Sequence Variation in Promoter of Ica1 Gene, Which Encodes Protein Implicated in Type 1 Diabetes, Causes Transcription Factor Autoimmune Regulator (AIRE) to Increase Its Binding and Down-regulate Expression

ICA69 (islet cell autoantigen 69 kDa) is a protein implicated in type 1 diabetes mellitus in both the non-obese diabetic (NOD) mouse model and humans. ICA69 is encoded by the Ica1 gene on mouse chromosome 6 A1-A2. We previously reported reduced ICA69 expression in the thymus of NOD mice compared with thymus of several non-diabetic mouse strains. We propose that reduced thymic ICA69 expression could result from variations in transcriptional regulation of the gene and that polymorphisms within the Ica1 core promoter may partially determine this transcriptional variability. We characterized the functional promoter of Ica1 in NOD mice and compared it with the corresponding portions of Ica1 in non-diabetic C57BL/6 mice. Luciferase reporter constructs demonstrated that the NOD Ica1 promoter region exhibited markedly reduced luciferase expression in transiently transfected medullary thymus epithelial (mTEC+) and B-cell (M12)-derived cell lines. However, in a non-diabetic strain, C57BL/6, the Ica1 promoter region was transcriptionally active when transiently transfected into the same cell lines. We concomitantly identified five single nucleotide polymorphisms within the NOD Ica1 promoter. One of these single nucleotide polymorphisms increases the binding affinity for the transcription factor AIRE (autoimmune regulator), which is highly expressed in thymic epithelial cells, where it is known to play a key role regulating self-antigen expression. We conclude that polymorphisms within the NOD Ica1 core promoter may determine AIRE-mediated down-regulation of ICA69 expression in medullary thymic epithelial cells, thus providing a novel mechanistic explanation for the loss of immunologic tolerance to this self-antigen in autoimmunity

Effect of Dienogest therapy on the size of the endometrioma

Studies have been published on the efficacy of Dienogest in the management of pain symptoms in endometriosis. Nonetheless, few data are available on the reducing effect on endometrioma’s size. The aim of the study was to evaluate if Dienogest could determine significant changes in size, as well as in symptoms. In this prospective observational study, patients were enrolled with pain symptoms and at least one endometrioma diagnosed via TV-US. The volume of the endometrioma and pain symptoms was measured according to the LxDxWx0.5233 formula and VAS, respectively. Dienogest 2 mg was administered daily. Follow-up visits were scheduled after 6 and 12 months of treatment to assess changes in patients’ symptoms and endometrioma’s volume. Seventy patients were enrolled, 63 patients completed a 6-month treatment. The reduction of the mean volume after 6 months was 66.71%. Fifty-eight patients completed the 12 month-treatment. The reduction of the mean volume after 12 months was 76.19%. Dysmenorrhea showed a 74.05% reduction after 6 months and a 96.55% reduction after 12 months. Patients reported a reduction in dyspareunia and chronic pelvic pain of 42.71% and 48.91% after 6 months and 51.93% and 59.96% after 12 months, respectively. Dienogest leads to a statistically significant reduction of endometrioma’s volume and pain symptoms

The Trigger System of the ICARUS Experiment

This paper presents the hardware architecture and the main features of the ICARUS trigger system. The ICARUS detector is a very massive liquid Argon Time Projection Chamber aimed at the study of some of the fundamental issues of astroparticle physics such as solar and atmospheric neutrino interactions, neutrinos following a Supernova explosion, neutrino oscillations with beams from particle accelerators and nucleon decay as predicted by Grand Unification Theories. The main feature of the proposed trigger design is its "segmentation," i.e:, the capability to trigger different sectors of the detector on different events allowing for the efficient detection of rare events

KI and WU Polyomavirus in Respiratory Samples of SARS-CoV-2 Infected Patients

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been declared a global pandemic. Our goal was to determine whether co-infections with respiratory polyomaviruses, such as Karolinska Institutet polyomavirus (KIPyV) and Washington University polyomavirus (WUPyV) occur in SARS-CoV-2 infected patients. Oropharyngeal swabs from 150 individuals, 112 symptomatic COVID-19 patients and 38 healthcare workers not infected by SARS-CoV-2, were collected from March 2020 through May 2020 and tested for KIPyV and WUPyV DNA presence. Of the 112 SARS-CoV-2 positive patients, 27 (24.1%) were co-infected with KIPyV, 5 (4.5%) were positive for WUPyV, and 3 (2.7%) were infected simultaneously by KIPyV and WUPyV. Neither KIPyV nor WUPyV DNA was detected in samples of healthcare workers. Significant correlations were found in patients co-infected with SARS-CoV-2 and KIPyV (p < 0.05) and between SARS-CoV-2 cycle threshold values and KIPyV, WUPyV and KIPyV and WUPyV concurrently detected (p < 0.05). These results suggest that KIPyV and WUPyV may behave as opportunistic respiratory pathogens. Additional investigations are needed to understand the epidemiology and the prevalence of respiratory polyomavirus in COVID-19 patients and whether KIPyV and WUPyV could potentially drive viral interference or influence disease outcomes by upregulating SARS-CoV-2 replicative potential

