Strategies against nonsense: oxadiazoles as translational readthrough-inducing drugs (TRIDs)

This review focuses on the use of oxadiazoles as translational readthrough-inducing drugs (TRIDs) to rescue the functional full-length protein expression in mendelian genetic diseases caused by nonsense mutations. These mutations in specific genes generate premature termination codons (PTCs) responsible for the translation of truncated proteins. After a brief introduction on nonsense mutations and their pathological effects, the features of various classes of TRIDs will be described discussing differences or similarities in their mechanisms of action. Strategies to correct the PTCs will be presented, particularly focusing on a new class of Ataluren-like oxadiazole derivatives in comparison to aminoglycosides. Additionally, recent results on the efficiency of new candidate TRIDs in restoring the production of the cystic fibrosis transmembrane regulator (CFTR) protein will be presented. Finally, a prospectus on complementary strategies to enhance the effect of TRIDs will be illustrated together with a conclusive paragraph about perspectives, opportunities, and caveats in developing small molecules as TRIDs

Evaluation of the IKKβ Binding of Indicaxanthin by Induced-Fit Docking, Binding Pose Metadynamics, and Molecular Dynamics

Background: Indicaxanthin, a betaxanthin belonging to the betalain class of compounds, has been recently demonstrated to exert significant antiproliferative effects inducing apoptosis of human melanoma cells through the inhibition of NF-κB as the predominant pathway. Specifically, Indicaxanthin inhibited IκBα degradation in A375 cells. In resting cells, NF-κB is arrested in the cytoplasm by binding to its inhibitor protein IκBα. Upon stimulation, IκBα is phosphorylated by the IKK complex, and degraded by the proteasome, liberating free NF-κB into the nucleus to initiate target gene transcription. Inhibition of the IKK complex leads to the arrest of the NF-κB pathway. Methods: To acquire details at the molecular level of Indicaxanthin’s inhibitory activity against hIKKβ, molecular modeling and simulation techniques including induced-fit docking (IFD), binding pose metadynamics (BPMD), molecular dynamics simulations, and MM-GBSA (molecular mechanics-generalized Born surface area continuum solvation) have been performed. Results: The computational calculations performed on the active and inactive form, and the allosteric binding site of hIKKβ, revealed that Indicaxanthin inhibits prevalently the active form of the hIKKβ. MM-GBSA computations provide further evidence of Indicaxanthin’s stability inside the active binding pocket with a binding free energy of −22.2 ± 4.3 kcal/mol with respect to the inactive binding pocket with a binding free energy of −20.7 ± 4.7 kcal/mol. BPMD and MD simulation revealed that Indicaxanthin is likely not an allosteric inhibitor of hIKKβ. Conclusion: As a whole, these in silico pieces of evidence show that Indicaxanthin can inhibit the active form of the hIKKβ adding novel mechanistic insights on its recently discovered ability to impair NF-κB signaling in melanoma A375 cells. Moreover, our results suggest the phytochemical as a new lead compound for novel, more potent IKKβ inhibitors to be employed in the treatment of cancer and inflammation-related conditions

IN THE SEARCH OF LEPTIN AGONISTS AS ANTI-OBESITY DRUGS: PROTEIN/PROTEIN DOCKING, MOLECULAR DYNAMICS, AND VIRTUAL SCREENING

The body weight control is a mechanism thinly regulated by several hormonal, metabolic, and nervous pathways (1). Recessive homozygous mutations in the ob/ob and db/db mouse strain cause extreme obesity. The products of the ob and db genes are leptin and its receptor, respectively. The leptin receptor is crucial for energy homeostasis and regulation of food uptake. Leptin is a 16 kDa hormone that is mainly secreted by fat cells into the bloodstream. Under normal circumstances, circulating leptin levels are proportionate to the fat body mass. Sensing of elevated leptin levels by the hypothalamic neurocircutry activates a negative feedback loop resulting in reduced food intake and increased energy expenditure. Decreased leptin concentrations lead to opposite effectsTherefore rational design of leptin agonists could be an appealing challenge in the battle against obesity. Unfortunately only the crystal structure of leptin is available, but not that of the leptin receptor. In this work, first, we built, by homology modelling, the leptin receptor starting from FASTA sequence and the similarity search of templates. The obtained model was used to perform a protein-protein docking with the crystal structure of leptine by means Gramm-X server, with the aim to define the complementary surfaces of the two proteins. The complex of leptin/leptin receptor was then used as starting point to carry out molecular dynamics simulations in water solvent to characterize the key residues involved into the protein-protein interaction. Snapshots of leptin were used as template to build a pharmacophore hypothesis to carry out virtual screening on a large database of compounds. (1) Friedman, J. M., Halaas, J. L. Nature 1998, 395, 763-770 IN THE SEARCH OF LEPTIN AGONISTS AS ANTI-OBESITY DRUGS: PROTEIN/PROTEIN DOCKING, MOLECULAR DYNAMICS, AND VIRTUAL SCREENIN

