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Additional file 1: Figure S1. Distribution of body weight in children, adolescents, and young adults receiving atezolizumab. Patients aged

TOPIC 1: Water molecules mediating polar interactions in ligand–protein complexes contribute to both binding affinity and specificity. To account for such water molecules in computer-aided drug discovery, we performed an extensive search in the Cambridge Structural Database (CSD) to identify the geometrical criteria defining interactions of water molecules with ligand and protein. In addition, ab initio calculations were used to derive the propensity of ligand hydration. Based on these information we developed an algorithm (AcquaAlta) to reproduce water molecules bridging polar interactions between ligand and protein moieties. This approach was validated using 20 crystal structures and yielded a match of 76% between experimental and calculated water positions. The solvation algorithm was then applied to the docking of oligopeptides to the periplasmic oligopeptide binding protein A (OppA), supported by a pharmacophore-based alignment tool. TOPIC 2: Drug metabolism, toxicity, and interaction profile are major issues in the drug discovery and lead optimization processes. The Cytochromes P450 (CYPs) 2D6 and 2C9 are enzymes involved in the oxidative metabolism of a majority of the marketed drugs. By identifying the binding mode using pharmacophore pre-alignement and automated flexible docking, and quantifying the binding affinity by multi-dimensional QSAR, we validated a model family of 56 compounds (46 training, 10 test) and 85 (68 training, 17 test) for CYP2D6 and CYP2C9, respectively. The correlation with the experimental data (cross- validated r2 = 0.811 for CYP2D6 and 0.687 for CYP2C9) suggests that our approach is suited for predicting the binding affinity of compounds towards the CYP2D6 and CYP2C9. The models were challenged by Y-scrambling, and by testing an external dataset of binding compounds (15 compounds for CYP2D6 and 40 for CYP2C9) and not binding compounds (64 compounds for CYP2D6 and 56 for CYP2C9). TOPIC 3: After injury, neurites from mammalian adult central nervous systems are inhibited to regenerate by inhibitory proteins such as the myelin-associated glycoprotein (MAG). The block of MAG with potent glycomimetic antagonists could be a fruitful approach to enhance axon regeneration. Libraries of MAG antagonists were derived and synthesized starting from the (general) sialic acid moiety. The binding data were rationalized by docking studies, molecular dynamics simulations and free energy perturbations on a homology model of MAG. The pharmacokinetic profile (i.e. stability in cerebrospinal fluid, logD, and blood-brain barrier permeation) of these compounds has been thoroughly investigated to evaluate the drug-likeness of the identified antagonists.

Techniques grounded on the simultaneous utilization of Tiecks' second order differential equations and spontaneous variability of mean arterial pressure (MAP) and mean cerebral blood flow velocity (MCBFV), recorded from middle cerebral arteries through a transcranial Doppler device, provide a characterization of cerebral autoregulation (CA) via the autoregulation index (ARI). These methods exploit two metrics for comparing the measured MCBFV series with the version predicted by Tiecks' model: normalized mean square prediction error (NMSPE) and normalized correlation rho. The aim of this study is to assess the two metrics for ARI computation in 13 healthy subjects (age: 27 & PLUSMN; 8 yrs., 5 males) at rest in supine position (REST) and during 60 head-up tilt (HUT) and in 19 patients (age: 64 & PLUSMN; 8 yrs., all males), scheduled for coronary artery bypass grafting, before (PRE) and after (POST) propofol general anesthesia induction. Analyses were carried out over the original MAP and MCBFV pairs and surrogate unmatched couples built individually via time-shifting procedure. We found that: i) NMSPE and rho metrics exhibited similar performances in passing individual surrogate test; ii) the two metrics could lead to different ARI estimates; iii) CA was not different during HUT or POST compared to baseline and this conclusion held regardless of the technique and metric for ARI estimation. Results suggest a limited impact of the sympathetic control on CA.

We present a framework for the linear parametric analysis of pairwise interactions in bivariate time series in the time and frequency domains, which allows the evaluation of total, causal and instantaneous interactions and connects time- and frequency-domain measures. The framework is applied to physiological time series to investigate the cerebrovascular regulation from the variability of mean cerebral blood flow velocity (CBFV) and mean arterial pressure (MAP), and the cardiovascular regulation from the variability of heart period (HP) and systolic arterial pressure (SAP). We analyze time series acquired at rest and during the early and late phase of head-up tilt in subjects developing orthostatic syncope in response to prolonged postural stress, and in healthy controls. The spectral measures of total, causal and instantaneous coupling between HP and SAP, and between MAP and CBFV, are averaged in the low-frequency band of the spectrum to focus on specific rhythms, and over all frequencies to get time-domain measures. The analysis of cardiovascular interactions indicates that postural stress induces baroreflex involvement, and its prolongation induces baroreflex dysregulation in syncope subjects. The analysis of cerebrovascular interactions indicates that the postural stress enhances the total coupling between MAP and CBFV, and challenges cerebral autoregulation in syncope subjects, while the strong sympathetic activation elicited by prolonged postural stress in healthy controls may determine an increased coupling from CBFV to MAP during late tilt. These results document that the combination of time-domain and spectral measures allows us to obtain an integrated view of cardiovascular and cerebrovascular regulation in healthy and diseased subjects.

Despite the acknowledged interaction between baroreflex and cerebral autoregulation (CA), their functional relationship remains controversial. The study investigates this relationship in a healthy population undergoing an orthostatic challenge. Thirteen healthy subjects (age: 27pm 8 yrs; 5 males) underwent electrocardiogram, arterial pressure (AP) and cerebral blood flow velocity (CBFV) recordings at supine resting (REST) and during 60° head-up tilt (TILT). CA was assessed via the autoregulation index (ARI) from spontaneous variations of mean AP and mean CBFV. The cardiac control and baroreflex were evaluated via frequency domain and transfer function analyses applied to systolic AP and heart period variability. We found at REST a borderline positive correlation between ARI and indexes of sympathetic modulation and a stronger negative correlation with markers of vagal modulation and baroreflex sensitivity. Correlations were lost during TILT. Our data support the hypothesis that, when sympathetic drive is limited, vagal control and cardiac baroreflex have a compensatory effect on CA and sympathetic control could play a favorable role on CA.