Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives

Alzheimer’s Disease (AD) is the most common cause of dementia, having a remarkable social and healthcare burden worldwide. Amyloid β (Aβ) and protein Tau aggregates are disease hallmarks and key players in AD pathogenesis. However, it has been hypothesized that microglia can contribute to AD pathophysiology, as well. Microglia are CNS-resident immune cells belonging to the myeloid lineage of the innate arm of immunity. Under physiological conditions, microglia are in constant motion in order to carry on their housekeeping function, and they maintain an anti-inflammatory, quiescent state, with low expression of cytokines and no phagocytic activity. Upon various stimuli (debris, ATP, misfolded proteins, aggregates and pathogens), microglia acquire a phagocytic function and overexpress cytokine gene modules. This process is generally regarded as microglia activation and implies that the production of pro-inflammatory cytokines is counterbalanced by the synthesis and the release of anti-inflammatory molecules. This mechanism avoids excessive inflammatory response and inappropriate microglial activation, which causes tissue damage and brain homeostasis impairment. Once the pathogenic stimulus has been cleared, activated microglia return to the naïve, anti-inflammatory state. Upon repeated stimuli (as in the case of Aβ deposition in the early stage of AD), activated microglia shift toward a less protective, neurotoxic phenotype, known as “primed” microglia. The main characteristic of primed microglia is their lower capability to turn back toward the naïve, anti-inflammatory state, which makes these cells prone to chronic activation and favours chronic inflammation in the brain. Primed microglia have impaired defence capacity against injury and detrimental effects on the brain microenvironment. Additionally, priming has been associated with AD onset and progression and can represent a promising target for AD treatment strategies. Many factors (genetics, environmental factors, baseline inflammatory status of microglia, ageing) generate an aberrantly activated phenotype that undergoes priming easier and earlier than normally activated microglia do. Novel, promising targets for therapeutic strategies for AD have been sought in the field of microglia activation and, importantly, among those factors influencing the baseline status of these cells. The CX3CL1 pathway could be a valuable target treatment approach in AD, although preliminary findings from the studies in this field are controversial. The current review aims to summarize state of the art on the role of microglia dysfunction in AD pathogenesis and proposes biochemical pathways with possible targets for AD treatment.     

Nanotechnology Meets Oncology: A Perspective on the Role of the Personalized Nanoparticle-Protein Corona in the Development of Technologies for Pancreatic Cancer Detection

In recent years nanotechnology has opened exciting opportunities in the struggle against cancer. In 2007 Dawson and coworkers demonstrated that nanomaterials exposed to biological fluids are coated with plasma proteins that form the so-called “protein corona”. A few years later our joint research team made of physicists, chemists, biotechnologists, surgeons, oncologists, and bioinformaticians introduced the concept of “personalized protein corona” and demonstrated that it is unique for each human condition. This concept paved the way for the development of nano-enabled blood (NEB) tests for the diagnosis of pancreatic ductal adenocarcinoma (PDAC). These studies gave an impetus to serious work in the field that came to maturity in the late 2010s. In this special issue, we provide the reader with a comprehensive overview of the most significant discoveries of our research team in the field of PDAC detection. We focus on the main achievements with an emphasis on the fundamental aspects of this arena and how they shaped the integration of different scientific backgrounds towards the development of advanced diagnostic technologies. We conclude the review by outlining future perspectives and opportunities to transform the NEB tests into a reliable clinical diagnostic technology for early diagnosis, follow-up, and management of PDAC patients.     

Development of an automated system for fuel reload patterns design

In this paper an automated system to generate fuel reload patterns for a boiling water reactor (BWR), based on heuristic search methods using engineers expertise is presented. The main components of the system are the knowledge base, the inference engine, the 3D BWR simulator PRESTO-B and the user interface. The knowledge base includes a generation knowledge base and a modification knowledge base, which are concerned with the way human experts generate reload patterns. The system has been developed and applied to the Laguna Verde Nuclear Power Plant, achieving similar patterns to those used in the operation. No optimization algorithm has been incorporated in this system, therefore the generated reload patterns are the best estimate according the knowledge and experience of the nuclear engineers. Future works are being developed in this area using evolutionary optimization techniques as a complement of this system.     

