Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that leads to renal failure in the majority of patients. The very first pharmacological treatment, tolvaptan, received Food and Drug Administration approval in 2018 after previous approval in Europe and other countries. However, tolvaptan is moderately effective and may negatively impact a patient's quality of life due to potentially significant side effects. Additional and improved therapies are still urgently needed, and several clinical trials are underway, which are discussed in the companion paper Müller and Benzing (Management of autosomal-dominant polycystic kidney disease-state-of-the-art) Clin Kidney J 2018; 11: i2-i13. Here, we discuss new therapeutic avenues that are currently being investigated at the preclinical stage. We focus on mammalian target of rapamycin and dual kinase inhibitors, compounds that target inflammation and histone deacetylases, RNA-targeted therapeutic strategies, glucosylceramide synthase inhibitors, compounds that affect the metabolism of renal cysts and dietary restriction. We discuss tissue targeting to renal cysts of small molecules via the folate receptor, and of monoclonal antibodies via the polymeric immunoglobulin receptor. A general problem with potential pharmacological approaches is that the many molecular targets that have been implicated in ADPKD are all widely expressed and carry out important functions in many organs and tissues. Because ADPKD is a slowly progressing, chronic disease, it is likely that any therapy will have to continue over years and decades. Therefore, systemically distributed drugs are likely to lead to potentially prohibitive extra-renal side effects during extended treatment. Tissue targeting to renal cysts of such drugs is one potential way around this problem. The use of dietary, instead of pharmacological, interventions is another

Supramolecular electron transfer-based switching involving pyrrolic macrocycles. A new approach to sensor development?

This Feature focuses on pyrrolic macrocycles that can serve as switches via energy- or electron transfer (ET) mechanisms. Macrocycles operating by both ground state (thermodynamic) and photoinduced ET pathways are reviewed and their ability to serve as the readout motif for molecular sensors is discussed. The aim of this article is to highlight the potential utility of ET in the design of systems that perform molecular switching or logic functions and their applicability in chemical sensor development. The conceptual benefits of this paradigm are illustrated with examples drawn mostly from the authors' laboratoriesThe work in Austin was supported by the U.S. National Science Foundation (grant CHE-1402004 to J.L.S.) and the Robert A. Welch Foundation (Grant F-1018 to J.L.S.). Financial support from the Spanish MICINN (CTQ2011-24187/BQU) and the Comunidad de Madrid (S2013/MIT-2841 FOTOCARBON) is acknowledge

The Zebrafish Homologue of the Human DYT1 Dystonia Gene Is Widely Expressed in CNS Neurons but Non-Essential for Early Motor System Development

DYT1 dystonia is caused by mutation of the TOR1A gene, resulting in the loss of a single glutamic acid residue near the carboxyl terminal of TorsinA. The neuronal functions perturbed by TorsinA[ΔE] are a major unresolved issue in understanding the pathophysiology of dystonia, presenting a critical roadblock to developing effective treatments. We identified and characterized the zebrafish homologue of TOR1A, as a first step towards elucidating the functions of TorsinA in neurons, in vivo, using the genetically-manipulable zebrafish model. The zebrafish genome was found to contain a single alternatively-spliced tor1 gene, derived from a common ancestral locus shared with the dual TOR1A and TOR1B paralogues found in tertrapods. tor1 was expressed ubiquitously during early embryonic development and in multiple adult tissues, including the CNS. The 2.1 kb tor1 mRNA encodes Torsin1, which is 59% identical and 78% homologous to human TorsinA. Torsin1 was expressed as major 45 kDa and minor 47 kDa glycoproteins, within the cytoplasm of neurons and neuropil throughout the CNS. Similar to previous findings relating to human TorsinA, mutations of the ATP hydrolysis domain of Torsin1 resulted in relocalization of the protein in cultured cells from the endoplasmic reticulum to the nuclear envelope. Zebrafish embryos lacking tor1 during early development did not show impaired viability, overt morphological abnormalities, alterations in motor behavior, or developmental defects in the dopaminergic system. Torsin1 is thus non-essential for early development of the motor system, suggesting that important CNS functions may occur later in development, consistent with the critical time window in late childhood when dystonia symptoms usually emerge in DYT1 patients. The similarities between Torsin1 and human TorsinA in domain organization, expression pattern, and cellular localization suggest that the zebrafish will provide a useful model to understand the neuronal functions of Torsins in vivo

