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BACKGROUND: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. In silico models built using existing data facilitate rapid acute toxicity predictions without using animals. OBJECTIVES: The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop in silico models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 (LD50 value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [LD50 (LD50≤50mg/kg)], and nontoxic chemicals (LD50>2,000mg/kg). METHODS: An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches. RESULTS: The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with in vivo results. DISCUSSION: CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for in vivo rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495.

International audience; The evolution of antibacterial resistance has arisen as the main downside in fighting bacterial infections pushing researchers to develop novel, more potent and multimodal alternative drugs.Silver and its complexes have long been used as antimicrobial agents in medicine due to the lack of silver resistance and the effectiveness at low concentration as well as to their low toxicities compared to the most commonly used antibiotics. N-Heterocyclic Carbenes (NHCs) have been extensively employed to coordinate transition metals mainly for catalytic chemistry. However, more recently, NHC ligands have been applied as carrier molecules for metals in anticancer applications. In the present study we selected from literature two NHC-carbene based on acridinescaffoldand detailed nonclassicalpyrazole derived mono NHC-Ag neutral and bis NHC-Ag cationic complexes. Their inhibitor effect on bacterial strains Gram-negative and positivewas evaluated. Imidazolium NHC silver complex containing the acridine chromophore showed effectiveness at extremely low MIC values. Although pyrazole NHC silver complexes are less active than the acridine NHC-silver, they represent the first example of this class of compounds with antimicrobial properties. Moreover all complexesare not toxic and they show not significant activity againstmammalian cells (Hek lines) after 4 and 24 h. Based on our experimental evidence, we are confident that this promising class of complexes could represent a valuable starting point for developing candidates for the treatment of bacterial infections, delivering great effectiveness and avoiding the development of resistance mechanisms.

Questa ricerca intende offrire un contributo per la ricostruzione delle più significative vicende legate alle ricerche archeologiche condotte nel Settecento in Puglia, segnatamente in Terra di Bari, al fine di esaminare i provvedimenti normativi che disciplinavano gli scavi archeologici, di disegnare il profilo dei funzionari deputati al controllo di tali attività e di riconoscere i rapporti tra istituzioni centrali e autorità locali impegnate a gestire la prassi delle incipienti forme di tutela del patrimonio culturale. La trascrizione e l’analisi di 64 documenti, quasi tutti inediti, datati 1751-1798 e conservati presso archivi istituzionali di Trani e Napoli, hanno permesso di delineare aspetti salienti relativi alla legislazione dei beni culturali e alle indagini archeologiche condotte nel XVIII secolo nell’Italia sud-orientale sotto la dinastia dei Borbone. This research intends to make a contribution to reconstruct the most significant events related to the archaeological research conducted in the eighteenth century in Apulia, particularly in the Terra di Bari, in order to examine the regulatory provisions governing archaeological excavations, to outline the profile of the officials appointed to control of these activities and to recognize the relationships between central institutions and local authorities committed to managing the practice of incipient forms of protection of cultural heritage. The transcription and analysis of 64 archival documents, dated 1751-1798 and preserved in the institutional archives of Trani and Naples, have allowed us to outline several salient aspects relating to the legislation of cultural heritage and archaeological investigations conducted in the 18th century in South-Eastern Italy under the Bourbon dynasty.

In H. Demo, S. Cappello & V. Macchia (Eds.), Didattica e inclusione scolastica – Inklusion im Bildungsbereich, Emergenze educative – Neue Horizonte (pp. 117–132).

