Push-push X band GaInP/GaAs VCO with a fully monolithic microstrip resonator

In this paper the design of a VCO using GaInP/GaAs HBT technology is presented. The VCO is designed to be a part of a PDH point to point radio system. To achieve low phase noise performances GaInP/GaAs HBT technology and push-push topology have been chosen. The MMIC includes predistorters to emphasize the second harmonic, f/sub 0//2 prescalers for PLL locking and buffer amplifiers. A fully monolithic microstrip resonator is coupled with integrated varactors to achieve the specified tuning bandwidth. Phase noise, bandwidth and power measurements will also be presente

The impact of radiosounding observations on numerical weather prediction analyses in the Arctic

The radiosounding network in the Arctic, despite being sparse, is a crucial part of the atmospheric observing system for weather prediction and reanalysis. The spatial coverage of the network was evaluated using a numerical weather prediction model, comparing radiosonde observations from Arctic land stations and expeditions in the central Arctic Ocean with operational analyses and background fields (12h forecasts) from ECMWF for January 2016 – September 2018. The results show that the impact of radiosonde observations on analyses has large geographical variation. In data‐sparse areas, such as the central Arctic Ocean, high‐quality radiosonde observations substantially improve the analyses, while satellite observations are not able to compensate for the large spatial gap in the radiosounding network. In areas where the network is reasonably dense, the quality of background field is more related to how radiosonde observations are utilized in the assimilation and to the quality of those observations

Spatial and temporal variability in summer snow pack in Dronning Maud Land, Antarctica

Peer reviewe

Erythropoietin (EPO) haplotype associated with all-cause mortality in a cohort of Italian patients with Type-2 Diabetes

Type-2 Diabetes (T2D), diabetic complications, and their clinical risk factors harbor a substantial genetic component but the genetic factors contributing to overall diabetes mortality remain unknown. Here, we examined the association between genetic variants at 21 T2D-susceptibility loci and all-cause mortality in an elderly cohort of 542 Italian diabetic patients who were followed for an average of 12.08 years. Univariate Cox regression analyses detected age, waist-to-hip ratio (WHR), glycosylated haemoglobin (HbA1c), diabetes duration, retinopathy, nephropathy, chronic kidney disease (CKD), and anaemia as predictors of all-cause mortality. When Cox proportional hazards multivariate models adjusted for these factors were run, three erythropoietin (EPO) genetic variants in linkage disequilibrium (LD) with each other (rs1617640-T/G, rs507392-T/C and rs551238-A/C) were significantly (False Discovery Rate < 0.1) associated with mortality. Haplotype multivariate analysis revealed that patients carrying the G-C-C haplotype have an increased probability of survival, while an opposite effect was observed among subjects carrying the T-T-A haplotype. Our findings provide evidence that the EPO gene is an independent predictor of mortality in patients with T2D. Thus, understanding the mechanisms by which the genetic variability of EPO affects the mortality of T2D patients may provide potential targets for therapeutic interventions to improve the survival of these patients

New DNA methylation signals for malignant pleural mesothelioma risk assessment

SIMPLE SUMMARY: Our study investigated DNA methylation differences in easily accessible white blood cells (WBCs) between malignant pleural mesothelioma (MPM) cases and asbestos-exposed cancer-free controls. A multiple regression model highlighted that the methylation level of two single CpGs (cg03546163 in FKBP5 and cg06633438 in MLLT1) are independent MPM markers. The epigenetic changes at the FKBP5 and MLLT1 genes were robustly associated with MPM in asbestos-exposed subjects. Interaction analyses showed that MPM cases and cancer-free controls showed DNAm differences which may be linked to asbestos exposure. ABSTRACT: Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (>0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = −0.09, 95% CI = −0.12|−0.06, p = 1.2 × 10(−7)), and (ii) cg06633438 in MLLT1, statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 × 10(−6)). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 × 10(−11)) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 × 10(−8)) genes compared to below-median asbestos exposure and hyper/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells); area under the curve, AUC = 0.75; BM + cg03546163 at FKBP5. AUC = 0.89, 2.1 × 10(−7); BM + cg06633438 at MLLT1. AUC = 0.89, 6.3 × 10(−8). Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects

Advances in understanding and parameterization of small-scalephysical processes in the marine Arctic climate system: a review

