MMsPred: a bioactivity and toxicology predictive system

In the last decade, the development and use of new methods in combinatorial chemistry and high-throughput screening has dramatically increased the number of known biologically active compounds. Paradoxically, the number of drugs reaching the market has not followed the same trend, often because many of the candidate drugs present poor qualities in absorption, distribution, metabolism, excretion, and toxicological properties (ADME-Tox). The ability to recognize and discard bad candidates early in the drug discovery steps would save lost investments in time and money. Machine learning techniques could provide solutions to this problem.
The goal of my research is to develop classifiers that accurately discriminate between active and inactive molecules for a specific target. To this end, I am comparing the effectiveness of the application of different machine learning techniques to this problem.	As a source of data we have selected a set of PubChem's public BioAssays1. In addition, with the objective of realizing a real-time query service with our predictors, we aim to keep the features describing the chemical compounds relatively simple.
At the end of this process, we should better understand how to build statistical models that are able to recognize molecules active in a specific bioassay, including how to select the most appropriate classification technique, and how to describe compounds in such a way that is not excessively resource-consuming to generate, yet contains sufficient information for the classification. We see immediate applications of such technology to recognize compounds with high-risk of toxicity, and also to suggest likely metabolic pathways that would process it

How does a dark compact object ringdown?

A generic feature of nearly out-of-equilibrium dissipative systems is that they resonate through a set of quasinormal modes. Black holes - the absorbing objects par excellence - are no exception. When formed in a merger, black holes vibrate in a process called "ringdown", which leaves the gravitational-wave footprint of the event horizon. In some models of quantum gravity which attempt to solve the information-loss paradox and the singularities of General Relativity, black holes are replaced by regular, horizonless objects with a tiny effective reflectivity. Motivated by these scenarios, here we develop a generic framework to the study of the ringdown of a compact object with various shades of darkness. By extending the black-hole membrane paradigm, we map the interior of any compact object in terms of the bulk and shear viscosities of a fictitious fluid located at the surface, with the black-hole limit being a single point in a three-dimensional parameter space. We unveil some remarkable features of the ringdown and some universal properties of the light ring in this framework. We also identify the region of the parameter space which can be probed by current and future gravitational-wave detectors. A general feature is the appearance of mode doublets which are degenerate only in the black-hole limit. We argue that the merger event GW150914 already imposes a strong lower bound on the compactness of the merger remnant of approximately 99% of the black-hole compactness. This places model-independent constraints on black-hole alternatives such as diffuse "fuzzballs" and nonlocal stars.Comment: 11+7 pages, 8 figures. v2: minor revisions to match the version to appear in PR

How time window influences biometrics performance: an EEG-based fingerprints connectivity study

EEG-based biometric represents a relatively recent research field that aims to recognize individuals based on their recorded brain activity by means of electroencephalography (EEG). Among the numerous features that have been proposed, connectivity-based approaches represent one of the more promising methods tested so far. In this paper, we investigate how the performance of an EEG biometric system varies with respect to different time windows to understand if it is possible to define the optimal duration of EEG signal that can be used to extract those distinctive features. Overall, the results have shown a pronounced effect of the time window on the biometric performance measured in terms of EER (equal error rate) and AUC (area under the curve), with an evident increase of the biometric performance with an increase of the time window. In conclusion, we want to highlight that EEG connectivity has the potential to represent an optimal candidate as EEG fingerprint and that, in this context, it is very important to define a sufficient time window able to collect the subject specific features. Moreover, our preliminary results show that extending the window size beyond a certain maximum does not improve biometric systems' performance

The Evolution of Primordial Black Holes and their Final Observable Spins

Primordial black holes in the mass range of ground-based gravitational-wave detectors can comprise a significant fraction of the dark matter. Mass and spin measurements from coalescences can be used to distinguish between an astrophysical or a primordial origin of the binary black holes. In standard scenarios the spin of primordial black holes is very small at formation. However, the mass and spin can evolve through the cosmic history due to accretion. We show that the mass and spin of primordial black holes are correlated in a redshift-dependent fashion, in particular primordial black holes with masses below ${\cal O}(30)M_\odot$ are likely non-spinning at any redshift, whereas heavier black holes can be nearly extremal up to redshift $z\sim10$. The dependence of the mass and spin distributions on the redshift can be probed with future detectors such as the Einstein Telescope. The mass and spin evolution affect the gravitational waveform parameters, in particular the distribution of the final mass and spin of the merger remnant, and that of the effective spin of the binary. We argue that, compared to the astrophysical-formation scenario, a primordial origin of black hole binaries might better explain the spin distribution of merger events detected by LIGO-Virgo, in which the effective spin parameter of the binary is compatible to zero except possibly for few high-mass events. Upcoming results from LIGO-Virgo third observation run might reinforce or weaken these predictions.Comment: 13 figures, 31 pages. v2: Section and appendix added. Results unchange

Predictors of response to erenumab after 12 months of treatment

Objective: Erenumab is a monoclonal antibody acting against calcitonin gene-related peptide receptor and approved for the preventive treatment of chronic migraine. The aim of the present study is to identify clinical predictors of good response in patients with chronic migraine and medication overuse-headache. Material and methods: This was a retrospective single-center not funded study. Enrolled patients were affected by chronic migraine and medication overuse-headache treated with erenumab monthly, up to 1 year. At 1 year, patients were classified as good responders if they displayed a ≥50% reduction in the number of headache days per months compared to the baseline. Results: After 1 year, a significant improvement in the number of headache days per months, analgesic consumption, 6-items headache impact test, and migraine disability assessment questionnaire scores were obtained compared to the baseline. Patients who obtained a ≥50% reduction in the number of headache days per month compared to the baseline displayed a longer history of medication overuse-headache, a higher number of painkillers taken per month at the baseline and a higher number of failed preventive treatments in the past. Conclusions: Patients with longer medication overuse-headache duration, higher analgesic intake, and a higher number of previous preventive treatment failures may receive less benefit with erenumab

Novel epigenetic target therapy for prostate cancer: a preclinical study.

Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-29-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours

Analysis of CYP2D6

The CYP2D6 enzyme is involved in the metabolism of many commonly prescribed drugs. The presence of polymorphisms in the CYP2D6 gene may modulate the enzyme level and activity affecting individual responses, to pharmacological treatment in drug level, response and adverse reactions. Aims. This study aimed to analyze the determination of allele frequencies in Sardinians and the comparison to frequencies found in the Caucasian Population. Methods and Materials. We used a Long PCR strategy coupled to direct genomic DNA sequencing analysis. An amplification allele-specific was carried out to infer the correct allelic phase. The TaqMan Gene Copy Number Assay (Applied Biosystems) was used to verify the presence of gene deletions/multiplications. Results and Conclusions. Our results indicated that CYP2D6 allele frequencies in Sardinians differed from those previously detected in the Caucasian Population. Moreover, three new SNPs and four novel haplotypes were identified

Wandering spleen with a ten-time twisted vascular pedicle

Torsion of a wandering spleen is a rare cause of acute abdomen in children, usually diagnosed with color-Doppler ultrasonography and enhanced computed tomography. We report a pediatric case of torsion of wandering spleen