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Selective glucocorticoid receptor properties of GSK866 analogs with cysteine reactive warheads

Synthetic glucocorticoids (GC) are the mainstay therapy for treatment of acute and chronic inflammatory disorders. Due to the high adverse effects associated with long-term use, GC pharmacology has focused since the nineties on more selective GC ligand-binding strategies, classified as selective glucocorticoid receptor (GR) agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). In the current study, GSK866 analogs with electrophilic covalent-binding warheads were developed with potential SEGRA properties to improve their clinical safety profile for long-lasting topical skin disease applications. Since the off-rate of a covalently binding drug is negligible compared to that of a non-covalent drug, its therapeutic effects can be prolonged and typically, smaller doses of the drug are necessary to reach the same level of therapeutic efficacy, thereby potentially reducing systemic side effects. Different analogs of SEGRA GSK866 coupled to cysteine reactive warheads were characterized for GR potency and selectivity in various biochemical and cellular assays. GR-and NF kappa B dependent reporter gene studies show favorable anti-inflammatory properties with reduced GR transactivation of two non-steroidal GSK866 analogs UAMC-1217 and UAMC-1218, whereas UAMC-1158 and UAMC-1159 compounds failed to modulate cellular GR activity. These results were further supported by GR immuno-localization and S211 phospho-GR western analysis, illustrating significant GR phosphoactivation and nuclear translocation upon treatment of GSK866, UAMC-1217, or UAMC-1218, but not in case of UAMC-1158 or UAMC-1159. Furthermore, mass spectrometry analysis of tryptic peptides of recombinant GR ligand-binding domain (LBD) bound to UAMC-1217 or UAMC-1218 confirmed covalent cysteine-dependent GR binding. Finally, molecular dynamics simulations, as well as glucocorticoid receptor ligand-binding domain (GR-LBD) coregulator interaction profiling of the GR-LBD bound to GSK866 or its covalently binding analogs UAMC-1217 or UAMC-1218 revealed subtle conformational differences that might underlie their SEGRA properties. Altogether, GSK866 analogs UAMC-1217 and UAMC-1218 hold promise as a novel class of covalent-binding SEGRA ligands for the treatment of topical inflammatory skin disorders

A biophysical insight of Camptothecin biodistribution: towards a molecular understanding of its pharmacokinetic issues

Camptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood–brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug’s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VDSS = 5.75 ± 0.932 L·Kg−1) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution.This work was supported by Fundação para a Ciência e Tecnologia (FCT) in the framework of the Strategic Funding [UID/FIS/04650/2019], and by the project CONCERT [POCI-01- 0145-FEDER-032651 and PTDC/NAN-MAT/326512017], co-financed by the European Regional Development Fund (ERDF), through COMPETE 2020, under Portugal 2020, and FCT I.P. The authors thank Elettra Sincrotone and Sigrid Bernstorff, Trieste, Italy, for beam time and support through the project 20155321. Marlene Lúcio thanks FCT and ERDF for doctoral position [CTTI-150/18-CF (1)] in the ambit of the project CONCERT. Andreia Almeida (SFRH/BD/118721/2016) and Eduarda Fernandes (SFRH/BD/147938/2019) grants are supported by FCT, POPH and FEDER/COMPETE

Interoperability Among Unmanned Maritime Vehicles: Review and First In-field Experimentation

