Integrating Synthetic Accessibility with AI-based Generative Drug Design

Generative models are frequently used for de novo design in drug discovery projects to propose new molecules. However, the question of whether or not the generated molecules can be synthesized is not systematically taken into account during generation, even though being able to synthesize the generated molecules is a fundamental requirement for such methods to be useful in practice. Methods have been developed to estimate molecule synthesizability, but, so far, there is no consensus on whether or not a molecule is synthesizable. In this paper we introduce the Retro-Score (RScore), which computes a synthetic feasibility score of molecules by performing a full retrosynthetic analysis through our data-driven synthetic planning software Spaya, and its dedicated API: Spaya-API (https://spaya.ai). After a comparison of RScore with other synthetic scores from the literature, we describe a pipeline to generate molecules that validate a list of targets while still being easy to synthesize. We further this idea by performing experiments comparing molecular generator outputs across a range of constraints and conditions. We show that the RScore can be learned by a Neural Network, which leads to a new score: RSPred. We demonstrate that using the RScore or RSPred as a constraint during molecular generation enables to obtain more synthesizable solutions, with higher diversity. The open-source Python code containing all the scores and the experiments can be found on https://github.com/iktos/generation-under-synthetic- constraint.

Integrating Synthetic Accessibility with AI-based Generative Drug Design

Generative models are frequently used for de novo design in drug discovery projects to propose new molecules. However, the question of whether or not the generated molecules can be synthesized is not systematically taken into account during generation, even though being able to synthesize the generated molecules is a fundamental requirement for such methods to be useful in practice. Methods have been developed to estimate molecule synthesizability, but, so far, there is no consensus on whether or not a molecule is synthesizable. In this paper we introduce the Retro-Score (RScore), which computes a synthetic feasibility score of molecules by performing a full retrosynthetic analysis through our data-driven synthetic planning software Spaya, and its dedicated API: Spaya-API (https://spaya.ai). After a comparison of RScore with other synthetic scores from the literature, we describe a pipeline to generate molecules that validate a list of targets while still being easy to synthesize. We further this idea by performing experiments comparing molecular generator outputs across a range of constraints and conditions. We show that the RScore can be learned by a Neural Network, which leads to a new score: RSPred. We demonstrate that using the RScore or RSPred as a constraint during molecular generation enables to obtain more synthesizable solutions, with higher diversity. The open-source Python code containing all the scores and the experiments can be found on https://github.com/iktos/generation-under-synthetic- constraint.

Confinement of Masonry Columns with Natural Lime-Based Mortar Composite: An Experimental Investigation

The paper presents the results of an experimental campaign on the confinement of masonry square columns with fiber-reinforced lime mortar (FRLM) composites made of a natural lime-based matrix. The experimental results show the effectiveness of such a composite for increasing both strength and ductility performances of strengthened columns. Predictive formulas from the literature and from the Italian guidelines CNR-DT 215/2018 do not perfectly fit the experimental outcomes and do not confirm the strength increase of the confined columns. The reason can be attributed to the very low mechanical properties of the natural matrix used to form such a composite. Therefore, considering that the use of a natural and sustainable matrix fully compatible with the masonry substrate is a fundamental requirement for strengthening masonry columns of buildings belonging to architectural heritage, an additional future effort should be made by researchers involved in this field. In particular, for a reliable prediction of the strength of masonry columns confined with composites made of natural matrices, wider experimental campaigns are necessary to refine available formulas with respect to different substrates and component materials.

Quarantine Hotels: The Adaptation of Hotels for Quarantine Use in Australia

The COVID-19 global health crisis has spatial implications concerning social isolation to control the spread of the virus. The preventive measures require travelers to stay in mandatory quarantine for 14 days upon arrival from another country. Due to a shortage of government facilities, more hotels have started to function as quarantine facilities. This research focuses on quarantine hotels in Australia, as one of the first countries to implement an international border restriction, to evaluate the spatial needs of users and what see outcomes can be identified. By primarily focusing on hotel users’ well-being during the isolation period, this paper responds to an information gap regarding the quarantine hotel system by providing user opinions on the negative and positive factors affecting their well-being. A survey with multiple-choice and open-ended questionnaire items was conducted with 54 participants to investigate their experiences in quarantine hotels. Among the nine key sources of well-being, the three highest-scored responses were an operable window (4.7), ventilation (4.5), and natural lighting (4.3). Access to the outdoor environment via a balcony or operable window was an acute and fundamental requirement for guests. Additionally, participants mentioned that they are unwilling to return to the hotel where they spent their quarantine, which raises issues regarding the future of hotels.

Relating a Sustained Monologue Speaking Production Test to CEFR: Towards Alignment

This article evaluates a sustained monologue speaking production test to validate its link to the CEFR model. The monologue test is a low-stakes production test that engages the test taker in sustained monologue tasks targeted at B2-C1 of the CEFR levels. The evaluation of the test included determining the extent to which the monologue speaking tasks and the single assessment criterion-related rating scale developed for the test are valid and reliably aligned to CEFR benchmarked descriptors. The socio-cognitive framework for test evaluation was adopted, and an explanatory sequential mixed-methods research design was implemented. The evaluation revealed some contentious points of contrast between the test items and the language demand that each item prompted in production. Consequently, selected items were improved or deleted to ensure the appropriate competency levelled at B2-C1 are correctly prompted. Additionally, the findings underlined the imperative need for test developers to adhere to five inter-related sets of procedures in the justification of a claim that the monologue speaking test is aligned to the CEFR. These include familiarisation, specification, standardisation and benchmarking, standard-setting, and validation. It emerged that thorough familiarity with the CEFR by test item writers and examiners is a fundamental requirement for a test closely related to CEFR construct and levels. Thus, familiarisation training of CEFR and its illustrative descriptors is a mandatory prerequisite for ensuring test items and assessment of the elicited production correspond to the levels and ratings described in the CEFR model.

