In this paper, we address the measurement of vulnerability at municipality level, by using novel non-aggregative tools for the construction of synthetic indicators and for the extraction of rankings, ...based on the theory of partially ordered sets. We compare the results of the non-aggregative procedure to those provided by the Italian National Institute of Statistics, through the Index of Social and Material Vulnerability (applied to 2011 census data) and show that, although the overall pictures rendered by the two approaches are very similar, they are not equivalent, some local areas being resolved and some municipalities being ranked differently. The synthetic vulnerability scores are complemented with a measure of the degree of diversity of the vulnerability patterns, to give a more faithful picture of the complexity of the phenomenon and provide policy-makers with a more realistic view on it.
The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (-)-Δ9-tetrahydrocannabinol (THC), eliciting distinct ...pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles.
The nutritional compound capsaicin is the major spicy ingredient of chili peppers. Although traditionally associated with analgesic activity, recent studies have shown that capsaicin has profound ...antineoplastic effects in several types of human cancers. However, the applications of capsaicin as a clinically viable drug are limited by its unpleasant side effects, such as gastric irritation, stomach cramps, and burning sensation. This has led to extensive research focused on the identification and rational design of second-generation capsaicin analogs, which possess greater bioactivity than capsaicin. A majority of these natural capsaicinoids and synthetic capsaicin analogs have been studied for their pain-relieving activity. Only a few of these capsaicin analogs have been investigated for their anticancer activity in cell culture and animal models. The present review summarizes the current knowledge of the growth-inhibitory activity of natural capsaicinoids and synthetic capsaicin analogs. Future studies that examine the anticancer activity of a greater number of capsaicin analogs represent novel strategies in the treatment of human cancers.
In this paper, we apply the novel Fuzzy First-Order Dominance (F-FOD) methodology to rank migrant subpopulations in Lombardy (Italy), in terms of multidimensional poverty and social fragility, for ...the year 2014, with the purpose to possibly provide useful support to policy-makers, in targeting relief interventions from poverty and discomfort. The F-FOD methodology allows for the direct comparison of different distributions of poverty and fragility, assessed by means of suitable ordinal multi-indicator systems, so extending to this more complex setting, the usual univariate first-order dominance criterion. It also provides complimentary “incomparability” scores, to assess to what extent the final rankings are reliable or instead forcing. It turns out that the levels of poverty and fragility of migrant subpopulations are quite different and, in particular, that the time since migrations has a key impact, on the identification of most critical cases, which typically involve recently migrated people. Evidence also emerges that the temporal poverty/fragility trajectories of migrants, distinguished by country of origin, follow different paths, suggesting how policy interventions must be properly, and differently, tuned to be effective.
The heterocyclic vanilloid compound capsaicin is responsible for the spicy and pungent flavor of chili peppers. Several convergent studies have shown that capsaicin suppresses the growth of multiple ...human cancers. Apart from capsaicin, natural and synthetic capsaicin-like compounds display growth suppressive activity in human cancers. The pharmacophore of capsaicin is comprised of three regions, namely region A (the aromatic ring), region B (the amide bond), and region C (the side chain). The present manuscript describes the isolation and synthesis of capsaicin analogs which have structural modifications in region B of the molecule. Furthermore, the pharmacokinetic properties, anticancer activity of region B capsaicin analogs, as well as the signaling pathways (underlying the growth-inhibitory effects of region B capsaicin analogs) have also been described. The discovery of novel, second-generation region B capsaicin analogs may foster the hope of innovative nutrition-based combination therapies in human cancers.
Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, ...including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo2,1-c1,4benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-2-(arylmethylene)hydrazono-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive
HCP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 μM concentration. Further concentration-response analysis revealed two compounds,
and
, as potent and selective CB2 ligands with sub-micromolar activities (
= 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound
were sought. Compound
was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.
As migrants settle in their destination country, for those who reunited the family or after childbirth childcare becomes a priority. Most studies on migrants’ childcare arrangements have focused on ...parental use of formal childcare rather than on different informal childcare solutions by analysing only families with preschool-age children. Italy poses an interesting case study because its welfare system is characterised by a familistic model of care, based on solidarity between generations. In familistic countries, migrants’ childcare solutions are more constrained. In this study, we analysed differences in informal childcare needs and arrangements for children younger than 14 between Italians and migrants from different countries of origin. We merged two surveys conducted by the Italian National Statistics Institute in 2011–2012: ‘Social Condition and Integration of Foreign Citizens’, a sample of households with at least one migrant with foreign citizenship, and ‘Multiscopo—Aspects of Daily Life’, a sample of households in Italy. We found that household composition and parents’ employment status play an important role in shaping informal childcare arrangements. Overall, migrants are less likely to use informal childcare, especially grandparents, than Italians but when they do, they rely more on other relatives and non-relatives than Italians. Moreover, differences emerge across migrant subgroups. This study is the first in Italy to contribute to an understanding of the role of migrant status in determining parents’ childcare arrangements for children up to 13 years.
We have demonstrated out-of-focus ultrafast pulsed laser processing of copper with a variable working distance, without the need for mechanical movement. This was achieved by employing a diffractive ...optical element. The method has been demonstrated in a practical application to reduce the secondary electron yield (SEY) of copper to below 1.3. We show that using an extended focus element not only increases the consistency of processing across a range of working distances, but also changes the topography of the produced structures, reducing the SEY. This presented approach shows promise in facilitating the Large Hadron Collider’s (LHC’s) upcoming high luminosity upgrade by preventing electron clouds.
Natural products are an abundant source of potential drugs, and their diversity makes them a rich and viable prospective source of bioactive cannabinoid ligands. Cannabinoid receptor 1 (CB1) ...antagonists are clinically established and well documented as potential therapeutics for treating obesity, obesity-related cardiometabolic disorders, pain, and drug/substance abuse, but their associated CNS-mediated adverse effects hinder the development of potential new drugs and no such drug is currently on the market. This limitation amplifies the need for new agents with reduced or no CNS-mediated side effects. We are interested in the discovery of new natural product chemotypes as CB1 antagonists, which may serve as good starting points for further optimization towards the development of CB1 therapeutics. In search of new chemotypes as CB1 antagonists, we screened the in silico purchasable natural products subset of the ZINC12 database against our reported CB1 receptor model using the structure-based virtual screening (SBVS) approach. A total of 18 out of 192 top-scoring virtual hits, selected based on structural diversity and key protein⁻ligand interactions, were purchased and subjected to in vitro screening in competitive radioligand binding assays. The in vitro screening yielded seven compounds exhibiting >50% displacement at 10 μM concentration, and further binding affinity (K
and IC
) and functional data revealed compound
as a potent and selective CB1 inverse agonist (K
= 121 nM and EC
= 128 nM) while three other compounds-
,
, and
-were potent but nonselective CB1 ligands with low micromolar binding affinity (K
). In order to explore the structure⁻activity relationship for compound
, we further purchased compounds with >80% similarity to compound
, screened them for CB1 and CB2 activities, and found two potent compounds with sub-micromolar activities. Most importantly, these bioactive compounds represent structurally new natural product chemotypes in the area of cannabinoid research and could be considered for further structural optimization as CB1 ligands.
PDF
