»An infant corpse on the bottom of the well«: infanticide in the criminal proceedings of mid-18th century Padua

V magistrskem delu predstavljam proces padovanskega sodišča, ki je poizvedovalo o detomoru iz leta 1754 v mestecu Este. Delikt detomora postavljam v širši evropski kontekst obdobja in pokažem tako skupne trende pravnih reform kot tudi nekatere razlike v kaznovanju. Prav tako kaznovanje detomora v Beneški republiki postavim v kontekst beneškega prava, ki za razliko od velike večine evropskih pravnih ureditev obdobja ni osnovano na rimskem pravu. V jedru se osredotočam na predstavitev podobe detomorilke, kakor so jo v zvezi z dvema glavnima osumljenkama na procesu oblikovala pričevanja na sodišču. Posebno pozornost namenim specifiki poklica domače služkinje, osebni časti, odnosom v skupnosti in govoricam. Namen naloge je prikazati vpliv govoric na konstrukcijo osumljenih detomorilk, prikazati delikt detomora v njegovi večplastnosti ter osvetliti glavne faktorje, ki so detomorilke privedli k temu, da so dejanje storile.The thesis presents a case of infanticide in a small Venetian town of Este, submitted to the Paduan court in 1754. Infanticide is placed within the broader European context of the era in order to aid in presenting both the incipient convergence of legal reform as well as specific divergence pertaining to penal law. The crime is also contextualized within Venetian law which is, unlike most other contemporary European legal systems, not based on Roman law. The main part is dedicated to the construction of the perpetrator of infanticide through court hearings on the two primary suspects. Special scrutiny is allotted to maidservants and their profession, to personal honor, to community relations, and to gossip and its role within the community. The chief aim of the thesis is to present the power of gossip to construct images of suspected infant killers, shed light on the multiplicity of layers to this specific type of crime, and list the main motivations behind the decision to perform an infanticide

Multiplexed experimental strategies for fragment library screening against challenging drug targets using SPR biosensors

Surface plasmon resonance (SPR) biosensor methods are ideally suited for fragment-based lead discovery. However, generally applicable experimental procedures and detailed protocols are lacking, especially for structurally or physico-chemically challenging targets or when tool compounds are not available. Success depends on accounting for the features of both the target and the chemical library, purposely designing screening experiments for identification and validation of hits with desired specificity and mode-of-action, and availability of orthogonal methods capable of confirming fragment hits. The range of targets and libraries amenable to an SPR biosensor-based approach for identifying hits is considerably expanded by adopting multiplexed strategies, using multiple complementary surfaces or experimental conditions. Here we illustrate principles and multiplexed approaches for using flow-based SPR biosensor systems for screening fragment libraries of different sizes (90 and 1056 compounds) against a selection of challenging targets. It shows strategies for the identification of fragments interacting with 1) large and structurally dynamic targets, represented by acetyl choline binding protein (AChBP), a Cys-loop receptor ligand gated ion channel homologue, 2) targets in multi protein complexes, represented by lysine demethylase 1 and a corepressor (LSD1/CoREST), 3) structurally variable or unstable targets, represented by farnesyl pyrophosphate synthase (FPPS), 4) targets containing intrinsically disordered regions, represented by protein tyrosine phosphatase 1B (PTP1B), and 5) aggregation-prone proteins, represented by an engineered form of human tau (tau K18M). Practical considerations and procedures accounting for the characteristics of the proteins and libraries, and that increase robustness, sensitivity, throughput and versatility are highlighted. The study shows that the challenges for addressing these types of targets is not identification of potentially useful fragments per se, but establishing methods for their validation and evolution into leads

In Silico Toxicology Data Resources to Support Read-Across and (Q)SAR

A plethora of databases exist online that can assist in in silico chemical or drug safety assessment. However, a systematic review and grouping of databases, based on purpose and information content, consolidated in a single source has been lacking. To resolve this issue, this review provides a comprehensive listing of the key in silico data resources relevant to: chemical identity and properties, drug action, toxicology (including nano-material toxicity), exposure, omics, pathways, Absorption, Distribution, Metabolism and Elimination (ADME) properties, clinical trials, pharmacovigilance, patents-related databases, biological (genes, enzymes, proteins, other macromolecules etc.) databases, protein-protein interactions (PPIs), environmental exposure related, and finally databases relating to animal alternatives in support of 3Rs policies. More than nine hundred databases were identified and reviewed against criteria relating to accessibility, data coverage, interoperability or application programming interface (API), appropriate identifiers, types of in vitro-in vivo -clinical data recorded and suitability for modelling, read-across or similarity searching. This review also specifically addresses the need for solutions for mapping and integration of databases into a common platform for better translatability of preclinical data to clinical data

