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

AIF-1 gene does not confer susceptibility to Behçet's disease: Analysis of extended haplotypes in Sardinian population

Background BehcEet's disease (BD) is a polygenic immune-mediated disorder characterized by a close association with the HLA-B∗51 allele. The HLA region has a strong linkage disequilibrium (LD) and carries several genetic variants (e.g. MIC-A, TNF-α genes) identified as associated to BD because of their LD with HLA-B∗51. In fact, the HLA-B∗51 is inherited as part of extended HLA haplotypes which are well preserved in patients with BD. Sardinian population is highly differentiated from other Mediterranean populations because of a distinctive genetic structure with very highly preserved HLA haplotypes. Patients and methods In order to identify other genes of susceptibility to BD within the HLA region we investigated the distribution of human Allograft Inflammatory Factor-1 (AIF-1) gene variants among BD patients and healthy controls from Sardinia. Six (rs2736182; rs2259571; rs2269475; rs2857597; rs13195276; rs4711274) AIF-1 single nucleotide polymorphisms (SNPs) and related extended haplotypes have been investigated as well as their LD within the HLA region and with HLA-B∗51. Overall, 64 BD patients, 43 HLA-B∗51 positive healthy controls (HC) and 70 random HC were enrolled in the study. Results HLA-B∗51 was the only allele with significantly higher frequency (pc = 0.0021) in BD patients (40.6%) than in HC (9.8%). The rs2259571TAIF-1 variant had a significantly reduced phenotypic, but not allelic frequency in BD patients (72.1%; pc = 0.014) compared to healthy population (91.3%). That was likely due to the LD between HLA-B∗51 and rs2259571G(pc= 9E-5), even though the rs2259571Gdistribution did not significantly differ between BD patients and HC. Conclusion No significant difference in distribution of AIF-1 SNPs haplotypes was observed between BD patients and HC and between HLA-B∗51 positive BD patients and HLA-B∗51 positive HC. Taken together, these results suggest that AIF-1 gene is not associated with susceptibility to BD in Sardinia

Mitochondrial dysfunction in Parkinsonian mesenchymal stem cells impairs differentiation

Sporadic cases account for 90-95% of all patients with Parkinson's Disease (PD). Atypical Parkinsonism comprises approximately 20% of all patients with parkinsonism. Progressive Supranuclear Palsy (PSP) belongs to the atypical parkinsonian diseases and is histopathologically classified as a tauopathy. Here, we report that mesenchymal stem cells (MSCs) derived from the bone marrow of patients with PSP exhibit mitochondrial dysfunction in the form of decreased membrane potential and inhibited NADH-dependent respiration. Furthermore, mitochondrial dysfunction in PSP-MSCs led to a significant increase in mitochondrial ROS generation and oxidative stress, which resulted in decrease of major cellular antioxidant GSH. Additionally, higher basal rate of mitochondrial degradation and lower levels of biogenesis were found in PSP-MSCs, together leading to a reduction in mitochondrial mass. This phenotype was biologically relevant to MSC stemness properties, as it heavily impaired their differentiation into adipocytes, which mostly rely on mitochondrial metabolism for their bioenergetic demand. The defect in adipogenic differentiation was detected as a significant impairment of intracellular lipid droplet formation in PSP-MSCs. This result was corroborated at the transcriptional level by a significant reduction of PPARγ and FABP4 expression, two key genes involved in the adipogenic molecular network. Our findings in PSP-MSCs provide new insights into the etiology of 'idiopathic' parkinsonism, and confirm that mitochondrial dysfunction is important to the development of parkinsonism, independent of the type of the cell

On-line booking and revenue management: Evidence from a low-cost airline

Using unique data on a low-cost airline posted prices and seat availability, this study sheds some light on whether the airline’s actual practice of yield management techniques conforms with some predictions from economic models of peak-load pricing under demand uncertainty. On the one hand, robust support is found to the notion that prices increase as the seat availability decreases; on the other, theoretical models that do not account for stochastic peak-load pricing fail to capture an important source of dispersion in the data