Sequence Variation in Promoter of Ica1 Gene, Which Encodes Protein Implicated in Type 1 Diabetes, Causes Transcription Factor Autoimmune Regulator (AIRE) to Increase Its Binding and Down-regulate Expression

ICA69 (islet cell autoantigen 69 kDa) is a protein implicated in type 1 diabetes mellitus in both the non-obese diabetic (NOD) mouse model and humans. ICA69 is encoded by the Ica1 gene on mouse chromosome 6 A1-A2. We previously reported reduced ICA69 expression in the thymus of NOD mice compared with thymus of several non-diabetic mouse strains. We propose that reduced thymic ICA69 expression could result from variations in transcriptional regulation of the gene and that polymorphisms within the Ica1 core promoter may partially determine this transcriptional variability. We characterized the functional promoter of Ica1 in NOD mice and compared it with the corresponding portions of Ica1 in non-diabetic C57BL/6 mice. Luciferase reporter constructs demonstrated that the NOD Ica1 promoter region exhibited markedly reduced luciferase expression in transiently transfected medullary thymus epithelial (mTEC(+)) and B-cell (M12)-derived cell lines. However, in a non-diabetic strain, C57BL/6, the Ica1 promoter region was transcriptionally active when transiently transfected into the same cell lines. We concomitantly identified five single nucleotide polymorphisms within the NOD Ica1 promoter. One of these single nucleotide polymorphisms increases the binding affinity for the transcription factor AIRE (autoimmune regulator), which is highly expressed in thymic epithelial cells, where it is known to play a key role regulating self-antigen expression. We conclude that polymorphisms within the NOD Ica1 core promoter may determine AIRE-mediated down-regulation of ICA69 expression in medullary thymic epithelial cells, thus providing a novel mechanistic explanation for the loss of immunologic tolerance to this self-antigen in autoimmunity

Test and Comparison of Photomultiplier Tubes at Liquid Argon Temperature

The most recent development in the field of photomultipliers operating at liquid Argon temperature is the Hamamatsu R11065 with peak QE up to about 35% A set of these photomultipliers has been extensively tested within the R&D program of the WArP Collaboration. During these tests the Hamamatsu PMTs showed extremely good performance and a light yield around 7 phel/keVee has been achieved in a Liquid Argon detector with a photocathodic coverage of 12%. This shows that this new type of PMT is suited for experimental applications, in particular for new direct Dark Matter searches with LAr-based experiments

Effects of Nitrogen and Oxygen contaminations in liquid Argon

Two dedicated and distinct tests of the effects of Nitrogen and Oxygen contaminations in liquid Argon (LAr) have been performed within the WArP R&D program. Purpose of the tests is to detect the reduction of the LAr scintillation light emission as a function of the amount of the contaminant injected in the Argon volume. The rate constant of the light quenching process induced by Nitrogen in LAr has been found to be k(N(2)) = 0-11 mu s(-1) ppm(-1) (part per million), while the rate constant for Oxygen has been found to be k'(O(2)) = 0.54 +/- 0.03 mu s(-1) ppm(-1). Direct PMT signals acquisition allowed to extract with high precision the main characteristics of the scintillation light emission in pure and contaminated LAr. In particular, the decreasing behavior in lifetime and relative amplitude of the slow component is found to be appreciable from O (1 ppm) of Nitrogen concentrations and from O (0.1 ppm) of Oxygen concentrations. (C) 2009 Elsevier B.V. All rights reserved

The WArP Experiment

Cryogenic noble liquid detectors are presently considered one of the best options for WIMP Dark Matter searches, especially when extensions to multi ton scale sensitive masses are foreseen. The WArP experiment is the first one that exploits the unique characteristics of liquid Argon to make a highly sensitive search for WIMP Dark Matter candidates. In 2008, a double phase detector has been assembled in the Gran Sasso National Laboratory with 140 kg sensitive mass and a discovery potential in the range of 5 x 10(-45) cm(2) in the spin-independent WIMP-nucleon cross-section. In addition to standard neutrons and gamma-rays passive shields, WArP implements an 8 ton liquid Argon active shield with 4 pi coverage. The detector was commissioned and put into operation during the first half of 2009 for a first technical run. This first run lasted about three months and then it was stopped for some detector repairs and modifications in the summer of 2009. A second run was started at the beginning of 2010. Detector design, construction and assembly are described, together with the results of the technical run and the very first results of the 2010 run