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Diabetic retinopathy (DR) is a microvascular disorder characterized by inner blood-retinal barrier (iBRB) breakdown and irreversible vision loss. While the symptoms of DR are known, disease mechanisms including basement membrane thickening, pericyte dropout and capillary damage remain poorly understood and interventions to repair diseased iBRB microvascular networks have not been developed. In addition, current approaches using animal models and in vitro systems lack translatability and predictivity to finding new target pathways. Here, we develop a diabetic iBRB-on-a-chip that produces pathophysiological phenotypes and disease pathways in vitro that are representative of clinical diagnoses. We show that diabetic stimulation of the iBRB-on-a-chip mirrors DR features, including pericyte loss, vascular regression, ghost vessels, and production of pro-inflammatory factors. We also report transcriptomic data from diabetic iBRB microvascular networks that may reveal drug targets, and examine pericyte-endothelial cell stabilizing strategies. In summary, our model recapitulates key features of disease, and may inform future therapies for DR. Here the authors develop perfusable inner blood-retinal barrier-specific microvascular networks with human primary retinal microvascular cells. They show that chronic diabetic stimulation leads to the generation of early hallmarks of diabetic retinopathy, including pericyte and capillary dropout, ghost vessels, and inflammation.

Inverse problems are prevalent in numerous scientific and engineering disciplines, where the objective is to determine unknown parameters within a physical system using indirect measurements or observations. The inherent challenge lies in deducing the most probable parameter values that align with the collected data. This study introduces an algorithm for reconstructing parameters by addressing an inverse problem formulated through differential equations underpinned by uncertain boundary conditions or variant parameters. We adopt a Bayesian approach for parameter inference, delineating the establishment of prior, likelihood, and posterior distributions, and the subsequent resolution of the maximum a posteriori problem via numerical optimization techniques. The proposed algorithm is applied to the task of magnetic field reconstruction within a conical domain, demonstrating precise recovery of the true parameter values.

Biofilms are currently considered as a predominant lifestyle of many bacteria in nature. While they promote survival of microbes, biofilms also potentially increase the threats to animal and public health in case of pathogenic species. They not only facilitate bacteria transmission and persistence, but also promote spreading of antibiotic resistance leading to chronic infections. In the case of Francisella tularensis, the causative agent of tularemia, biofilms have remained largely enigmatic. Here, applying live and static confocal microscopy, we report growth and ultrastructural organization of the biofilms formed in vitro by these microorganisms over the early transition from coccobacillary into coccoid shape during biofilm assembly. Using selective dispersing agents, we provided evidence for extracellular DNA (eDNA) being a major and conserved structural component of mature biofilms formed by both F. subsp. novicida and a human clinical isolate of F. philomiragia. We also observed a higher physical robustness of F. novicida biofilm as compared to F. philomiragia one, a feature likely promoted by specific polysaccharides. Further, F. novicida biofilms resisted significantly better to ciprofloxacin than their planktonic counterparts. Importantly, when grown in biofilms, both Francisella species survived longer in cold water as compared to free-living bacteria, a trait possibly associated with a gain in fitness in the natural aquatic environment. Overall, this study provides information on survival of Francisella when embedded with biofilms that should improve both the future management of biofilm-related infections and the design of effective strategies to tackle down the problematic issue of bacteria persistence in aquatic ecosystems.

High failure rates in clinical trials for neurodegenerative disorders such as Alzheimer’s disease have been linked to an insufficient predictive validity of current animal-based disease models. This has created an increasing demand for alternative, human-based models capable of emulating key pathological phenotypes in vitro . Here, a three-dimensional Alzheimer’s disease model was developed using a compartmentalized microfluidic device that combines a self-assembled microvascular network of the human blood-brain barrier with neurospheres derived from Alzheimer’s disease-specific neural progenitor cells. To shorten microfluidic co-culture times, neurospheres were pre-differentiated for 21 days to express Alzheimer’s disease-specific pathological phenotypes prior to the introduction into the microfluidic device. In agreement with post-mortem studies and Alzheimer’s disease in vivo models, after 7 days of co-culture with pre-differentiated Alzheimer’s disease-specific neurospheres, the three-dimensional blood-brain barrier network exhibited significant changes in barrier permeability and morphology. Furthermore, vascular networks in co-culture with Alzheimer’s disease-specific microtissues displayed localized β-amyloid deposition. Thus, by interconnecting a microvascular network of the blood-brain barrier with pre-differentiated neurospheres the presented model holds immense potential for replicating key neurovascular phenotypes of neurodegenerative disorders in vitro .

