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Computationally driven discovery of phenyl(piperazin-1-yl)methanone derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors
No full textMonoacylglycerol lipase (MAGL) is an attractive therapeutic target for many pathologies, including neurodegenerative diseases, cancer as well as chronic pain and inflammatory pathologies. The identification of reversible MAGL inhibitors, devoid of the side effects associated to prolonged MAGL inactivation, is a hot topic in medicinal chemistry. In this study, a novel phenyl(piperazin-1-yl)methanone inhibitor of MAGL was identified through a virtual screening protocol based on a fingerprint-driven consensus docking (CD) approach. Molecular modeling and preliminary structure-based hit optimization studies allowed the discovery of derivative 4, which showed an efficient reversible MAGL inhibition (IC 50 = 6.1 µM) and a promising antiproliferative activity on breast and ovarian cancer cell lines (IC 50 of 31–72 µM), thus representing a lead for the development of new and more potent reversible MAGL inhibitors. Moreover, the obtained results confirmed the reliability of the fingerprint-driven CD approach herein developed
New insight into structure-activity of furan-based salicylate synthase (MbtI) inhibitors as potential antitubercular agents
No full textStarting from the analysis of the hypothetical binding mode of our previous furan-based hit (I), we successfully achieved our objective to replace the nitro moiety, leading to the disclosure of a new lead exhibiting a strong activity against MbtI. Our best candidate 1 h displayed a K i of 8.8 µM and its antimycobacterial activity (MIC 99 = 250 µM) is conceivably related to mycobactin biosynthesis inhibition. These results support the hypothesis that 5-phenylfuran-2-carboxylic derivatives are a promising class of MbtI inhibitors
Novel routes for urban bio-waste management: A combined acidic fermentation and anaerobic digestion process for platform chemicals and biogas production
No full textA combined acidic fermentation and anaerobic digestion (AD) treatment has been developed on pilot scale for urban bio-waste conversion into volatile fatty acid (VFA) and biogas. The specific waste mixture was composed by the pre-treated organic fraction of municipal solid waste (OFMSW) and waste activated sludge (WAS), both produced inside the Treviso (northeast Italy) municipality. The effect of temperature (37 °C and 55 °C) was investigated in both steps. Only the mesophilic fermentation process provided a VFA-rich stream (19.5 g COD VFA /L) with stable physical-chemical features, with no need of chemicals addition for pH control. The sludge buffering capacity made this step technically feasible. The AD step was performed on the solid-rich fraction of fermented bio-waste, after dilution with excess WAS. No relevant differences were observed under the two investigated temperature: in the steady state (organic loading rate of 2.5 kg VS/m 3 d), the specific biogas production was 0.40 and 0.45 m 3 /kg VS at 37 °C and 55 °C respectively, with similar CH 4 content (63–64% v/v). The scaled-up version of the system (in an average urban municipality of 170,000 Person Equivalent) revealed that the whole process is thermally sustainable if both reactors are operated at mesophilic temperature: 36% of surplus thermal energy and 13,03 MWh/d of produced electricity, which corresponds to a revenue of 609,605 €/year. In addition, 2,262 kg COD VFA /d are available for parallel purposes, such as the synthesis of bio-products with higher added value than bio-methane (e.g. biopolymers)
Predicting the performance of cosmopolitan species: dynamic energy budget model skill drops across large spatial scales
No full textIndividual-based models are increasingly used by marine ecologists to predict species responses to environmental change on a mechanistic basis. Dynamic Energy Budget (DEB) models allow the simulation of physiological processes (maintenance, growth, reproduction) in response to variability in environmental drivers. High levels of computational capacity and remote-sensing technologies provide an opportunity to apply existing DEB models across global spatial scales. To do so, however, we must first test the assumption of stationarity, i.e., that parameter values estimated for populations in one location/time are valid for populations elsewhere. Using a validated DEB model parameterized for the cosmopolitan intertidal mussel Mytilus galloprovincialis, we ran growth simulations for native, Mediterranean Sea, populations and non-native, South African populations. The model performed well for native populations, but overestimated growth for non-native ones. Overestimations suggest that: (1) unaccounted variables may keep the physiological performance of non-native M. galloprovincialis in check, and/or (2) phenotypic plasticity or local adaptation could modulate responses under different environmental conditions. The study shows that stationary mechanistic models that aim to describe dynamics in complex physiological processes should be treated carefully when implemented across large spatial scales. Instead, we suggest placing the necessary effort into identifying the nuances that result in non-stationarity and explicitly accounting for them in geographic-scale mechanistic models
