processing, logistical inconsistencies, and households. Main food waste prevention strategies have been revealed in this paper include policy solutions, packaging solutions, date-labelling solutions, logistics solutions, changing consumers’ behaviours, and reuse and redistribution solutions. Future research directions such as using value chain models to reduce food waste and forecasting food waste have been identified in this paper. This study makes a contribution to the extant literature in the field of food waste management by discovering main causes of food waste in the value chain and eliciting prevention strategies that can be used to reduce/eliminate relevant food waste

Digital technology enablers for resilient and customer driven food value chains

Food production chains have to respond to disrupted global markets and dynamic customer demands. They are coming under pressure to move from a supply to a demand-driven business model. The inherent difficulties in the lifecycle management of food products, their perishable nature, the volatility in global and regional supplier and customer markets, and the mix of objective and subjective drivers of customer demand and satisfaction, compose a challenging food production landscape. Businesses need to navigate through dynamically evolving operational risks and ensure targeted performance in terms of supply chain resilience and agility, as well as transparency and product assurance. While the industrial transition to digitalised and automated food production chains is seen as a response to such challenges, the contribution of industry 4.0 technology enablers towards this aim is not sufficiently well understood. This paper outlines the key features of high performing food production chains and performs a mapping between them and enabling technologies. As digitalisation initiatives gain priority, such mapping can help with the prioritisation of technology enablers on delivering key aspects of high performing food production chains

Impaired Cytoskeletal and Membrane Biophysical Properties of Acanthocytes in Hypobetalipoproteinemia – A Case Study

Familial hypobetalipoproteinemia is a metabolic disorder mainly caused by mutations in the apolipoprotein B gene. In its homozygous form it can lead without treatment to severe ophthalmological and neurological manifestations. In contrast, the heterozygous form is generally asymptomatic but associated with a low risk of cardiovascular disease. Acanthocytes or thorny red blood cells (RBCs) are described for both forms of the disease. However, those morphological changes are poorly characterized and their potential consequences for RBC functionality are not understood. Thus, in the present study, we asked whether, to what extent and how acanthocytes from a patient with heterozygous familial hypobetalipoproteinemia could exhibit altered RBC functionality. Acanthocytes represented 50% of the total RBC population and contained mitoTracker-positive surface patches, indicating the presence of mitochondrial fragments. While RBC osmotic fragility, calcium content and ATP homeostasis were preserved, a slight decrease of RBC deformability combined with an increase of intracellular free reactive oxygen species were observed. The spectrin cytoskeleton was altered, showing a lower density and an enrichment in patches. At the membrane level, no obvious modification of the RBC membrane fatty acids nor of the cholesterol content were detected but the ceramide species were all increased. Membrane stiffness and curvature were also increased whereas transversal asymmetry was preserved. In contrast, lateral asymmetry was highly impaired showing: (i) increased abundance and decreased functionality of sphingomyelin-enriched domains; (ii) cholesterol enrichment in spicules; and (iii) ceramide enrichment in patches. We propose that oxidative stress induces cytoskeletal alterations, leading to increased membrane stiffness and curvature and impaired lipid lateral distribution in domains and spicules. In addition, ceramide- and spectrin-enriched patches could result from a RBC maturation defect. Altogether, the data indicate that acanthocytes are associated with cytoskeletal and membrane lipid lateral asymmetry alterations, while deformability is only mildly impaired. In addition, familial hypobetalipoproteinemia might also affect RBC precursors leading to disturbed RBC maturation. This study paves the way for the potential use of membrane biophysics and lipid vital imaging as new methods for diagnosis of RBC disorders

Nuclear import of the DSCAM-cytoplasmic domain drives signaling capable of inhibiting synapse formation