Intersection of two signalling pathways: extracellular nucleotides regulate pollen germination and pollen tube growth via nitric oxide

Plant and animal cells release or secrete ATP by various mechanisms, and this activity allows extracellular ATP to serve as a signalling molecule. Recent reports suggest that extracellular ATP induces plant responses ranging from increased cytosolic calcium to changes in auxin transport, xenobiotic resistance, pollen germination, and growth. Although calcium has been identified as a secondary messenger for the extracellular ATP signal, other parts of this signal transduction chain remain unknown. Increasing the extracellular concentration of ATPγS, a poorly-hydrolysable ATP analogue, inhibited both pollen germination and pollen tube elongation, while the addition of AMPS had no effect. Because pollen tube elongation is also sensitive to nitric oxide, this raised the possibility that a connection exists between the two pathways. Four approaches were used to test whether the germination and growth effects of extracellular ATPγS were transduced via nitric oxide. The results showed that increases in extracellular ATPγS induced increases in cellular nitric oxide, chemical agonists of the nitric oxide signalling pathway lowered the threshold of extracellular ATPγS that inhibits pollen germination, an antagonist of guanylate cyclase, which can inhibit some nitric oxide signalling pathways, blocked the ATPγS-induced inhibition of both pollen germination and pollen tube elongation, and the effects of applied ATPγS were blocked in nia1nia2 mutants, which have diminished NO production. The concurrence of these four data sets support the conclusion that the suppression of pollen germination and pollen tube elongation by extracellular nucleotides is mediated in part via the nitric oxide signalling pathway

Low False-Positive Rate of Kepler Candidates Estimated From A Combination Of Spitzer And Follow-Up Observations

(Abridged) NASA's Kepler mission has provided several thousand transiting planet candidates, yet only a small subset have been confirmed as true planets. Therefore, the most fundamental question about these candidates is the fraction of bona fide planets. Estimating the rate of false positives of the overall Kepler sample is necessary to derive the planet occurrence rate. We present the results from two large observational campaigns that were conducted with the Spitzer telescope during the the Kepler mission. These observations are dedicated to estimating the false positive rate (FPR) amongst the Kepler candidates. We select a sub-sample of 51 candidates, spanning wide ranges in stellar, orbital and planetary parameter space, and we observe their transits with Spitzer at 4.5 microns. We use these observations to measures the candidate's transit depths and infrared magnitudes. A bandpass-dependent depth alerts us to the potential presence of a blending star that could be the source of the observed eclipse: a false-positive scenario. For most of the candidates (85%), the transit depths measured with Kepler are consistent with the depths measured with Spitzer as expected for planetary objects, while we find that the most discrepant measurements are due to the presence of unresolved stars that dilute the photometry. The Spitzer constraints on their own yield FPRs between 5-40%, depending on the KOIs. By considering the population of the Kepler field stars, and by combining follow-up observations (imaging) when available, we find that the overall FPR of our sample is low. The measured upper limit on the FPR of our sample is 8.8% at a confidence level of 3 sigma. This observational result, which uses the achromatic property of planetary transit signals that is not investigated by the Kepler observations, provides an independent indication that Kepler's false positive rate is low.Comment: 33 pages, 16 figures, 3 tables; accepted for publication in ApJ on February 7, 201

NLTT 41135: a field M-dwarf + brown dwarf eclipsing binary in a triple system, discovered by the MEarth observatory

We report the discovery of an eclipsing companion to NLTT 41135, a nearby M5 dwarf that was already known to have a wider, slightly more massive common proper motion companion, NLTT 41136, at 2.4 arcsec separation. Analysis of combined-light and radial velocity curves of the system indicates that NLTT 41135B is a 31-34 +/- 3 MJup brown dwarf (where the range depends on the unknown metallicity of the host star) on a circular orbit. The visual M-dwarf pair appears to be physically bound, so the system forms a hierarchical triple, with masses approximately in the ratio 8:6:1. The eclipses are grazing, preventing an unambiguous measurement of the secondary radius, but follow-up observations of the secondary eclipse (e.g. with the James Webb Space Telescope) could permit measurements of the surface brightness ratio between the two objects, and thus place constraints on models of brown dwarfs.Comment: 15 pages, 6 figures, 10 tables, emulateapj format. Accepted for publication in Ap