The collected data reported in this document gives mainly positive feedback on Virtual Toolkit (IO2), highlighting some interesting and relevant elements that can be further developed in its final release. The group of respondents have a quite long average experience in managing inter-institutional projects and belong to the EU-defined main participants groups of Managers (22), Teachers/Trainers/Researchers/Youth workers (17), Technicians (3) and Administrative staff (5). Of the 8 indicators outlined in the original ONE Meeting Project proposal, 5 were met, 3 not. The 4 reached indicators were Usefulness & Relevance, Impact on Virtual Transnational Collaboration, Willingness to recommend to a colleague or professional contact and Willingness to use the IO2 Virtual Toolkit by decision makers. Willingness to use Virtual Toolkit by decision makers was positive result, with room for improvement. In addition, the following 3 indicators which reached improvable result need a closer analysis. Impact on Managerial and Digital Competences (the target was 90%, we reached 82%). All respondents who gave less positive answers were highly experienced and they left a detailed response including tool suggestions to the open question. Impact on Transnational Project Design and Implementation (the target was 90%/we reached 64%). Less positive evaluations tended to come from respondents with higher degrees of experience. This may indicate that experienced project managers while already using a wide variety of digital tools in their daily work had higher expectations for the Virtual Toolkit. Willingness to use IO2 Virtual Toolkit by project managers (the target was 70%/we reached 51%) reached improvable results. According to the Net Promoter Score (NPS) tool (Reichheld, 2003), 55 % is generally seen as a good result in terms of product reception. The answers to the final open question provided valuable information. Half of the 48 respondents gave useful feedback which was analysed based on the themes that emerged from the data. These eight themes were identified: Appreciation for the Virtual Toolkit, Accessibility and Usability, Open source/fee based, Sustainability, Layout and Graphical design, Tips for improvement, Relevance (for target group) and Dissemination. Some themes recurred through different answers, some of them were unique to a specific response. There was also one new theme, GDPR issues, that was not asked in the survey but that was mentioned by several respondents. Since this theme was relevant for the ONE Meeting Project, it was added into the analysis of the data. When proceeding with the analysis, we grouped the themes found in the three areas of impact envisioned for the ONE Meeting Project: Methods and tools, Collaborative Project Management, Environmental Awareness & Sustainability. Some of the suggestions coming from the reviewers were highlighted and attributed to a priority level which was based on the issue how relevant they were for the “ONE Meeting Approach”. High priority was given to GDPR issues (adding a GDPR logo into each tool and a link to web pages were GDPR information is available) and Dissemination (Adding Virtual Toolkit in the European Lifelong Learning Platform) and Tips for Improvement (Create links from the table of content into each tool). Medium priority was given to Tips for improvement (Create anchors/links from the overview to the tools in page 5 in the Virtual Toolkit) and Sustainability (Ensure the sustainability of Virtual Toolkit after ONE Meeting project has ended). nonPeerReviewed

This study presents the metaphors that emerged from a group of 22 teachers interviewed about their switch to remote instruction during the COVID-19 pandemic. The main theoretical framework adopted to study the emergency teaching situation (Hodges et al., 2020) was that of smart learning, defined as ‘context-aware ubiquitous learning’ (Hwang, 2014) and as centred on content, rather than on devices (Gwak, 2010). Primary school teachers from Italy were interviewed about online and smart learning. Following the idea that proficiency can not exist without the ability to reflect on and about actions (Nuzzaci 201), participants were asked to describe their experiences by choosing images or ideas that would represent them. The use of metaphors allowed us to better understand their feelings related to the condition of emergency teaching. Data from the interviews was classified in four emerging themes used by participants: a. distance – picturing themselves as TV characters only available to students through a screen, or as pictures hanging from a wall, teachers felt the weight of barriers over their relationships with classes; b. responsibility and co-responsibility – reflection became an opportunity to question responsibility, as teachers felt like a lighthouse for their pupils, trying to help in overcoming their difficulties; other sea-related metaphors, like that of a lone sailor and a huge storm, or a deep abyss, tell the story of a very difficult situation in which references were lost; on a more positive note, some teachers saw this situation as a possibility for the blooming of new competencies and new co-responsibility links with families – a kite built with pupils but led by a teacher; c. the wasteland – this group of metaphors mostly involved Special Education teachers, who felt disconnected from pupils ‘like a rock at the bottom of a river’, or screaming in a nightmare depicted as a variant of Munch’s Scream; the difficulty or impossibility to have meaningful relationships with children with special needs affected the teachers’ morale and sense of fear; d. travelling between two worlds – seeing the remote teaching experience as a journey, teachers felt like abandoning a well-known habitat to explore distant and unexplored worlds, mostly based on an ‘analogic vs digital’ discourse; many participants felt that this change was non-reversible, as the future scenarios will always have to come to terms with what happened during the pandemic period.

