Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit <i>Trypanosoma brucei </i>Pteridine Reductase in Support of Early-Stage Drug Discovery

Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 μM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained

Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion\u2013toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 (TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain

The wide world of technological telerehabilitation for pediatric neurologic and neurodevelopmental disorders – a systematic review

IntroductionThe use of Information and Communication Technology (ICT) for assessing and treating cognitive and motor disorders is promoting home-based telerehabilitation. This approach involves ongoing monitoring within a motivating context to help patients generalize their skills. It can also reduce healthcare costs and geographic barriers by minimizing hospitalization. This systematic review focuses on investigating key aspects of telerehabilitation protocols for children with neurodevelopmental or neurological disorders, including technology used, outcomes, caregiver involvement, and dosage, to guide clinical practice and future research.MethodThis systematic review adhered to PRISMA guidelines and was registered in PROSPERO. The PICO framework was followed to define the search strategy for technology-based telerehabilitation interventions targeting the pediatric population (aged 0–18) with neurological or neurodevelopmental disorders. The search encompassed Medline/PubMed, EMBASE, and Web of Science databases. Independent reviewers were responsible for selecting relevant papers and extracting data, while data harmonization and analysis were conducted centrally.ResultsA heterogeneous and evolving situation emerged from our data. Our findings reported that most of the technologies adopted for telerehabilitation are commercial devices; however, research prototypes and clinical software were also employed with a high potential for personalization and treatment efficacy. The efficacy of these protocols on health or health-related domains was also explored by categorizing the outcome measures according to the International Classification of Functioning, Disability, and Health (ICF). Most studies targeted motor and neuropsychological functions, while only a minority of papers explored language or multi-domain protocols. Finally, although caregivers were rarely the direct target of intervention, their role was diffusely highlighted as a critical element of the home-based rehabilitation setting.DiscussionThis systematic review offers insights into the integration of technological devices into telerehabilitation programs for pediatric neurologic and neurodevelopmental disorders. It highlights factors contributing to the effectiveness of these interventions and suggests the need for further development, particularly in creating dynamic and multi-domain rehabilitation protocols. Additionally, it emphasizes the importance of promoting home-based and family-centered care, which could involve caregivers more actively in the treatment, potentially leading to improved clinical outcomes for children with neurological or neurodevelopmental conditions.Systematic review registrationPROSPERO (CRD42020210663)

Spinning and weaving in a pile dwelling of four thousand years ago: data from the excavations at Lucone di Polpenazze del Garda (BS)

The pile-dwelling sites around Lake Garda in northern Italy, datable primarily to Early Bronze Age, provide important information regarding the spinning and weaving of linen and other vegetable fibres. In these settlements, not only tools for textile production in clay, bone-antler and wood, but also fragments of fabrics were found. In addition to the Trentino site of Ledro, already known for numerous fragments of linen fabric, the site of Lucone di Polpenazze is taking on considerable importance thanks to the new excavations underway since 2007. Various settlements have been identified in the inframorenic basin of the Lucone. To Lucone A, excavated from 1965 to 1971, which had already yielded various interesting materials, including numerous textile fragments, now has been added Lucone D, where numerous fragments of fabric, a spool with wound thread and various tools for spinning and weaving have been found. This paper summarises the preliminary analysis of spindle whorls, loom weights, some of the linen textile fragments and the thread preserved on a spool, which attests the intermediate stage of splicing at Lucone

Le « Lavagnone » de Desenzano del Garda (BS)

Après un historique des recherches menées depuis 1974 dans la cuvette lacustre du Lavagnone afin de comprendre la dynamique de peuplement du site en liaison avec les variations climatiques et environnementales, les Auteurs présentent l’organisation du village et les aspects architecturaux des habitations (chemin de planches, palissades, supports de plates-formes…) au cours des différentes phases du Bronze ancien I et II, et mettent en évidence une occupation alternée des zones proches du plan d’eau (palafitte) et des zones riveraines situées à une cote plus élevée.Longhi Cristina, Mangani Claudia, Rapi Marta, Sidoli Candida. Le « Lavagnone » de Desenzano del Garda (BS). In: Architectures protohistoriques en Europe occidentale du Néolithique final à l'âge du Fer. Actes du 127e Congrès national des sociétés historiques et scientifiques, « Le travail et les hommes », Nancy, 2002. Paris : Editions du CTHS, 2005. pp. 481-486. (Actes du Congrès national des sociétés savantes, 127

Neolithic and Bronze Age textiles and textile tools from Northern Italy: the cases of Palù di Livenza (Pordenone) and Lucone di Polpenazze del Garda (Brescia)

Some of the earliest evidence of textile production in Northern Italy comes from an advanced stage of the Neo- lithic (5th–4th millennium BC). It is at this time that loom weights and spindle whorls become widespread on nu- merous archaeological sites. The contexts that have provided useful information are primarily located in humid areas and are often of pile-dwelling type. Recent information comes from the currently excavated site of Palù di Livenza (UD). After a decline in data during the third millennium BC, the evidence for textile production in- creases significantly with the beginning of the Early Bronze Age (2200–1600 BC), when the pile-dwelling model spreads across the region, particularly in the area around Lake Garda, where the surrounding pile-dwelling sites, datable primarily to Early Bronze Age, provide important evidence regarding the spinning and weaving of linen and other vegetable fibres. In these settlements, not only tools for textile production in clay, bone-antler and wood, but also fragments of fabrics have been found. In addition to the Trentino site of Molina di Ledro, well known for the numerous fragments of linen fabrics, the site of Lucone di Polpenazze is gaining considerable importance thanks to the new excavations underway since 2007. Various settlements have been identified in the inframorenic basin of the Lucone. To Lucone A, which was excavated from 1965 to 1971 and had already yielded various relevant materials, including numerous fragments of fabric, Lucone D has now been added, where several fragments of fabric, a spool with wound thread and various tools for spinning and weaving have been found. In this contribution, we present the preliminary results of the analysis of the textile tools, the fabric and textile fragments, as well as the thread preserved on a spool, which attests the intermediate stage of splicing at Lucone. The material will be placed in the wider context of textile production in prehistoric northern Italy

I siti del Neolitico, dell’età del Bronzo e della prima età del Ferro

Si presentano i risultati preliminari sui materiali ceramici rinvenuti nel sito di Casina Colombarazza (Cremona), individuato durante lavori di metanizzazione SNA

High-resolution sediment analysis reveals Middle Bronze Age byre-houses at the site of Oppeano (Verona province, NE Italy)

High-resolution sediment analysis allowed us to identify two Middle Bronze Age (MBA 1, 1650–1550 cal a BCE) byre-houses at the waterlogged site of Oppeano “4D”, south of Verona (Veneto region, NE Italy). The site lies in a low-lying valley incised by the Adige River in its LGM alluvial fan. In this fluvio-palustrine environment burial and taphonomic conditions were such that the archaeological record was extremely well preserved. The wooden elements making up basal parts of nine ‘huts’ were in fact exposed at Oppeano, and so were their internal accretion deposits. These featured finely laminated dung units deriving from the stalling of small herbivores, possibly ovicaprids, intercalated with repeated accumulations of wood ash. This was produced in large and multi-stratified hearths that were exposed within each hut. Organic petrology provided evidence of the production of wood tar inside one of the studied structures. At Oppeano 4D it was thus demonstrated that these structures were not just byres or stables, but spaces that housed humans together with animals at least during some periods of the year, hence byre-houses. The identification of byrehouses in a Middle Bronze Age settlement is key for the reconstruction of socio-economic aspects of Bronze Age economy and production systems