Calibration of a finite element model of Prescale film for wheel-rail normal contact area measurements

This article presents the latest of a series of research activities aimed to determine the deviation originated when Prescale pressure measurement film is used to measure the size and shape of the wheel-rail contact area. Despite being an attractive solution due to the simplicity of the measurement procedure, it is well known that the contact interaction is altered by the presence of the film. Consequently, characterizing and filtering out the systematic measurement error is a fundamental requirement for accurate quantitative assessments. Nevertheless, the complexity of the wheel-rail contact problem, which lacks an analytical solution, hinders the direct determination of correction values. The approach presented here builds on error corrections for simpler Hertzian geometries to calibrate a film model for further use in the wheel-rail contact scenario. The results highlight the marked dependency of the measurement error on wheel and rail roughness and underline the importance of including the film into finite element models that are validated by comparison with experimental observations.

A Smart Contract-based Access Control Architecture for Telemedicine During Covid-19

In the fight against the COVID-19 epidemic that is currently a major global public health issue, social distancing has been imposed to prevent the massive transmission, thus doctors in hospitals have turned to telemedicine in order to be able to monitor their patient notably those suffering from chronic diseases. To do so, patients need to share their physiological data with doctors. In order to share this data safely, prevent malicious users from tampering with it and protect the privacy of patients, access control becomes a fundamental requirement. In order to set up a real-time (Internet of Thing) IoT enabled healthcare system (HS) scenario like telemedicine, Fog computing (FC) seems to be the best solution comparing to Cloud computing since it provides low latency, highly mobile and geo-distributed services and temporary storage. In this paper, the focus is on access control in the telemedicine systems. Our proposal is based, on one hand, the concept of Fog computing to ensure the distributed aspect needed in the monitoring of patient health remotely; and on the other hand Blockchain (BC) smart contracts, in order to provide a dynamic, optimized and self-adjusted access control.

Second-Personal Evidence

This chapter draws on Hohfeld’s scheme of jural opposites and correlatives to identify the irreducibly second-personal nature of legal entitlements and the interplay between the right-holder’s authority and the duty-bearer’s accountability. Based on that insight, the author argues that facts that courts need to ascertain and—critically—the procedures that courts must carry out in ascertaining those facts, ought to be second-personal as well. As a corollary, courts must only rely upon second-personal evidence, that is: upon information concerning the alleged jural relationship between the holder of the underlying entitlement and the bearer of the correlative duty or obligation. Further, this fundamental requirement defines the modus operandi of the Anglo-American system of evidence and its core rules.

Elucidation of sub-cellular H2S metabolism in Solanum lycopersicum L. and its assessment under development and biotic stress

The signalling molecules serve as a fundamental requirement in plants and respond to various internal and external cues. Among several signalling molecules, the significance of gasotransmitters has been realized in several plant developmental and environmental constraints. The hydrogen sulfide (H2S) is a novel signalling molecule in higher plants and is involved in several physiological processes right from seed germination to flowering and fruit ripening. Moreover, H2S also assist plants in managing biotic and abiotic stresses, therefore serves as one of the imperative choice of chemical priming. Yet, the metabolism of H2S is not much explored and only appraisal study is made till date from Arabidopsis thaliana. Therefore, the present investigation explored the elucidation of H2S metabolism in crop plant Solanum lycopersicum L. Through in silico investigations the study demonstrated the participation of 29 proteins involved in H2S metabolism, which are mainly localized in cytosol, chloroplast, and mitochondria. Additionally, the relevant protein-protein interactomes were also inferred for sub-cellular compartments and expression data were explored under development and biotic stresses namely PAMPs treatment and bacterial infection. The information generated here will be of high relevance to better target the H2S metabolism to enhance the tomato prospects and also serve a preliminary investigation to be adopted in other agronomic important crops.

CTCF knockout in zebrafish induces alterations in regulatory landscapes and developmental gene expression

Coordinated chromatin interactions between enhancers and promoters are critical for gene regulation. The architectural protein CTCF mediates chromatin looping and is enriched at the boundaries of topologically associating domains (TADs), which are sub-megabase chromatin structures. In vitro CTCF depletion leads to a loss of TADs but has only limited effects over gene expression, challenging the concept that CTCF-mediated chromatin structures are a fundamental requirement for gene regulation. However, how CTCF and a perturbed chromatin structure impacts gene expression during development remains poorly understood. Here we link the loss of CTCF and gene regulation during patterning and organogenesis in a ctcf knockout zebrafish model. CTCF absence leads to loss of chromatin structure and affects the expression of thousands of genes, including many developmental regulators. Our results demonstrate the essential role of CTCF in providing the structural context for enhancer-promoter interactions, thus regulating developmental genes.