Ursolic acid inhibits the initiation, progression of prostate cancer and prolongs the survival of TRAMP mice by modulating pro-inflammatory pathways

10.1371/journal.pone.0032476PLoS ONE73

Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease

Purpose To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010–2020). Methods All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation sequencing panel of 15 additional cystic genes including PKHD1 and HNF1B. Two patients underwent exome or genome sequencing. Results Likely causative PKD1 or PKD2 variants were detected in 30 infants with PKD-VEO, 16 of whom presented in utero. Twenty-one of 30 (70%) had two variants with biallelic in trans inheritance confirmed in 16/21, 1 infant had biallelic PKD2 variants, and 2 infants had digenic PKD1/PKD2 variants. There was no known family history of ADPKD in 13 families (43%) and a de novo pathogenic variant was confirmed in 6 families (23%). Conclusion We report a high prevalence of hypomorphic PKD1 variants and likely biallelic disease in infants presenting with PKD-VEO with major implications for reproductive counseling. The diagnostic interpretation and reporting of these variants however remains challenging using current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Association of Clinical Genetic Science (ACGS) variant classification guidelines in PKD-VEO and other diseases affected by similar variants with incomplete penetrance

The positive effect of selective prostaglandin E2 receptor EP2 and EP4 blockade on cystogenesis in vitro is counteracted by increased kidney inflammation in vivo

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a major cause of end-stage kidney disease in man. The central role of cyclic adenosine monophosphate (cAMP) in ADPKD pathogenesis has been confirmed by numerous studies including positive clinical trial data. Here, we investigated the potential role of another major regulator of renal cAMP, prostaglandin E2 (PGE2), in modifying disease progression in ADPKD models using selective receptor modulators to all four PGE2 receptor subtypes (EP1-4). In 3D-culture model systems utilizing dog (MDCK) and patient-derived (UCL93, OX161-C1) kidney cell lines, PGE2 strikingly promoted cystogenesis and inhibited tubulogenesis by stimulating proliferation while reducing apoptosis. The effect of PGE2 on tubulogenesis and cystogenesis in 3D-culture was mimicked or abolished by selective EP2 and EP4 agonists or antagonists but not those specific to EP1 or EP3. In a Pkd1 mouse model (Pkd1nl/nl), kidney PGE2 and COX-2 expression were increased by two-fold at the peak of disease (week four). However, Pkd1nl/nl mice treated with selective EP2 (PF-04418948) or EP4 (ONO-AE3-208) antagonists from birth for three weeks had more severe cystic disease and fibrosis associated with increased cell proliferation and macrophage infiltration. A similar effect was observed for the EP4 antagonist ONO-AE3-208 in a second Pkd1 model (Pax8rtTA-TetO-Cre-Pkd1f/f). Thus, despite the positive effects of slowing cyst growth in vitro, the more complex effects of inhibiting EP2 or EP4 in vivo resulted in a worse outcome, possibly related to unexpected pro-inflammatory effects

β -decay half-lives of neutron-rich nuclides in the A=100-110 mass region

β-decay half-lives of neutron-rich nuclides in the A=100-110 mass region have been measured using an implantation station installed inside of the Summing NaI(Tl) (SuN) detector at the National Superconducting Cyclotron Laboratory. Accurate half-lives for these nuclides are important for nuclear astrophysics, nuclear structure, and nuclear technology. The half-lives from the present work are compared with previous measurements, showing overall good agreement

