Notes on the p-spin glass studied via Hamilton-Jacobi and Smooth-Cavity techniques

In these notes, we continue our investigation of classical toy models of disordered statistical mechanics through various techniques recently developed and tested mainly on the paradigmatic SK spin glass. Here we consider the p-spin-glass model with Ising spins and interactions drawn from a normal distribution N[0,1]. After a general presentation of its properties (e.g. self-averaging of the free energy, existence of a suitable thermodynamic limit), we study its equilibrium behavior within the Hamilton-Jacobi framework and the smooth cavity approach. Through the former we find both the RS and the 1RSB expressions for the free energy, coupled with their self-consistent relations for the overlaps. Through the latter, we recover these results as irreducible expression, and we study the generalization of the overlap polynomial identities suitable for this model; a discussion on their deep connection with the structure of the internal energy and the entropy closes the investigation.Comment: To appear on JM

Replica symmetry breaking in mean field spin glasses trough Hamilton-Jacobi technique

During the last years, through the combined effort of the insight, coming from physical intuition and computer simulation, and the exploitation of rigorous mathematical methods, the main features of the mean field Sherrington-Kirkpatrick spin glass model have been firmly established. In particular, it has been possible to prove the existence and uniqueness of the infinite volume limit for the free energy, and its Parisi expression, in terms of a variational principle, involving a functional order parameter. Even the expected property of ultrametricity, for the infinite volume states, seems to be near to a complete proof. The main structural feature of this model, and related models, is the deep phenomenon of spontaneous replica symmetry breaking (RSB), discovered by Parisi many years ago. By expanding on our previous work, the aim of this paper is to investigate a general frame, where replica symmetry breaking is embedded in a kind of mechanical scheme of the Hamilton-Jacobi type. Here, the analog of the "time" variable is a parameter characterizing the strength of the interaction, while the "space" variables rule out quantitatively the broken replica symmetry pattern. Starting from the simple cases, where annealing is assumed, or replica symmetry, we build up a progression of dynamical systems, with an increasing number of space variables, which allow to weaken the effect of the potential in the Hamilton-Jacobi equation, as the level of symmetry braking is increased. This new machinery allows to work out mechanically the general K-step RSB solutions, in a different interpretation with respect to the replica trick, and lightens easily their properties as existence or uniqueness.Comment: 24 pages, no figure

Granzyme B expression in visceral adipose tissue associates with local inflammation and glyco-metabolic alterations in obesity

Granzyme B (GrB) is a serine protease produced by immune and non-immune cells, able to promote multiple processes, like apoptosis, inflammation, extracellular matrix remodeling and fibrosis. GrB expression in visceral adipose tissue (VAT) was associated with tissue damage, local inflammation and insulin resistance in obesity murine model, but there is no data in humans. Aim of this study was to explore the expression of GrB in VAT from obese subjects in relation to adipose tissue injury, inflammation, metabolic alterations and GrB circulating levels. For this purpose, 85 obese individuals undergoing bariatric surgery and 35 healthy subjects (as control) were recruited at Sapienza University, Rome, Italy. Study participants underwent clinical work-up and routine biochemistry. mRNA expression of GrB in VAT and of a panel of VAT inflammatory markers was analyzed by real-time PCR. Serum GrB levels were measured by Elisa Affymetrix EBIO. We observed that 80% of obese patients expressed GrB mRNA in VAT, and GrB VAT expression was associated with the presence of local inflammation and glucose homeostasis alterations. Moreover, GrB serum levels, which were higher in obese subjects compared to non-obese healthy individuals, were associated with GrB expression in VAT and glyco-metabolic impairment. Our data show, for the first time in humans, that obese subjects with “sick” fat and altered glucose tolerance exhibit GrB expression in VAT, and suggest that GrB might contribute to obesity-related VAT inflammatory remodeling and glucose homeostasis dysregulation. Moreover, increased circulating GrB levels might represent a possible peripheral marker of VAT dysfunction in metabolic diseases

The Italian tremor Network (TITAN): rationale, design and preliminary findings.