Accelerating the discovery of drugs for Neglected Tropical Diseases using biophysical methods

Even though they account for 10% of the global disease burden and besides the new record of funding in 2018, tropical diseases are still neglected by the majority of pharmaceutical companies and public funding. The reason can be mostly found in the fact that for these diseases a conventional drug discovery process is often too expensive. The development of new approaches in the early stage of drug discovery has therefore a key role in fighting Neglected Tropical Diseases (NTD). AEGIS is a European network which relates on collaborations for a multidisciplinary approach, in order to “accelerate” drugs development – hence reducing the costs. As part of the network, this project is focused on a rational exploration of the chemical space, together with an in depth-analysis of molecular interactions for a better characterization of targets involved in NTD. One cost-efficient way for exploring pharmacologically relevant chemical space is fragment based lead discovery (FBLD). This approach requires an extensive understanding of the target properties; therefore, a pipeline of orthogonal methods was developed to validate the suitability of the target for FBLD. The choice of a fragment library has a significant impact on the experimental strategy. Not only the validation of the target, but also practical issues concerning technology, orthogonal validation and applicability have to be considered when initiating a fragment screening campaign. Another rational approach for the discovery of new drugs is looking at the target structure, especially when considering protein complexes interaction. Through the structural analysis of the protein-protein interface, several short peptides derived from the binding partner were analysed in their interaction with the target both in vitro and in cell. This allowed to identify the key sequence for the binding to the target and the internalization of the complex, both crucial information for a structure-based approach.   The internalization process of the target was characterized by a real-time cell binding assay (RT-CBA), revealing a higher level of complexity than what was previously described. Implementing RT-CBA in the early stage is a strategy that might improve the success rate of drug development. The possibility to develop an intracellular time resolved molecular interaction assay between small molecules and a model target fused to a fluorescent protein was therefore explored. From a fragment screening campaign to a structure-based approach, culminating with a real time intracellular validation of hits, all the assays developed address the different possibilities for accelerating the drug discovery process in the early stages

Accelerating the discovery of drugs for Neglected Tropical Diseases using biophysical methods

Even though they account for 10% of the global disease burden and besides the new record of funding in 2018, tropical diseases are still neglected by the majority of pharmaceutical companies and public funding. The reason can be mostly found in the fact that for these diseases a conventional drug discovery process is often too expensive. The development of new approaches in the early stage of drug discovery has therefore a key role in fighting Neglected Tropical Diseases (NTD). AEGIS is a European network which relates on collaborations for a multidisciplinary approach, in order to “accelerate” drugs development – hence reducing the costs. As part of the network, this project is focused on a rational exploration of the chemical space, together with an in depth-analysis of molecular interactions for a better characterization of targets involved in NTD. One cost-efficient way for exploring pharmacologically relevant chemical space is fragment based lead discovery (FBLD). This approach requires an extensive understanding of the target properties; therefore, a pipeline of orthogonal methods was developed to validate the suitability of the target for FBLD. The choice of a fragment library has a significant impact on the experimental strategy. Not only the validation of the target, but also practical issues concerning technology, orthogonal validation and applicability have to be considered when initiating a fragment screening campaign. Another rational approach for the discovery of new drugs is looking at the target structure, especially when considering protein complexes interaction. Through the structural analysis of the protein-protein interface, several short peptides derived from the binding partner were analysed in their interaction with the target both in vitro and in cell. This allowed to identify the key sequence for the binding to the target and the internalization of the complex, both crucial information for a structure-based approach.   The internalization process of the target was characterized by a real-time cell binding assay (RT-CBA), revealing a higher level of complexity than what was previously described. Implementing RT-CBA in the early stage is a strategy that might improve the success rate of drug development. The possibility to develop an intracellular time resolved molecular interaction assay between small molecules and a model target fused to a fluorescent protein was therefore explored. From a fragment screening campaign to a structure-based approach, culminating with a real time intracellular validation of hits, all the assays developed address the different possibilities for accelerating the drug discovery process in the early stages

Epidemiology of cerebral palsy in north east Italy

none4noneM. BOTTOS; P. ALLIBRIO; S. OPASSI; P. FACCHINM., Bottos; P., Allibrio; S., Opassi; Facchin, Paol