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

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

5-(carbamoylmethylene)-oxazolidin-2-ones as a promising class of heterocycles inducing apoptosis triggered by increased ROS levels and mitochondrial dysfunction in breast and cervical cancer

Oxazolidinones are antibiotics that inhibit protein synthesis by binding the 50S ribosomal subunit. Recently, numerous worldwide researches focused on their properties and possible involvement in cancer therapy have been conducted. Here, we evaluated in vitro the antiproliferative activity of some 5-(carbamoylmethylene)-oxazolidin-2-ones on MCF-7 and HeLa cells. The tested compounds displayed a wide range of cytotoxicity on these cancer cell lines, measured by MTT assay, exhibiting no cytotoxicity on non-tumorigenic MCF-10A cells. Among the nine tested derivatives, four displayed a good anticancer potential. Remarkably, OI compound showed IC50 values of 17.66 and 31.10 µM for MCF-7 and HeLa cancer cells, respectively. Furthermore, we assessed OI effect on the cell cycle by FACS analysis, highlighting a G1 phase arrest after 72 h, supported by a low expression level of Cyclin D1 protein. Moreover, mitochondrial membrane potential was reduced after OI treatment driven by high levels of ROS. These findings demonstrate that OI treatment can inhibit MCF-7 and HeLa cell proliferation and induce apoptosis by caspase-9 activation and cytochrome c release in the cytosol. Hence, 5-(carbamoylmethylene)-oxazolidin-2-ones have a promising anticancer activity, in particular, OI derivative could represent a good candidate for in vivo further studies and potential clinical use

Measuring and modeling broadband magnetic losses versus temperature and aging effects in CoO-doped Mn-Zn ferrites

We analyze the physical mechanisms associated with addition of CoO to sintered Mn-Zn ferrites and the ensuing stabilization versus temperature of their magnetic properties. We determine, in particular, the value and behavior of the magnetic anisotropy as a function of doping and temperature and we model in physical terms the evolution of the energy loss in the investigated frequency (DC - 1 GHz) and temperature (20 degrees C - +130 degrees C) ranges. We show that magnetic aging by long exposure of the CoO-doped ferrites at 200 degrees C is minimized by additional TiO2 doping. This is observed to restrain the increase of the extra-anisotropy induced by directional ordering of the Co2+ cations

Magnetic Losses in Soft Ferrites

We review the basic phenomenology of magnetic losses from DC to 1 GHz in commercial and laboratory-prepared soft ferrites considering recent concepts regarding their physical interpretation. This is based, on the one hand, on the identification of the contributions to the magnetization process provided by spin rotations and domain walls and, on the other hand, the concept of loss separation. It additionally contemplates a distinction between the involved microscopic dissipation mechanisms: spin damping and eddy currents. Selected experimental results on the broadband behavior of complex permeability and losses in Mn-Zn ferrites provide significant examples of their dependence on sintering methods, solute elements, and working temperature. We also highlight the peculiar frequency and temperature response of Ni-Zn ferrites, which can be heavily affected by magnetic aftereffects. The physical modeling of the losses brings to light the role of the magnetic anisotropy and the way its magnitude distribution, affected by the internal demagnetizing fields, acts upon the magnetization process and its dependence on temperature and frequency. It is shown that the effective anisotropy governs the interplay of domain wall and rotational processes and their distinctive dissipation mechanisms, whose contributions are recognized in terms of different loss components

The multifaceted nature of aminopeptidases ERAP1, ERAP2, and LNPEP: from evolution to disease

In the human genome, the aminopeptidases ERAP1, ERAP2 and LNPEP lie contiguously on chromosome 5. They share sequence homology, functions and associations with immune-mediated diseases. By analyzing their multifaceted activities as well as their expression in the zoological scale, we suggest here that the progenitor of the three aminopeptidases might be LNPEP from which the other two aminopeptidases could have derived by gene duplications. We also propose that their functions are partially redundant. More precisely, the evolutionary story of the three aminopeptidases might have been dictated by their role in regulating the renin–angiotensin system, which requires their controlled and coordinated expression. This hypothesis is supported by the many species that lack one or the other gene as well as by the lack of ERAP2 in rodents and a null expression in 25% of humans. Finally, we speculate that their role in antigen presentation has been acquired later on during evolution. They have therefore been diversified between those residing in the ER, ERAP1 and ERAP2, whose role is to refine the MHC-I peptidomes, and LNPEP, mostly present in the endosomal vesicles where it can contribute to antigen cross-presentation or move to the cell membrane as receptor for angiotensin IV. Their association with autoinflammatory/autoimmune diseases can therefore be two-fold: as “contributors” to the shaping of the immune-peptidomes as well as to the regulation of the vascular response

