7,157 research outputs found

    Towards Autonomous Selective Harvesting: A Review of Robot Perception, Robot Design, Motion Planning and Control

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    This paper provides an overview of the current state-of-the-art in selective harvesting robots (SHRs) and their potential for addressing the challenges of global food production. SHRs have the potential to increase productivity, reduce labour costs, and minimise food waste by selectively harvesting only ripe fruits and vegetables. The paper discusses the main components of SHRs, including perception, grasping, cutting, motion planning, and control. It also highlights the challenges in developing SHR technologies, particularly in the areas of robot design, motion planning and control. The paper also discusses the potential benefits of integrating AI and soft robots and data-driven methods to enhance the performance and robustness of SHR systems. Finally, the paper identifies several open research questions in the field and highlights the need for further research and development efforts to advance SHR technologies to meet the challenges of global food production. Overall, this paper provides a starting point for researchers and practitioners interested in developing SHRs and highlights the need for more research in this field.Comment: Preprint: to be appeared in Journal of Field Robotic

    A Design Science Research Approach to Smart and Collaborative Urban Supply Networks

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    Urban supply networks are facing increasing demands and challenges and thus constitute a relevant field for research and practical development. Supply chain management holds enormous potential and relevance for society and everyday life as the flow of goods and information are important economic functions. Being a heterogeneous field, the literature base of supply chain management research is difficult to manage and navigate. Disruptive digital technologies and the implementation of cross-network information analysis and sharing drive the need for new organisational and technological approaches. Practical issues are manifold and include mega trends such as digital transformation, urbanisation, and environmental awareness. A promising approach to solving these problems is the realisation of smart and collaborative supply networks. The growth of artificial intelligence applications in recent years has led to a wide range of applications in a variety of domains. However, the potential of artificial intelligence utilisation in supply chain management has not yet been fully exploited. Similarly, value creation increasingly takes place in networked value creation cycles that have become continuously more collaborative, complex, and dynamic as interactions in business processes involving information technologies have become more intense. Following a design science research approach this cumulative thesis comprises the development and discussion of four artefacts for the analysis and advancement of smart and collaborative urban supply networks. This thesis aims to highlight the potential of artificial intelligence-based supply networks, to advance data-driven inter-organisational collaboration, and to improve last mile supply network sustainability. Based on thorough machine learning and systematic literature reviews, reference and system dynamics modelling, simulation, and qualitative empirical research, the artefacts provide a valuable contribution to research and practice

    Targeting Fusion Proteins of HIV-1 and SARS-CoV-2

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    Viruses are disease-causing pathogenic agents that require host cells to replicate. Fusion of host and viral membranes is critical for the lifecycle of enveloped viruses. Studying viral fusion proteins can allow us to better understand how they shape immune responses and inform the design of therapeutics such as drugs, monoclonal antibodies, and vaccines. This thesis discusses two approaches to targeting two fusion proteins: Env from HIV-1 and S from SARS-CoV-2. The first chapter of this thesis is an introduction to viruses with a specific focus on HIV-1 CD4 mimetic drugs and antibodies against SARS-CoV-2. It discusses the architecture of these viruses and fusion proteins and how small molecules, peptides, and antibodies can target these proteins successfully to treat and prevent disease. In addition, a brief overview is included of the techniques involved in structural biology and how it has informed the study of viruses. For the interested reader, chapter 2 contains a review article that serves as a more in-depth introduction for both viruses as well as how the use of structural biology has informed the study of viral surface proteins and neutralizing antibody responses to them. The subsequent chapters provide a body of work divided into two parts. The first part in chapter 3 involves a study on conformational changes induced in the HIV-1 Env protein by CD4-mimemtic drugs using single particle cryo-EM. The second part encompassing chapters 4 and 5 includes two studies on antibodies isolated from convalescent COVID-19 donors. The former involves classification of antibody responses to the SARS-CoV-2 S receptor-binding domain (RBD). The latter discusses an anti-RBD antibody class that binds to a conserved epitope on the RBD and shows cross-binding and cross-neutralization to other coronaviruses in the sarbecovirus subgenus.</p