Delphi consensus on the current clinical and therapeutic knowledge on Anderson-Fabry disease

BACKGROUND: Management of Anderson-Fabry disease (AFD) is contentious, particularly regarding enzyme replacement therapy (ERT). We report results of a Delphi consensus panel on AFD management. METHODS: A survey to gauge consensus among AFD experts was distributed online and responses were analysed. Statements on: 1) diagnosis; 2) when starting ERT; 3) management of ERT infusion and adverse reactions; and 4) follow-up/monitoring response to therapy and progression of disease were included. Responses without consensus were discussed with an enlarged panel and modified to reach consensus. RESULTS: 15 experts responded to the survey. After plenary discussion among the enlarged panel, consensus was reached on most statements. Key points were the use of a target organ biopsy to show Gb3 deposits in symptomatic women with negative molecular analysis, the need for ERT in symptomatic women and in all patients with persistent signs and symptoms±organ damage. It was agreed to assess vital signs before ERT administration and use a 0.2μL filter on infusion to reduce the risk of adverse reactions, that serum should be drawn prior to the first infusion for anti-agalsidase antibody analysis to have a baseline value if a subsequent adverse reaction appears, and that pre-medication is required in those with prior infusion reactions. Holter ECG monitoring, cardiac and brain MRI, renal parameters, and abdominal ultrasound were considered important for the assessment of disease progression and response at ERT. CONCLUSIONS: This consensus supplies guidance to healthcare providers on best practice in the management of patients with AFD and indicates a need for more guidanc

Diagnostic accuracy of magnetic resonance enterography and small bowel ultrasound for the extent and activity of newly diagnosed and relapsed Crohn's disease (METRIC): a multicentre trial

Magnetic resonance enterography (MRE) and ultrasound are used to image Crohn's disease, but their comparative accuracy for assessing disease extent and activity is not known with certainty. Therefore, we did a multicentre trial to address this issue. We recruited patients from eight UK hospitals. Eligible patients were 16 years or older, with newly diagnosed Crohn's disease or with established disease and suspected relapse. Consecutive patients had MRE and ultrasound in addition to standard investigations. Discrepancy between MRE and ultrasound for the presence of small bowel disease triggered an additional investigation, if not already available. The primary outcome was difference in per-patient sensitivity for small bowel disease extent (correct identification and segmental localisation) against a construct reference standard (panel diagnosis). This trial is registered with the International Standard Randomised Controlled Trial, number ISRCTN03982913, and has been completed. 284 patients completed the trial (133 in the newly diagnosed group, 151 in the relapse group). Based on the reference standard, 233 (82%) patients had small bowel Crohn's disease. The sensitivity of MRE for small bowel disease extent (80% [95% CI 72-86]) and presence (97% [91-99]) were significantly greater than that of ultrasound (70% [62-78] for disease extent, 92% [84-96] for disease presence); a 10% (95% CI 1-18; p=0·027) difference for extent, and 5% (1-9; p=0·025) difference for presence. The specificity of MRE for small bowel disease extent (95% [85-98]) was significantly greater than that of ultrasound (81% [64-91]); a difference of 14% (1-27; p=0·039). The specificity for small bowel disease presence was 96% (95% CI 86-99) with MRE and 84% (65-94) with ultrasound (difference 12% [0-25]; p=0·054). There were no serious adverse events. Both MRE and ultrasound have high sensitivity for detecting small bowel disease presence and both are valid first-line investigations, and viable alternatives to ileocolonoscopy. However, in a national health service setting, MRE is generally the preferred radiological investigation when available because its sensitivity and specificity exceed ultrasound significantly. National Institute of Health and Research Health Technology Assessment. [Abstract copyright: Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Table olives: An overview on effects of processing on nutritional and sensory quality