The Arctic climate system includes numerous highly interactive small-scale physical processes in the atmosphere, sea ice, and ocean. During and since the International Polar Year 2007–2009, significant advances have been made in understanding these processes. Here, these recent advances are reviewed, synthesized, and discussed. In atmospheric physics, the primary advances have been in cloud physics, radiative transfer, mesoscale cyclones, coastal, and fjordic processes as well as in boundary layer processes and surface fluxes. In sea ice and its snow cover, advances have been made in understanding of the surface albedo and its relationships with snow properties, the internal structure of sea ice, the heat and salt transfer in ice, the formation of superimposed ice and snow ice, and the small-scale dynamics of sea ice. For the ocean, significant advances have been related to exchange processes at the ice–ocean interface, diapycnal mixing, double-diffusive convection, tidal currents and diurnal resonance. Despite this recent progress, some of these small-scale physical processes are still not sufficiently understood: these include wave–turbulence interactions in the atmosphere and ocean, the exchange of heat and salt at the ice–ocean interface, and the mechanical weakening of sea ice. Many other processes are reasonably well understood as stand-alone processes but the challenge is to understand their interactions with and impacts and feedbacks on other processes. Uncertainty in the parameterization of small-scale processes continues to be among the greatest challenges facing climate modelling, particularly in high latitudes. Further improvements in parameterization require new year-round field campaigns on the Arctic sea ice, closely combined with satellite remote sensing studies and numerical model experiments.publishedVersio

Dna methylation of fkbp5 as predictor of overall survival in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 7 10 129 ) OS-related differential methylation of a single-CpG (cg03546163), located in the 5\u2032 UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm 65 0.45 (mean: 243 versus 534 days; p value< 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM

Historical Perspectives and Guidelines for Botulinum Neurotoxin Subtype Nomenclature

Botulinum neurotoxins are diverse proteins. They are currently represented by at least seven serotypes and more than 40 subtypes. New clostridial strains that produce novel neurotoxin variants are being identified with increasing frequency, which presents challenges when organizing the nomenclature surrounding these neurotoxins. Worldwide, researchers are faced with the possibility that toxins having identical sequences may be given different designations or novel toxins having unique sequences may be given the same designations on publication. In order to minimize these problems, an ad hoc committee consisting of over 20 researchers in the field of botulinum neurotoxin research was convened to discuss the clarification of the issues involved in botulinum neurotoxin nomenclature. This publication presents a historical overview of the issues and provides guidelines for botulinum neurotoxin subtype nomenclature in the future.Peer reviewe

Regulatory T cells from patients with end-stage organ disease can be isolated, expanded and cryopreserved according good manufacturing practice improving their function

Background Here, we isolated, expanded and functionally characterized regulatory T cells (Tregs) from patients with end stage kidney and liver disease, waiting for kidney/liver transplantation (KT/LT), with the aim to establish a suitable method to obtain large numbers of immunomodulatory cells for adoptive immunotherapy post-transplantation. Methods We first established a preclinical protocol for expansion/isolation of Tregs from peripheral blood of LT/KT patients. We then scaled up and optimized such protocol according to good manufacturing practice (GMP) to obtain high numbers of purified Tregs which were phenotypically and functionally characterized in vitro and in vivo in a xenogeneic acute graft-versus-host disease (aGVHD) mouse model. Specifically, immunodepressed mice (NOD-SCID-gamma KO mice) received human effector T cells with or without GMP-produced Tregs to prevent the onset of xenogeneic GVHD. Results Our small scale Treg isolation/expansion protocol generated functional Tregs. Interestingly, cryopreservation/thawing did not impair phenotype/function and DNA methylation pattern of FOXP3 gene of the expanded Tregs. Fully functional Tregs were also isolated/expanded from KT and LT patients according to GMP. In the mouse model, GMP Tregs from LT or KT patient proved to be safe and show a trend toward reduced lethality of acute GVHD. Conclusions These data demonstrate that expanded/thawed GMP-Tregs from patients with end-stage organ disease are fully functional in vitro. Moreover, their infusion is safe and results in a trend toward reduced lethality of acute GVHD in vivo, further supporting Tregs-based adoptive immunotherapy in solid organ transplantation