    RNA pull-down-confocal nanoscanning (RP-CONA), a novel method for studying RNA/protein interactions in cell extracts that detected potential drugs for Parkinson’s disease targeting RNA/HuR complexes

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    MicroRNAs (miRNAs, miRs) are a class of small non-coding RNAs that regulate gene expression through specific base-pair targeting. The functional mature miRNAs usually undergo a two-step cleavage from primary miRNAs (pri-miRs), then precursor miRNAs (pre-miRs). The biogenesis of miRNAs is tightly controlled by different RNA-binding proteins (RBPs). The dysregulation of miRNAs is closely related to a plethora of diseases. Targeting miRNA biogenesis is becoming a promising therapeutic strategy. HuR and MSI2 are both RBPs. MiR-7 is post-transcriptionally inhibited by the HuR/MSI2 complex, through a direct interaction between HuR and the conserved terminal loop (CTL) of pri-miR-7-1. Small molecules dissociating pri-miR-7/HuR interaction may induce miR-7 production. Importantly, the miR-7 levels are negatively correlated with Parkinson’s disease (PD). PD is a common, incurable neurodegenerative disease causing serious motor deficits. A hallmark of PD is the presence of Lewy bodies in the human brain, which are inclusion bodies mainly composed of an aberrantly aggregated protein named α-synuclein (α-syn). Decreasing α-syn levels or preventing α-syn aggregation are under investigation as PD treatments. Notably, α-syn is negatively regulated by several miRNAs, including miR-7, miR-153, miR-133b and others. One hypothesis is that elevating these miRNA levels can inhibit α-syn expression and ameliorate PD pathologies. In this project, we identified miR-7 as the most effective α-syn inhibitor, among the miRNAs that are downregulated in PD, and with α-syn targeting potentials. We also observed potential post-transcriptional inhibition on miR-153 biogenesis in neuroblastoma, which may help to uncover novel therapeutic targets towards PD. To identify miR-7 inducers that benefit PD treatment by repressing α-syn expression, we developed a novel technique RNA Pull-down Confocal Nanoscaning (RP-CONA) to monitor the binding events between pri-miR-7 and HuR. By attaching FITC-pri-miR-7-1-CTL-biotin to streptavidin-coated agarose beads and incubating them in human cultured cell lysates containing overexpressed mCherry-HuR, the bound RNA and protein can be visualised as quantifiable fluorescent rings in corresponding channels in a confocal high-content image system. A pri-miR-7/HuR inhibitor can decrease the relative mCherry/FITC intensity ratio in RP-CONA. With this technique, we performed several small-scale screenings and identified that a bioflavonoid, quercetin can largely dissociate the pri-miR-7/HuR interaction. Further studies proved that quercetin was an effective miR-7 inducer as well as α-syn inhibitor in HeLa cells. To understand the mechanism of quercetin mediated α-syn inhibition, we tested the effects of quercetin treatment with miR-7-1 and HuR knockout HeLa cells. We found that HuR was essential in this pathway, while miR-7 hardly contributed to the α-syn inhibition. HuR can directly bind an AU-rich element (ARE) at the 3’ untranslated region (3’-UTR) of α-syn mRNA and promote translation. We believe quercetin mainly disrupts the ARE/HuR interaction and disables the HuR-induced α-syn expression. In conclusion, we developed and optimised RP-CONA, an on-bead, lysate-based technique detecting RNA/protein interactions, as well as identifying RNA/protein modulators. With RP-CONA, we found quercetin inducing miR-7 biogenesis, and inhibiting α-syn expression. With these beneficial effects, quercetin has great potential to be applied in the clinic of PD treatment. Finally, RP-CONA can be used in many other RNA/protein interactions studies