DSCAM and DSCAML1 are immunoglobulin and cell adhesion‐type receptors serving important neurodevelopmental functions including control of axon growth, branching, neurite self‐avoidance, and neuronal cell death. The signal transduction mechanisms or effectors of DSCAM receptors, however, remain poorly characterized. We used a human ORFeome library to perform a high‐throughput screen in mammalian cells and identified novel cytoplasmic signaling effector candidates including the Down syndrome kinase Dyrk1a, STAT3, USP21, and SH2D2A. Unexpectedly, we also found that the intracellular domains (ICDs) of DSCAM and DSCAML1 specifically and directly interact with IPO5, a nuclear import protein of the importin beta family, via a conserved nuclear localization signal. The DSCAM ICD is released by γ‐secretase‐dependent cleavage, and both the DSCAM and DSCAML1 ICDs efficiently translocate to the nucleus. Furthermore, RNA sequencing confirms that expression of the DSCAM as well as the DSCAML1 ICDs alone can profoundly alter the expression of genes associated with neuronal differentiation and apoptosis, as well as synapse formation and function. Gain‐of‐function experiments using primary cortical neurons show that increasing the levels of either the DSCAM or the DSCAML1 ICD leads to an impairment of neurite growth. Strikingly, increased expression of either full‐length DSCAM or the DSCAM ICD, but not the DSCAML1 ICD, significantly decreases synapse numbers in primary hippocampal neurons. Taken together, we identified a novel membrane‐to‐nucleus signaling mechanism by which DSCAM receptors can alter the expression of regulators of neuronal differentiation and synapse formation and function. Considering that chromosomal duplications lead to increased DSCAM expression in trisomy 21, our findings may help uncover novel mechanisms contributing to intellectual disability in Down syndrome

A novel missense variant in ATP11C is associated with reduced red blood cell phosphatidylserine flippase activity and mild hereditary hemolytic anemia.

Adenosine Triphosphatase (ATPase) Phospholipid Transporting 11C gene (ATP11C) encodes the major phosphatidylserine (PS) flippase in human red blood cells (RBCs). Flippases actively transport phospholipids (e.g., PS) from the outer to the inner leaflet to establish and maintain phospholipid asymmetry of the lipid bilayer of cell membranes. This asymmetry is crucial for survival since externalized PS triggers phagocytosis by splenic macrophages. Here we report on pathophysiological consequences of decreased flippase activity, prompted by a patient with hemolytic anemia and hemizygosity for a novel c.2365C > T p.(Leu789Phe) missense variant in ATP11C. ATP11C protein expression was strongly reduced by 58% in patient-derived RBC ghosts. Furthermore, functional characterization showed only 26% PS flippase activity. These results were confirmed by recombinant mutant ATP11C protein expression in HEK293T cells, which was decreased to 27% compared to wild type, whereas PS-stimulated ATPase activity was decreased by 57%. Patient RBCs showed a mild increase in PS surface exposure when compared to control RBCs, which further increased in the most dense RBCs after RBC storage stress. The increase in PS was not due to higher global membrane content of PS or other phospholipids. In contrast, membrane lipid lateral distribution showed increased abundance of cholesterol-enriched domains in RBC low curvature areas. Finally, more dense RBCs and subtle changes in RBC morphology under flow hint toward alterations in flow behavior of ATP11C-deficient RBCs. Altogether, ATP11C deficiency is the likely cause of hemolytic anemia in our patient, thereby underlining the physiological role and relevance of this flippase in human RBCs

Industry 4.0 and the circular economy: a proposed research agenda and original roadmap for sustainable operations

This work makes a case for the integration of the increasingly popular and largely separate topics of Industry 4.0 and the circular economy (CE). The paper extends the state-of-the-art literature by proposing a pioneering roadmap to enhance the application of CE principles in organisations by means of Industry 4.0 approaches. Advanced and digital manufacturing technologies are able to unlock the circularity of resources within supply chains; however, the connection between CE and Industry 4.0 has not so far been explored. This article therefore contributes to the literature by unveiling how different Industry 4.0 technologies could underpin CE strategies, and to organisations by addressing those technologies as a basis for sustainable operations management decision-making. The main results of this work are: (a) a discussion on the mutually beneficial relationship between Industry 4.0 and the CE; (b) an in-depth understanding of the potential contributions of smart production technologies to the ReSOLVE model of CE business models; (c) a research agenda for future studies on the integration between Industry 4.0 and CE principles based on the most relevant management theories