TXNIP is a Mediator of ER Stress-Induced β-Cell Inflammation and Apoptosis: A Dissertation

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia. The pathogenesis of these diseases involves β-cell dysfunction and death. The primary function of β-cells is to tightly regulate the secretion, production, and storage of insulin in response to blood glucose levels. In order to manage insulin biosynthesis, β-cells have an elaborate endoplasmic reticulum (ER). The ER is an essential organelle for the proper processing and folding of proteins such as proinsulin. Proteins fold properly when the ER protein load balances with the ER folding capacity that handles this load. Disruption of this ER homeostasis by genetic and environmental stimuli leads to an accumulation of misfolded and unfolded proteins, a condition known as ER stress. Upon ER stress, the unfolded protein response (UPR) is activated. The UPR is a signaling network that aims to alleviate ER stress and restore ER homeostasis promoting cell survival. Hence, the UPR allows β-cells to handle the physiological fluctuations of insulin demand. However upon severe unresolvable ER stress conditions such as during diabetes progression, the UPR switches to pathological outputs leading to β-cell dysfunction and apoptosis. Severe ER stress may also trigger inflammation and accumulating evidence suggests that inflammation also contributes to β-cell failure, but the mechanisms remain elusive. In this dissertation, we demonstrate that thioredoxin interacting protein (TXNIP) mediates ER stress induced β-cell inflammation and apoptosis. During a DNA microarray analysis to identify novel survival and death components of the UPR, we identified TXNIP as an interesting proapoptotic candidate as it has been linked to glucotoxicity in β-cells. During our detailed investigation, we discovered that TXNIP is selectively expressed in β-cells of the pancreas and is strongly induced by ER stress through the IRE1α and PERK-eIF2α arms of the UPR and specifically its transcription is regulated by activating transcription factor 5 (ATF5) and carbohydrate response element binding protein (ChREBP) transcription factors. As TXNIP has been shown to activate the Nod-like receptor protein 3 (NLRP3) inflammasome leading to the production of the inflammatory cytokine interleukin-1β (IL- 1β), we hypothesized that perhaps TXNIP has a role in IL-1β production under ER stress. We show that ER stress can induce IL-1β production and that IL-1β is capable of binding to IL-1 type 1 receptor (IL-1R1) on the surface of β-cells stimulating its own expression. More importantly, we demonstrate that TXNIP does indeed play a role in ER stress mediated IL-1β production through the NLRP3 inflammasome. Furthermore, we also confirmed that TXNIP is a mediator of β-cell apoptosis under ER stress partially through IL-1β signaling. Collectively, we provide significant novel findings that TXNIP is a component of the UPR, mediates IL-1β production and autostimulation, and induces cell death under ER stress in β-cells. It is becoming clear that TXNIP has a role in the pathogenesis of diabetes and is a link between ER stress, oxidative stress and inflammation. Understanding the molecular mechanisms involved in TXNIP expression, activity, and function as we do here will shed light on potential therapeutic strategies to tackle diabetes

Limits on the Mass, Velocity and Orbit of PSR J1933−-6211

We present a high-precision timing analysis of PSR J1933$-$6211, a millisecond pulsar (MSP) with a 3.5-ms spin period and a white dwarf (WD) companion, using data from the Parkes radio telescope. Since we have accurately measured the polarization properties of this pulsar we have applied the matrix template matching approach in which the times of arrival are measured using full polarimetric information. We achieved a weighted root-mean-square timing residuals (rms) of the timing residuals of 1.23 $\rm \mu s$, 15.5$\%$ improvement compared to the total intensity timing analysis. After studying the scintillation properties of this pulsar we put constraints on the inclination angle of the system. Based on these measurements and on $\chi^2$ mapping we put a 2-$\sigma$ upper limit on the companion mass (0.44 M$_\odot$). Since this mass limit cannot reveal the nature of the companion we further investigate the possibility of the companion to be a He WD. Applying the orbital period-mass relation for such WDs, we conclude that the mass of a He WD companion would be about 0.26$\pm$0.01 M$_\odot$ which, combined with the measured mass function and orbital inclination limits, would lead to a light pulsar mass $\leqslant$ 1.0 M$_\odot$. This result seems unlikely based on current neutron star formation models and we therefore conclude that PSR J1933$-$6211 most likely has a CO WD companion, which allows for a solution with a more massive pulsar

A deep campaign to characterize the synchronous radio/X-ray mode switching of PSR B0943+10