    Defining Service Level Agreements in Serverless Computing

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    The emergence of serverless computing has brought significant advancements to the delivery of computing resources to cloud users. With the abstraction of infrastructure, ecosystem, and execution environments, users could focus on their code while relying on the cloud provider to manage the abstracted layers. In addition, desirable features such as autoscaling and high availability became a provider’s responsibility and can be adopted by the user\u27s application at no extra overhead. Despite such advancements, significant challenges must be overcome as applications transition from monolithic stand-alone deployments to the ephemeral and stateless microservice model of serverless computing. These challenges pertain to the uniqueness of the conceptual and implementation models of serverless computing. One of the notable challenges is the complexity of defining Service Level Agreements (SLA) for serverless functions. As the serverless model shifts the administration of resources, ecosystem, and execution layers to the provider, users become mere consumers of the provider’s abstracted platform with no insight into its performance. Suboptimal conditions of the abstracted layers are not visible to the end-user who has no means to assess their performance. Thus, SLA in serverless computing must take into consideration the unique abstraction of its model. This work investigates the Service Level Agreement (SLA) modeling of serverless functions\u27 and serverless chains’ executions. We highlight how serverless SLA fundamentally differs from earlier cloud delivery models. We then propose an approach to define SLA for serverless functions by utilizing resource utilization fingerprints for functions\u27 executions and a method to assess if executions adhere to that SLA. We evaluate the approach’s accuracy in detecting SLA violations for a broad range of serverless application categories. Our validation results illustrate a high accuracy in detecting SLA violations resulting from resource contentions and provider’s ecosystem degradations. We conclude by presenting the empirical validation of our proposed approach, which could detect Execution-SLA violations with accuracy up to 99%

    Innovative Hybrid Approaches for Vehicle Routing Problems

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    This thesis deals with the efficient resolution of Vehicle Routing Problems (VRPs). The first chapter faces the archetype of all VRPs: the Capacitated Vehicle Routing Problem (CVRP). Despite having being introduced more than 60 years ago, it still remains an extremely challenging problem. In this chapter I design a Fast Iterated-Local-Search Localized Optimization algorithm for the CVRP, shortened to FILO. The simplicity of the CVRP definition allowed me to experiment with advanced local search acceleration and pruning techniques that have eventually became the core optimization engine of FILO. FILO experimentally shown to be extremely scalable and able to solve very large scale instances of the CVRP in a fraction of the computing time compared to existing state-of-the-art methods, still obtaining competitive solutions in terms of their quality. The second chapter deals with an extension of the CVRP called the Extended Single Truck and Trailer Vehicle Routing Problem, or simply XSTTRP. The XSTTRP models a broad class of VRPs in which a single vehicle, composed of a truck and a detachable trailer, has to serve a set of customers with accessibility constraints making some of them not reachable by using the entire vehicle. This problem moves towards VRPs including more realistic constraints and it models scenarios such as parcel deliveries in crowded city centers or rural areas, where maneuvering a large vehicle is forbidden or dangerous. The XSTTRP generalizes several well known VRPs such as the Multiple Depot VRP and the Location Routing Problem. For its solution I developed an hybrid metaheuristic which combines a fast heuristic optimization with a polishing phase based on the resolution of a limited set partitioning problem. Finally, the thesis includes a final chapter aimed at guiding the computational evaluation of new approaches to VRPs proposed by the machine learning community

    A guide to designing photocontrol in proteins: methods, strategies and applications

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    Light is essential for various biochemical processes in all domains of life. In its presence certain proteins inside a cell are excited, which either stimulates or inhibits subsequent cellular processes. The artificial photocontrol of specifically proteins is of growing interest for the investigation of scientific questions on the organismal, cellular and molecular level as well as for the development of medicinal drugs or biocatalytic tools. For the targeted design of photocontrol in proteins, three major methods have been developed over the last decades, which employ either chemical engineering of small-molecule photosensitive effectors (photopharmacology), incorporation of photoactive non-canonical amino acids by genetic code expansion (photoxenoprotein engineering), or fusion with photoreactive biological modules (hybrid protein optogenetics). This review compares the different methods as well as their strategies and current applications for the light-regulation of proteins and provides background information useful for the implementation of each technique

    Walking with the Earth: Intercultural Perspectives on Ethics of Ecological Caring