Upscaling ecosystem service maps to administrative levels: beyond scale mismatches
No full textAs Ecosystem Services (ES) are the products of complex socio–ecological systems, their mapping requires a deep understanding of the spatial relationships and pattern that underpin ES provision. Upscaling ES maps is often carried out to avoid mismatches between the scale of ES assessment and that of their level of management. However, so far only a few efforts have been made to quantify how information loss occurs as data are aggregated to coarser scales. In the present study this was analyzed for three distinct case studies in the eastern Alps by comparing ES maps of outdoor recreation at the municipality level and at finer scales, i.e. high-resolution grids. Specifically, we adopt an innovative and flexible methodology based on Exploratory Spatial Data Analysis (ESDA), to disentangle the problem of the scale from the perspective of different levels of jurisdiction, by assessing in an iterative process how ES patterns change when upscaling high-resolution maps. Furthermore, we assess the sensitivity to the modifiable areal unit problem (MAUP) by calculating global statistics over three grid displacements. Our results demonstrate that spatial clusters tend to disappear when their extent becomes smaller than the features to which values are upscaled, leading to substantial information loss. Moreover, cross-comparison among grids and the municipality level highlights local anomalies that global spatial autocorrelation indicators fail to detect, revealing hidden clusters and inconsistencies among multiple scales. We conclude that, whenever ES maps are aggregated to a coarser scale, our methodology represents a suitable and flexible approach to explore clustering trends, shape and position of upscaling units, through graphs and maps showing spatial autocorrelation statistics. This can be crucial to finding the best compromise among scale mismatches, information loss and statistical bias that can directly affect the targeted ES mapping
To build or not to build? Megaprojects, resources, and environment: an emergy synthesis for a systemic evaluation of a major highway expansion
No full textSystems thinking and emergy synthesis are applied to transport studies in order to assess the socio-ecological convenience of a civil infrastructure: they are presented as comprehensive evaluation tools to go beyond conventional approaches like cost-benefit analyses, while geobiophysically including the overall resource consumption and the release of pollutants. Focusing on road systems, the massive expansion works on the mountainous section of Italian major highway A1 are chosen as a case study: such recently completed project is compared with the no- build option, considering alternative scenarios ranging from dedicated mobility policies using the old infrastructure to a partial modal shift to rail transport. Results are expressed in terms of total invested emergy, emergy per passenger-kilometer, and per ton-kilometer; data can be easily read also in terms of environmental, physical, and financial units. The convenience of the expansion works results highly questionable: the annually required emergy is shown to significantly increase: +24% for passengers and +51% for freight averagely (i.e., with or without services besides energy and material inputs). A key role is played by saved travelling time (computed as driving labor), able to mitigate but not to reverse the situation while representing a controversial accounting item. Instead, alternative uses and policies for the old infrastructure would all have yielded significant savings. In light of the above, some conclusions are drawn on societal priorities, including a critical reappraisal of time saving as an often unsustainable driver within a still mostly unquestioned 'more and faster' mantra. The need to support ecologically and strategically sustainable societal decision-making in the transportation sector is therefore framed in wider thoughts on economic planning and resource allocation, while envisaging a transformation towards a prosperous and sustainable future
