TAMEing ADPKD with metformin:safe and effective?

The biguanide metformin has been safely and widely used in the treatment of type 2 diabetes mellitus for decades. Preclinical studies have suggested that it may have a role in slowing disease progression in autosomal dominant polycystic kidney disease. In this issue, Perrone et al. report results from the Trial of Administration of Metformin in PKD (TAME PKD) study, a phase 2 randomized controlled trial investigating the safety and tolerability of metformin in patients in the early stages of autosomal dominant polycystic kidney disease. We discuss the implications of these findings and how they relate to a major phase 3 trial in autosomal dominant polycystic kidney disease that will start later in 2021

The cAMP Signaling pathway and direct protein kinase a phosphorylation regulate polycystin-2 (TRPP2) Channel Function

Polycystin-2 (PC2) is aTRP-type, Ca2+-permeable non-selective cation channel that plays an important role in Ca2+ signaling in renal and non-renal cells. The effect(s) of the cAMP pathway and kinase mediated phosphorylation of PC2 seem to be relevant to PC2 trafficking and its interaction with polycystin-1. However, the role of PC2 phosphorylation in channel function is still poorly defined. Here we reconstituted apical membranes of term human syncytiotrophoblast (hST), containing endogenous PC2 (PC2hst), and in vitro translated channel protein (PC2iv). Addition of the catalytic subunit of PKA increased by 566% the spontaneous PC2hst channel activity in the presence of ATP. Interestingly, 8-Br-cAMP also stimulated spontaneous PC2hst channel activity in the absence of the exogenous kinase. Either stimulation was inhibited by addition of alkaline phosphatase, which in turn, was reversed by the phosphatase inhibitor vanadate. Neither maneuver modified the single channel conductance but instead increased channel mean open time. PKA directly phosphorylated PC2, which increased the mean open time but not the single channel conductance of the channel. PKA phosphorylation did not modify either R742X truncated or S829A-mutant PC2iv channel function. The data indicate that the cAMP pathway regulates PC2-mediated cation transport in the hST. The relevant PKA site for PC2 channel regulation centers on a single residue serine 829, in the carboxyl terminus.Fil: Cantero, Maria del Rocio. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Biofísica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Velázquez, Irina Florencia. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Biofísica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Streets, Andrew J.. University of Sheffield Medical School; Reino UnidoFil: Ong, Albert C. M.. University of Sheffield Medical School; Reino UnidoFil: Cantiello, Horacio Fabio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Biofísica; Argentin

Probing the origin of VHE emission from M 87 with MWL observations in 2010

The large majority of extragalactic very high energy (VHE; E>100 GeV) sources belongs to the class of active galactic nuclei (AGN), in particular the BL Lac sub-class. AGNs are characterized by an extremely bright and compact emission region, powered by a super-massive black hole (SMBH) and an accretion disk, and relativistic outflows (jets) detected all across the electro-magnetic spectrum. In BL Lac sources the jet axis is oriented close to the line of sight, giving rise to a relativistic boosting of the emission. In radio galaxies, on the other hand, the jet makes a larger angle to the line of sight allowing to resolve the central core and the jet in great details. The giant radio galaxy M 87 with its proximity (1 6Mpc) and its very massive black hole ((3-6) x 10^9 M_solar) provides a unique laboratory to investigate VHE emission in such objects and thereby probe particle acceleration to relativistic energies near SMBH and in jets. M 87 has been established as a VHE emitter since 2005. The VHE emission displays strong variability on time-scales as short as a day. It has been subject of a large joint VHE and multi-wavelength (MWL) monitoring campaign in 2008, where a rise in the 43 GHz VLBA radio emission of the innermost region (core) was found to coincide with a flaring activity at VHE. This had been interpreted as a strong indication that the VHE emission is produced in the direct vicinity of the SMBH black hole. In 2010 again a flare at VHE was detected triggering further MWL observations with the VLBA, Chandra, and other instruments. At the same time M 87 was also observed with the Fermi-LAT telescope at GeV energies and the European VLBI Network (EVN). In this contribution preliminary results from the campaign will be presented.Comment: 5 pages, 2 figures, in the proceedings of the "International Workshop on Beamed and Unbeamed Gamma-Rays from Galaxies" 11-15 April 2011, Lapland Hotel Olos, Muonio, Finland, Journal of Physics: Conference Series Volume 355, 201

