Targeting Serotonin 2A and Adrenergic α1 Receptors for Ocular Antihypertensive Agents: Discovery of 3,4‐Dihydropyrazino[1,2‐b]indazol‐1(2H)‐one Derivatives

Glaucoma affects millions of people worldwide and causes optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and decreasing IOP is the key therapeutic target of current pharmacological treatments. As potential ocular hypotensive agents, we studied compounds that act on two receptors (serotonin 2A and adrenergic α₁) linked to the regulation of aqueous humour dynamics. Herein we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic N2‐alkyl‐indazole‐amide derivatives. This study identified a 3,4‐dihydropyrazino[1,2‐b]indazol‐1(2H)‐one derivative with potent serotonin 2A receptor antagonism, >100‐fold selectivity over other serotonin subtype receptors, and high affinity for the α₁ receptor. Moreover, upon local administration, this compound showed superior ocular hypotensive action in vivo relative to the clinically used reference compound timolol.     

Lipidomics of Bioactive Lipids in Alzheimer’s and Parkinson’s Diseases: Where Are We?

Lipids are not only constituents of cellular membranes, but they are also key signaling mediators, thus acting as “bioactive lipids”. Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation, and maintenance of homeostasis. Accumulated evidence indicates the existence of a bidirectional relationship between the immune and nervous systems, and lipids can interact particularly with the aggregation and propagation of many pathogenic proteins that are well-renowned hallmarks of several neurodegenerative disorders, including Alzheimer’s (AD) and Parkinson’s (PD) diseases. In this review, we summarize the current knowledge about the presence and quantification of the main classes of endogenous bioactive lipids, namely glycerophospholipids/sphingolipids, classical eicosanoids, pro-resolving lipid mediators, and endocannabinoids, in AD and PD patients, as well as their most-used animal models, by means of lipidomic analyses, advocating for these lipid mediators as powerful biomarkers of pathology, diagnosis, and progression, as well as predictors of response or activity to different current therapies for these neurodegenerative diseases.     

Ice‐Templated Scaffolds with Microridged Pores Direct DRG Neurite Growth

Successful spinal cord repair is thought to be promoted with hierarchically structured scaffolds. These should combine aligned porosity with additional linear features on the micrometer scale to guide axons across multiple length scales. Such scaffolds are generated through the carefully controlled directional solidification of an aqueous biopolymer solution, followed by lyophilization. Under specific freezing conditions this yields a highly regular and aligned lamellar architecture. This architecture exhibits uniform ridges of controlled height and width on the lamellar surface. These ridges run parallel to the pore axis, serving as secondary guidance features. The ridges are capable of linearly aligning 62.4% of chick dorsal root ganglia neurites to within ±10° of the ridge direction. Notably, neurites sprouting perpendicular to the ridge are guided into alignment with these microridged features.     

Reversible Fragmentation and Self‐Assembling of Nematic Liquid Crystal Droplets on Functionalized Pyroelectric Substrates

Investigation on the behavior of nematic liquid crystals on functionalized polar dielectric crystal substrates is accomplished. Very interesting effects can be observed in maneuvering liquid crystal droplets on the substrate surface, driven by electric fields generated by pyroelectric effect. Reversible drops fragmentation and self‐assembling in different configurations can be achieved. The dynamics of the observed phenomena is studied and the repeatability of the process is full assessed.     

Materials systems for interleave toughening in polymer composites

We review the literature describing the use of interleaves to increase interlaminar fracture toughness in fibre-reinforced polymer composites and hence to improve damage tolerance. From an analysis of data provided in the literature from the use of microfibre and nanofibre interleaves, we show that the performance of these widely researched systems is clearly differentiated when plotted against the mean coverage of the interleaf. Using a simple analysis, we suggest that this can be attributed to the influence of their porous architectures on the infusion of resin. We show also that the superior toughening performance of microfibre interleaves is only weakly influenced by the choice of fibre. We find also that the inclusion of carbon nanotubes within interleaves to deliver multifunctional composites can be optimised by using a hybrid system with microfibres.

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Adsorption of pharmaceuticals from aqueous solutions on synthetic zeolites

The objectives of this study were to measure the sorption capacity of a dilute solution of drugs in water on hydrophobic zeolites and to quantify aspects of their adsorption mechanisms for potential use in wastewater remediation. The removal of three drugs, erythromycin (ERY), carbamazepine (CBZ) and levofloxacin (FLX) from water using three organophilic zeolites (Y, mordenite (MOR), ZSM-5) was investigated. Adsorption isotherms show that these three drugs are adsorbed in remarkable amounts by Y. These data were confirmed by thermogravimetric analysis. The presence of these drugs inside the Y cage was revealed by unit cell parameter variations and structural deformations obtained by X-ray structure analyses carried out using the Rietveld method on zeolite after adsorption. Our results indicate that the adsorption properties of zeolitic materials do not only depend on micropore size and that zeolite shape selectivity also depends on structural features which are difficult to determine “a priori”. In order to test the ability of organophilic zeolites in removing drugs from wastewater, the adsorption of ERY, FLX and CBZ on zeolite Y from water samples collected at the outlet of a wastewater treatment plant located in Northern Italy was determined. These drugs were almost completely adsorbed by Y zeolite, confirming that this material is suitable for removing drugs from wastewater.     

Subcontracting in commercial and residential construction: an empirical investigation

Some twenty years ago Robert Eccles argued for the theoretical existence of the quasifirm, a semi-integrated form of production in the construction industry, following a field study of home building firms in the USA. The study was aimed at substantiating some aspects of Williamson's transaction cost theory. The present work has similar intents, and illustrates the results of two recent field studies of homebuilders and commercial contractors, and the specific features of their subcontracting practice. Given the difficulty of an effective measurement of transaction costs in construction, Williamson's concept of atmosphere is suggested to explain the different approaches observed in subcontracting.     

Project affinity: the role of emotional attachment in construction projects

Although a wide range of human and organizational factors have been found to be important in the operation of projects, those determined by cultural variables are less well defined. One such influence concerns the notion of ‘project affinity’, the commitment and attachment by stakeholders and participants to projects and their outcomes. The temporal nature and transient involvement context provided by construction projects arguably presents a climate in which many participants are less likely to display commitment to its goals. This note is concerned with the issue of whether an attachment to a project's goals or to the completed product can lead to improved commitment among those involved. The concept of project affinity was developed in the course of a case study investigation in which operatives' attitudes towards the construction of a cancer research facility were explored. Because of the contribution of the facility to the future care of cancer sufferers, the concept of project affinity proved helpful in understanding a factor that appeared to be influencing the commitment of those involved. The results suggest a complementary concept to that of ‘project chemistry’ (c.f. Nicolini, 2002 Nicolini, D. 2002. In search of ‘project chemistry’.. Construction Management and Economics, 20: 167–77.  ).