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Due to its central role in pain, inflammation, and related disorders, the Transient Receptor Potential (TPR) Vanilloid Type-1 (TRPV1) ion channel represents an attractive target for the development of novel antinociceptive and anti-inflammatory agents. Capsaicin, the natural component of chili peppers, is one of the most investigated agonists of this receptor. Several modifications of its structure have been attempted, aiming at finding TRPV1 agonists with improved characteristics, but, to date, no capsaicin-derived agents have reached the market. Based on our previous knowledge of the design and synthesis of TRPV1 agonists, in this paper we propose two small series of indole-2-carboxamides as novel and selective agonists for this ion channel. The newly developed compounds have been structurally characterized and tested in vitro for their ability to modulate TRPV1, in terms of efficacy, potency (EC50), and desensitization (IC50) properties. For the most promising derivatives, selectivity over the TRP ankyrin-1 (TRPA1) channel has been reported. From our study, compound 6g arose as a promising candidate for further evaluation, also in correlation with its in silico-predicted drug-like properties.

Due to its central role in pain, inflammation, and related disorders, the Transient Receptor Potential (TPR) Vanilloid Type-1 (TRPV1) ion channel represents an attractive target for the development of novel antinociceptive and anti-inflammatory agents. Capsaicin, the natural component of chili peppers, is one of the most investigated agonists of this receptor. Several modifications of its structure have been attempted, aiming at finding TRPV1 agonists with improved characteristics, but, to date, no capsaicin-derived agents have reached the market. Based on our previous knowledge of the design and synthesis of TRPV1 agonists, in this paper we propose two small series of indole-2-carboxamides as novel and selective agonists for this ion channel. The newly developed compounds have been structurally characterized and tested in vitro for their ability to modulate TRPV1, in terms of efficacy, potency (EC50), and desensitization (IC50) properties. For the most promising derivatives, selectivity over the TRP ankyrin-1 (TRPA1) channel has been reported. From our study, compound 6g arose as a promising candidate for further evaluation, also in correlation with its in silico-predicted drug-like properties. [ABSTRACT FROM AUTHOR]

The past offers important lessons with regard to facing the future with greater awareness. In this context, school plays a key role in spreading knowledge of natural phenomena and in promoting behavior change. Together with researchers, teachers can be strong allies to build more resilient future citizens. The Istituto Nazionale di Geofisica e Vulcanologia (INGV) school training activities provide tools to prepare for the next earthquake and/or tsunami. Approximately 5000 students, from both middle schools (ISCED 2) and high schools (ISCED 3), were involved in active learning activities based on a flipped-up approach during specific online scientific events during the pandemic. Online lab activities were conducted during European Researchers’ Night (“Earthquakes: history teaches us the future: researchers for a day with experimentation in didactics for ESL”) and during both World Water Day 2021 and World Earth Day 2021 (“Tsunamis: history teaches us the future researchers for a day with experimentation in didactics for ESL”). These two Episodes of Situated Learning (ESL) experiences triggered students’ interest, favoring remote learning, developing life skills, and focusing on historical seismic studies of both past earthquakes and tsunamis.

Objectives This study aims to evaluate oncological outcomes in women affected by locally advanced cervical cancer (LACC) treated by neoadjuvant chemotherapy before radical surgery (NACT + RS) or concurrent chemo-radiotherapy (CCRT). Methods This was a multicenter retrospective analysis of data related to women with LACC (FIGO stage IB2-IVA), who were treated by NACT + RS or CCRT between November 2006 and January 2018. The first endpoints were the evaluation of disease-free survival (DFS) and overall survival (OS); univariate and multivariate analyses were performed for identifying the prognostic factors independently associated with these oncological outcomes. Results Overall, 106 women were included in the analysis; 55 of them (51.9%) underwent NACT + RS and 51 (48.1%) CCRT, respectively. Patients in the NACT + RS group had a significant better five-year DFS and five-year OS than those in the CCRT group (77.4% vs. 33.4%, p