Endothelial programmed death‐ligand 1 (PD‐L1) expression is higher in tumors than in normal tissues. Also, tumoral vasculatures tend to be leakier than normal vessels leading to a higher trans‐endothelial or transmural fluid flow. However, it is not clear whether such elevated transmural flow can control endothelial PD‐L1 expression. Here, a new microfluidic device is developed to investigate the relationship between transmural flow and PD‐L1 expression in microvascular networks (MVNs). After treating the MVNs with transmural flow for 24 h, the expression of PD‐L1 in endothelial cells is upregulated. Additionally, CD8 T cell activation by phytohemagglutinin (PHA) is suppressed when cultured in the MVNs pre‐conditioned with transmural flow. Moreover, transmural flow is able to further increase PD‐L1 expression in the vessels formed in the tumor microenvironment. Finally, by utilizing blocking antibodies and knock‐out assays, it is found that transmural flow‐driven PD‐L1 upregulation is controlled by integrin αVβ3. Overall, this study provides a new biophysical explanation for high PD‐L1 expression in tumoral vasculatures. Elevated endothelial programmed death‐ligand 1 (PD‐L1) in tumor vasculature remains unexplained. Using a microfluidic device, it is found that transmural flow upregulates PD‐L1 in microvascular networks, suppressing CD8 T cell activation. Transmural flow also enhances PD‐L1 expression in tumor microenvironment vessels, controlled by integrin αVβ3. The study provides a biophysical explanation for upregulated PD‐L1 in tumoral vasculature.

Epidemiological studies based on data from the UK Biobank and the English Longitudinal Study of Ageing (ELSA), suggest that diabetes is associated with increased risk of dementia, cognitive decline and neurodegenerative disorders. There are diverse hypotheses regarding the downstream pathways driving hyperglycaemia-induced neuropathophysiology, including disruption of the blood-brain barrier (BBB) and impaired function of the cells that form the BBB; endothelial cells (ECs), astrocytes and pericytes. However, the mechanism is still to be elucidated. Most in vitro systems utilised to study the BBB are planar and do not recapitulate the physiological complexity of the 3D architecture under flow conditions. Therefore, our aim was to determine the adverse effect of hyperglycaemia on BBB integrity using a complex, self- organising, 3D BBB model.ECs, astrocytes and pericytes were seeded into the microfluidic chip and perfusable vascular networks were allowed to form for 7 days when they were treated with either high glucose (30mM D-glucose), an osmotic control (30mM L-glucose) or normal glucose (5mM D- glucose) for 72 hours. Hyperglycaemia increased vascular permeability versus controls using Texas Red-labelled dextran (40 kDa) and live confocal imaging. Disorganisation of BBB vascular networks, (reduced tube area, branching & vessel length) was observed with alterations in cell morphology. Interestingly, areas of punctate staining were observed, indicative of cell death/apoptosis requiring further validation. Transcriptomic analysis using high quality total RNA from the chips revealed differential expression of 548 transcriptomes (165 genes upregulated and 382 genes downregulated) in high D-glucose treated BBB samples as compared to L-glucose treated samples.We have established a physiologically relevant model to understand the pathological effect of diabetes on the BBB. Identification of damaging and/or protective mechanism/s underlying diabetes-induced BBB disruption could lead to novel therapeutic strategies.

Blood-neural barriers regulate nutrient supply to neuronal tissues and prevent neurotoxicity. In particular, the inner blood-retinal barrier (iBRB) and blood–brain barrier (BBB) share common origins in development, and similar morphology and function in adult tissue, while barrier breakdown and leakage of neurotoxic molecules can be accompanied by neurodegeneration. Therefore, pre-clinical research requires human in vitro models that elucidate pathophysiological mechanisms and support drug discovery, to add to animal in vivo modeling that poorly predict patient responses. Advanced cellular models such as microphysiological systems (MPS) recapitulate tissue organization and function in many organ-specific contexts, providing physiological relevance, potential for customization to different population groups, and scalability for drug screening purposes. While human-based MPS have been developed for tissues such as lung, gut, brain and tumors, few comprehensive models exist for ocular tissues and iBRB modeling. Recent BBB in vitro models using human cells of the neurovascular unit (NVU) showed physiological morphology and permeability values, and reproduced brain neurological disorder phenotypes that could be applicable to modeling the iBRB. Here, we describe similarities between iBRB and BBB properties, compare existing neurovascular barrier models, propose leverage of MPS-based strategies to develop new iBRB models, and explore potentials to personalize cellular inputs and improve pre-clinical testing.