Table olives are a pickled food product obtained by a partial/total debittering and subsequent fermentation of drupes. Their peculiar sensory properties have led to a their widespread use, especially in Europe, as an appetizer or an ingredient for culinary use. The most relevant literature of the last twenty years has been analyzed in this review with the aim of giving an up-to-date overview of the processing and storage effects on the nutritional and sensory properties of table olives. Analysis of the literature has revealed that the nutritional properties of table olives are mainly influenced by the processing method used, even if preharvest-factors such as irrigation and fruit ripening stage may have a certain weight. Data revealed that the nutritional value of table olives depends mostly on the balanced profile of polyunsaturated and monounsaturated fatty acids and the contents of health-promoting phenolic compounds, which are best retained in natural table olives. Studies on the use of low salt brines and of selected starter cultures have shown the possibility of producing table olives with an improved nutritional profile. Sensory characteristics are mostly process-dependent, and a relevant contribute is achieved by starters, not only for reducing the bitterness of fruits, but also for imparting new and typical taste to table olives. Findings reported in this review confirm, in conclusion, that table olives surely constitute an important food source for their balanced nutritional profile and unique sensory characteristics

Integrated geophysical and aerial sensing methods for archaeology: A case history in the Punic site of Villamar (Sardinia, Italy)

In this paper, the authors present a recent integrated survey carried out on an archaeological urban site, generally free of buildings, except some temporary structures related to excavated areas where multi-chamber tombs were found. The two methods used to investigate this site were thermal infrared and ground penetrating radar (GPR). The thermography was carried out with the sensor mounted under a helium balloon simultaneously with a photographic camera. In order to have a synthetic view of the surface thermal behavior, a simplified version of the existing night thermal gradient algorithm was applied. By this approach, we have a wide extension of thermal maps due to the balloon oscillation, because we are able to compute the maps despite collecting few acquisition samples. By the integration of GPR and the thermal imaging, we can evaluate the depth of the thermal influence of possible archaeological targets, such as buried Punic tombs or walls belonging to the succeeding medieval buildings, which have been subsequently destroyed. The thermal anomalies present correspondences to the radar time slices obtained from 30 to 50 cm. Furthermore, by superimposing historical aerial pictures on the GPR and thermal imaging data, we can identify these anomalies as the foundations of the destroyed building

Intestinal microbial ecology and fillet metal chemistry of wild grey mullets reflect the variability of the aquatic environment in a western mediterranean coastal lagoon (Santa giusta, sardinia, italy)

Fish populations play an active role in the maintenance of aquatic ecosystems biodiversity. Their intestinal microbiota and fillet chemistry depend on abiotic and biotic factors of the water environments that they inhabit. The present study investigated the grey mullets’ gut microbiota from a transitional aquatic ecosystem (Santa Giusta Lagoon, Sardinia, Italy) by a multidisciplinary approach which refers the results of (1) gut cultivable microbiota analyses (MA), (2) the trace metal assessment of fish muscle (TM), (3) the physico‐chemical water monitoring (PC). MA detected the greatest number of total aerobic heterotrophic bacteria, Enterobacteriaceae and coliforms in Autumn (mean values 1.3 × 105, 2.4 × 104, 1.1 × 104 cfu g−1, respectively) when the accumulated rain and mean values of nutrients (reactive phosphorous and silica) were the highest. Marine bacteria were more numerous in Summer (mean value 7.4 × 105 cfu g−1) when the highest mean values of water temperature and salinity were registered. The gut bacteria were identified as Pseudomonas spp. (64%), Aeromonas spp. (17%), Ochrobactrum pseudogrignonense (10%), Providencia spp. (5%), Enterobacter ludwigii (2%) and Kocuria tytonicola (2%). TM showed that Ca, Na, B and Ni increased their concentrations in Winter while maxima of P, Zn, Cu and Fe were found in muscles of fish sampled in Summer. This study highlighted that the fish intestinal microbiota and metal composition of the fillet reflected the seasonal aquatic environmental variability