The Neurovascular Unit Dysfunction in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.     

Exogenous Integrin αIIbβ3 Inhibitors Revisited: Past,Present and Future Applications

The integrin αIIbβ3 is the most abundant integrin on platelets. Upon platelet activation, the integrin changes its conformation (inside-out signalling) and outside-in signalling takes place leading to platelet spreading, platelet aggregation and thrombus formation. Bloodsucking parasites such as mosquitoes, leeches and ticks express anticoagulant and antiplatelet proteins, which represent major sources of lead compounds for the development of useful therapeutic agents for the treatment of haemostatic disorders or cardiovascular diseases. In addition to hematophagous parasites, snakes also possess anticoagulant and antiplatelet proteins in their salivary glands. Two snake venom proteins have been developed into two antiplatelet drugs that are currently used in the clinic. The group of proteins discussed in this review are disintegrins, low molecular weight integrin-binding cysteine-rich proteins, found in snakes, ticks, leeches, worms and horseflies. Finally, we highlight various oral antagonists, which have been tested in clinical trials but were discontinued due to an increase in mortality. No new αIIbβ3 inhibitors are developed since the approval of current platelet antagonists, and structure-function analysis of exogenous disintegrins could help find platelet antagonists with fewer adverse side effects.     

Out-of-Field Hippocampus from Partial-Body Irradiated Mice Displays Changes in Multi-Omics Profile and Defects in Neurogenesis

The brain undergoes ionizing radiation exposure in many clinical situations, particularly during radiotherapy for brain tumors. The critical role of the hippocampus in the pathogenesis of radiation-induced neurocognitive dysfunction is well recognized. The goal of this study is to test the potential contribution of non-targeted effects in the detrimental response of the hippocampus to irradiation and to elucidate the mechanisms involved. C57Bl/6 mice were whole body (WBI) or partial body (PBI) irradiated with 0.1 or 2.0 Gy of X-rays or sham irradiated. PBI consisted of the exposure of the lower third of the mouse body, whilst the upper two thirds were shielded. Hippocampi were collected 15 days or 6 months post-irradiation and a multi-omics approach was adopted to assess the molecular changes in non-coding RNAs, proteins and metabolic levels, as well as histological changes in the rate of hippocampal neurogenesis. Notably, at 2.0 Gy the pattern of early molecular and histopathological changes induced in the hippocampus at 15 days following PBI were similar in quality and quantity to the effects induced by WBI, thus providing a proof of principle of the existence of out-of-target radiation response in the hippocampus of conventional mice. We detected major alterations in DAG/IP3 and TGF-β signaling pathways as well as in the expression of proteins involved in the regulation of long-term neuronal synaptic plasticity and synapse organization, coupled with defects in neural stem cells self-renewal in the hippocampal dentate gyrus. However, compared to the persistence of the WBI effects, most of the PBI effects were only transient and tended to decrease at 6 months post-irradiation, indicating important mechanistic difference. On the contrary, at low dose we identified a progressive accumulation of molecular defects that tended to manifest at later post-irradiation times. These data, indicating that both targeted and non-targeted radiation effects might contribute to the pathogenesis of hippocampal radiation-damage, have general implications for human health.     

Rationally designed inhibitors as tools for comparing the mechanism of squalene-hopene cyclase with oxidosqualene cyclase

The inhibition of squalene-hopene cyclase (SHC) (E.C. 5.4.99.-), an enzyme of bacterial membranes catalyzing the formation of pentacyclic sterol-like triterpenes, was studied by using different classes of compounds originally developed as inhibitors of oxidosqualene cyclase (OCS) (E.C. 5.4.99.7), the enzyme of eukaryotes responsible for the formation of tetracyclic precursors of sterols. The mechanism of cyclization of squalene by SHC, beginning with a protonation of the 2,3 double bond by an acidic residue of the enzyme, followed by a series of electrophilic additions of the carbocationic intermediates to the double bonds, is similar to the mechanism of cyclization of 2,3-oxidosqualene by OSC. The inhibitors studied included: (i) analogs of the carbocationic intermediates formed during cyclization, such as aza-analogs of squalene and 2,3-oxidosqualene; (ii) affinity-labeling inhibitors bearing a methylidene reactive group; and (iii) vinyldioxidosqualenes and vinylsulfide derivatives of the substrates. Comparison of the results obtained with the two enzymes, SHC and OSC, showed that many of the most effective inhibitors of OSC were also able to inhibit SHC, while some derivatives acted as specific inhibitors. Differences could be easily explained on the basis of the different substrate specificity of the two enzymes.     