Further oblique-incidence ionospheric soundings over Central Europe to test nowcasting and long term prediction models

After a first oblique-incidence ionospheric sounding campaign over Central Europe performed during the period 2003-2004 over the radio links between Inskip (UK, 53.5° N, 2.5° W) and Rome (Italy, 41.8 N, 12.5E) and between Inskip and Chania (Crete, 35.7° N, 24.0° E), new and more extensive analysis of systematic MUF measurements from January 2005 to December 2006 have been performed. MUF measurements collected during moderately disturbed days (17 ≤ Ap ≤ 32), disturbed days (32 50), have been used to test the long term prediction models (ASAPS, ICEPAC and SIRM&LKW), and the now casting models (SIRMUP&LKW and ISWIRM&LKW). The performances of the different prediction methods in terms of r.m.s are shown for selected range of geomagnetic activity and for each season.Submitted3.9. Fisica della magnetosfera, ionosfera e meteorologia spazialeN/A or not JCRope

Theoretical Determination of the pK a Values of Betalamic Acid Related to the Free Radical Scavenger Capacity: Comparison Between Empirical and Quantum Chemical Methods

Health benefits of dietary phytochemicals have been suggested in recent years. Among 1000s of different compounds, Betalains, which occur in vegetables of the Cariophyllalae order (cactus pear fruits and red beet), have been considered because of reducing power and potential to affect redox-modulated cellular processes. The antioxidant power of Betalains is strictly due to the dissociation rate of the acid moieties present in all the molecules of this family of phytochemicals. Experimentally, only the pK a values of betanin were determined. Recently, it was evidenced it was evidenced as the acid dissociation, at different environmental pHs, affects on its electron-donating capacity, and further on its free radical scavenging power. The identical correlation was studied on another Betalains family compound, Betalamic Acid. Experimental evidences showed that the free radical scavenging capacity of this compound drastically decreases at pH > 5, but pK a values were experimentally not measured. With the aim to justify the Betalamic Acid behavior as free radical scavenger, in this paper we tried to predict in silico the pK a values by means different approaches. Starting from the known experimental pK as of acid compounds, both phytochemicals and small organic, two empirical approaches and quantum-mechanical calculation were compared to give reliable prediction of the pK as of Betalamic Acid. Results by means these computational approaches are consistent with the experimental evidences. As shown herein, in silico, the totally dissociated species, at the experimental pH > 5 in solution, is predominant, exploiting the higher electron-donating capability (HOMO energy). Therefore, the computational estimated pK a values of Betalamic Acid resulted very reliable

Machine learning in predicting respiratory failure in patients with COVID-19 pneumonia - challenges, strengths, and opportunities in a global health emergency.

Aims- The aim of this study was to estimate a 48 hour prediction of moderate to severe respiratory failure, requiring mechanical ventilation, in hospitalized patients with COVID-19 pneumonia. Methods- This was an observational study that comprised consecutive patients with COVID-19 pneumonia admitted to hospital from 21 February to 6 April 2020. The patients\u2019 medical history, demographic, epidemiologic and clinical data were collected in an electronic patient chart. The dataset was used to train predictive models using an established machine learning framework leveraging a hybrid approach where clinical expertise is applied alongside a data-driven analysis. The study outcome was the onset of moderate to severe respiratory failure defined as PaO 2 /FiO 2 ratio <150 mmHg in at least one of two consecutive arterial blood gas analyses in the following 48 hours. Shapley Additive exPlanations values were used to quantify the positive or negative impact of each variable included in each model on the predicted outcome. Results- A total of 198 patients contributed to generate 1068 usable observations which allowed to build 3 predictive models based respectively on 31-variables signs and symptoms, 39-variables laboratory biomarkers and 91-variables as a composition of the two. A fourth \u201cboosted mixed model\u201d included 20 variables was selected from the model 3, achieved the best predictive performance (AUC=0.84) without worsening the FN rate. Its clinical performance was applied in a narrative case report as an example. Conclusion- This study developed a machine model with 84% prediction accuracy, which is able to assist clinicians in decision making process and contribute to develop new analytics to improve care at high technology readiness levels

