Novel multifunctional tacrine–donepezil hybrids against Alzheimer's disease: Design synthesis and bioactivity studies

A series of tacrine-donepezil hybrids were synthesized as potential multifunctional anti-Alzheimer's disease (AD) compounds. For this purpose, tacrine and the benzylpiperidine moiety of donepezil were fused with a hydrazone group to achieve a small library of tacrine-donepezil hybrids. In agreement with the design, all compounds showed inhibitory activity toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values in the low micromolar range. Kinetic studies on the most potent cholinesterase (ChE) inhibitors within the series showed a mixed-type inhibition mechanism on both enzymes. Also, the docking studies indicated that the compounds inhibit ChEs by dual binding site (DBS) interactions. Notably, tacrine-donepezil hybrids also exhibited significant neuroprotection against H2O2-induced cell death in a differentiated human neuroblastoma (SH-SY5Y) cell line at concentrations close to their IC50 values on ChEs and showed high to medium blood-brain barrier (BBB) permeability on human cerebral microvascular endothelial cells (HBEC-5i). Besides, the compounds do not cause remarkable toxicity in a human hepatocellular carcinoma cell line (HepG2) and SH-SY5Y cells. Additionally, the compounds were predicted to also have good bioavailability. Among the tested compounds, H4, H16, H17, and H24 stand out with their biological profile. Taken together, the proposed novel tacrine-donepezil scaffold represents a promising starting point for the development of novel anti-ChE multifunctional agents against AD.Novel tacrine-donepezil hybrids were designed and synthesized. The compounds exhibited cholinesterase (ChE) inhibitory activity at the low micromolar level, neuroprotective effect on SH-SY5Y cells, and noncytotoxicity on HepG2 cells, at similar concentrations to their ChE inhibitory activity. Compounds H4, H16, H17, and H24 stand out for their promising biological profile. imag

In tema di selettività del sistema assicurativo INAIL

Il saggio esplora la crisi del principio di selettività della tutela, sul piano soggettivo ed oggettivo, che ha caratterizzato alle origini il sistema normativo dell'assicurazione obbligatoria per gli infortuni e le malattie professional

Latin American migrants as offenders and victims. Rethinking the binomial

In the chapter, the theoretical approach of Nils Christie’s term of the ideal victim is applied to the context of Latin American migration to the United States, a phenomenon that has occurred in increasing numbers since the turn of the century. In that regard, the chapter provides a background outline of Latin American migration to the US and questions whether these subjects fit Christie’s narrative. From the viewpoint of victimology, this case study becomes interesting because it questions the binary opposition between victims and offenders. The study highlights that Latin American migrants can be both perceived as ideal victims and ideal offenders, which is emphasized by multiple external actors like the former US-president Donald Trump or migration NGOs, which use different strategies to either underline the vulnerable or the deviant side of the migrants. Most importantly, the final part of the chapter focuses on the media reactions to the argument of Latin American migration, primarily concerning the situation of migrant children in detention camps at the US-border separated from their parents, and how different media outlet frame migration discourse for their own ideological purpose, finding significant differences in the portrayal of this population

Genetic Sex and Origin Identification Suggests Differential Migration of Male and Female Atlantic Bluefin Tuna (Thunnus thynnus) in the Northeast Atlantic

Knowledge about sex-specific difference in life-history traits—like growth, mortality, or behavior—is of key importance for management and conservation as these parameters are essential for predictive modeling of population sustainability. We applied a newly developed molecular sex identification method, in combination with a SNP (single nucleotide polymorphism) panel for inferring the population of origin, for more than 300 large Atlantic bluefin tuna (ABFT) collected over several years from newly reclaimed feeding grounds in the Northeast Atlantic. The vast majority (95%) of individuals were genetically assigned to the eastern Atlantic population, which migrates between spawning grounds in the Mediterranean and feeding grounds in the Northeast Atlantic. We found a consistent pattern of a male bias among the eastern Atlantic individuals, with a 4-year mean of 63% males (59%–65%). Males were most prominent within the smallest (<230 cm) and largest (>250 cm) length classes, while the sex ratio was close to 1:1 for intermediate sizes (230–250 cm). The results from this new, widely applicable, and noninvasive approach suggests differential occupancy or migration timing of ABFT males and females, which cannot be explained alone by sex-specific differences in growth. Our findings are corroborated by previous traditional studies of sex ratios in dead ABFT from the Atlantic, the Mediterranean, and the Gulf of Mexico. In concert with observed differences in growth and mortality rates between the sexes, these findings should be recognized in order to sustainably manage the resource, maintain productivity, and conserve diversity within the specie

