Asymmetric synthesis of (1R, 5S)-2-methyl-6, 7-benzomorphan via Aza-Prins reaction

(1R, 5S)-2-Methyl-6, 7-benzomorphan has been synthesised from (R)-(benzyloxy)(phenyl)acetaldehyde. On a 2-mmol scale Bi (OTf)3 promoted Aza-Prins reaction with N-tosylhomoallylamine afforded an 88/12 mixture of 6-oxa-2-azabicyclo[3.2.1]octanes. Major diastereoisomer was converted to enantiomerically pure (2S, 4S)-2-benzyl-1- methylpiperidin-4-ol via a high-yielding sequence hydrogenolysis/N-detosylation/N-methylation. Acid-catalysed intramolecular Friedel-Crafts cyclisation of the piperidinol afforded (1R, 5S)-2-methyl-6, 7-benzomorphan in five steps with a yield of 25%. © 2021 The Authors. Chirality published by Wiley Periodicals LLC

Design, synthesis and structure-activity evaluation of novel 2-pyridone-based inhibitors of a-synuclein aggregation with potentially improved BBB permeability

The treatment of Parkinson''s disease (PD), the second most common neurodegenerative human disorder, continues to be symptomatic. Development of drugs able to stop or at least slowdown PD progression would benefit several million people worldwide. SynuClean-D is a low molecular weight 2-pyridone-based promising drug candidate that inhibits the aggregation of a-synuclein in human cultured cells and prevents degeneration of dopaminergic neurons in a Caenorhabditis elegans model of PD. Improving SynuClean-D pharmacokinetic/pharmacodynamic properties, performing structure/activity studies and testing its efficacy in mammalian models of PD requires the use of gr-amounts of the compound. However, not enough compound is on sale, and no synthetic route has been reported until now, which hampers the molecule progress towards clinical trials. To circumvent those problems, we describe here an efficient and economical route that enables the synthesis of SynuClean-D with good yields as well as the synthesis of SynuClean-D derivatives. Structure-activity comparison of the new compounds with SynuClean-D reveals the functional groups of the molecule that can be disposed of without activity loss and those that are crucial to interfere with a-synuclein aggregation. Several of the derivatives obtained retain the parent''s compound excellent in vitro anti-aggregative activity, without compromising its low toxicity. Computational predictions and preliminary testing indicate that the blood brain barrier (BBB) permeability of SynuClean-D is low. Importantly, several of the newly designed and obtained active derivatives are predicted to display good BBB permeability. The synthetic route developed here will facilitate their synthesis for BBB permeability determination and for efficacy testing in mammalian models of PD. © 2021 The Author

Descriptive Analysis of the Performance of a Vegetated Swale through Long-Term Hydrological Monitoring: A Case Study from Coventry, UK

Vegetated swales are a popular sustainable drainage system (SuDS) used in a wide range of environments from urban areas and transport infrastructure, to rural environments, sub-urban and natural catchments. Despite the fact that vegetated swales, also known as grassed swales, have received scientific attention over recent years, especially from a hydrological perspective, there is a need for further research in the field, with long-term monitoring. In addition, vegetated swales introduce further difficulties, such as the biological growth occurring in their surface layer, as well as the biological evolution taking place in them. New developments, such as the implementation of thermal devices within the cross-section of green SuDS for energy saving purposes, require a better understanding of the long-term performance of the surface temperature of swales. This research aims to contribute to a better understanding of these knowledge gaps through a descriptive analysis of a vegetated swale in Ryton, Coventry, UK, under a Cfb Köppen climatic classification and a mixed rural and peri-urban scenario. Precipitation and temperature patterns associated with seasonality effects were identified. Furthermore, a level of biological evolution was described due to the lack of periodical and planned maintenance activities, reporting the presence of both plant species and pollinators. Only one event of flooding was identified during the three hydrological years monitored in this research study, showing a robust performance

Development of a Multicriteria Scheme for the Identification of Strategic Areas for SUDS Implementation:A Case Study from Gijón, Spain

Spain has been pinpointed as one of the European countries at major risk of extreme urban events. Thus, Spanish cities pursue new urban plans to increase their resilience. In this scenario, experiences in the implementation of Sustainable Urban Drainage Systems (SUDS) have increased substantially. Nevertheless, few cities have developed a global urban strategy for SUDS, lacking, in many cases, a method to identify strategic areas to maximize their synergetic benefits. Furthermore, there is still a need for a holistic Multicriteria Decision Analysis (MCDA) framework that considers the four pillars of SUDS design. The city of Gijón, NW Spain, has been selected as a case study due to its environmental and climatic stresses. This research presents the methodology developed for this city, which aims to analyze the need for SUDS implementation throughout the identification of strategic areas. With this aim, a combination of Geographic Information System (GIS) software and the MCDA Analytical Hierarchical Process (AHP) were proposed. The results show the potential for SUDS’ implementation, according to nine criteria related to the SUDS’ design pillars. We found that the areas where the implementation of SUDS would bring the greatest functional, environmental and social benefits are mainly located in consolidated urban areas

Evaluating the thermal performance of Wet Swales housing Ground Source Heat Pump elements through laboratory modelling

The authors wish to acknowledge the CAWR, Coventry University, for the administrative support; and the GITECO Research Group, University of Cantabria, for housing the laboratory experiments.Land-use change due to rapid urbanization poses a threat to urban environments, which are in need of multifunctional green solutions to face complex future socio-ecological and climate scenarios. Urban regeneration strategies, bringing green infrastructure, are currently using sustainable urban drainage systems to exploit the provision of ecosystem services and their wider benefits. The link between food, energy and water depicts a technological knowledge gap, represented by previous attempts to investigate the combination between ground source heat pump and permeable pavement systems. This research aims to transfer these concepts into greener sustainable urban drainage systems like wet swales. A 1:2 scaled laboratory models were built and analysed under a range of ground source heat pump temperatures (20–50 ºC). Behavioral models of vertical and inlet/outlet temperature difference within the system were developed, achieving high R2, representing the first attempt to describe the thermal performance of wet swales in literature when designed alongside ground source heat pump elements. Statistical analyses showed the impact of ambient temperature and the heating source at different scales in all layers, as well as, the resilience to heating processes, recovering their initial thermal state within 16 h after the heating stage