Search for radio pulsations in LS I +61 303

Context. LS I +61 303 is a member of the select group of gamma-ray binaries: galactic binary systems that contain a massive star and a compact object, show a changing milliarcsecond morphology and a similar broad spectral energy distribution (SED) that peaks at MeV-TeV energies and is modulated by the orbital motion. The nature of the compact object is unclear in LS I +61 303, LS 5039 and HESS J0632+057, whereas PSR B1259-63 harbours a 47.74 ms radio pulsar. Aims. A scenario in which a young pulsar wind interacts with the stellar wind has been proposed to explain the very high energy (VHE, E > 100 GeV) gamma-ray emission detected from LS I +61 303, although no pulses have been reported from this system at any wavelength. We aim to find evidence of the pulsar nature of the compact object. Methods. We performed phased array observations with the Giant Metrewave Radio Telescope (GMRT) at 1280 MHz centred at phase 0.54. Simultaneous data from the multi-bit phased array (PA) back-end with a sampling time of tsamp = 128 microsec and from the polarimeter (PMT) back-end with tsamp = 256 microsec where taken. Results. No pulses have been found in the data set, with a minimum detectable mean flux density of \sim 0.38 mJy at 8-sigma level for the pulsed emission from a putative pulsar with period P >2 ms and duty cycle D = 10% in the direction of LS I +61 303. Conclusions. The detection of posible radio pulsations will require deep and sensitive observations at frequencies \sim0.5-5 GHz and orbital phases 0.6-0.7. However, it may be unfeasible to detect pulses if the putative pulsar is not beamed at the Earth or if there is a strong absorption within the binary system.Comment: 8 pages. 5 figures. Accepted for publication in Astronomy and Astrophysic

Multiwavelength Observations of LS I +61 303 with VERITAS, Swift and RXTE

We present results from a long-term monitoring campaign on the TeV binary LSI +61 303 with VERITAS at energies above 500 GeV, and in the 2-10 keV hard X-ray bands with RXTE and Swift, sampling nine 26.5 day orbital cycles between September 2006 and February 2008. The binary was observed by VERITAS to be variable, with all integrated observations resulting in a detection at the 8.8 sigma (2006/2007) and 7.3 sigma (2007/2008) significance level for emission above 500 GeV. The source was detected during active periods with flux values ranging from 5 to 20% of the Crab Nebula, varying over the course of a single orbital cycle. Additionally, the observations conducted in the 2007-2008 observing season show marginal evidence (at the 3.6 sigma significance level) for TeV emission outside of the apastron passage of the compact object around the Be star. Contemporaneous hard X-ray observations with RXTE and Swift show large variability with flux values typically varying between 0.5 and 3.0*10^-11 ergs cm^-2 s^-1 over a single orbital cycle. The contemporaneous X-ray and TeV data are examined and it is shown that the TeV sampling is not dense enough to detect a correlation between the two bands.Comment: 30 pages, 5 figures, 2 table, Accepted for publication in The Astrophysical Journa

Long-term monitoring of the TeV emission from Mrk 421 with the ARGO-YBJ experiment

ARGO-YBJ is an air shower detector array with a fully covered layer of resistive plate chambers. It is operated with a high duty cycle and a large field of view. It continuously monitors the northern sky at energies above 0.3 TeV. In this paper, we report a long-term monitoring of Mrk 421 over the period from 2007 November to 2010 February. This source was observed by the satellite-borne experiments Rossi X-ray Timing Explorer and Swift in the X-ray band. Mrk 421 was especially active in the first half of 2008. Many flares are observed in both X-ray and gamma-ray bands simultaneously. The gamma-ray flux observed by ARGO-YBJ has a clear correlation with the X-ray flux. No lag between the X-ray and gamma-ray photons longer than 1 day is found. The evolution of the spectral energy distribution is investigated by measuring spectral indices at four different flux levels. Hardening of the spectra is observed in both X-ray and gamma-ray bands. The gamma-ray flux increases quadratically with the simultaneously measured X-ray flux. All these observational results strongly favor the synchrotron self-Compton process as the underlying radiative mechanism.Comment: 30 pages, 8 figure

