HLA Class I or Class II and Disease Association: Catch the Difference if You Can

The association of autoimmune diseases with HLA has been known for many decades. To date, however, the underlying mechanisms have not been fully understood. The recently introduced genome-wide association studies (GWAS) have suggested that several genes converging in common pathways contribute to the genetic susceptibility in such disorders. Nevertheless, for most autoimmune/autoinflammatory diseases, the HLA genes are by far the strongest risk factors. The basis of some associations has now been elucidated, particularly in those cases in which exogenous factors are involved

Ankylosing Spondylitis: a trade Off of HLA-B27, ERAP, and pathogen interconnections? Focus on Sardinia

The frequency of HLA-B27 in patients with Ankylosing Spondylitis (AS) is over 85%. There are more than 170 recognized HLA-B27 alleles but the majority of them is not sufficiently represented for genetic association studies. So far only two alleles, the HLA-B*2706 in Asia and the HLA-B*2709 in Sardinia, have not been found to be associated with AS. The highly homogenous genetic structure of the Sardinian population has favored the search of relevant variants for disease-association studies. Moreover, malaria, once endemic in the island, has been shown to have contributed to shape the native population genome affecting the relative allele frequency of relevant genes. In Sardinia, the prevalence of HLA-B*2709, which differs from the strongly AS-associated B*2705 prototype for one amino acid (His/Asp116) in the F pocket of the peptide binding groove, is around 20% of all HLA-B27 alleles. We have previously hypothesized that malaria could have contributed to the establishment of this allele in Sardinia. Based on our recent findings, in this perspective article we speculate that the Endoplasmic Reticulum Amino Peptidases, ERAP1 and 2, associated with AS and involved in antigen presentation, underwent co-selection by malaria. These genes, besides shaping the immunopeptidome of HLA-class I molecules, have other biological functions that could also be involved in the immunosurveillance against malaria

Synchronization of dynamical hypernetworks: dimensionality reduction through simultaneous block-diagonalization of matrices

We present a general framework to study stability of the synchronous solution for a hypernetwork of coupled dynamical systems. We are able to reduce the dimensionality of the problem by using simultaneous block-diagonalization of matrices. We obtain necessary and sufficient conditions for stability of the synchronous solution in terms of a set of lower-dimensional problems and test the predictions of our low-dimensional analysis through numerical simulations. Under certain conditions, this technique may yield a substantial reduction of the dimensionality of the problem. For example, for a class of dynamical hypernetworks analyzed in the paper, we discover that arbitrarily large networks can be reduced to a collection of subsystems of dimensionality no more than 2. We apply our reduction techique to a number of different examples, including a class of undirected unweighted hypermotifs of three nodes.Comment: 9 pages, 6 figures, accepted for publication in Phys. Rev.

Adaptive coupling for achieving stable synchronization of chaos

We consider synchronization of coupled chaotic systems and propose an adaptive strategy that aims at evolving the strength of the coupling to achieve stability of the synchronized evolution. We test this idea in a simple configuration in which two chaotic systems are unidirectionally coupled (a sender and a receiver) and we study conditions for the receiver to adaptively synchronize with the sender. Numerical simulations show that, under certain conditions, our strategy is successful in dynamically evolving the coupling strength until it converges to a value that is compatible with synchronization.Comment: 12 Pages, 9 figures, accepted for publication in Physical Review

The stability of adaptive synchronization of chaotic systems

In past works, various schemes for adaptive synchronization of chaotic systems have been proposed. The stability of such schemes is central to their utilization. As an example addressing this issue, we consider a recently proposed adaptive scheme for maintaining the synchronized state of identical coupled chaotic systems in the presence of a priori unknown slow temporal drift in the couplings. For this illustrative example, we develop an extension of the master stability function technique to study synchronization stability with adaptive coupling. Using this formulation, we examine local stability of synchronization for typical chaotic orbits and for unstable periodic orbits within the synchronized chaotic attractor (bubbling). Numerical experiments illustrating the results are presented. We observe that the stable range of synchronism can be sensitively dependent on the adaption parameters, and we discuss the strong implication of bubbling for practically achievable adaptive synchronization.Comment: 21 pages, 6 figure