A pyrene-inhibitor fluorescent probe with large stokes shift for the staining of Aβ1–42, α-synuclein, and amylin amyloid fibrils as well as amyloid-containing staphylococcus aureus biofilms

Amyloid fibrils formed by a variety of peptides are biological markers of different human diseases, such as Alzheimer, Parkinson or Type II diabetes, and are structural constituents of bacterial biofilms. Novel fluorescent probes offering improved sensitivity or specificity towards that diversity of amyloid fibrils, or providing alternative spectral windows are needed to improve the detection or the identification of amyloid structures. One potential source for such new probes is offered by molecules known to interact with fibrils, such as the inhibitors of amyloid aggregation found in drug discovery projects. Here, we show the feasibility of the approach by designing, synthesizing and testing several pyrene-based fluorescent derivatives of a previously discovered inhibitor of the aggregation of the Aβ1-42 peptide. All the derivatives tested retain the interaction with the amyloid architecture and allow its staining. The more soluble derivative, compound 1D, stains similarly well amyloid fibrils formed by Aβ1-42, α-synuclein or amylin, provides a sensitivity only slightly lower than that of Thioflavin T, displays a large Stokes shift, allows an efficient excitation in the UV spectral region,and it is not cytotoxic. Compound 1D can also stain amyloid fibrils formed by Staphylococcal peptides present in biofilm matrices and can be used to distinguish, by direct staining,S. aureus biofilms containing amyloid forming phenol soluble modulins from those lacking them.IL is supported by the Spanish Ministry of Economy and Competitiveness grant BIO2014-53530-R. SVis supported by grant BIO2016-783-78310-R and by ICREA (ICREA Academia 2015). MDD is supported by the Government of Aragon (GA E-102). JS is supported by grants BFU2016-78232-P (MINECO, Spain) and E45_17R (Gobierno de Aragón, Spain). JS and IL acknowledge financial support from grant CI-2017/001-3 (Campus Iberus, Spain). AM was a recipient of a predoctoral FPU fellowship from the Spanish Government

Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase

Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ¿¿Gb values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

TEMPORAL AND SPATIAL VARIABILITY OF ATMOSPHERIC PARTICLE NUMBER SIZE DISTRIBUTIONS ACROSS SPAIN

This study synthesizes for the first time results from simultaneous aerosol measurements performed at seven diverse locations distributed all over the Spanish geography. The observations were carried out during two field campaigns in 2012–2013, one-month each and during different seasons. These field campaigns were performed in the framework of the Spanish Network of DMAs (REDMAAS) activities. Measurement sites were grouped as polluted sites (urban background) and clean sites (rural background and high-altitude sites). Seasonal differences were more important at polluted sites, mainly related to meteorology and aerosol sources. Higher total particle concentrations were found during the cold period, driven mainly by Aitken-mode particles (traffic-related aerosol particles).This work has been financed by the Ministry of Science and Innovation (CGL2011-15008-E, CGL2010-1777, CGL2011-27020, CGL2014-52877-R, CGL2010-11095-E, CGL2012-39623-C02-01, CGL2014-55230-R & PI15/0051

Selective targeting of human and animal pathogens of the helicobacter genus by flavodoxin inhibitors: Efficacy, synergy, resistance and mechanistic studies

Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter py-lori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradication therapies poses great challenges and urges the development of novel, ideally narrow spectrum, antimicrobials targeting H. pylori. Here, we describe the antimicrobial spectrum of a family of nitrobenzoxadiazol-based antimicrobials initially discovered as inhibitors of flavodoxin: an essential H. pylori protein. Two groups of inhibitors are described. One group is formed by nar-row-spectrum compounds, highly specific for H. pylori, but ineffective against enterohepatic Helico-bacter species and other Gram-negative or Gram-positive bacteria. The second group includes ex-tended-spectrum antimicrobials additionally targeting Gram-positive bacteria, the Gram-negative Campylobacter jejuni, and most Helicobacter species, but not affecting other Gram-negative pathogens. To identify the binding site of the inhibitors in the flavodoxin structure, several H. pylori-flavodoxin variants have been engineered and tested using isothermal titration calorimetry. An initial study of the inhibitors capacity to generate resistances and of their synergism with antimicrobials commonly used in H. pylori eradication therapies is described. The narrow-spectrum inhibitors, which are ex-pected to affect the microbiota less dramatically than current antimicrobial drugs, offer an oppor-tunity to develop new and specific H. pylori eradication combinations to deal with AMR in H. pylori. On the other hand, the extended-spectrum inhibitors constitute a new family of promising antimi-crobials, with a potential use against AMR Gram-positive bacterial pathogens. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Trastornos psicóticos en el servicio de urgencias de un Hospital General.

El presente artículo pretende reflexionar acerca del papel que los Servicios de Urgencia Psiquiátrica están teniendo en la atención del paciente psicótico no institucionalizado, en el marco particular de un Area Sanitaria en plena reestructuración. Para ello se analizan diversos datos de los pacientes atendidos en el Servicio General de Urgencias de un Hospital General que fueron diagnosticados como trastornos psicóticos, tratándose de valorar los factores que influyen en la decisión de ingreso así como la interrelación entre la Urgencia Psiquiátrica y el resto de los dispositivos asistenciales