ONTOLOGY IN DIALOGUE

In its first section the volume contains contributions dealing with the debate between the German philosopher Markus Gabriel and some scholars in Palermo who discussed the fundaments of his ontology. In the next sections are gathered essays on critical ontology in the modern age, essays on intersubjectivity in social ontology and on ontology of arts and aesthetics

Galactic observatory science with the ASTRI Mini-Array at the Observatorio del Teide

The ASTRI (Astrofisica con Specchi a Tecnologia Replicante Italiana) Mini-Array will be composed of nine imaging atmospheric Cherenkov telescopes at the Observatorio del Teide site. The array will be best suited for astrophysical observations in the 0.3-200 TeV range with an angular resolution of few arc-minutes and an energy resolution of 10-15%. A core-science programme in the first four years will be devoted to a limited number of key targets, addressing the most important open scientific questions in the very-high energy domain. At the same time, thanks to a wide field of view of about 10 degrees, ASTRI Mini-Array will observe many additional field sources, which will constitute the basis for the long-term observatory programme that will eventually cover all the accessible sky. In this paper, we review different astrophysical Galactic environments, e.g. pulsar wind nebulae, supernova remnants, and gamma -ray binaries, and show the results from a set of ASTRI Mini-Array simulations of some of these field sources made to highlight the expected performance of the array (even at large offset angles) and the important additional observatory science that will complement the core-science program

Follow-up observations of GW170817 with the MAGIC telescopes

The discovery of the electromagnetic counterpart AT2017gfo and the GRB 170817A, associated to the binary neutron star merger GW170817, was one of the major advances in the study of gamma-ray bursts (GRBs) and the hallmark of the multi-messenger astronomy with gravitational waves. Another breakthrough in GRB physics is represented by the discovery of the highly energetic, teraelectronvolt (TeV) component in the GRB 190114C, possibly an universal component in all GRBs. This conclusion is also suggested by the hint of TeV emission in the short GRB 160821B and a few more events reported in the literature. The missing observational piece is the joint detection of TeV emission and gravitational waves from a short GRB and its progenitor. MAGIC observed the counterpart AT2017gfo as soon as the visibility conditions allowed it, namely from January to June 2018. These observations correspond to the maximum flux level observed in the radio and X-ray bands. The upper limits derived from TeV observations are compared with the modelling of the late non-thermal emission using the multi-frequency SED

MAGIC observations of the nearby short GRB 160821B

Gamma-ray bursts (GRBs), the most luminous explosions in the universe, have at least two types known. One of them, short GRBs, have been thought to originate from binary neutron star (BNS) mergers. The discovery of GW170817 together with a GRB was the first and only direct proof of the hypothesis, and thus the properties of the short GRBs are poorly known yet. Aiming to clarify the underlying physical mechanisms of the short GRBs, we analyzed GRB 160821B, one of the nearest short GRBs known at z=0.162, observed with the MAGIC telescopes. A hint of a gamma-ray signal is found above 0.5 TeV at a significance of >3 sigma during observations from 24 seconds until 4 hours after the burst, as presented in the past. Recently, multi-wavelength data of its afterglow emission revealed a well-sampled kilonova component from a BNS merger, and the importance of GRB 160821B increased concerning GRB-GW studies. Accordingly, we investigated GRB afterglow models again, using the revised multi-wavelength data. We found that the straightforward interpretation with one-zone synchrotron self-Compton model from the external forward shock is in tension with the observed TeV flux, contradicting the suggestion reported previously. In this contribution we discuss the implication from the TeV observation, including alternative scenarios where the TeV emission can be enhanced. We also give a brief outlook of future GeV-TeV observations of short GRBs with imaging atmospheric Cherenkov telescopes, which could shed more light on the GRB-BNS merger relation