Envenomations by snakes represent a neglected health problem in tropical and subtropical countries. In South America, Lachesis muta occasionally causes severe human envenomation, with treatment being conditioned to an unspecific antivenom. In this work, we examined the neutralizing ability of Coutarea hexandra stem bark hydroalcoholic extract (Ch‐E), including the commercial phytochemicals coumarin and quinine, on the neuromuscular blockade induced by L. m. muta venom in mouse phrenic nerve‐diaphragm preparation. Biological assays were performed following conventional myographic technique ex vivo. Ch‐E was phytochemically characterized to detect the presence of coumarin and quinine using analytical methods. Ch‐E and commercial phytochemicals were tested separately or combined under pre‐ and post‐venom incubation protocols. Ch‐E attenuated the venom‐induced neuromuscular blockade only under the pre‐venom incubation protocol. Quinine was not detected in Ch‐E. Commercial coumarin and quinine exhibited a concentration‐dependent counteracting effect on the venom‐induced neuromuscular blockade. The pre‐venom incubation protocol showed to be efficient in attenuating the L. m. muta venom–induced neuromuscular blockade, most likely due to the presence of coumarin derivatives and unknown alkaloids in this extract. [ABSTRACT FROM AUTHOR]

We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood-brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity. Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol and behaves as a cannabinoid (CB1/CB2) receptor indirect agonist. Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin. Given these evidence, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.

Educational and training initiatives for natural hazard reduction, climate change, and environmental sustainability are increasingly common. We describe educational games in which the protagonist, a fictional character girl, saves herself and others from natural disasters. This girl faces risk situations, from earthquake to flood to environmental challenges, and for each of these she is the protagonist of educational quizzes and of an escape room. These games were designed and played online during the COVID-19 pandemic, to introduce an engaging activity, reducing the difficulties of both students and teachers in distance learning. Simultaneous challenges between several classes were played during special scientific events, with a total of more than 8000 students flanked by about 500 teachers, always with very positive feedback. We pooled our knowledge to embrace innovation in gamification at school. Our games aim at increasing the response capacity of future more resilient citizens to protect themselves and others, adapting to natural risks, and to spread good practices in support of the civil protection. Each online race between classes from primary and middle school (ISCDE 2) is based on cooperative learning and followed by an important debriefing moment of reflective learning, guided by researchers to deeply analyze scientific topics.

Quercetin and ferulic acid are two phytochemicals extensively represented in the plant kingdom and daily consumed in considerable amounts through diets. Due to a common phenolic structure, these two molecules share several pharmacological properties, e.g., antioxidant and free radical scavenging, anti-cancer, anti-inflammatory, anti-arrhythmic, and vasorelaxant. The aim of the present work was the combination of the two molecules in a single chemical entity, conceivably endowed with more efficacious vasorelaxant activity. Preliminary in silico studies herein described suggested that the new hybrid compound bound spontaneously and with high affinity on the KCa1.1 channel. Thus, the synthesis of the 3′-ferulic ester derivative of quercetin was achieved and its structure confirmed by 1H- and 13C-NMR spectra, HSQC and HMBC experiments, mass spectrometry, and elementary analysis. The effect of the new hybrid compound on vascular KCa1.1 and CaV1.2 channels revealed a partial loss of the stimulatory activity that characterizes the parent compound quercetin. Therefore, further studies are necessary to identify a better strategy to improve the vascular properties of this flavonoid.

Traditional tsunami catalogues are conceived as a collection of tsunamis classified by the generating cause, providing a general description of the effects observed for each tsunami. Those catalogues, even if they provide fundamental information, are not suitable for producing an exhaustive picture of the geographical distribution of the tsunami effects. In this paper we introduce the new Italian Tsunami Effects Database (ITED), a collection of evidence documenting the effects along the Italian coasts from historical times to present. The database comes forth the Euro-Mediterranean Tsunami Catalogue (EMTC) and focusses on the effects of tsunamis observed along the Italian coasts providing descriptive and quantitative information for each OP. The information reported in ITED does not only concern the effects produced by Italian tsunamis, but also those effects produced by tsunamis originated outside the Italian territory. ITED contains 318 OPs, related to 73 Italian tsunamis and to four tsunamis which occurred outside Italy. The database can be accessed through a WebApp that displays for each OP the description of effects, quantitative data (run-up, inundation, withdrawal, etc.) and tsunami intensity with the corresponding bibliographic references. The database also provides the tsunami intensity distribution along time (tsunami-history) for each site, allowing the end user to know how a place has been affected by tsunamis over the time. The information contained in ITED makes this database a useful tool to understand how tsunamis have affected the Italian territory and emphasizes the importance of studying the tsunami hazard along the Italian coasts.