In the histories formulation of quantum theory, sets of coarse-grained histories, that are called consistent, obey classical probability rules. It has been argued that these sets can describe the semi-classical behaviour of closed quantum systems. Most physical scenarios admit multiple different consistent sets and one can view each consistent set as a separate context. Using propositions from different consistent sets to make inferences leads to paradoxes such as the contrary inferences first noted by Kent [Physical Review Letters, 78(15):2874, 1997]. Proponents of the consistent histories formulation argue that one should not mix propositions coming from different consistent sets in making logical arguments, and that paradoxes such as the aforementioned contrary inferences are nothing else than the usual microscopic paradoxes of quantum contextuality as first demonstrated by Kochen and Specker theorem. In this contribution we use the consistent histories to describe a macroscopic (semi-classical) system to show that paradoxes involving contextuality (mixing different consistent sets) persist even in the semi-classical limit. This is distinctively different from the contextuality of standard quantum theory, where the contextuality paradoxes do not persist in the semi-classical limit. Specifically, we consider different consistent sets for the arrival time of a semi-classical wave packet in an infinite square well. Surprisingly, we get consistent sets that disagree on whether the motion of the semi-classical system, that started within a subregion, ever left that subregion or not. Our results point to the need for constraints, additional to the consistency condition, to recover the correct semi-classical limit in this formalism and lead to the motto `all consistent sets are equal', but `some consistent sets are more equal than others'.

Inverse problems are prevalent in numerous scientific and engineering disciplines, where the objective is to determine unknown parameters within a physical system using indirect measurements or observations. The inherent challenge lies in deducing the most probable parameter values that align with the collected data. This study introduces an algorithm for reconstructing parameters by addressing an inverse problem formulated through differential equations underpinned by uncertain boundary conditions or variant parameters. We adopt a Bayesian approach for parameter inference, delineating the establishment of prior, likelihood, and posterior distributions, and the subsequent resolution of the maximum a posteriori problem via numerical optimization techniques. The proposed algorithm is applied to the task of magnetic field reconstruction within a conical domain, demonstrating precise recovery of the true parameter values.

The increasing sophistication of telecommunications infrastructures and, in particular, the introduction of broadband transmission and switching technologies together with advanced services that exhibit guaranteed Quality of Service characteristics, have necessitated the use of sophisticated management facilities. The Telecommunications Management Network (TMN) is being developed by the ITU-T as the framework to support the open management of telecommunications networks and services, exploiting the capabilities of emerging broadband technologies and harnessing their power. It projects a hierarchical distributed paradigm in which interactions are object-oriented (O-O) in information specifications terms. On the other hand, it is mainly a communications concept, and, as such, it does not address software realisation aspects. The TMN uses currently OSI Systems Management (OSI-SM) as its base technology. The complexity of the combined OSI-SM/TMN architectural framework and the fact that non object-oriented approaches have been initially adopted for its realisation has resulted in doubts about its feasibility, implementability, performance and eventual deployment. This thesis proposes first a number of modifications and extensions to the TMN model and architecture. The modifications aim at the simplification of the overall framework and rely on the fact that this thesis shows that full scale OSI-SM/TMN technology is both feasible and performant. The extensions introduce distribution and discovery facilities through the OSI Directory and aim to support the TMN as a large scale distributed system. The thesis subsequently shows that the inherent object-oriented aspects of the OSI-SM/TMN framework can be exploited through an object-oriented realisation model that hides protocol aspects, bears similarities to recently emerging O-O distributed systems frameworks and has good performance characteristics without requiring excessive computing resources. The environment in which these concepts were validated is known as OSIMIS (OSI Management Information Service) and can be used as a TMN distributed O-O platform that enables the rapid development and deployment of TMN systems. It predated similar products by some years and influenced a number of subsequent commercial developments. Open Distributed Processing (ODP) has recently emerged as the theoretical framework for object-oriented distributed systems. The Object Management Group (OMG) Common Object Request Broker Architecture (CORBA) can be seen as its pragmatic counterpart. Since the appearance of CORBA, a lot of research has addressed its use in TMN environments, because of its generality, better distribution paradigm and potentially better performance. Despite the relevant efforts though, there is no complete solution as yet that retains the full OSI-SM expressive power. This thesis proposes a solution that will make possible the seamless replacement of the OSI SM and Directory with CORBA as the base technology for the TMN.