INTRODUCTION: The recently released classification has revised the nosology of tremor, defining essential tremor (ET) as a syndrome and fueling an enlightened debate about some newly conceptualized entities such as ET-plus. As a result, precise information of demographics, clinical features, and about the natural history of these conditions are lacking. METHODS: The ITAlian tremor Network (TITAN) is a multicenter data collection platform, the aim of which is to prospectively assess, according to a standardized protocol, the phenomenology and natural history of tremor syndromes. RESULTS: In the first year of activity, 679 patients have been recruited. The frequency of tremor syndromes varied from 32% of ET and 41% of ET-plus to less than 3% of rare forms, including focal tremors (2.30%), task-specific tremors (1.38%), isolated rest tremor (0.61%), and orthostatic tremor (0.61%). Patients with ET-plus were older and had a higher age at onset than ET, but a shorter disease duration, which might suggest that ET-plus is not a disease stage of ET. Familial aggregation of tremor and movement disorders was present in up to 60% of ET cases and in about 40% of patients with tremor combined with dystonia. The body site of tremor onset was different between tremor syndromes, with head tremor being most commonly, but not uniquely, associated with dystonia. CONCLUSIONS: The TITAN study is anticipated to provide clinically relevant prospective information about the clinical correlates of different tremor syndromes and their specific outcomes and might serve as a basis for future etiological, pathophysiological, and therapeutic research

Artificial intelligence of imaging and clinical neurological data for predictive, preventive and personalized (P3) medicine for Parkinson Disease: the NeuroArtP3 protocol for a multi-center research study

Background The burden of Parkinson Disease (PD) represents a key public health issue and it is essential to develop innovative and cost-effective approaches to promote sustainable diagnostic and therapeutic interventions. In this perspective the adoption of a P3 (predictive, preventive and personalized) medicine approach seems to be pivotal. The NeuroArtP3 (NET-2018-12366666) is a four-year multi-site project co-funded by the Italian Ministry of Health, bringing together clinical and computational centers operating in the field of neurology, including PD. Objective The core objectives of the project are: i) to harmonize the collection of data across the participating centers, ii) to structure standardized disease-specific datasets and iii) to advance knowledge on disease’s trajectories through machine learning analysis. Methods The 4-years study combines two consecutive research components: i) a multi-center retrospective observational phase; ii) a multi-center prospective observational phase. The retrospective phase aims at collecting data of the patients admitted at the participating clinical centers. Whereas the prospective phase aims at collecting the same variables of the retrospective study in newly diagnosed patients who will be enrolled at the same centers. Results The participating clinical centers are the Provincial Health Services (APSS) of Trento (Italy) as the center responsible for the PD study and the IRCCS San Martino Hospital of Genoa (Italy) as the promoter center of the NeuroartP3 project. The computational centers responsible for data analysis are the Bruno Kessler Foundation of Trento (Italy) with TrentinoSalute4.0 –Competence Center for Digital Health of the Province of Trento (Italy) and the LISCOMPlab University of Genoa (Italy). Conclusions The work behind this observational study protocol shows how it is possible and viable to systematize data collection procedures in order to feed research and to advance the implementation of a P3 approach into the clinical practice through the use of AI models

Prediction of Protein Binding Regions in Disordered Proteins

Many disordered proteins function via binding to a structured partner and undergo a disorder-to-order transition. The coupled folding and binding can confer several functional advantages such as the precise control of binding specificity without increased affinity. Additionally, the inherent flexibility allows the binding site to adopt various conformations and to bind to multiple partners. These features explain the prevalence of such binding elements in signaling and regulatory processes. In this work, we report ANCHOR, a method for the prediction of disordered binding regions. ANCHOR relies on the pairwise energy estimation approach that is the basis of IUPred, a previous general disorder prediction method. In order to predict disordered binding regions, we seek to identify segments that are in disordered regions, cannot form enough favorable intrachain interactions to fold on their own, and are likely to gain stabilizing energy by interacting with a globular protein partner. The performance of ANCHOR was found to be largely independent from the amino acid composition and adopted secondary structure. Longer binding sites generally were predicted to be segmented, in agreement with available experimentally characterized examples. Scanning several hundred proteomes showed that the occurrence of disordered binding sites increased with the complexity of the organisms even compared to disordered regions in general. Furthermore, the length distribution of binding sites was different from disordered protein regions in general and was dominated by shorter segments. These results underline the importance of disordered proteins and protein segments in establishing new binding regions. Due to their specific biophysical properties, disordered binding sites generally carry a robust sequence signal, and this signal is efficiently captured by our method. Through its generality, ANCHOR opens new ways to study the essential functional sites of disordered proteins

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3 years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0 years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013