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

Context-Based Defading of Archive Photographs

We present an algorithm for the enhancement of contrast in digitized archive photographic prints. It aims at producing an adaptive enhancement based on the local context of each pixel and is able to operate without direct user's intervention. A relation between the variation of contrast at different resolutions and the local Lipschitz regularity of the image is exploited. In this way, each pixel is defaded according to its nature: noise, edge, or smooth region. This strategy provides for an algorithm that drastically reduces typical, annoying artifacts like halo effects and noise amplification

MULTI-SCALE SEMI-TRANSPARENT BLOTCH REMOVAL ON ARCHIVED PHOTOGRAPHS USING BAYESIAN MATTING TECHNIQUES AND VISIBILITY LAWS

ABSTRACT This paper presents an automatic technique to remove semitransparent blotches (due to moisture) from archived photographs and documents. Blotches are processed in the HSV space. While chroma components are processed using a simple texture synthesis method, the intensity component is split into an over-complete wavelet representation. In the approximation band, the blotch is modelled as an alpha matte which reduces the intensity of the image in a non-uniform yet smooth manner. The alpha matte is estimated using a Bayesian approach and its effect reversed. Wavelet details are left unchanged in the case of perfect semi-transparency or attenuated using visibility laws whenever dirt and dust cause spurious edges. Experimental results achieved on many historical photographs show the effectiveness of the proposed approach

Sirt1 activity in pbmcs as a biomarker of different heart failure phenotypes

Heart Failure (HF) is a syndrome, which implies the existence of different phenotypes. The new categorization includes patients with preserved ejection fraction (HFpEF), mid-range EF (HFmrEF), and reduced EF (HFrEF) but the molecular mechanisms involved in these HF phenotypes have not yet been exhaustively investigated. Sirt1 plays a crucial role in biological processes strongly related to HF. This study aimed to evaluate whether Sirt1 activity was correlated with EF and other parameters in HFpEF, HFmrEF, and HFrEF. Seventy patients, HFpEF (n = 23), HFmrEF (n = 23) and HFrEF (n = 24), were enrolled at the Cardiology Unit of the University Hospital of Salerno. Sirt1 activity was measured in peripheral blood mononuclear cells (PBMCs). Angiotensin-Converting Enzyme 2 (ACE2) activity, Tumor Necrosis Factor-alpha (TNF-α) and Brain Natriuretic Peptide (BNP) levels were quantified in plasma. HFpEF showed lower Sirt1 and ACE2 activities than both HFmrEF and HFrEF (p < 0.0001), without difference compared to No HF controls. In HFmrEF and HFrEF a very strong correlation was found between Sirt1 activity and EF (r2 = 0.899 and r2 = 0.909, respectively), and between ACE2 activity and Sirt1 (r2 = 0.801 and r2 = 0.802, respectively). HFrEF showed the highest TNF-α levels without reaching statistical significance. Significant differences in BNP were found among the groups, with the highest levels in the HFrEF. Determining Sirt1 activity in PBMCs is useful to distinguish the HF patients’ phenotypes from each other, especially HFmrEF/HFrEF from HFpEF

Combination of an implantable defibrillator multi-sensor heart failure index and an apnea index for the prediction of atrial high-rate events

Aims Patients with atrial fibrillation frequently experience sleep disorder breathing, and both conditions are highly prevalent in presence of heart failure (HF). We explored the association between the combination of an HF and a sleep apnoea (SA) index and the incidence of atrial high-rate events (AHRE) in patients with implantable defibrillators (ICDs). Methods and results Data were prospectively collected from 411 consecutive HF patients with ICD. The IN-alert HF state was measured by the multi-sensor HeartLogic Index (>16), and the ICD-measured Respiratory Disturbance Index (RDI) was computed to identify severe SA. The endpoints were as follows: daily AHRE burden of ≥5 min, ≥6 h, and ≥23 h. During a median follow-up of 26 months, the time IN-alert HF state was 13% of the total observation period. The RDI value was ≥30 episodes/h (severe SA) during 58% of the observation period. An AHRE burden of ≥5 min/day was documented in 139 (34%) patients, ≥6 h/ day in 89 (22%) patients, and ≥23 h/day in 68 (17%) patients. The IN-alert HF state was independently associated with AHRE regardless of the daily burden threshold: hazard ratios from 2.17 for ≥5 min/day to 3.43 for ≥23 h/day (P < 0.01). An RDI ≥ 30 episodes/h was associated only with AHRE burden ≥5 min/day [hazard ratio 1.55 (95% confidence interval: 1.11–2.16), P = 0.001]. The combination of IN-alert HF state and RDI ≥ 30 episodes/h accounted for only 6% of the follow-up period and was associated with high rates of AHRE occurrence (from 28 events/100 patient-years for AHRE burden ≥5 min/day to 22 events/100 patient-years for AHRE burden ≥23 h/day). Conclusions In HF patients, the occurrence of AHRE is independently associated with the ICD-measured IN-alert HF state and RDI ≥ 30 episodes/h. The coexistence of these two conditions occurs rarely but is associated with a very high rate of AHRE occurrence

A Randomized Controlled Trial of an Integrated Brain, Body, and Social Intervention for Children With ADHD

Objective: This study evaluated the efficacy of an Integrated Brain, Body, and Social (IBBS) intervention for children with ADHD. Treatment consisted of computerized cognitive remediation training, physical exercises, and a behavior management strategy. Method: Ninety-two children aged 5 to 9 years with ADHD were randomly assigned to 15 weeks of IBBS or to treatment-as-usual. Primary outcome measures included blinded clinician ratings of ADHD symptoms and global clinical functioning. Secondary outcome measures consisted of parent and teacher ratings of ADHD and neurocognitive tests. Results: No significant treatment effects were found on any of our primary outcome measures. In terms of secondary outcome measures, the IBBS group showed significant improvement on a verbal working memory task; however, this result did not survive correction for multiple group comparisons. Conclusion: These results suggest that expanding cognitive training to multiple domains by means of two training modalities does not lead to generalized improvement of ADHD symptomatology

Structure-Function Studies of Sponge-Derived Compounds on the Cardiac CaV3.1 Channel

T-type calcium (CaV3) channels are involved in cardiac automaticity, development, and excitation–contraction coupling in normal cardiac myocytes. Their functional role becomes more pronounced in the process of pathological cardiac hypertrophy and heart failure. Currently, no CaV3 channel inhibitors are used in clinical settings. To identify novel T-type calcium channel ligands, purpurealidin analogs were electrophysiologically investigated. These compounds are alkaloids produced as secondary metabolites by marine sponges, and they exhibit a broad range of biological activities. In this study, we identified the inhibitory effect of purpurealidin I (1) on the rat CaV3.1 channel and conducted structure–activity relationship studies by characterizing the interaction of 119 purpurealidin analogs. Next, the mechanism of action of the four most potent analogs was investigated. Analogs 74, 76, 79, and 99 showed a potent inhibition on the CaV3.1 channel with IC50′s at approximately 3 µM. No shift of the activation curve could be observed, suggesting that these compounds act like a pore blocker obstructing the ion flow by binding in the pore region of the CaV3.1 channel. A selectivity screening showed that these analogs are also active on hERG channels. Collectively, a new class of CaV3 channel inhibitors has been discovered and the structure–function studies provide new insights into the synthetic design of drugs and the mechanism of interaction with T-type CaV channels