EVALUATION OF RETROSPECTIVE REGIONAL CLIMATE MODEL RUNS WITH VERA WITHIN THE PROJECT RECLIP:MORE

The 3-year project “Research for Climate Protection: Model Run Evaluation” (reclip:more) is a cooperation of five academic institutions in Austria The major aim of the project is to evaluate the capability of dynamical and statistical downscaling methods in the Alpine region to create climate scenarios at mesoscale and microscale resolutions. Two regional circulation models ALADIN and the PSU/NCAR mesoscale model MM5 will be driven by ERA-40 reanalysis data and ECHAM5 global circulation model (GCM) results, representing current (1991-2000) and future (2041-2050) climate to accomplish dynamical downscaling from the coarse GCM resolution (spectral truncation T106, i.e. ~120 km horizontal resolution) to 10-15 km. The evaluation of the 2D surface fields of the retrospective runs are performed with the Vienna Enhanced Resolution Analyses (VERA) scheme. VERA produces model independent 2D analyses of meteorological parameters on a regular grid. The comparison will cover single extreme events, an annual cycle and a ten year period. The results will serve as a criteria to find the best model set up for the prospective runs

Vorticity production through rotation, shear and baroclinicity

In the absence of rotation and shear, and under the assumption of constant temperature or specific entropy, purely potential forcing by localized expansion waves is known to produce irrotational flows that have no vorticity. Here we study the production of vorticity under idealized conditions when there is rotation, shear, or baroclinicity, to address the problem of vorticity generation in the interstellar medium in a systematic fashion. We use three-dimensional periodic box numerical simulations to investigate the various effects in isolation. We find that for slow rotation, vorticity production in an isothermal gas is small in the sense that the ratio of the root-mean-square values of vorticity and velocity is small compared with the wavenumber of the energy-carrying motions. For Coriolis numbers above a certain level, vorticity production saturates at a value where the aforementioned ratio becomes comparable with the wavenumber of the energy-carrying motions. Shear also raises the vorticity production, but no saturation is found. When the assumption of isothermality is dropped, there is significant vorticity production by the baroclinic term once the turbulence becomes supersonic. In galaxies, shear and rotation are estimated to be insufficient to produce significant amounts of vorticity, leaving therefore only the baroclinic term as the most favorable candidate. We also demonstrate vorticity production visually as a result of colliding shock fronts.Comment: 9 pages, 10 figures, Accepted for publication in A&

EVALUATION OF RETROSPECTIVE REGIONAL CLIMATE MODEL RUNS WITH VERA WITHIN THE PROJECT RECLIP:MORE

The 3-year project “Research for Climate Protection: Model Run Evaluation” (reclip:more) is a cooperation of five academic institutions in Austria The major aim of the project is to evaluate the capability of dynamical and statistical downscaling methods in the Alpine region to create climate scenarios at mesoscale and microscale resolutions. Two regional circulation models ALADIN and the PSU/NCAR mesoscale model MM5 will be driven by ERA-40 reanalysis data and ECHAM5 global circulation model (GCM) results, representing current (1991-2000) and future (2041-2050) climate to accomplish dynamical downscaling from the coarse GCM resolution (spectral truncation T106, i.e. ~120 km horizontal resolution) to 10-15 km. The evaluation of the 2D surface fields of the retrospective runs are performed with the Vienna Enhanced Resolution Analyses (VERA) scheme. VERA produces model independent 2D analyses of meteorological parameters on a regular grid. The comparison will cover single extreme events, an annual cycle and a ten year period. The results will serve as a criteria to find the best model set up for the prospective runs

Characterization and Diagnostic Potential

Funding Information: R.M. is supported by Fundação para a Ciência e a Tecnologia (CEEC position, 2019–2025 investigator). This article is a result of the projects (iNOVA4Health—UIDB/04462/2020), supported by Lisboa Portugal Regional Operational Programme (Lisboa2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work is also funded by FEDER funds through the COMPETE 2020 Programme and National Funds through FCT—Portuguese Foundation for Science and Technology under the projects number PTDC/BTM-TEC/30087/2017 and PTDC/BTM-TEC/30088/2017. Publisher Copyright: © 2022 by the authors.Diffuse large B cell lymphoma (DLBCL) is an aggressive B cell lymphoma characterized by a heterogeneous behavior and in need of more accurate biological characterization monitoring and prognostic tools. Extracellular vesicles are secreted by all cell types and are currently established to some extent as representatives of the cell of origin. The present study characterized and evaluated the diagnostic and prognostic potential of plasma extracellular vesicles (EVs) proteome in DLBCL by using state-of-the-art mass spectrometry. The EV proteome is strongly affected by DLBCL status, with multiple proteins uniquely identified in the plasma of DLBCL. A proof-of-concept classifier resulted in highly accurate classification with a sensitivity and specificity of 1 when tested on the holdout test data set. On the other hand, no proteins were identified to correlate with non-germinal center B-cell like (non-GCB) or GCB subtypes to a significant degree after correction for multiple testing. However, functional analysis suggested that antigen binding is regulated when comparing non-GCB and GCB. Survival analysis based on protein quantitative values and clinical parameters identified multiple EV proteins as significantly correlated to survival. In conclusion, the plasma extracellular vesicle proteome identifies DLBCL cancer patients from healthy donors and contains potential EV protein markers for prediction of survival.publishersversionpublishe

