Progress on Autosomal Dominant Polycystic Kidney Disease

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common life threatening hereditary disease of the kidney. It is a systemic disease characterized by multiple, bilateral renal cysts that result in massive renal enlargement and progressive functional impairment. This review discusses the current understanding of the epidemiology, genetics, clinical manifestations, natural history of the disease, the accuracy and reliability of diagnostic approaches, renal replacement therapy and emerging therapeutic strategies that are being evaluated in ADPKD. Review: ADPKD is a genetically heterogeneous disease with significant inter-familial and intra-familial variability. The responsible genes were localized to separate loci on chromosome 16 (PKD1 gene) accounting for the majority of ADPKD cases, and chromosome 4 (PKD2 gene) accounting for the remainder. Each child of an affected parent has a 50% chance of inheriting the mutated gene, which is completely penetrant. Clinical manifestations include renal and cyst enlargement, impaired urine concentration capacity, hematuria, nephrolithiasis, proteinuria, hypertension, polycystic liver disease, abdominal wall hernia and intracranial aneurysms. The diagnosis of ADPKD usually relies on renal imaging. Ongoing research has engendered crucial insight into the disease’s underlying genetic, cellular and pathogenetic mechanisms and made possible the design and implementation of clinical trials testing promising treatments. Renin Angiotensin Aldosterone System (RAAS) blockade, vasopressin antagonists, somatostatin, rapamycin, sirolimus and everolimus are currently being evaluated for a potential therapeutic role in the management of ADPKD. Conclusion: Current clinical trials investigating multiple therapeutic targets bring hope for treatments that may impede the progression of ADPKD. Keywords: ADPKD, autosomal dominant polycystic kidney disease, kidney failur

Atomistic Theory of Coherent Spin Transfer between Molecularly Bridged Quantum Dots

Time-resolved Faradary rotation experiments have demonstrated coherent transfer of electron spin between CdSe colloidal quantum dots coupled by conjugated molecules. We employ here a Green's function approach, using semi-empirical tight-binding to treat the nanocrystal Hamiltonian and Extended Huckel theory to treat the linking molecule Hamiltonian, to obtain the coherent transfer probabilities from atomistic calculations, without the introduction of any new parameters. Calculations on 1,4-dithiolbenzene and 1,4-dithiolcyclohexane linked nanocrystals agree qualitatively with experiment and provide support for a previous transfer Hamiltonian model. We find a striking dependence on the transfer probabilities as a function of nanocrystal surface site attachment and linking molecule conformation. Additionally, we predict quantum interference effects in the coherent transfer probabilities for 2,7-dithiolnaphthalene and 2,6-dithiolnaphthalene linking molecules. We suggest possible experiments based on these results that would test the coherent, through-molecule transfer mechanism.Comment: 12 pages, 9 figures. Submitted Phys. Rev.

Norepinephrine-induced acute renal failure: A reversible ischemic model of acute renal failure

Several studies have shown that acute renal failure (ARF) can be produced in the dog by infusing norepinephrine (NE) into a renal artery [1, 2]. In these studies the injury appeared to be confined to the infused kidney, with no changes occurring in systemic hemodynamics or in the function of the contralateral kidney. The hemodynamic changes noted in the infused kidney were comparable to those seen in human ARF. A major criticism of these studies, however, is that the renal failure was not shown to be reversible, as it typically is in man. In the present study, we have reexamined the NE-induced model of ARF in the dog with the particular purpose of finding a set condition which would cause ARF and yet allow recovery of renal function within a period of time comparable to that usually seen in the human disease

Effect of nitric oxide donors on renal tubular epithelial cell-matrix adhesion

Effect of nitric oxide donors on renal tubular epithelial cell-matrix adhesion.BackgroundNitric oxide (NO) and its metabolite, peroxynitrite (ONOO-), are involved in renal tubular cell injury. We postulated that if NO/ONOO- has an effect to reduce cell adhesion to the basement membrane, this may contribute to tubular obstruction and may be partially responsible for the harmful effect of NO on the tubular epithelium during acute renal failure (ARF).MethodsWe examined the effect of the NO donors (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO), spermine NONOate (SpNO), and the ONOO- donor 3-morpholinosydnonimine (SIN-1) on cell-matrix adhesion to collagen types I and IV and fibronectin using three renal tubular epithelial cell lines: LLC-PK1, BSC-1, and OK.ResultsIn LLC-PK1 cells, DETA/NO (500 μm) had no effect, and SpNO (500 μm) had a modest effect on cell adhesion compared with controls. Exposure to SIN-1 caused a dose-dependent impairment in cell-matrix adhesion. Similar results were obtained in the different cell types and matrix proteins. The effect of SIN-1 (500 μm) on LLC-PK1 cell adhesion was not associated with either cell death or alteration of matrix protein and was attenuated by either the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, the superoxide scavenger superoxide dismutase, or the ONOO- scavenger uric acid in a dose-dependent manner.ConclusionsThese results therefore support the possibility that ONOO- generated in the tubular epithelium during ischemia/reperfusion has the potential to impair the adhesion properties of tubular cells, which then may contribute to the tubular obstruction in ARF