Building a network of ADPKD reference centres across Europe: the EuroCYST initiative

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic inherited kidney disease, affecting an estimated 600 000 individuals in Europe. The disease is characterized by age-dependent development of a multiple cysts in the kidneys, ultimately leading to end-stage renal failure and the need of renal replacement therapy in the majority of patients, typically by the fifth or sixth decade of life. The variable disease course, even within the same family, remains largely unexplained. Similarly, assessing disease severity and prognosis in an individual with ADPKD remains difficult. Epidemiological studies are limited due to the fragmentation of ADPKD research in Europe. METHODS: The EuroCYST initiative aims: (i) to harmonize and develop common standards for ADPKD research by starting a collaborative effort to build a network of ADPKD reference centres across Europe and (ii) to establish a multicentric observational cohort of ADPKD patients. This cohort will be used to study factors influencing the rate of disease progression, disease modifiers, disease stage-specific morbidity and mortality, health economic issues and to identify predictive disease progression markers. Overall, 1100 patients will be enrolled in 14 study sites across Europe. Patients will be prospectively followed for at least 3 years. Eligible patients will not have participated in a pharmaceutical clinical trial 1 year before enrollment, have clinically proven ADPKD, an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m(2) and above, and be able to provide written informed consent. The baseline visit will include a physical examination and collection of blood, urine and DNA for biomarker and genetic studies. In addition, all participants will be asked to complete questionnaires detailing self-reported health status, quality of life, socioeconomic status, health-care use and reproductive planning. All subjects will undergo annual follow-up. A magnetic resonance imaging (MRI) scan will be carried out at baseline, and patients are encouraged to undergo a second MRI at 3-year follow-up for qualitative and quantitative kidney and liver assessments. CONCLUSIONS: The ADPKD reference centre network across Europe and the observational cohort study will enable European ADPKD researchers to gain insights into the natural history, heterogeneity and associated complications of the disease as well as how it affects the lives of patients across Europ

VERITAS Upper Limit on the VHE Emission from the Radio Galaxy NGC 1275

The recent detection by the Fermi gamma-ray space telescope of high-energy gamma-rays from the radio galaxy NGC 1275 makes the observation of the very high energy (VHE: E > 100 GeV) part of its broadband spectrum particularly interesting, especially for the understanding of active galactic nuclei (AGN) with misaligned multi-structured jets. The radio galaxy NGC 1275 was recently observed by VERITAS at energies above 100 GeV for about 8 hours. No VHE gamma-ray emission was detected by VERITAS from NGC 1275. A 99% confidence level upper limit of 2.1% of the Crab Nebula flux level is obtained at the decorrelation energy of approximately 340 GeV, corresponding to 19% of the power-law extrapolation of the Fermi Large Area Telescope (LAT) result.Comment: Accepted for publication in ApJ Letter

Evolution with hole doping of the electronic excitation spectrum in the cuprate superconductors

The recent scanning tunnelling results of Alldredge et al on Bi-2212 and of Hanaguri et al on Na-CCOC are examined from the perspective of the BCS/BEC boson-fermion resonant crossover model for the mixed-valent HTSC cuprates. The model specifies the two energy scales controlling the development of HTSC behaviour and the dichotomy often now alluded to between nodal and antinodal phenomena in the HTSC cuprates. Indication is extracted from the data as to how the choice of the particular HTSC system sees these two basic energy scales (cursive-U, the local pair binding energy and, Delta-sc, the nodal BCS-like gap parameter) evolve with doping and change in degree of metallization of the structurally and electronically perturbed mixed-valent environment.Comment: 19 pages, 5 figure