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    It is commonly believed that considering nature different from us, human beings (qua rational, cultural, religious and social actors), is detrimental to our engagement for the preservation of nature. An obvious example is animal rights, a deep concern for all living beings, including non-human living creatures, which is understandable only if we approach nature, without fearing it, as something which should remain outside of our true home. “Walking with the earth” aims at questioning any similar preconceptions in the wide sense, including allegoric-poetic contributions. We invited 14 authors from 4 continents to express all sorts of ways of saying why caring is so important, why togetherness, being-with each others, as a spiritual but also embodied ethics is important in a divided world

    Cis-Regulation of Gremlin1 Expression during Mouse Limb Bud Development and its Diversification during Vertebrate Evolution

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    Embryonic development and organogenesis rely on tightly controlled gene expression, which is achieved by cis-regulatory modules (CRMs) interacting with distinct transcription factors (TFs) that control spatio-temporal and tissue-specific gene expression. During organogenesis, gene regulatory networks (GRNs) with selfregulatory feedback properties coordinately control growth and patterning and provide systemic robustness against genetic and/or environmental perturbations. During limb bud development, various interlinked GRNs control outgrowth and patterning along all three limb axes. A paradigm network is the epithelial-mesenchymal (e-m) SHH/GREM1/AER-FGF feedback signaling system which controls limb bud outgrowth and digit patterning. The BMP antagonist GREMLIN1 (GREM1) is central to this e-m interactions as its antagonism of BMP activity is essential to maintain both AER-Fgf and Shh expression. In turn, SHH signaling upregulates Grem1 expression, which results in establishment of a self-regulatory signaling network. One previous study provided evidence that several CRMs could regulate Grem1 expression during limb bud development. However, the cis-regulatory logics underlying the spatio-temporal regulation of the Grem1 expression dynamics remained obscure. From an evolutionary point of view, diversification of CRMs can result in diversification of gene regulation which can drive the establishment of morphological novelties and adaptions. This was evidenced by the observed differences in Grem1 expression in different species that correlates with the evolutionary plasticity of tetrapod digit patterning. Hence, a better understanding of spatio-temporal regulation of the Grem1 expression dynamics and underlying cis-regulatory logic is of interest from both adevelopmental and an evolutionary perspective. Recently, multiple candidate CRMs have been identified that might be functionally relevant for Grem1 expression during mouse limb bud development. For my PhD project, I genetically analyzed which of these CRMs are involved in the regulation of the spatial-temporal Grem1 expression dynamics in limb buds. Therefore, we generated various single and compound CRM mutant alleles using CRISPR/Cas9. Our CRMs allelic series revealed a complex Grem1 cis-regulation among a minimum of six CRMs, where a subset of CRMs regulates Grem1 transcript levels in an additive manner. Surprisingly, phenotypic robustness depends not on threshold transcript levels but the spatial integrity of the Grem1 expression domain. In particular, interactions among five CRMs control the characteristic asymmetrical and posteriorly biased Grem1 expression in mouse limb buds. Our results provide an example of how multiple seemingly redundant limb-specific CRMs provide phenotypical robustness by cooperative/synergistic regulation of the spatial Grem1 expression dynamics. Three CRMs are conserved along the phylogeny of extant vertebrates with paired appendages. Of those, the activities of two CRMs recapitulate the major spatiotemporal aspects of Grem1 expression in mouse limb buds. In order to study their functions in species-specific regulation of Grem1 expression and their functional diversification in tetrapods, I tested the orthologous of both CRMs from representative species using LacZ reporter assays in transgenic mice, in comparison to the endogenous Grem1 expression in limb buds of the species of origin. Surprisingly, the activities of CRM orthologues display high evolutionary plasticity, which correlates better with the Grem1 expression pattern in limb buds of the species of origin than its mouse orthologue. This differential responsiveness to the GRNs in mouse suggests that TF binding site alterations in CRMs could underlie the spatial diversification of Grem1 in limb buds during tetrapod evolution. While the fish fin and tetrapod limb share some homologies of proximal bones, the autopod is a neomorphic feature of tetrapods. The Grem1 requirement for digit patterning and conserved expression in fin buds prompted us to assess the enhancer activity of fish CRM orthologues in transgenic mice. Surprisingly, all tested fish CRMs are active in the mouse autopod primordia providing strong evidence that Grem1 CRMs are active in fin buds and that they predate the fin-to-limb transition. Our results corroborate increasing evidence that CRMs governing autopodial gene expression have been co-opted during the emergence of tetrapod autopod. Furthermore, as part of a collaboration with Dr. S. Jhanwar, I contributed to the study of shared and species-specific epigenomic and genomic variations during mouse and chicken limb bud development. In this analysis, Dr. S. Jhanwar identified putative enhancers that show higher chicken-specific sequence turnover rates in comparison to their mouse orthologues, which defines them as so-called chicken accelerated regions (CARs). Here, I analyzed the CAR activities in comparison to their mouse orthologues by transgenic LacZ reporter assays, which was complemented by analysis of the endogenous gene expression in limb buds of both species. This analysis indicates that diversified activity of CARs and their mouse orthologues could be linked to the differential gene expression patterns in limb buds of both species