Trapping Solids at the Inner Edge of the Dead Zone: 3-D Global MHD Simulations

The poorly-ionized interior of the protoplanetary disk is the location where dust coagulation processes may be most efficient. However even here, planetesimal formation may be limited by the loss of solid material through radial drift, and by collisional fragmentation of the particles. Our aim is to investigate the possibility that solid particles are trapped at local pressure maxima in the dynamically evolving disk. We perform the first 3-D global non-ideal MHD calculations of the disk treating the turbulence driven by the magneto-rotational instability. The domain contains an inner MRI-active region near the young star and an outer midplane dead zone, with the transition between the two modeled by a sharp increase in the magnetic diffusivity. The azimuthal magnetic fields generated in the active zone oscillate over time, changing sign about every 150 years. We thus observe the radial structure of the `butterfly pattern' seen previously in local shearing-box simulations. The mean magnetic field diffuses from the active zone into the dead zone, where the Reynolds stress nevertheless dominates. The greater total accretion stress in the active zone leads to a net reduction in the surface density, so that after 800 years an approximate steady state is reached in which a local radial maximum in the midplane pressure lies near the transition radius. We also observe the formation of density ridges within the active zone. The dead zone in our models possesses a mean magnetic field, significant Reynolds stresses and a steady local pressure maximum at the inner edge, where the outward migration of planetary embryos and the efficient trapping of solid material are possible.Comment: 17 pages, 30 *.ps files for figures. Accepted 16 November 2009 in A&

Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression

Uromodulin (UMOD) mutations are responsible for three autosomal dominant tubulo-interstitial nephropathies including medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease. Symptoms include renal salt wasting, hyperuricemia, gout, hypertension and end-stage renal disease. MCKD is part of the ‘nephronophthisis-MCKD complex', a group of cystic kidney diseases. Both disorders have an indistinguishable histology and renal cysts are observed in either. For most genes mutated in cystic kidney disease, their proteins are expressed in the primary cilia/basal body complex. We identified seven novel UMOD mutations and were interested if UMOD protein was expressed in the primary renal cilia of human renal biopsies and if mutant UMOD would show a different expression pattern compared with that seen in control individuals. We demonstrate that UMOD is expressed in the primary cilia of renal tubules, using immunofluorescent studies in human kidney biopsy samples. The number of UMOD-positive primary cilia in UMOD patients is significantly decreased when compared with control samples. Additional immunofluorescence studies confirm ciliary expression of UMOD in cell culture. Ciliary expression of UMOD is also confirmed by electron microscopy. UMOD localization at the mitotic spindle poles and colocalization with other ciliary proteins such as nephrocystin-1 and kinesin family member 3A is demonstrated. Our data add UMOD to the group of proteins expressed in primary cilia, where mutations of the gene lead to cystic kidney diseas

Long-Term Transplantation Outcomes in Patients With Primary Hyperoxaluria Type 1 Included in the European Hyperoxaluria Consortium (OxalEurope) Registry

INTRODUCTION: In primary hyperoxaluria type 1 (PH1), oxalate overproduction frequently causes kidney stones, nephrocalcinosis, and kidney failure. As PH1 is caused by a congenital liver enzyme defect, combined liver–kidney transplantation (CLKT) has been recommended in patients with kidney failure. Nevertheless, systematic analyses on long-term transplantation outcomes are scarce. The merits of a sequential over combined procedure regarding kidney graft survival remain unclear as is the place of isolated kidney transplantation (KT) for patients with vitamin B6-responsive genotypes. METHODS: We used the OxalEurope registry for retrospective analyses of patients with PH1 who underwent transplantation. Analyses of crude Kaplan–Meier survival curves and adjusted relative hazards from the Cox proportional hazards model were performed. RESULTS: A total of 267 patients with PH1 underwent transplantation between 1978 and 2019. Data of 244 patients (159 CLKTs, 48 isolated KTs, 37 sequential liver–KTs [SLKTs]) were eligible for comparative analyses. Comparing CLKTs with isolated KTs, adjusted mortality was similar in patients with B6-unresponsive genotypes but lower after isolated KT in patients with B6-responsive genotypes (adjusted hazard ratio 0.07, 95% CI: 0.01–0.75, P = 0.028). CLKT yielded higher adjusted event-free survival and death-censored kidney graft survival in patients with B6-unresponsive genotypes (P = 0.025, P < 0.001) but not in patients with B6-responsive genotypes (P = 0.145, P = 0.421). Outcomes for 159 combined procedures versus 37 sequential procedures were comparable. There were 12 patients who underwent pre-emptive liver transplantation (PLT) with poor outcomes. CONCLUSION: The CLKT or SLKT remains the preferred transplantation modality in patients with PH1 with B6-unresponsive genotypes, but isolated KT could be an alternative approach in patients with B6-responsive genotypes