The 33 M black hole Gaia BH3 is part of the disrupted ED-2 star cluster

Context. The Gaia Collaboration has recently reported the detection of a 33 M-circle dot black hole in a wide binary system located in the solar neighbourhood. Aims. Here we explore the relationship between this black hole, known as Gaia BH3, and the nearby ED-2 halo stellar stream. Methods. We studied the orbital characteristics of the Gaia BH3 binary and present measurements of the chemical abundances of ED-2 member stars derived from high-resolution spectra obtained with the VLT. Results. We find that the Galactic orbit of the Gaia BH3 system and its metallicity are entirely consistent with being part of the ED-2 stream. The characteristics of the stream, particularly its negligible spread in metallicity and in other chemical elements, as well as its single stellar population, suggest that it originated from a disrupted star cluster of low mass. Its age is comparable to that of the globular cluster M92 that has been estimated to be as old as the Universe. Conclusions. This is the first black hole unambiguously associated with a disrupted star cluster. We infer the plausible mass range for the cluster to be relatively narrow, between 2 x 10(3) M(circle dot )and 5.2 x 10(4) M-circle dot. This implies that the black hole could have formed directly from the collapse of a massive very metal-poor star, but that the alternative scenario of binary interactions inside the cluster environment also deserves to be explored

Evaluation of the WHO standards to assess quality of care for children with acute respiratory infections: findings of a baseline multicentre assessment (CHOICE) in Italy

Background Experience is lacking on the implementation of the WHO standards for improving the quality of care (QOC) for children at facility level. We describe the use of 10 prioritised WHO standard-based quality measures to assess provision of care for children with acute respiratory infections (ARI) in Italy. Methods In a multicentre observational study across 11 emergency departments with different characteristics, we collected 10 WHO standard-based quality measures related to case management of children with ARI and no emergency/priority signs. Univariate and multivariate analyses were conducted. Results Data from 3145 children were collected. Major differences in QOC across facilities were observed: documentation of saturation level and respiratory rate varied from 34.3% to 100% and from 10.7% to 62.7%, respectively (p<0.001); antibiotic prescription rates ranged from 22.6% to 80.0% (p<0.001), with significant differences in the pattern of prescribed antibiotic; hospitalisations rates ranged between 2.3% and 30.6% (p<0.001). When corrected for children’s individual sociodemographic and clinical characteristics, the variable more consistently associated with each analysed outcome was the individual facility where the child was managed. Higher rates of antibiotics prescription (+33.1%, p<0.001) and hospitalisation (+24.7%, p<0.001) were observed for facilities in Southern Italy, while university centres were associated with lower hospitalisation rates (−13.1%, p<0.001), independently from children’s characteristics. Conclusions The use of 10 WHO standard-based measures can help quickly assess QOC for children with ARI. There is an urgent need to invest more in implementation research to identify sustainable and effective interventions to ensure that all children receive high QOC

Magnetic and Thermal Behavior of a Planar Toroidal Transformer

This paper presents a study on the magnetic and thermal behaviors of a planar toroidal transformer, comprising two planar toroidal coils. In our configuration, the primary coil consists of twenty turns, while the secondary coil consists of ten turns. This design combines the advantages of both toroidal and planar transformers: it employs flat coils, akin to those utilized in planar transformers, while retaining a toroidal shape for its magnetic core. This combination enables leveraging the distinctive characteristics of both transformer types. This study delves into electromagnetic and thermal behaviors. Electromagnetic behavior is elucidated through Maxwell’s equations, offering insights into the distribution of magnetic fields, potentials, and electric current densities. Fluid flow is modeled via the Navier–Stokes equations. By coupling these equation sets, a more comprehensive and accurate portrayal of the thermal phenomena surrounding electrical equipment is attained. Such research is invaluable in the design and optimization of electrical systems, empowering engineers to forecast and manage thermal effects more efficiently. Consequently, this aids in enhancing the reliability, durability, and performance optimization of electrical equipment. The mathematical model was solved using the finite element method integrated into the COMSOL Multiphysics software v. 6.0. The COMSOL Multiphysics simulation showed correct behavior of potential, electric field, current density, and uniformly distributed temperature. In addition, this planar toroidal coil transformer model offers many advantages, such as small dimensions, high resonance frequency, and high operating reliability. This study made it possible to identify the range of its optimal functioning