GJ 3236: a new bright, very low-mass eclipsing binary system discovered by the MEarth observatory

We report the detection of eclipses in GJ 3236, a bright (I = 11.6) very low mass binary system with an orbital period of 0.77 days. Analysis of light- and radial velocity curves of the system yielded component masses of 0.38 +/- 0.02 and 0.28 +/- 0.02 Msol. The central values for the stellar radii are larger than the theoretical models predict for these masses, in agreement with the results for existing eclipsing binaries, although the present 5% observational uncertainties limit the significance of the larger radii to approximately 1 sigma. Degeneracies in the light curve models resulting from the unknown configuration of surface spots on the components of GJ 3236 currently dominate the uncertainties in the radii, and could be reduced by obtaining precise, multi-band photometry covering the full orbital period. The system appears to be tidally synchronized and shows signs of high activity levels as expected for such a short orbital period, evidenced by strong Halpha emission lines in the spectra of both components. These observations probe an important region of mass-radius parameter space around the predicted transition to fully-convective stellar interiors, where there are a limited number of precise measurements available in the literature.Comment: 14 pages, 5 figures, 10 tables, emulateapj format. Accepted for publication in Ap

Follow-up observations at 16 and 33 GHz of extragalactic sources from WMAP 3-year data: I - Spectral properties

We present follow-up observations of 97 point sources from the Wilkinson Microwave Anisotropy Probe (WMAP) 3-year data, contained within the New Extragalactic WMAP Point Source (NEWPS) catalogue between declinations of -4 and +60 degrees; the sources form a flux-density-limited sample complete to 1.1 Jy (approximately 5 sigma) at 33 GHz. Our observations were made at 16 GHz using the Arcminute Microkelvin Imager (AMI) and at 33 GHz with the Very Small Array (VSA). 94 of the sources have reliable, simultaneous -- typically a few minutes apart -- observations with both telescopes. The spectra between 13.9 and 33.75 GHz are very different from those of bright sources at low frequency: 44 per cent have rising spectra (alpha < 0.0), where flux density is proportional to frequency^-alpha, and 93 per cent have spectra with alpha < 0.5; the median spectral index is 0.04. For the brighter sources, the agreement between VSA and WMAP 33-GHz flux densities averaged over sources is very good. However, for the fainter sources, the VSA tends to measure lower values for the flux densities than WMAP. We suggest that the main cause of this effect is Eddington bias arising from variability.Comment: 12 pages, 13 figures, submitted to MNRA

Kepler-68: Three Planets, One With a Density Between That of Earth and Ice Giants

NASA's Kepler Mission has revealed two transiting planets orbiting Kepler-68. Follow-up Doppler measurements have established the mass of the innermost planet and revealed a third jovian-mass planet orbiting beyond the two transiting planets. Kepler-68b, in a 5.4 day orbit has mass 8.3 +/- 2.3 Earth, radius 2.31 +/- 0.07 Earth radii, and a density of 3.32 +/- 0.92 (cgs), giving Kepler-68b a density intermediate between that of the ice giants and Earth. Kepler-68c is Earth-sized with a radius of 0.953 Earth and transits on a 9.6 day orbit; validation of Kepler-68c posed unique challenges. Kepler-68d has an orbital period of 580 +/- 15 days and minimum mass of Msin(i) = 0.947 Jupiter. Power spectra of the Kepler photometry at 1-minute cadence exhibit a rich and strong set of asteroseismic pulsation modes enabling detailed analysis of the stellar interior. Spectroscopy of the star coupled with asteroseismic modeling of the multiple pulsation modes yield precise measurements of stellar properties, notably Teff = 5793 +/- 74 K, M = 1.079 +/- 0.051 Msun, R = 1.243 +/- 0.019 Rsun, and density 0.7903 +/- 0.0054 (cgs), all measured with fractional uncertainties of only a few percent. Models of Kepler-68b suggest it is likely composed of rock and water, or has a H and He envelope to yield its density of about 3 (cgs).Comment: 32 pages, 13 figures, Accepted to Ap