Effect of glycine on prelethal and postlethal increases in calpain activity in rat renal proximal tubules

Effect of glycine on prelethal and postlethal increases in calpain activity in rat renal proximal tubules. The effect of glycine on hypoxia- and ionomycin-induced increases in calpain activity in rat proximal tubules was determined. Calpain activity was determined both in vitro and in the intact cell using the fluorescent substrate N-succinyl-Leu-Leu-Val-Tyr-7- amido-4-methyl coumarin (N-succinyl-Leu-Leu-Val-Tyr-AMC) and Western blotting for calpain-specific spectrin breakdown products (BDP), respectively. At 7.5 minutes of hypoxia (prelethal injury model) there was a significant (10-fold) increase in in vitro calpain activity that was not inhibited by glycine. At 15 minutes of hypoxia (postlethal injury model) there was a further increase in calpain activity that was inhibited by glycine. Normoxic tubules incubated with the calcium ionophore ionomy-cin (5 µM) for two minutes and 10 minutes had a significant increase in calpain activity that was not inhibited by glycine. After 15 minutes of hypoxia in the presence of glycine, there was an increase in calpain-specific spectrin breakdown products (BDP) in both Triton X-100 soluble and cytosolic extracts from proximal tubules. Glycine in concentrations up to 10mM had no direct effect on the in vitro calpain activity of purified calpains. The present study demonstrates that: (1) prelethal increases in calpain activity stimulated by hypoxia and ionomycin treatment are not affected by glycine; (2) calpain-mediated spectrin breakdown during hypoxia occurs in the presence of glycine; (3) glycine does prevent the additional postlethal increase in calpain activity probably by maintaining membrane integrity to calcium influx

ras Oncogene Activation Does Not Induce Sensitivity to Natural Killer Cell—Mediated Lysis in Human Melanoma

An important phenomenon in tumor immunology that has come under recent attention is the impact of oncogene activation in tumor cells on the sensitivity to lysis by immune effector cells. Several studies suggested that transfer of an activated ras oncogene into cultured rodent fibroblasts induces susceptibility to natural killer cell (NK)-mediated lysis. Experiments using human tumor cells, however, have produced conflicting data on the effect of ras activation in this respect. In studying the activation of the oncogene c-myc, which is often overexpressed in human melanoma, we have found that in cell lines expressing high levels of Myc protein, the sensitivity to lysis by NK cells was dramatically increased due to reduced expression of Human Leukocyte Antigen B locus products. Since the N-ras oncogene was found to be activated in 15% of human melanomas, we examined the possibility that in melanoma, in analogy to the murine systems, the mutated ras oncogene may influence NK susceptibility of human melanoma cells. Two N-ras genes harboring frequently found mutations were cloned into an expression vector. Transfection of the IGR39D melanoma cell line with wildtype and mutant N-ras constructs yielded several ras-expressing clones that were tested for NK sensitivity. Neither high expression of the wildtype N-ras protein, nor expression of two mutant proteins (N61-arg, N61-lys) was shown to result in enhanced NK-mediated lysis. We conclude that activation of ras oncogenes does not lead to the induction of an NK-sensitive phenotype in human melanoma cells. J Invest Dermatol 103:117S–121S, 199

ECTACI: European Climatology and Trend Atlas of Climate Indices (1979–2017)

A fundamental key to understanding climate change and its implications is the availability of databases with wide spatial coverage, over a long period of time, with constant updates and high spatial resolution. This study describes a newly gridded data set and its map viewer “European Climatology and Trend Atlas of Climate Indices” (ECTACI), which contains four statistical parameters (climatology, coefficient of variation, slope, and significant trend) from 125 standard climate indices for the whole Europe at 0.25° grid intervals from 1979 to 2017 at various temporal scales (monthly, seasonal, and annual). In addition, this study shows, for the first time, the general trends of a wide variety of updated standard climate indices at seasonal and annual scales for the whole of Europe, which could be a useful tool for climate analysis and its impact on different sectors and socioeconomic activities. The data set and ECTACI map viewer are available for free (http://ECTACI.csic.es/)