Neutral weak currents in pion electroproduction on the nucleon

Parity violating asymmetry in inclusive scattering of longitudinally polarized electrons by unpolarized protons with $\pi^0$ or $\pi^+$ meson production, is calculated as a function of the momentum transfer squared $Q^2$ and the total energy $W$ of the $\pi N$-system. This asymmetry, which is induced by the interference of the one-photon exchange amplitude with the parity-odd part of the $Z^0$-exchange amplitude, is calculated for the $\gamma^*(Z^*)+p\to N+\pi$ processes ($\gamma^*$ is a virtual photon and $Z^*$ a virtual Z-boson) considering the $\Delta$-contribution in the $s-$channel, the standard Born contributions and vector meson ($\rho$ and $\omega$) exchanges in the $t-$channel. Taking into account the known isotopic properties of the hadron electromagnetic and neutral currents, we show that the P-odd term is the sum of two contributions. The main term is model independent and it can be calculated exactly in terms of fundamental constants. It is found to be linear in $Q^2$. The second term is a relatively small correction which is determined by the isoscalar component of the electromagnetic current. Near threshold and in the $\Delta$-region, this isoscalar part is much smaller (in absolute value) than the isovector one: its contribution to the asymmetry depend on the polarization state (longitudinal or transverse) of the virtual photon.Comment: 30 pages 9 figure

Gamma-ray Observations Under Bright Moonlight with VERITAS

Imaging atmospheric Cherenkov telescopes (IACTs) are equipped with sensitive photomultiplier tube (PMT) cameras. Exposure to high levels of background illumination degrades the efficiency of and potentially destroys these photo-detectors over time, so IACTs cannot be operated in the same configuration in the presence of bright moonlight as under dark skies. Since September 2012, observations have been carried out with the VERITAS IACTs under bright moonlight (defined as about three times the night-sky-background (NSB) of a dark extragalactic field, typically occurring when Moon illumination > 35%) in two observing modes, firstly by reducing the voltage applied to the PMTs and, secondly, with the addition of ultra-violet (UV) bandpass filters to the cameras. This has allowed observations at up to about 30 times previous NSB levels (around 80% Moon illumination), resulting in 30% more observing time between the two modes over the course of a year. These additional observations have already allowed for the detection of a flare from the 1ES 1727+502 and for an observing program targeting a measurement of the cosmic-ray positron fraction. We provide details of these new observing modes and their performance relative to the standard VERITAS observations

Total absorption spectroscopy of the β decay of Zr 101,102 and Tc 109

20 pags., 9 figs., 5 tabs.The β decay of Zr101,102 and Tc109 was studied using the technique of total absorption spectroscopy. The experiment was performed at the National Superconducting Cyclotron Laboratory using the Summing NaI(Tl) (SuN) detector in the first-ever application of total absorption spectroscopy with a fast beam produced via projectile fragmentation. The β-decay feeding intensity and Gamow-Teller transition strength distributions were extracted for these three decays. The extracted distributions were compared to three different quasiparticle random-phase approximation (QRPA) models based on different mean-field potentials. A comparison with calculations from one of the QRPA models was performed to learn about the ground-state shape of the parent nucleus. For Zr101 and Zr102, calculations assuming a pure shape configuration (oblate or prolate) were not able to reproduce the extracted distributions. These results may indicate that some type of mixture between oblate and prolate shapes is necessary to reproduce the extracted distributions. For Tc109, a comparison of the extracted distributions with QRPA calculations suggests a dominant oblate configuration. The other two QRPA models are commonly used to provide β-decay properties in r-process network calculations. This work shows the importance of making comparisons between the experimental and theoretical β-decay distributions, rather than just half-lives and β-delayed neutron emission probabilities, as close to the r-process path as possible.A.A. acknowledges support from the Spanish Ministerio de Economía y Competitividad under Grants No. FPA2011-24553, No. FPA2014-52823-C2-1-P, and No. FPA2017-83946-C2-1-P and the program Severo Ochoa (SEV-2014-0398). P.S. acknowledges support from MCIU/AEI/FEDER,UE (Spain) under Contract No. PGC2018-093636-B-I00. S.V. acknowledges support from Czech Science Foundation Project No. 19-14048 and the Charles University Project No. UNCE/SCI/013. This work was supported by the National Science Foundation under Grants No. PHY 1565546 (NSCL), No. PHY 1430152 (JINA-CEE), and No. PHY 1350234 (CAREER). This material is based upon work supported by the Department of Energy National Nuclear Security Administration through the Nuclear Science and Security Consortium under Awards No. DE-NA0003180 and/or No. DE-NA000097