    Investigating the role of R2TP-like co-chaperone complexes during axonemal dynein assembly

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    Motile cilia are specialised cell-types which in humans have important roles in the linings of the airways, the reproductive system and the brain. The movement, required for this type of cilia to function, is facilitated by structures called axonemal dynein motor complexes. These are large, multi-subunit structures, and so it is crucial that they are assembled correctly. In humans, if the motility of these is defective, it can lead to a disorder called Primary Ciliary Dyskinesia, or PCD. This is a heterogeneous, autosomal recessive disorder – symptoms of which include abnormally positioned organs, chronic respiratory infections and infertility. Therefore, the development and structure of the motile cilia is tightly regulated by multiple proteins including chaperones, dynein axonemal assembly factors (DNAAFs), microtubule inner proteins (MIPs), the outer arm docking complex (ODA-DC) and the nexin-dynein regulatory complex (N-DRC). Chaperones work with co-chaperones to regulate their many functions within the cell. One of these co-chaperones is the R2TP complex, which was originally discovered in yeast but is conserved in higher organisms. This multi-protein co-chaperone is involved in the assembly of multi-subunit complexes such as the axonemal dynein motors. Two of the R2TP subunits, Pontin and Reptin, are involved in many cellular functions both in this co-chaperone complex and independently. It is thought that as some DNAAFs share similar protein domains to the components of the R2TP complex, they may form R2TP-like complexes. However, the specific details surrounding the roles of these complexes during the assembly process remains unclear. The structure of motile cilia is highly conserved throughout evolution and Drosophila melanogaster has been shown previously to be an excellent model for furthering understanding into the development and function of these structures as only two cell types in the fly contain axonemal dynein motor complexes. These are the chordotonal neuron, which has a motile ciliated dendrite essential for its mechanosensory function, and the sperm flagellum. In this thesis, I use the Drosophila model to further characterise putative ciliary genes (Wdr16 and Dpcd) identified by a transcriptome analysis previously carried out in the lab. RNAi knockdown experiments as well as expression analysis supported motile cilia functions. The diversity which has been identified regarding the roles of these two putative ciliary genes highlights how proteins can be involved in motile cilia in different ways. I also use this genetically tractable model to further understand the roles of the individual proteins of a previously identified R2TP-like complex (R2DP3). Electron microscopy, proteomics and investigation into how the localisation of dynein subsets was affected in null mutants (generated using CRISPR/Cas9) allowed for the role of this R2TP-like complex in the dynein assembly process to be further specified. Using co-immunoprecipitation and affinity purification, we identified an additional protein complex featuring Pontin and Reptin of the R2TP complex, alongside the DNAAF Heatr2 and the putative DNAAF Dpcd. As well as a role in dynein assembly, both DNAAFs are additionally expressed in the neuroblasts of the CNS, and disruption to their function results in a late larval lethality. Therefore, we have found these genes to not be specific to the dynein assembly process and hypothesise that Dpcd may have an additional function (working with Pontin, Reptin and potentially Heatr2) in the regulation of AKT signalling and therefore impact cell proliferation
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