Long-read sequencing identifies a common transposition haplotype predisposing for CLCNKB deletions

BACKGROUND: Long-read sequencing is increasingly used to uncover structural variants in the human genome, both functionally neutral and deleterious. Structural variants occur more frequently in regions with a high homology or repetitive segments, and one rearrangement may predispose to additional events. Bartter syndrome type 3 (BS 3) is a monogenic tubulopathy caused by deleterious variants in the chloride channel gene CLCNKB, a high proportion of these being large gene deletions. Multiplex ligation-dependent probe amplification, the current diagnostic gold standard for this type of mutation, will indicate a simple homozygous gene deletion in biallelic deletion carriers. However, since the phenotypic spectrum of BS 3 is broad even among biallelic deletion carriers, we undertook a more detailed analysis of precise breakpoint regions and genomic structure. METHODS: Structural variants in 32 BS 3 patients from 29 families and one BS4b patient with CLCNKB deletions were investigated using long-read and synthetic long-read sequencing, as well as targeted long-read sequencing approaches. RESULTS: We report a ~3 kb duplication of 3'-UTR CLCNKB material transposed to the corresponding locus of the neighbouring CLCNKA gene, also found on ~50 % of alleles in healthy control individuals. This previously unknown common haplotype is significantly enriched in our cohort of patients with CLCNKB deletions (45 of 51 alleles with haplotype information, 2.2 kb and 3.0 kb transposition taken together, p=9.16×10-9). Breakpoint coordinates for the CLCNKB deletion were identifiable in 28 patients, with three being compound heterozygous. In total, eight different alleles were found, one of them a complex rearrangement with three breakpoint regions. Two patients had different CLCNKA/CLCNKB hybrid genes encoding a predicted CLCNKA/CLCNKB hybrid protein with likely residual function. CONCLUSIONS: The presence of multiple different deletion alleles in our cohort suggests that large CLCNKB gene deletions originated from many independently recurring genomic events clustered in a few hot spots. The uncovered associated sequence transposition haplotype apparently predisposes to these additional events. The spectrum of CLCNKB deletion alleles is broader than expected and likely still incomplete, but represents an obvious candidate for future genotype/phenotype association studies. We suggest a sensitive and cost-efficient approach, consisting of indirect sequence capture and long-read sequencing, to analyse disease-relevant structural variant hotspots in general

Determinants of Kidney Failure in Primary Hyperoxaluria Type 1:Findings of the European Hyperoxaluria Consortium

INTRODUCTION: Primary hyperoxaluria type 1 (PH1) has a highly heterogeneous disease course. Apart from the c.508G&gt;A (p.Gly170Arg) AGXT variant, which imparts a relatively favorable outcome, little is known about determinants of kidney failure. Identifying these is crucial for disease management, especially in this era of new therapies. METHODS: In this retrospective study of 932 patients with PH1 included in the OxalEurope registry, we analyzed genotype-phenotype correlations as well as the impact of nephrocalcinosis, urolithiasis, and urinary oxalate and glycolate excretion on the development of kidney failure, using survival and mixed model analyses.RESULTS: The risk of developing kidney failure was the highest for 175 vitamin-B6 unresponsive ("null") homozygotes and lowest for 155 patients with c.508G&gt;A and c.454T&gt;A (p.Phe152Ile) variants, with a median age of onset of kidney failure of 7.8 and 31.8 years, respectively. Fifty patients with c.731T&gt;C (p.Ile244Thr) homozygote variants had better kidney survival than null homozygotes ( P = 0.003). Poor outcomes were found in patients with other potentially vitamin B6-responsive variants. Nephrocalcinosis increased the risk of kidney failure significantly (hazard ratio [HR] 3.17 [2.03-4.94], P &lt; 0.001). Urinary oxalate and glycolate measurements were available in 620 and 579 twenty-four-hour urine collections from 117 and 87 patients, respectively. Urinary oxalate excretion, unlike glycolate, was higher in patients who subsequently developed kidney failure ( P = 0.034). However, the 41% intraindividual variation of urinary oxalate resulted in wide confidence intervals. CONCLUSION: In conclusion, homozygosity for AGXT null variants and nephrocalcinosis were the strongest determinants for kidney failure in PH1. </p

ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.ope