We report on simultaneous X-ray and radio observations of the mode-switching pulsar PSR B0943+10 obtained with the XMM-Newton satellite and the LOFAR, LWA and Arecibo radio telescopes in November 2014. We confirm the synchronous X-ray/radio switching between a radio-bright (B) and a radio-quiet (Q) mode, in which the X-ray flux is a factor ~2.4 higher than in the B-mode. We discovered X-ray pulsations, with pulsed fraction of 38+/-5% (0.5-2 keV), during the B-mode, and confirm their presence in Q-mode, where the pulsed fraction increases with energy from ~20% up to ~65% at 2 keV. We found marginal evidence for an increase in the X-ray pulsed fraction during B-mode on a timescale of hours. The Q-mode X-ray spectrum requires a fit with a two-component model (either a power-law plus blackbody or the sum of two blackbodies), while the B-mode spectrum is well fit by a single blackbody (a single power-law is rejected). With a maximum likelihood analysis, we found that in Q-mode the pulsed emission has a thermal blackbody spectrum with temperature ~3.4x10^6 K and the unpulsed emission is a power-law with photon index ~2.5, while during B-mode both the pulsed and unpulsed emission can be fit by either a blackbody or a power law with similar values of temperature and photon index. A Chandra image shows no evidence for diffuse X-ray emission. These results support a scenario in which both unpulsed non-thermal emission, likely of magnetospheric origin, and pulsed thermal emission from a small polar cap (~1500 m^2) with a strong non-dipolar magnetic field (~10^{14} G), are present during both radio modes and vary in intensity in a correlated way. This is broadly consistent with the predictions of the partially screened gap model and does not necessarily imply global magnetospheric rearrangements to explain the mode switching.Comment: To be published on The Astrophysical Journa

The PULSE@Parkes project: A new observing technique for long-term pulsar monitoring

The PULSE@Parkes project has been designed to monitor the rotation of radio pulsars over time spans of days to years. The observations are obtained using the Parkes 64-m and 12-m radio telescopes by Australian and international high school students. These students learn the basis of radio astronomy and undertake small projects with their observations. The data are fully calibrated and obtained with the state-of-the-art pulsar hardware available at Parkes. The final data sets are archived and are currently being used to carry out studies of 1) pulsar glitches, 2) timing noise, 3) pulse profile stability over long time scales and 4) the extreme nulling phenomenon. The data are also included in other projects such as gamma-ray observatory support and for the Parkes Pulsar Timing Array project. In this paper we describe the current status of the project and present the first scientific results from the Parkes 12-m radio telescope. We emphasise that this project offers a straightforward means to enthuse high school students and the general public about radio astronomy while obtaining scientifically valuable data sets.Comment: accepted for publication by PAS

The UTMOST pulsar timing programme I: overview and first results

We present an overview and the first results from a large-scale pulsar timing programme that is part of the UTMOST project at the refurbished Molonglo Observatory Synthesis Radio Telescope (MOST) near Canberra, Australia. We currently observe more than 400 mainly bright southern radio pulsars with up to daily cadences. For 205 (8 in binaries, 4 millisecond pulsars) we publish updated timing models, together with their flux densities, flux density variability, and pulse widths at 843 MHz, derived from observations spanning between 1.4 and 3 yr. In comparison with the ATNF pulsar catalogue, we improve the precision of the rotational and astrometric parameters for 123 pulsars, for 47 by at least an order of magnitude. The time spans between our measurements and those in the literature are up to 48 yr, which allows us to investigate their long-term spin-down history and to estimate proper motions for 60 pulsars, of which 24 are newly determined and most are major improvements. The results are consistent with interferometric measurements from the literature. A model with two Gaussian components centred at 139 and $463~\text{km} \: \text{s}^{-1}$ fits the transverse velocity distribution best. The pulse duty cycle distributions at 50 and 10 per cent maximum are best described by log-normal distributions with medians of 2.3 and 4.4 per cent, respectively. We discuss two pulsars that exhibit spin-down rate changes and drifting subpulses. Finally, we describe the autonomous observing system and the dynamic scheduler that has increased the observing efficiency by a factor of 2-3 in comparison with static scheduling.Comment: 31 pages, 14 figures, 6 tables, accepted for publication in MNRA

