Candidate Binding Sites for Allosteric Inhibition of the SARS-CoV-2 Main Protease from the Analysis of Large-Scale Molecular Dynamics Simulations

We analyzed a 100 μs MD trajectory of the SARS-CoV-2 main protease by a non-parametric data analysis approach which allows characterizing a free energy landscape as a simultaneous function of hundreds of variables. We identified several conformations that, when visited by the dynamics, are stable for several hundred nanoseconds. We explicitly characterize and describe these metastable states. In some of these configurations, the catalytic dyad is less accessible. Stabilizing them by a suitable binder could lead to an inhibition of the enzymatic activity. In our analysis we keep track of relevant contacts between residues which are selectively broken or formed in the states. Some of these contacts are formed by residues which are far from the catalytic dyad and are accessible to the solvent. Based on this analysis we propose some relevant contact patterns and three possible binding sites which could be targeted to achieve allosteric inhibition

Assessing heterogeneity of treatment effect in multiple sclerosis trials

Multiple sclerosis (MS) is heterogeneous with respect to outcomes, and evaluating possible heterogeneity of treatment effect (HTE) is of high interest. HTE is non-random variation in the magnitude of a treatment effect on a clinical outcome across levels of a covariate (i.e. a patient attribute or set of attributes). Multiple statistical techniques can evaluate HTE. The simplest but most bias-prone is conventional one variable-at-a-time subgroup analysis. Recently, multivariable predictive approaches have been promoted to provide more patient-centered results, by accounting for multiple relevant attributes simultaneously. We review approaches used to estimate HTE in clinical trials of MS

Melittobia digitata dahms (hymenoptera: eulophidae) y monodontomerus mexicanus gahan (hym.: pteromalidae) on a nest of trypoxylon (trypargilum) mexicanum (saussure) (hym.: crabronidae) collected near Xalapa, Veracruz, Mexico

In a mud-nest built by Trypoxylon mexicanum, collected near Xalapa, Veracruz, Mexico, we recorded the presence of two parasitoids Monodontomerus mexicanus (Pteromalidae) and Melittobia digitata (Eulophidae), and one ant: Solenopsis geminata (Formicidae). The pteromalid is reported for the first time from Veracruz while the eulophid is reported from Mexico attacking another hymenopteran. The presence of an ant inside an empty cell is possibly just a coincidence.

A dynamical mechanism for the origin of nuclear rings

We develop a dynamical theory for the origin of nuclear rings in barred galaxies. In analogy with the standard theory of accretion discs, our theory is based on shear viscous forces among nested annuli of gas. However, the fact that gas follows non circular orbits in an external barred potential has profound consequences: it creates a region of reverse shear in which it is energetically favourable to form a stable ring which does not spread despite dissipation. Our theory allows us to approximately predict the size of the ring given the underlying gravitational potential. The size of the ring is loosely related to the location of the Inner Lindblad Resonance in the epicyclic approximation, but the predicted location is more accurate and is also valid for strongly barred potentials. By comparing analytical predictions with the results of hydrodynamical simulations, we find that our theory provides a viable mechanism for ring formation if the effective sound speed of the gas is low (\cs\lesssim1\kms), but that nuclear spirals/shocks created by pressure destroy the ring when the sound speed is high (\cs\simeq10\kms). We conclude that whether this mechanism for ring formation is relevant for real galaxies ultimately depends on the effective equation of state of the ISM. Promising confirmation comes from simulations in which the ISM is modelled using state-of-the-art cooling functions coupled to live chemical networks, but more tests are needed regarding the role of turbulence driven by stellar feedback. If the mechanism is relevant in real galaxies, it could provide a powerful tool to constrain the gravitational potential, in particular the bar pattern speed.Comment: Accepted for publication in MNRA

thalamic damage predicts the evolution of primary progressive multiple sclerosis at 5 years