Treatment of Vascular Dementia: The Route of Prevention

Vascular dementia (VaD), rather than being considered as a univocal nosological entity, should be regarded as a heterogeneous clinical entity which differs in clinical-pathological phenotype as well as in pathophysiological mechanisms, but shares cerebrovascular disease (CVD), resulting from vascular or circulatory pathology, as the cause of dementia. The aim of this review is to discuss VaD treatment focusing particularly on more prevalent ischemic forms. Due to the fact that there are presently no treatments capable of obtaining considerable results once VaD is clinically established, specific emphasis will be given to the therapeutic strategies aimed at the prevention of CVD risk factors. The therapeutic strategies aimed at slowing the progression of the disease will also be discussed

A simplex method for the calibration of a MEG device

MagnetoEncephaloGraphy (MEG) devices are helmet-shaped arrays of sensors that measure the tiny magnetic fields produced by neural currents. As they operate at low temperature, they are typically immersed in liquid helium. However, during the cooling process the sensor position and shape can change, with respect to nominal values, due to thermal stress. This implies that an accurate sensor calibration is required before a MEG device is utilized in either neuroscientific research or clinical workflow. Here we describe a calibration scheme developed for the optimal use of a MEG system recently realized at the "Istituto di Cibernetica e Biofisica" of the Italian CNR. To achieve the calibration goal a dedicated magnetic source is used (calibration device) and the geometric parameters of the sensors are determined through an optimisation procedure, based on the Nelder-Mead algorithm, which maximises the correlation coefficient between the predicted and the recorded magnetic field. Then the sensitivity of the sensors is analytically estimated. The developed calibration procedure is validated with synthetic data mimicking a real scenario

An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse expression of the two genes

The Endoplasmatic Reticulum Aminopeptidases ERAP1 and ERAP2 are implicated in a variety of immune and non-immune functions. Most studies however have focused on their role in shaping the HLA class I peptidome by trimming peptides to the optimal size. Genome Wide Association Studies highlighted non-synonymous polymorphisms in their coding regions as associated with several immune mediated diseases. The two genes lie contiguous and oppositely oriented on the 5q15 chromosomal region. Very little is known about the transcriptional regulation and the quantitative variations of these enzymes. Here, we correlated the level of transcripts and proteins of the two aminopeptidases in B-lymphoblastoid cell lines from 44 donors harbouring allelic variants in the intergenic region between ERAP1 and ERAP2. We found that the presence of a G instead of an A at SNP rs75862629 in the ERAP2 gene promoter strongly influences the expression of the two ERAPs with a down-modulation of ERAP2 coupled with a significant higher expression of ERAP1. We therefore show here for the first time a coordinated quantitative regulation of the two ERAP genes, which can be relevant for the setting of specific therapeutic approaches

Capturing the Biologic Onset of Inflammatory Bowel Diseases: Impact on Translational and Clinical Science

While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)-both ulcerative colitis (UC) and Crohn's Disease (CD)-as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage-as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients' first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions

Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies

In skeletal muscle, Ca2+ necessary for muscle contraction is stored and released from the sarcoplasmic reticulum (SR), a specialized form of endoplasmic reticulum through the mechanism known as excitation-contraction (E-C) coupling. Following activation of skeletal muscle contraction by the E-C coupling mechanism, replenishment of intracellular stores requires reuptake of cytosolic Ca2+ into the SR by the activity of SR Ca2+-ATPases, but also Ca2+ entry from the extracellular space, through a mechanism called store-operated calcium entry (SOCE). The fine orchestration of these processes requires several proteins, including Ca2+ channels, Ca2+ sensors, and Ca2+ buffers, as well as the active involvement of mitochondria. Mutations in genes coding for proteins participating in E-C coupling and SOCE are causative of several myopathies characterized by a wide spectrum of clinical phenotypes, a variety of histological features, and alterations in intracellular Ca2+ balance. This review summarizes current knowledge on these myopathies and discusses available knowledge on the pathogenic mechanisms of disease