The Performance and Calibration of the CRAFT Fly's Eye Fast Radio Burst Survey

Since January 2017, the Commensal Real-time ASKAP Fast Transients survey (CRAFT) has been utilising commissioning antennas of the Australian SKA Pathfinder (ASKAP) to survey for fast radio bursts (FRBs) in fly's eye mode. This is the first extensive astronomical survey using phased array feeds (PAFs), and a total of 20 FRBs have been reported. Here we present a calculation of the sensitivity and total exposure of this survey, using the pulsars B1641-45 (J1644-4559) and B0833-45 (J0835-4510, i.e.\ Vela) as calibrators. The design of the survey allows us to benchmark effects due to PAF beamshape, antenna-dependent system noise, radio-frequency interference, and fluctuations during commissioning on timescales from one hour to a year. Observation time, solid-angle, and search efficiency are calculated as a function of FRB fluence threshold. Using this metric, effective survey exposures and sensitivities are calculated as a function of the source counts distribution. The implied FRB rate is significantly lower than the $37$\,sky$^{-1}$\,day$^{-1}$ calculated using nominal exposures and sensitivities for this same sample by \citet{craft_nature}. At the Euclidean power-law index of $-1.5$, the rate is $10.7_{-1.8}^{+2.7}\,{\rm (sys)} \, \pm \, 3\,{\rm (stat)}$\,sky$^{-1}$\,day$^{-1}$ above a threshold of $57\pm6\,{\rm (sys)}$\,Jy\,ms, while for the best-fit index for this sample of $-2.1$, it is $16.6_{-1.5}^{+1.9} \,{\rm (sys)}\, \pm 4.7\,{\rm (stat)}$\,sky$^{-1}$\,day$^{-1}$ above a threshold of $41.6\pm1.5\,{\rm (sys)}$\,Jy\,ms. This strongly suggests that these calculations be performed for other FRB-hunting experiments, allowing meaningful comparisons to be made between them.Comment: 21 pages, 15 figures, 2 tables, accepted for publication in PAS

The UTMOST: A hybrid digital signal processor transforms the MOST

The Molonglo Observatory Synthesis Telescope (MOST) is an 18,000 square meter radio telescope situated some 40 km from the city of Canberra, Australia. Its operating band (820-850 MHz) is now partly allocated to mobile phone communications, making radio astronomy challenging. We describe how the deployment of new digital receivers (RX boxes), Field Programmable Gate Array (FPGA) based filterbanks and server-class computers equipped with 43 GPUs (Graphics Processing Units) has transformed MOST into a versatile new instrument (the UTMOST) for studying the dynamic radio sky on millisecond timescales, ideal for work on pulsars and Fast Radio Bursts (FRBs). The filterbanks, servers and their high-speed, low-latency network form part of a hybrid solution to the observatory's signal processing requirements. The emphasis on software and commodity off-the-shelf hardware has enabled rapid deployment through the re-use of proven 'software backends' for its signal processing. The new receivers have ten times the bandwidth of the original MOST and double the sampling of the line feed, which doubles the field of view. The UTMOST can simultaneously excise interference, make maps, coherently dedisperse pulsars, and perform real-time searches of coherent fan beams for dispersed single pulses. Although system performance is still sub-optimal, a pulsar timing and FRB search programme has commenced and the first UTMOST maps have been made. The telescope operates as a robotic facility, deciding how to efficiently target pulsars and how long to stay on source, via feedback from real-time pulsar folding. The regular timing of over 300 pulsars has resulted in the discovery of 7 pulsar glitches and 3 FRBs. The UTMOST demonstrates that if sufficient signal processing can be applied to the voltage streams it is possible to perform innovative radio science in hostile radio frequency environments.Comment: 12 pages, 6 figure

MeerTime - the MeerKAT Key Science Program on Pulsar Timing

The MeerKAT telescope represents an outstanding opportunity for radio pulsar timing science with its unique combination of a large collecting area and aperture efficiency (effective area $\sim$7500 m$^2$), system temperature ($T<20$K), high slew speeds (1-2 deg/s), large bandwidths (770 MHz at 20cm wavelengths), southern hemisphere location (latitude $\sim -30^\circ$) and ability to form up to four sub-arrays. The MeerTime project is a five-year program on the MeerKAT array by an international consortium that will regularly time over 1000 radio pulsars to perform tests of relativistic gravity, search for the gravitational wave signature induced by supermassive black hole binaries in the timing residuals of millisecond pulsars, explore the interiors of neutron stars through a pulsar glitch monitoring programme, explore the origin and evolution of binary pulsars, monitor the swarms of pulsars that inhabit globular clusters and monitor radio magnetars. In addition to these primary programmes, over 1000 pulsars will have their arrival times monitored and the data made immediately public. The MeerTime pulsar backend comprises two server-class machines each of which possess four Graphics Processing Units. Up to four pulsars can be coherently dedispersed simultaneously up to dispersion measures of over 1000 pc cm$^{-3}$. All data will be provided in psrfits format. The MeerTime backend will be capable of producing coherently dedispersed filterbank data for timing multiple pulsars in the cores of globular clusters that is useful for pulsar searches of tied array beams. All MeerTime data will ultimately be made available for public use, and any published results will include the arrival times and profiles used in the results.Comment: 15 pages, MeerKAT Science: On the Pathway to the SKA, 25-27 May, 2016, Stellenbosch, South Africa, available at: https://pos.sissa.it/277/011/pd