Surface wind over Europe: Data and variability

This work improves the characterization and knowledge of the surface wind climatology over Europe with the development of an observational database with unprecedented quality control (QC), the European Surface Wind Observational database (EuSWiO). EuSWiO includes more than 3,829 stations with sub-daily resolution for wind speed and direction, with a number of sites spanning the period of 1880–2017, a few hundred time series starting in the 1930s and relatively good spatial coverage since the 1970s. The creation of EuSWiO entails the merging of eight different data sets and its submission to a common QC. About 5% of the total observations were flagged, correcting a great part of the extreme and unrealistic values, which have a discernible impact on the statistics of the database. The daily wind variability was characterized by means of a classification technique, identifying 11 independent subregions with distinct temporal wind variability over the 2000–2015 period. Significant decreases in the wind speed during this period are found in five regions, whereas two regions show increases. Most regions allow for extending the analysis to earlier decades. Caution in interpreting long-term trends is needed as wind speed data have not been homogenized. Nevertheless, decreases in the wind speed since the 1980s can be noticed in most of the regions. This work contributes to a deeper understanding of the temporal and spatial surface wind variability in Europe. It will allow from meteorological to climate and climate change studies, including potential applications to the analyses of extreme events, wind power assessments or the evaluation of reanalysis or model-data comparison exercises at continental scales

Impact of climate model resolution on soil moisture projections in central-western Europe

Global climate models project widespread decreases in soil moisture over large parts of Europe. This paper investigates the impact of model resolution on the magnitude and seasonality of future soil drying in central-western Europe. We use the general circulation model EC-Earth to study two 30-year periods representative of the start and end of the 21st century under low-to-moderate greenhouse gas forcing (RCP4.5). In our study area, central-western Europe, at high spatial resolution (∼25&thinsp;km) soil drying is more severe and starts earlier in the season than at standard resolution (∼112&thinsp;km). Here, changes in the large-scale atmospheric circulation and local soil moisture feedbacks lead to enhanced evapotranspiration in spring and reduced precipitation in summer. A more realistic position of the storm track at high model resolution leads to reduced biases in precipitation and temperature in the present-day climatology, which act to amplify future changes in evapotranspiration in spring. Furthermore, in the high-resolution model a stronger anticyclonic anomaly over the British Isles extends over central-western Europe and supports soil drying. The resulting drier future land induces stronger soil moisture feedbacks that amplify drying conditions in summer. In addition, soil-moisture-limited evapotranspiration in summer promotes sensible heating of the boundary layer, which leads to a lower relative humidity with less cloudy conditions, an increase in dry summer days, and more incoming solar radiation. As a result a series of consecutive hot and dry summers appears in the future high-resolution climate. The enhanced drying at high spatial resolution suggests that future projections of central-western European soil drying by CMIP5 models have been potentially underestimated. Whether these results are robust has to be tested with other global climate models with similar high spatial resolutions.</p

Evaluation of onset, cessation and seasonal precipitation of the Southeast Asia rainy season in CMIP5 regional climate models and HighResMIP global climate models

Representing the rainy season of the maritime continent is a challenge for global and regional climate models. Here, we compare regional climate models (RCMs) based on the coupled model intercomparison project phase 5 (CMIP5) model generation with high-resolution global climate models with a comparable spatial resolution from the HighResMIP experiment. The onset and the total precipitation of the rainy season for both model experiments are compared against observational datasets for Southeast Asia. A realistic representation of the monsoon rainfall is essential for agriculture in Southeast Asia as a delayed onset jeopardizes the possibility of having three annual crops. In general, the coupled historical runs (Hist-1950) and the historical force atmosphere run (HighresSST) of the high-resolution model intercomparison project (HighResMIP) suite were consistently closer to the observations than the RCM of CMIP5 used in this study. We find that for the whole of Southeast Asia, the HighResMIP models simulate the onset date and the total precipitation of the rainy season over the region closer to the observations than the other model sets used in this study. High-resolution models in the HighresSST experiment showed a similar performance to their low-resolution equivalents in simulating the monsoon characteristics. The HighresSST experiment simulated the anomaly of the onset date and the total precipitation for different El Niño-southern oscillation conditions best, although the magnitude of the onset date anomaly was underestimated. © 2021 The Authors. International Journal of Climatology published by John Wiley Sons Ltd on behalf of Royal Meteorological Society