During the COVID-19 pandemic, the need for digitalized teaching and learning materials became prominent, especially in simpler forms of asynchronous teaching (Daniel, 2020), generating inequalities in opportunities for access (Jæger & Blaabæk, 2020) as well as organizational issues at various levels (Kerres, 2020). The production of inclusive, digital learning materials became a priority for many teachers, who had to upgrade their digital skills. As a possible way to lower barriers to this process, we propose a simple technique to create “augmented PDF files”. This technique is based on very low technological requirements (i.e., free software that most people already have on their computers) and requires very low levels of multimedia production skills (i.e., it is possible to incorporate various types of content in the same document in a very intuitive way). The teacher can hence concentrate on content selection and teaching strategy (Mangiatordi, 2019). Initial testing of this technique with a group of in-service teachers (N=114) showed that it was perceived as compatible with a wide array of digital literacy levels, making the application of UDL guidelines and checkpoints (Meyer & Hall, 2006; Rose & Meyer, 2002) easier and more sustainable. Using again the UDL framework, we evaluated the learning materials produced in the context of a university course about educational technology for prospective teachers (N=99) after a specific class about possible inclusive uses of augmented PDF files. By observing the digital learning materials produced by participants and the short descriptions of their intended use, we were able to confirm that also users with lower levels of perceived self-efficacy in technology use could take advantage of this technique to comply with major UDL principles. The main principle that participants could invest in was that of “providing multiple means of representation”, but also the areas of “engagement” and “action and expression” could be empowered. The main issue we observed, requiring immediate attention especially in distant learning scenarios generated by the pandemic, is the high risk of cognitive overload that could derive from excessive or not focused use of this kind of learning materials. References Daniel, S. J. (2020). Education and the COVID-19 pandemic. PROSPECTS, 49(1–2), 91–96. https://doi.org/10.1007/s11125-020-09464-3 Jæger, M. M., & Blaabæk, E. H. (2020). Inequality in learning opportunities during Covid-19: Evidence from library takeout. Research in Social Stratification and Mobility, 68, 100524. https://doi.org/10.1016/J.RSSM.2020.100524 Kerres, M. (2020). Against All Odds: Education in Germany Coping with Covid-19. Postdigital Science and Education, 2(3), 690–694. https://doi.org/10.1007/s42438-020-00130-7 Mangiatordi, A. (2019). Costruire inclusione. Progettazione universale e risorse digitali per la didattica. Milano: Guerini. Meyer, A., & Hall, T. E. (2006). Applying universal design for learning in the classroom. New York: The Guilford Press. Retrieved from http://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:Universal+Design+for+Learning+in+the+Classroom#8 Rose, D., & Meyer, A. (2002). Teaching Every Student in the Digital Age: Universal Design for Learning. Alexandria, VA: ASCD.

Mindfulness can be defined as the ability to pay attention intentionally, in the present moment and in a non-judgmental manner. Some studies have demonstrated its effectiveness as a clinical therapy applied to children with ADHD, who manifest an inability to regulate their behavior according to the passage of time, the goals to be achieved and the demands of the environment. The objective is to investigate the effects produced by the Mindfulness program “Il Fiore Dentro” in children with ADHD. It is hypothesized to find differences between the pre-training situation and the post-training situation in attention, executive function, working memory, hyperactivity and impulsivity. Ten children, divided into two groups, with a diagnosis of ADHD, were selected and given specific assessment instruments. Subsequently they took part in the 8 meetings of the program and at the end the tests were administered again. The research design is a mixed design: both the difference between the two groups, which excluded the possible influence of different settings and operators, and the difference between pre- and post-training tests were tested. The training produces positive results in several dimensions: selective and sustained visuospatial attention, executive functions, visual memory, impulsivity and hyperactivity. The increase in social withdrawal is worthy of attention and could be linked to an initial stage of reorganization of one's behavior with the peer group. The results allowed to confirm the effectiveness of Mindfulness in the treatment of ADHD in the sample that took part in the training. The limitations of the research include the small sample size, the absence of a control group and follow-up. Finally, due to the COVID-19 Pandemic (still ongoing) the research suffered in terms of data collection.

Purpose: SARS-CoV-2 is a new pandemic influenza caused by a coronavirus which main route of transmission is through exhaled droplets that primarily infect the nose and the nasopharynx. The aim of this paper is to evaluate the effect of acetic acid, the active component of vinegar, as a potential disinfectant agent for upper airways. Methods: Twenty-nine patients were enrolled and divided into two groups: group 1 (14 patients) was composed of patients treated with off-label hydroxychloroquine and lopinavir/ritonavir, whereas group 2 (15 patients) was composed of patients treated with hydroxychloroquine only, combined with the inhalation of acetic acid disinfectant at a 0.34% concentration. A questionnaire-based evaluation of symptoms was performed after 15days in both groups. Results: It appears that the number of patients treated with acetic acid (group 2) that experienced improvement in individual symptoms was double that of the other group of patients (group 1), although numbers are too small for robust statistical analysis. Conclusions: Considering its potential benefits and high availability, acetic acid disinfection appears to be a promising adjunctive therapy in cases of non-severe COVID-19 and deserves further investigation.