Is idiopathic intracranial hypertension without papilledema a risk factor for migraine progression?

The association of chronic migraine (CM) with an idiopathic intracranial hypertension without papilledema (IIHWOP), although much more prevalent than expected in clinical series of CM sufferers, is not included among the risk factors for migraine progression. We discuss the available evidence supporting the existence of a pathogenetic link between CM and idiopathic intracranial hypertensive disorders and suggest a causative role for IIHWOP in migraine progression

Improving performance of the hospitalization process by applying the principles of Lean Thinking

Purpose: The goal was to improve the quality of the hospitalization process and the management of patients, allowing the reduction of costs and the minimization of the preoperative Length of Hospital Stay (LOS). Design/methodology/approach: The methodology used to improve the quality of the hospitalization process and patient management was Lean Thinking. Therefore, the Lean tools (Value stream map and Ishikawa diagram) were used to identify waste and inefficiencies, improving the process with the implementation of corrective actions. The data was collected through personal observations, patient interviews, brainstorming and from printed medical records of 151 patients undergoing oral cancer surgery in the period from 2006 to 2018. Findings: The authors identified, through Value Stream Map, waste and inefficiencies during preoperative activities, consequently influencing preoperative LOS, considered the best performance indicator. The main causes were identified through the Ishikawa diagram, allowing reflection on possible solutions. The main corrective action was the introduction of the pre-hospitalization service. A comparative statistical analysis showed the significance of the solutions implemented. The average preoperative LOS decreased from 4.90 to 3.80 days (−22.40%) with a p-value of 0.001. Originality/value: The methodology allowed to highlight the improvement of the patient hospitalization process with the introduction of the pre-hospitalization service. Therefore, by adopting the culture of continuous improvement, the flow of hospitalization was redrawn. The benefits of the solutions implemented are addressed to the patient in terms of lower LOS and greater service satisfaction and to the hospital for lower patient management costs and improved process quality. This article will be useful for those who need examples on how to apply Lean tools in healthcare

Fibroblasts to keratinocytes redox signaling: The possible role of ROS in psoriatic plaque formation

Although the role of reactive oxygen species-mediated (ROS-mediated) signalling in physiologic and pathologic skin conditions has been proven, no data exist on the skin cells ROS-mediated communication. Primary fibroblasts were obtained from lesional and non-lesional skin of psoriatic patients. ROS, superoxide anion, calcium and nitric oxide levels and lipoperoxidation markers and total antioxidant content were measured in fibroblasts. NADPH oxidase activity and NOX1, 2 and 4 expressions were assayed and NOX4 silencing was performed. Fibroblasts and healthy keratinocytes co-culture was performed. MAPK pathways activation was studied in fibroblasts and in co-cultured healthy keratinocytes. Increased intracellular calcium, •NO and ROS levels as well as an enhanced NADPH oxidase 4 (NOX4)–mediated extracellular ROS release was shown in lesional psoriatic vs. control fibroblasts. Upon co-culture with lesional fibroblasts, keratinocytes showed p38 and ERK MAPKs pathways activation, ROS, Ca2+ and •NO increase and cell cycle acceleration. Notably, NOX4 knockdown significantly reduced the observed effects of lesional fibroblasts on keratinocyte cell cycle progression. Co-culture with non-lesional psoriatic and control fibroblasts induced slight cell cycle acceleration, but notable intracellular ROS accumulation and ERK MAPK activation in keratinocytes. Collectively, our data demonstrate that NOX4 expressed in dermal fibroblasts is essential for the redox paracrine regulation of epidermal keratinocytes proliferation