Liposuction: procedure for focal volume reduction and body contour remodeling

Liposuction is the most commonly used procedure for focal reduction of body fat deposits and remodeling the body contour. The procedure consists in aspirating fat from lamellar deposits using a vacuum source connected to a cannula that is passed bluntly through fatty tissue. Adjuncts to the procedure include infiltration of solutions to aid in fat removal or to limit blood loss and the application of ultrasonic energy to lyse fat cells before suction aspiration. Surgical history, theory, procedures, indications, potential complications, and guidelines are discussed herein.     

Quantum Erasure of Decoherence

We consider the classical algebra of observables that are diagonal in a given orthonormal basis, and define a complete decoherence process as a completely positive map that asymptotically converts any quantum observable into a diagonal one, while preserving the elements of the classical algebra. For quantum systems in dimension two and three any decoherence process can be undone by collecting classical information from the environment and using such an information to restore the initial system state. As a relevant example, we illustrate the quantum eraser of Scully et al. [Nature 351, 111 (1991)] as an example of environment-assisted correction, and present the generalization of the eraser setup for d-dimensional systems. Presented at the 38th Symposium on Mathematical Physics “Quantum Entanglement & Geometry”, Toruń, June 4–7, 2006.     

Context awareness in network selection for dynamic environments

Mobile devices of new generation are able to connect to multiple networks and to constitute new infrastructureless networks. These dynamic environments require new security paradigms and automatic mechanisms to minimize user intervention. Our goal is the definition of a new concept of distance that considers the current domain constraints and the user preferences. This paper addresses some of the problems of these complex environments by using Multidimensional Scaling (MDS) techniques. We also propose collaborative mechanisms for automatic environment marking. Based on these ideas we have developed Pervasive Interaction Manager (PervsIM), a decision mechanism that selects the most appropriate network or peer to interact with. Besides we have defined an embedded access control module which ensures that PervsIM decisions are followed by all applications. Furthermore, several simulation results and implementation details outline how these results can be incorporated in today’s mobile devices.     

Influence of sulfur and Mn/S ratio on the hot ductility of steels during continuous casting

The influence of S and (Mn/S) on the crack susceptibility of continuous casting steels was studied. It is theoretically demonstrated that there is a critical value of the (Mn/S) ratio, (Mn/S)_c, under which a high susceptibility to cracking, during casting or deformation of as-cast material, is expected. The value of (Mn/S)_c increases as the S content of the steel decreases. Based on literature data and results from rolling continuous casting billets the following experimental equation has been found: (Mn/S)_c = 1.345 · S^?0.7934. A high similarity between this experimental equation and the theoretical one is achieved. A comparison between the equation found and previous expressions from literature was carried out. The MSC index as the ratio between the (Mn/S) ratio of a steel and the corresponding critical one was defined. The MSC index is a useful tool for the analysis of experimental results from literature.     

Combined effects of a simultaneous exposure to noise and toluene on hearing function

The effect of incentive was investigated upon performance in the antisaccade (AS), memory saccade (MS) and reflexive saccade (RS) task, alone and following performance in tasks of a psychometric battery. Accuracy performance (correct saccades) in the AS and MS task is dependent on two prefrontal functions, the preservation of transient information across short time intervals and the inhibition of prepotent but inappropriate responses, and is impaired in patient populations with known prefrontal dysfunction. It was predicted that, in normal humans, incentive will improve accuracy performance in the AS and MS task, leaving performance in the RS task unaffected (study 1). Saccades were recorded in 24 healthy young male volunteers. Measurements of saccades were performed (in the presence and absence of monetary incentive) alone or following performance on a psychometric test battery that included tasks of working memory, vigilance, attention and psychomotor activity. Incentive increased the number of correct saccades in the AS task and the performance index in the working memory task. No other direct changes were seen in the presence of incentive. The role of dopamine in performance in the AS compared to the RS task was investigated subsequently in study 2. Twenty healthy young male volunteers received levodopa and benserazide (100 and 25 mg, respectively) orally, and 1 and 5 h later measurements of AS and RS were performed. Levodopa significantly decreased the number of correct saccades in the AS task. No other effects were seen. These data, taken together, suggest, first, that the accuracy performance in the AS task is more sensitive than in the MS or RS task, to positive incentive due to monetary reward; and second, that the dopaminergic system may mediate such an effect, because levodopa, a dopaminergic drug, influenced the same performance measurement. The relationship, however, between these two manipulations (incentive and administration of dopaminergic drugs) is not clear, because incentive improved and levodopa impaired performance.