A general method for the synthesis of pyrrolizidine derivatives using an intramolecular hydroaminomethylation protocol (HAM) under microwave (MW) dielectric heating is reported. Starting from a 3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-vinylpyrrolidine, MW-assisted intramolecular HAM in the presence of gaseous H2 and CO gave the natural alkaloid hyacinthacine A2 protected as benzyl ether. The same approach gave a lentiginosine analogue starting from the corresponding vinyl N-hydroxypyrrolidine. The nature of the reaction products and the yields were strongly influenced by the relative stereochemistry of the starting pyrrolidines, as well as by the catalyst/ligand employed. The use of ethanol as a solvent provides environmentally friendly conditions, while the ligand/catalyst system can be recovered by separating the alkaloid product with an SCX column and recycling the ethanolic solution. HAM worked up to three times with the recycled catalyst solution without any significant impact on yield.

In the frame of the Interreg Italy-Croatia program, the EU has funded the PMO-GATE project, focusing on the prevention and mitigation of the socioeconomic impact of natural hazards in the Adriatic region. The Database of Adriatic Tsunamis and Meteotsunamis (DAMT) is one of the deliverables of this project. DAMT is a collection of data documenting both meteotsunami and tsunami effects along the Eastern and Western Adriatic coasts, and it was realized by starting from the available database and catalogues, with the inclusion of new data gained from recent studies, newspapers and websites. For each tsunami and meteotsunami, the database provides an overview of the event and a detailed description of the effects observed at each affected location and gives a picture of the geographical distribution of the effects. The database can be accessed through a GIS WebApp, which allows the user to visualize the georeferenced information on a map. The DAMT WebApp includes three layers: (1) Adriatic Tsunami Sources, (2) Adriatic Tsunami Observation Points and (3) Adriatic Meteotsunamis Observation Points. The database contains 57 observations of tsunami effects related to 27 tsunamis along the Italian, Croatian, Montenegrin and Albanian coasts and 102 observations of meteotsunami effects related to 33 meteotsunamis.

The past offers important lessons with regard to facing the future with greater awareness. In this context, school plays a key role in spreading knowledge of natural phenomena and in promoting behavior change. Together with researchers, teachers can be strong allies to build more resilient future citizens. The Istituto Nazionale di Geofisica e Vulcanologia (INGV) school training activities provide tools to prepare for the next earthquake and/or tsunami. Approximately 5000 students, from both middle schools (ISCED 2) and high schools (ISCED 3), were involved in active learning activities based on a flipped-up approach during specific online scientific events during the pandemic. Online lab activities were conducted during European Researchers' Night ("Earthquakes: history teaches us the future: researchers for a day with experimentation in didactics for ESL") and during both World Water Day 2021 and World Earth Day 2021 ("Tsunamis: history teaches us the future researchers for a day with experimentation in didactics for ESL"). These two Episodes of Situated Learning (ESL) experiences triggered students' interest, favoring remote learning, developing life skills, and focusing on historical seismic studies of both past earthquakes and tsunamis. [ABSTRACT FROM AUTHOR]

In the recent original research published on International Journal of Fertility and Sterility the association between tumor necrosis factor-alpha (TNF-α) genetic polymorphisms and endometriosis in 150 Iranian patients suffered this disease. The authors notably found a lower frequency of TNF-α -863C/A allele A among the affected patients in comparison with healthy women, although this difference was not significant by adjusting multiple testing. We deem that the authors should specify, if these patients had peritoneal nodules, ovarian endometrioma/deep infiltrating endometriosis (DIE) nodules or combination of them, since it has been hypothesized that these phenotypes may represent three distinct pathogenetic entities of endometriosis.

Based on a careful analysis of Palazzeschi’s works and of the correspondence between him and Marinetti, the essay casts a new light on the origin of futurist synthetic theatre. With his prose and verses Palazzeschi is in fact the first to make use of synthetic writing and to bring a fulmineous dialogic form within the Futurism; he also develops a grotesque way to futurist theatre and between 1910 and 1911 plans to write a collection of Futurist Dramas, some elements of which can be found in some short proses published afterwards by the author.