[Image: see text] In the face of the clinical challenge posed by non-small cell lung cancer (NSCLC), the present need for new therapeutic approaches is genuine. Up to now, no proof existed that 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a viable target for treating this disease. Synthesis of a rationally designed library of 2,5-disubstituted furan derivatives followed by biological screening led to the discovery of 17β-HSD1 inhibitor 1, capable of fully inhibiting human NSCLC Calu-1 cell proliferation. Its pharmacological profile renders it eligible for further in vivo studies. The very high selectivity of 1 over 17β-HSD2 was investigated, revealing a rational approach for the design of selective inhibitors. 17β-HSD1 and 1 hold promise in fighting NSCLC.

Drug-induced blockade of the human ether-à-go-go-related gene (

Besides their nutritional value, whey protein (WP) peptides are food components retaining important pharmacological properties for controlling hypertension. We herein report how the use of complementary experimental and theoretical investigations allowed the identification of novel angiotensin converting enzyme inhibitory (ACEI) peptides obtained from a WP hydrolysate and addressed the rational design of even shorter sequences based on molecular pruning. Thus, after bromelain digestion followed by a 5 kDa cutoff ultrafiltration, WP hydrolysate with ACEI activity was fractioned by RP-HPLC; 2 out of 23 collected fractions retained ACEI activity and were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In the face of 128 identified peptides, molecular docking was carried out to prioritize peptides and to rationally guide the design of novel shorter and bioactive sequences. Therefore, 11 peptides, consisting of 3-6 amino acids and with molecular weights in the range from 399 to 674 Da, were rationally designed and then purchased to determine the IC50 value. This approach allowed the identification of two novel peptides: MHI and IAEK with IC50 ACEI values equal to 11.59 and 25.08 μM, respectively. Interestingly, we also confirmed the well-known ACEI IPAVF with an IC50 equal to 9.09 μM. In light of these results, this integrated approach could pave the way for high-throughput screening and identification of new peptides in dairy products. In addition, the herein proposed ACEI peptides could be exploited for novel applications both for food production and pharmaceuticals.

A series of eleven ethoxysubstituted chalcones (E1-E11) were synthesized and investigated for their inhibitory potential towards human recombinant monoamine oxidase A and B (hMAO-A and hMAO-B, respectively) and acetylcholinesterase (AChE). IC50 values of 4.63 +/- 0.15 and 0.053 +/- 0.003 mu M were obtained for MAO-A and MAO-B, respectively, by the most interesting compound (2E)-1-(4-ethoxyphenyl)-3-(4-fluorophenyl)prop-2-en-1-one (E7), and it was characterized by a high selectivity index (SI=87.4) for MAO-B. Inhibitions by E7 against MAO-A and MAO-B were recovered (75.9 and 74.5%, respectively) to near the levels of reversible references (77.1 and 77.4%, respectively). The inhibition modes of E7 for MAO-A and MAO-B were competitive with K-i values of 2.65 +/- 0.064 and 0.011 +/- 0.0011 mu M, respectively. Compounds (2E)-1-(4-ethoxyphenyl)-3-(4-ethylphenyl) prop-2-en-1-one (E10) and (2E)-1-(4-ethoxyphenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one (E11) showed good inhibitions against AChE with IC50 values of 2.86 +/- 0.041 and 3.23 +/- 0.0073 mu M, respectively. A combined molecular docking/MM-GBSA approach was used that employed quantum mechanics (QM) partial charges; this technique revealed the molecular rationale behind the observed MAO-B selectivity for this molecular series. Taken together, these results indicate that E7 is a potent, selective and reversible competitive inhibitor of MAO-B with moderately potent AChE inhibitory activity that has potential as a multi-targeting drug

Despite the increasing incidence of hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that lysophosphatidic acid receptor 6 (LPAR6) supports HCC growth and that 9-xanthenylacetic acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)-2-(9H-xanthen-9-yl)propanoic acid (compound 4 - MC9), (±)-2-(9H-xanthen-9-yl)butanoic acid (compound 5 - MC6), (±)-2-(9H-xanthen-9-yl)hexanoic acid (compound 7 - MC11), and (±)-2-(9H-xanthen-9-yl)octanoic acid (compound 8 - MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α-carbon atom. Two of these compounds were characterized by X-ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti-HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA-based LPAR6 antagonists.