On requirement verification for evolving Statecharts specifications

Software development processes have been evolving from rigid, pre-specified, and sequential to incremental, and iterative. This evolution has been dictated by the need to accommodate evolving user requirements and reduce the delay between design decision and feedback from users. Formal verification techniques, however, have largely ignored this evolution and even when they made enormous improvements and found significant uses in practice, like in the case of model checking, they remained confined into the niches of safety-critical systems. Model checking verifies if a system’s model \(\mathcal{M}\) satisfies a set of requirements, formalized as a set of logic properties \(\Phi\) . Current model-checking approaches, however, implicitly rely on the assumption that both the complete model \(\mathcal{M}\) and the whole set of properties \(\Phi\) are fully specified when verification takes place. Very often, however, \(\mathcal{M}\) is subject to change because its development is iterative and its definition evolves through stages of incompleteness, where alternative design decisions are explored, typically to evaluate some quality trade-offs. Evolving systems specifications of this kind ask for novel verification approaches that tolerate incompleteness and support incremental analysis of alternative designs for certain functionalities. This is exactly the focus of this paper, which develops an incremental model-checking approach for evolving Statecharts. Statecharts have been chosen both because they are increasingly used in practice natively support model refinements.     

Online Coloring of Bipartite Graphs with and without Advice

In the online version of the well-known graph coloring problem, the vertices appear one after the other together with the edges to the already known vertices and have to be irrevocably colored immediately after their appearance. We consider this problem on bipartite, i.e., two-colorable graphs. We prove that at least ?1.13746?log₂(n)?0.49887? colors are necessary for any deterministic online algorithm to be able to color any given bipartite graph on n vertices, thus improving on the previously known lower bound of ?log₂ n?+1 for sufficiently large n. Recently, the advice complexity was introduced as a method for a fine-grained analysis of the hardness of online problems. We apply this method to the online coloring problem and prove (almost) tight linear upper and lower bounds on the advice complexity of coloring a bipartite graph online optimally or using 3 colors. Moreover, we prove that \(O(\sqrt{n})\) advice bits are sufficient for coloring any bipartite graph on n vertices with at most ?log₂ n? colors.     

Occurrence patterns of alien freshwater turtles in a large urban pond ‘Archipelago’ (Rome,Italy): Suggesting hypotheses on root causes

The patterns of the occurrence and distribution of alien freshwater turtle species in an urban pond archipelago (Rome, Italy) were analysed, with the aim of exploring the role of a set of factors (type of ponds, landscape context, size area, distance from the nearest road) with a generalized linear model approach. A total of 311 ponds subdivided in three types (fountains, small basins, lakes) embedded in different landscape contexts (public parks, private parks, urban areas) at differing distances from the nearest road were sampled. Six non‐native freshwater turtle species in 31 sites were recorded (9.97%). Lakes exhibited the highest occurrence rates of alien freshwater turtles, compared to small basins and fountains. Freshwater turtle species in urbanized areas were only observed in parks (both public and private). In both the public and private parks, the lakes exhibited the highest percentage of occupied sites, with fountains being the lowest. A direct and significant relationship was observed between pond size and species richness. The distance from the nearest road did not appear to affect species richness. A first interpretation of the data from this study facilitated the postulation of two a posteriori hypotheses that should be tested, as follows: (i) the causal process of turtle release is random, and the rate of extinction (and recapture) is higher in smaller ponds, thus producing the observed pattern; and (ii) the turtle release is not random, and people actively select the ponds they consider more suitable for their pet animals. In this study, it appears the lakes were perceived by those who abandon their pets as the most ecologically suitable habitats among other pond types to accommodate the different species of turtles. Knowledge of people's attitudes in regard to releasing pet animals also might assist managers of public green spaces to develop strategies aimed to preserve local biodiversity, and to educate the public about the conservation issue represented by the alien species.     

Synthesis and characterization of polyurea microcapsules containing essential oils with antigerminative activity

In this paper we report on the preparation and characterization of polyurea‐based microencapsulated systems, containing essential oils as core materials, for potential applications in controlled‐release formulations of agrochemicals. Microcapsules were synthesized by interfacial polymerization in o/w emulsion between polyfunctional isocyanates and diamines, to investigate the effect of the monomer kind on the morphology and properties of the produced samples. The synthetic conditions that gave the best results were used to microencapsulate four essential oils, able to interfere with the seed germination and radicle elongation of some test plants. The produced samples were characterized, with the aim to analyze their morphology and to verify the effectiveness of essential oil microencapsulation. Moreover, preliminary bioassay based on seed germination and subsequent radical growth were carried out to study the effects of the microencapsulated essential oils. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Surface properties of fluorinated hybrid coatings

A commercial perfluoropolyether containing alkoxysilane functionalities was employed to prepare organic–inorganic hybrid coatings by using the sol‐gel process in the presence of tetraethoxysilane. Contact angle analysis revealed a strong hydrophobic and oleophobic character of the coatings almost independently from the molecular weight of the starting fluorinated oligomer. Surface tension values were in the range of 14–16 mN/m, suggesting a preferential segregation of fluorinated segments onto the surface of the coating. Atomic force microscopy showed the presence very smooth surfaces permitting to neglect the contribution of the surface roughness to wettability. Friction coefficient values were markedly lower with respect to the value of uncoated glass substrate. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 1483–1488, 2006