Complex maritime missions, both above and below the surface, have traditionally been carried out by manned surface ships and submarines equipped with advanced sensor systems. Unmanned Maritime Vehicles (UMVs) are increasingly demonstrating their potential for improving existing naval capabilities due to their rapid deployability, easy scalability, and high reconfigurability, offering a reduction in both operational time and cost. In addition, they mitigate the risk to personnel by leaving the man far-from-the-risk but in-the-loop of decision making. In the long-term, a clear interoperability framework between unmanned systems, human operators, and legacy platforms will be crucial for effective joint operations planning and execution. However, the present multi-vendor multi-protocol solutions in multi-domain UMVs activities are hard to interoperate without common mission control interfaces and communication protocol schemes. Furthermore, the underwater domain presents significant challenges that cannot be satisfied with the solutions developed for terrestrial networks. In this paper, the interoperability topic is discussed blending a review of the technological growth from 2000 onwards with recent authors' in-field experience; finally, important research directions for the future are given. Within the broad framework of interoperability in general, the paper focuses on the aspect of interoperability among UMVs not neglecting the role of the human operator in the loop. The picture emerging from the review demonstrates that interoperability is currently receiving a high level of attention with a great and diverse deal of effort. Besides, the manuscript describes the experience from a sea trial exercise, where interoperability has been demonstrated by integrating heterogeneous autonomous UMVs into the NATO Centre for Maritime Research and Experimentation (CMRE) network, using different robotic middlewares and acoustic modem technologies to implement a multistatic active sonar system. A perspective for the interoperability in marine robotics missions emerges in the paper, through a discussion of current capabilities, in-field experience and future advanced technologies unique to UMVs. Nonetheless, their application spread is slowed down by the lack of human confidence. In fact, an interoperable system-of-systems of autonomous UMVs will require operators involved only at a supervisory level. As trust develops, endorsed by stable and mature interoperability, human monitoring will be diminished to exploit the tremendous potential of fully autonomous UMVs

Mobile Crowd Sensing in Edge Computing Environment

abstract: The mobile crowdsensing (MCS) applications leverage the user data to derive useful information by data-driven evaluation of innovative user contexts and gathering of information at a high data rate. Such access to context-rich data can potentially enable computationally intensive crowd-sourcing applications such as tracking a missing person or capturing a highlight video of an event. Using snippets and pictures captured from multiple mobile phone cameras with specific contexts can improve the data acquired in such applications. These MCS applications require efficient processing and analysis to generate results in real time. A human user, mobile device and their interactions cause a change in context on the mobile device affecting the quality contextual data that is gathered. Usage of MCS data in real-time mobile applications is challenging due to the complex inter-relationship between: a) availability of context, context is available with the mobile phones and not with the cloud, b) cost of data transfer to remote cloud servers, both in terms of communication time and energy, and c) availability of local computational resources on the mobile phone, computation may lead to rapid battery drain or increased response time. The resource-constrained mobile devices need to offload some of their computation. This thesis proposes ContextAiDe an end-end architecture for data-driven distributed applications aware of human mobile interactions using Edge computing. Edge processing supports real-time applications by reducing communication costs. The goal is to optimize the quality and the cost of acquiring the data using a) modeling and prediction of mobile user contexts, b) efficient strategies of scheduling application tasks on heterogeneous devices including multi-core devices such as GPU c) power-aware scheduling of virtual machine (VM) applications in cloud infrastructure e.g. elastic VMs. ContextAiDe middleware is integrated into the mobile application via Android API. The evaluation consists of overheads and costs analysis in the scenario of ``perpetrator tracking" application on the cloud, fog servers, and mobile devices. LifeMap data sets containing actual sensor data traces from mobile devices are used to simulate the application run for large scale evaluation.Dissertation/ThesisDoctoral Dissertation Electrical Engineering 201

e-Business challenges and directions: important themes from the first ICE-B workshop

A three-day asynchronous, interactive workshop was held at ICE-B’10 in Piraeus, Greece in July of 2010. This event captured conference themes for e-Business challenges and directions across four subject areas: a) e-Business applications and models, b) enterprise engineering, c) mobility, d) business collaboration and e-Services, and e) technology platforms. Quality Function Deployment (QFD) methods were used to gather, organize and evaluate themes and their ratings. This paper summarizes the most important themes rated by participants: a) Since technology is becoming more economic and social in nature, more agile and context-based application develop methods are needed. b) Enterprise engineering approaches are needed to support the design of systems that can evolve with changing stakeholder needs. c) The digital native groundswell requires changes to business models, operations, and systems to support Prosumers. d) Intelligence and interoperability are needed to address Prosumer activity and their highly customized product purchases. e) Technology platforms must rapidly and correctly adapt, provide widespread offerings and scale appropriately, in the context of changing situational contexts