BACKGROUND AND PURPOSE: Reliable markers to monitor PPMS are still needed. We investigated whether conventional and DTI measures of thalamic damage are predictive of long-term disability accumulation in PPMS. MATERIALS AND METHODS: Brain conventional and DTI scans were obtained at baseline and after a mean follow-up of 15 months in 54 patients with PPMS and 8 healthy controls. Patients were reassessed clinically after 5 years. At baseline and follow-up, measures of lesion load, brain atrophy, and NTV were obtained. MD and FA histograms of the NAWM, the whole GM without the thalami, and the thalami were obtained. A multivariate analysis evaluated the predictors of long-term neurologic deterioration. RESULTS: At follow-up, 35 patients showed disability worsening. At baseline, compared with healthy controls, patients with PPMS had lower NTV ( P P = .002) and higher thalamic ( P = .002) and whole GM without the thalami ( P = .005) MD. During follow-up, the change of thalamic FA was higher in PPMS versus healthy controls ( P = .01). Baseline NTV and thalamic DTI quantities differed significantly between patients with PPMS with and without thalamic lesions. Baseline thalamic quantities were significantly correlated with the extent of brain T2 lesions and the severity of NAWM damage. The multivariate model included average NAWM MD (OR = 1.46, P = .005) and FA thalamic change (OR = 0.84, P = .02) as independent predictors of EDSS score deterioration (Nagelkerke R 2 = 0.55). CONCLUSIONS: Short-term accrual of thalamic damage and the severity of NAWM involvement predict the long-term accumulation of disability in PPMS

Acquisition and preliminary analysis of multi-channel seismic reflection data, acquired during the oceanographic cruises of the TOMO-ETNA experiment

The TOMO-ETNA experiment was performed in the framework of the FP7 “MED-SUV” (MEDiterranean SUpersite Volcanoes) in order to gain a detailed geological and structural model of the continental and oceanic crust concerning Etna and Aeolian Islands volcanoes (Sicily, Italy), by means of active and passive seismic exploration methodologies. Among all data collected, some 1410 km of marine multi-channel seismic (MCS) reflection profiles were acquired in the Ionian and Tyrrhenian Seas during two of the three oceanographic cruises of the TOMO-ETNA experiment, in July and November 2014, with the aim of shading light to deep, intermediate and shallow stratigraphy and crustal structure of the two above mentioned areas. The MCS sections, targeted to deep exploration, were acquired during the oceanographic cruise on board of the R/V “Sarmiento de Gamboa”, using an active seismic source of 16 air-guns, for a total volume of 4340 cu. in., and a 3000 m long, 240-channels digital streamer as receiving system. High-resolution seismic profiles were instead collected through the R/V “Aegaeo”, using two smaller air-guns (overall 270 cu. in. volume) and a 96 channels, 300 m long digital streamer. This paper provides a detailed description of the acquisition parameters and main processing steps adopted for the MCS data. Some processed lines are shown and preliminarily interpreted, to highlight the overall good quality and the high potential of the MCS sections collected during the TOMO-ETNA experiment. © 2016 by the Istituto Nazionale di Geofisica e Vulcanologia. All rights reserved

Defining responders to therapies by a statistical modeling approach applied to randomized clinical trial data

Background: Personalized medicine is the tailoring of treatment to the individual characteristics of patients. Once a treatment has been tested in a clinical trial and its effect overall quantified, it would be of great value to be able to use the baseline patients' characteristics to identify patients with larger/lower benefits from treatment, for a more personalized approach to therapy. Methods: We show here a previously published statistical method, aimed at identifying patients' profiles associated to larger treatment benefits applied to three identical randomized clinical trials in multiple sclerosis, testing laquinimod vs placebo (ALLEGRO, BRAVO, and CONCERTO). We identified on the ALLEGRO patients' specific linear combinations of baseline variables, predicting heterogeneous response to treatment on disability progression. We choose the best score on the BRAVO, based on its ability to identify responders to treatment in this dataset. We finally got an external validation on the CONCERTO, testing on this new dataset the performance of the score in defining responders and non-responders. Results: The best response score defined on the ALLEGRO and the BRAVO was a linear combination of age, sex, previous relapses, brain volume, and MRI lesion activity. Splitting patients into responders and non-responders according to the score distribution, in the ALLEGRO, the hazard ratio (HR) for disability progression of laquinimod vs placebo was 0.38 for responders, HR = 1.31 for non-responders (interaction p = 0.0007). In the BRAVO, we had similar results: HR = 0.40 for responders and HR = 1.24 for non-responders (interaction p = 0.006). These findings were successfully replicated in the CONCERTO study, with HR = 0.44 for responders and HR=1.08 for non-responders (interaction p = 0.033). Conclusions: This study demonstrates the possibility to refine and personalize the treatment effect estimated in randomized studies by using the baseline demographic and clinical characteristics of the included patients. The method can be applied to any randomized trial in any medical condition to create a treatment-specific score associated to different levels of response to the treatment tested in the trial. This is an easy and affordable method toward therapy personalization, indicating patient profiles related to a larger benefit from a specific drug, which may have implications for taking clinical decisions in everyday clinical practice