Gray-box inference for structured Gaussian process models

We develop an automated variational infer- ence method for Bayesian structured prediction problems with Gaussian process (gp) priors and linear-chain likelihoods. Our approach does not need to know the details of the structured likelihood model and can scale up to a large number of observations. Furthermore, we show that the required expected likelihood term and its gradients in the variational objective (ELBO) can be estimated efficiently by using expectations over very low-dimensional Gaussian distributions. Optimization of the ELBO is fully parallelizable over sequences and amenable to stochastic optimization, which we use along with control variate techniques to make our framework useful in practice. Results on a set of natural language processing tasks show that our method can be as good as (and sometimes better than, in particular with respect to expected log-likelihood) hard-coded approaches including svm-struct and crfs, and overcomes the scalability limitations of previous inference algorithms based on sampling. Overall, this is a fundamental step to developing automated inference methods for Bayesian structured prediction

Purchasing food to counteract Mafia in Italy

Purpose The paper aims to investigate pro-social behaviour of Italian consumers during the decision-making process of buying food produced in lands confiscated from Mafia-type organisations. This is assumed as a form of buycotting, thus as an ethical purchasing choice to contribute to social change. Design/methodology/approach Data from 339 interviews were elaborated with a cluster analysis. The difference between groups was confirmed using MANOVA, whereas the multivariate multiple regression analysis was carried out to assess the difference between clusters. Findings Three types of consumer groups are identified: absolutists, exceptionists and subjectivists. Coherent with previous studies, findings also highlight the relevance of information acquisition and of the self-effectiveness perception as key factors to stimulate pro-social behaviours. Originality/value With a social marketing perspective, the paper offers useful suggestions to promote political consumerism as a critical choice to contribute to fight against Mafia-type organisations and to spread a culture of lawfulness

Peptidomimetics as potent dual SARS-CoV-2 cathepsin-L and main protease inhibitors: In silico design, synthesis and pharmacological characterization

In this paper we present the design, synthesis, and biological evaluation of a new series of peptidomimetics acting as potent anti-SARS-CoV-2 agents. Starting from our previously described Main Protease (MPro) and Papain Like Protease (PLPro) dual inhibitor, CV11, here we disclose its high inhibitory activity against cathepsin L (CTSL) (IC50 = 19.80 ± 4.44 nM), an emerging target in SARS-CoV-2 infection machinery. An in silico design, inspired by the structure of CV11, led to the development of a library of peptidomimetics showing interesting activities against CTSL and Mpro, allowing us to trace the chemical requirements for the binding to both enzymes. The screening in Vero cells infected with 5 different SARS-CoV-2 variants of concerns, highlighted sub-micromolar activities for most of the synthesized compounds (13, 15, 16, 17 and 31) in agreement with the enzymatic inhibition assays results. The compounds showed lack of activity against several different RNA viruses except for the 229E and OC43 human coronavirus strains, also characterized by a cathepsin-L dependent release into the host cells. The most promising derivatives were also evaluated for their chemical and metabolic in-vitro stability, with derivatives 15 and 17 showing a suitable profile for further preclinical characterization

Web site quality evaluation: Lightweight or Heavyweight Models?

One of the most critical decisions in a quality evaluation project is to establish the level at which to analyse the characteristics of the Web sites. This choice should be driven by the underlying goals of the evaluation. Scalability and flexibility are thus desiderable features of the models used to evaluate the quality of a Web site. In this paper we describe two separate studies of Regional Tourist Boards in the Alps that were conducted instantiating the meta-model 2QCV3Q (7Loci). Specifically, we will show that the results of the first study - based on a lightweight model - are consistent with those obtained with the more detailed heavyweight model in the second study

Anti-Angiogenic Effects of Natural Compounds in Diet-Associated Hepatic Inflammation

Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most common causes of chronic liver disease and are increasingly emerging as a global health problem. Such disorders can lead to liver damage, resulting in the release of pro-inflammatory cytokines and the activation of infiltrating immune cells. These are some of the common features of ALD progression in ASH (alcoholic steatohepatitis) and NAFLD to NASH (non-alcoholic steatohepatitis). Hepatic steatosis, followed by fibrosis, lead to a continuous progression accompanied by angiogenesis. This process creates hypoxia, which activates vascular factors, initiating pathological angiogenesis and further fibrosis. This forms a vicious cycle of ongoing damage and progression. This condition further exacerbates liver injury and may contribute to the development of comorbidities, such as metabolic syndrome as well as hepatocellular carcinoma. Increasing evidence suggests that anti-angiogenic therapy may have beneficial effects on these hepatic disorders and their exacerbation. Therefore, there is a great interest to deepen the knowledge of the molecular mechanisms of natural anti-angiogenic products that could both prevent and control liver diseases. In this review, we focus on the role of major natural anti-angiogenic compounds against steatohepatitis and determine their potential therapeutic benefits in the treatment of liver inflammation caused by an imbalanced diet

Metabolomics-assisted discovery of a new anticancer GLS-1 inhibitor chemotype from a nortopsentin-inspired library: From phenotype screening to target identification

The enzyme glutaminase-1 (GLS-1) has shown a clear and coherent implication in the progression and exacerbation of different aggressive tumors such as glioblastoma, hepatocarcinoma, pancreas, bone, and triple-negative breast cancer. Few chemotypes are currently available as selective GLS-1 inhibitors, and still, fewer of them are at the clinical stage. In the present paper, starting from a naturally-inspired antitumor compound library, metabolomics has been used to putatively identify the molecular mechanism underlying biological activity. GLS-1 was identified as a potential target. Biochemical analysis confirmed the hypothesis leading to the identification of a new hit compound acting as a GLS-1 selective inhibitor (IC50 = 3.96 ± 1.05 μM), compared to the GLS-2 isoform (IC50 = 12.90 ± 0.87 μM), with remarkable antitumor potency over different aggressive tumor cell lines. Molecular modelling studies revealed new insight into the drug-target interaction providing robust SAR clues for the rational hit-to-lead development. The approach undertaken underlines the wide potential of metabolomics applied to drug discovery, particularly in target identification and hit discovery following phenotype screening

In Silico Identification and In Vitro Evaluation of New ABCG2 Transporter Inhibitors as Potential Anticancer Agents

Different molecular mechanisms contribute to the development of multidrug resistance in cancer, including increased drug efflux, enhanced cellular repair mechanisms and alterations of drug metabolism or drug targets. ABCG2 is a member of the ATP-binding cassette superfamily transporters that promotes drug efflux, inducing chemotherapeutic resistance in malignant cells. In this context, the development of selective ABCG2 inhibitors might be a suitable strategy to improve chemotherapy efficacy. Thus, through a multidisciplinary approach, we identified a new ABCG2 selective inhibitor (8), highlighting its ability to increase mitoxantrone cytotoxicity in both hepatocellular carcinoma (EC50from 8.67 ± 2.65 to 1.25 ± 0.80 μM) and transfected breast cancer cell lines (EC50from 9.92 ± 2.32 to 2.45 ± 1.40 μM). Moreover, mitoxantrone co-administration in both transfected and non-transfected HEK293 revealed that compound 8 notably lowered the mitoxantrone EC50, demonstrating its efficacy along with the importance of the ABCG2 extrusion pump overexpression in MDR reversion. These results were corroborated by evaluating the effect of inhibitor 8 on mitoxantrone cell uptake in multicellular tumor spheroids and via proteomic experiments