Bile Acids and Bilirubin Role in Oxidative Stress and Inflammation in Cardiovascular Diseases

Bile acids (BAs) and bilirubin, primarily known for their role in lipid metabolism and as heme catabolite, respectively, have been found to have diverse effects on various physiological processes, including oxidative stress and inflammation. Indeed, accumulating evidence showed that the interplay between BAs and bilirubin in these processes involves intricate regulatory mechanisms mediated by specific receptors and signaling pathways under certain conditions and in specific contexts. Oxidative stress plays a significant role in the development and progression of cardiovascular diseases (CVDs) due to its role in inflammation, endothelial dysfunction, hypertension, and other risk factors. In the cardiovascular (CV) system, recent studies have suggested that BAs and bilirubin have some opposite effects related to oxidative and inflammatory mechanisms, but this area of research is still under investigation. This review aims to introduce BAs and bilirubin from a biochemical and physiological point of view, emphasizing their potential protective or detrimental effects on CVDs. Moreover, clinical studies that have assessed the association between BAs/bilirubin and CVD were examined in depth to better interpret the possible link between them

Extended dynamic mode decomposition for model reduction in fluid dynamics simulations

High computational cost and storage/memory requirements of fluid dynamics simulations constrain their usefulness as a predictive tool. Reduced-order models (ROMs) provide a viable solution to this challenge by extracting the key underlying dynamics of a complex system directly from data. We investigate the efficacy and robustness of an extended dynamic mode decomposition (xDMD) algorithm in constructing ROMs of three-dimensional cardiovascular computations. Focusing on the ROMs’ accuracy in representation and interpolation, we relate these metrics to the truncation rank of singular value decomposition, which underpins xDMD and other approaches to ROM construction. Our key innovation is to relate the truncation rank to the singular values of the original flow problem. This result establishes a priori guidelines for the xDMD deployment and its likely success as a means of data compression and reconstruction of the system’s dynamics from dominant spatiotemporal structures present in the data

EWOCS-I: The catalog of X-ray sources in Westerlund 1 from the Extended Westerlund 1 and 2 Open Clusters Survey

Context. With a mass exceeding several 104 Msun and a rich and dense population of massive stars, supermassive young star clusters represent the most massive star-forming environment that is dominated by the feedback from massive stars and gravitational interactions among stars. Aims: In this paper we present the Extended Westerlund 1 and 2 Open Clusters Survey (EWOCS) project, which aims to investigate the influence of the starburst environment on the formation of stars and planets, and on the evolution of both low and high mass stars. The primary targets of this project are Westerlund 1 and 2, the closest supermassive star clusters to the Sun. Methods: The project is based primarily on recent observations conducted with the Chandra and JWST observatories. Specifically, the Chandra survey of Westerlund 1 consists of 36 new ACIS-I observations, nearly co-pointed, for a total exposure time of 1 Msec. Additionally, we included 8 archival Chandra/ACIS-S observations. This paper presents the resulting catalog of X-ray sources within and around Westerlund 1. Sources were detected by combining various existing methods, and photon extraction and source validation were carried out using the ACIS-Extract software. Results: The EWOCS X-ray catalog comprises 5963 validated sources out of the 9420 initially provided to ACIS-Extract, reaching a photon flux threshold of approximately 2 × 10−8 photons cm−2 s−1. The X-ray sources exhibit a highly concentrated spatial distribution, with 1075 sources located within the central 1 arcmin. We have successfully detected X-ray emissions from 126 out of the 166 known massive stars of the cluster, and we have collected over 71 000 photons from the magnetar CXO J164710.20-455217