Crystal structure solution via precession electron diffraction data: the BEA algorithm

The statistical features of the amplitudes obtained via precession electron diffraction have been studied, with particular concern with their effects on direct phasing procedures. A new algorithm, denoted by BEA, is described: according to it, the average amplitude of the symmetry equivalent reflections is used in the Direct Methods step. Once an even imperfect structural model is available, the best amplitude among the equivalent reflections is used to improve the model. It is shown that BEA is able to provide more complete structural models, to make the phasing process more straightforward and to end with crystallographic residual much better than those usually obtained by electron diffraction.     

Stability Is Not Everything: The Case of the Cyclisation of a Thrombin-Binding Aptamer

With the aim of developing a new approach to obtain improved aptamers, a cyclic thrombin-binding aptamer (TBA) analogue (cycTBA) has been prepared by exploiting a copper(I)-assisted azide–alkyne cycloaddition. The markedly increased serum resistance and exceptional thermal stability of the G-quadruplex versus TBA were associated with halved thrombin inhibition, which suggested that some flexibility in the TBA structure was necessary for protein recognition.     

The Impact of the ‘Mis-Peptidome’ on HLA Class I-Mediated Diseases: Contribution of ERAP1 and ERAP2 and Effects on the Immune Response

The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of the Spondyloarthropathies (SpA), the Behçet’s disease (BD), the Psoriasis (Ps) and the Birdshot Chorioretinopathy (BSCR) are HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02, respectively. Despite the strength of the association, the HLA pathogenetic role in these diseases is far from being thoroughly understood. Furthermore, Genome-Wide Association Studies (GWAS) have highlighted other important susceptibility factors such as Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and, less frequently, ERAP2 that refine the peptidome presented by HLA class I molecules to CD8⁺ T cells. Mass spectrometry analysis provided considerable knowledge of HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02 immunopeptidome. However, the combined effect of several ERAP1 and ERAP2 allelic variants could generate an altered pool of peptides accounting for the “mis-immunopeptidome” that ranges from suboptimal to pathogenetic/harmful peptides able to induce non-canonical or autoreactive CD8⁺ T responses, activation of NK cells and/or garbling the classical functions of the HLA class I molecules. This review will focus on this class of epitopes as possible elicitors of atypical/harmful immune responses which can contribute to the pathogenesis of chronic inflammatory diseases.     

Autonomic Nervous System in Obesity and Insulin-Resistance—The Complex Interplay between Leptin and Central Nervous System

The role of the autonomic nervous system in obesity and insulin-resistant conditions has been largely explored. However, the exact mechanisms involved in this relation have not been completely elucidated yet, since most of these mechanisms display a bi-directional effect. Insulin-resistance, for instance, can be caused by sympathetic activation, but, in turn, the associated hyperinsulinemia can activate the sympathetic branch of the autonomic nervous system. The picture is made even more complex by the implicated neural, hormonal and nutritional mechanisms. Among them, leptin plays a pivotal role, being involved not only in appetite regulation and glucose homeostasis but also in energy expenditure. The purpose of this review is to offer a comprehensive view of the complex interplay between leptin and the central nervous system, providing further insights on the impact of autonomic nervous system balance on adipose tissue and insulin-resistance. Furthermore, the link between the circadian clock and leptin and its effect on metabolism and energy balance will be evaluated.     

A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors

Multiple sclerosis is a complex, multifactorial, dysimmune disease prevalent in women. Its etiopathogenesis is extremely intricate, since each risk factor behaves as a variable that is interconnected with others. In order to understand these interactions, sex must be considered as a determining element, either in a protective or pathological sense, and not as one of many variables. In particular, sex seems to highly influence immune response at chromosomal, epigenetic, and hormonal levels. Environmental and genetic risk factors cannot be considered without sex, since sex-based immunological differences deeply affect disease onset, course, and prognosis. Understanding the mechanisms underlying sex-based differences is necessary in order to develop a more effective and personalized therapeutic approach.     

Structure–Activity Relationships of Benzenesulfonamide‐Based Inhibitors towards Carbonic Anhydrase Isoform Specificity

Carbonic anhydrases (CAs) are implicated in a wide range of diseases, including the upregulation of isoforms CA IX and XII in many aggressive cancers. However, effective inhibition of disease‐implicated CAs should minimally affect the ubiquitously expressed isoforms, including CA I and II, to improve directed distribution of the inhibitors to the cancer‐associated isoforms and reduce side effects. Four benzenesulfonamide‐based inhibitors were synthesized by using the tail approach and displayed nanomolar affinities for several CA isoforms. The crystal structures of the inhibitors bound to a CA IX mimic and CA II are presented. Further in silico modeling was performed with the inhibitors docked into CA I and XII to identify residues that contributed to or hindered their binding interactions. These structural studies demonstrated that active‐site residues lining the hydrophobic pocket, especially positions 92 and 131, dictate the positional binding and affinity of inhibitors, whereas the tail groups modulate CA isoform specificity. Geometry optimizations were performed on each ligand in the crystal structures and showed that the energetic penalties of the inhibitor conformations were negligible compared to the gains from active‐site interactions. These studies further our understanding of obtaining isoform specificity when designing small molecule CA inhibitors.     

Exposure to urban stressor and effects on free testosterone in female workers

BACKGROUND: The aim of the study is to evaluate if occupational exposure to chemical, physical and psycho-social urban stressor could cause alterations in plasma free testosterone (T) levels and related diseases in female traffic police vs. control group. PATIENTS AND METHODS: The research was carried out on initial sample of 468 female Municipal Police employees (209 traffic police and 259 controls). After excluding the principal confounding factors, traffic police were matched with controls by age, working life, menstrual cycle day, BMI, drinking habit, cigarette smoking habit, liquorice and soy intake in diet, habitual consumption of Italian coffee. There were 96 female traffic police and 96 controls included in the study. RESULTS: T mean levels were significantly higher in female traffic police compared to controls (p=0.000). The distribution of T values in traffic police and in controls was significant (p=0.000). No significant differences were found comparing the percentage in traffic police and controls concerning dystocial, premature and post-term birth. An increase in mental health disorders was found in traffic police compared to controls but the difference was not significant. CONCLUSION: The increase in T plasma levels observed in traffic police vs. controls can be due to a chronic working exposure to low doses of environmental chemical urban stressor. According to our previous researches T could be used as an early biological marker even before the onset of the related disorders.     

Chemorheology and ultimate behavior of epoxy‐amine mixtures modified with a liquid oligomer

Rubber toughening of epoxy resins has been actively studied since the 1960s with clear progress in understanding of the ultimate properties: microstructure relationships. The morphology, obtained after curing of the modified thermosetting matrix, is a function of the process conditions as well as of the materials used because both influence the thermodynamics and the kinetics of phase separation. In this work several amounts of poly(oxypropylentriamine) (POPTA), have been added as modifier to a diglycidyl ether of bisphenol‐A (DGEBA)‐based epoxy matrix cured with a cycloaliphatic amine. Molecular weight of the neat resin and amine/epoxy stoichiometric ratio have also been used as variables. This investigation has focused upon the importance of cure chemorheology for microstructure formation by using both physicochemical (isothermal and dynamic calorimetry) and rheological techniques. In the second part of this study, the influence of the molecular weight of the epoxy resin in the ultimate properties of 15 wt % POPTA‐modified epoxy matrices is also analyzed. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 76: 1269–1279, 2000