Global microRNA profiling in human urinary exosomes reveals novel disease biomarkers and cellular pathways for Autosomal Dominant Polycystic Kidney Disease

MicroRNAs (miRNAs) play an important role in regulating gene expression in health and disease but their role in modifying disease expression in Autosomal Dominant Polycystic Kidney Disease (ADPKD) remains uncertain. Here, we profiled human urinary exosome miRNA by global small RNA-sequencing in an initial discovery cohort of seven patients with ADPKD with early disease (eGFR over 60ml/min/1.73m2), nine with late disease (eGFR under 60ml/min/1.73m2), and compared their differential expression with six age and sex matched healthy controls. Two kidney-enriched candidate miRNA families were identified (miR-192/miR-194-2 and miR-30) and selected for confirmatory testing in a 60 patient validation cohort by quantitative polymerase chain reaction. We confirmed that miR-192-5p, miR-194- 5p, miR-30a-5p, miR-30d-5p and miR-30e-5p were significantly downregulated in patient urine exosomes, in murine Pkd1 cystic kidneys and in human PKD1 cystic kidney tissue. All five miRNAs showed significant correlations with baseline eGFR and ultrasound-determined mean kidney length and improved the diagnostic performance (area under the curve) of mean kidney length for the rate of disease progression. Finally, inverse correlations of these two miRNA families with increased expression in their predicted target genes in patient PKD1 cystic tissue identified dysregulated pathways and transcriptional networks including novel interactions between miR-194-5p and two potentially relevant candidate genes, PIK3R1 and ANO1. Thus, our results identify a subset of urinary exosomal miRNAs that could serve as novel biomarkers of disease progression and suggest new therapeutic targets in ADPKD

The First VERITAS Telescope

The first atmospheric Cherenkov telescope of VERITAS (the Very Energetic Radiation Imaging Telescope Array System) has been in operation since February 2005. We present here a technical description of the instrument and a summary of its performance. The calibration methods are described, along with the results of Monte Carlo simulations of the telescope and comparisons between real and simulated data. The analysis of TeV $\gamma$-ray observations of the Crab Nebula, including the reconstructed energy spectrum, is shown to give results consistent with earlier measurements. The telescope is operating as expected and has met or exceeded all design specifications.Comment: Accepted by Astroparticle Physic

The common PKD1 p.(Ile3167Phe) variant is hypomorphic and associated with very early onset, biallelic polycystic kidney disease

Biallelic PKD1 variants, including hypomorphic variants, can cause very early onset polycystic kidney disease (VEO-PKD). A family with unexplained recurrent VEO-PKD and neonatal demise in one dizygotic twin was referred for clinical testing. Further individuals with the putative hypomorphic PKD1 variant, p.(Ile3167Phe), were identified from the UK 100,000 genomes project (100 K), UK Biobank (UKBB), and a review of the literature. We identified a likely pathogenic PKD1 missense paternal variant and the putative hypomorphic PKD1 variant from the unaffected mother in the deceased twin but only the paternal PKD1 variant in the surviving dizygotic twin. Analysis of 100 K cases identified a second family with two siblings with similar biallelic inheritance who presented at birth with VEO-PKD and reached kidney failure in their teens unlike other affected relatives. Finally, a survey of 618 UKBB cases confirmed that adult patients monoallelic for PKD1 p.(Ile3167Phe) had normal kidney function. Our data reveals that p.(Ile3167Phe) is the second most common PKD1 hypomorphic variant identified and is neutral in heterozygosity but is associated with VEO-PKD when inherited in trans with a pathogenic PKD1 variant. Care should be taken to ensure that it is not automatically filtered from sequence data for VEO cases