A rapid turnaround gene panel for severe autoinflammation: Genetic results within 48 hours

There is an important unmet clinical need for fast turnaround next generation sequencing (NGS) to aid genetic diagnosis of patients with acute and sometimes catastrophic inflammatory presentations. This is imperative for patients who require precise and targeted treatment to prevent irreparable organ damage or even death. Acute and severe hyper- inflammation may be caused by primary immunodeficiency (PID) with immune dysregulation, or more typical autoinflammatory diseases in the absence of obvious immunodeficiency. Infectious triggers may be present in either immunodeficiency or autoinflammation. We compiled a list of 25 genes causing monogenetic immunological diseases that are notorious for their acute first presentation with fulminant inflammation and which may be amenable to specific treatment, including hemophagocytic lymphohistiocytosis (HLH); and autoinflammatory diseases that can present with early-onset stroke or other irreversible neurological inflammatory complications. We designed and validated a pipeline that enabled return of clinically actionable results in hours rather than weeks: the Rapid Autoinflammation Panel (RAP). We demonstrated accuracy of this new pipeline, with 100% sensitivity and 100% specificity. Return of results to clinicians was achieved within 48-hours from receiving the patient's blood or saliva sample. This approach demonstrates the potential significant diagnostic impact of NGS in acute medicine to facilitate precision medicine and save "life or limb" in these critical situations

A LOFAR mini-survey for low-frequency radio emission from the nearest brown dwarfs

We have conducted a mini-survey for low-frequency radio emission from some of the closest brown dwarfs to the Sun with rapid rotation rates: SIMP J013656.5 +093347, WISEPC 150649.97+702736.0, and WISEPA J174124.26+255319.5.We have placed robust 3s upper limits on the flux density in the 111 – 169 MHz frequency range for these targets: WISE 1506: < 0:72 mJy; WISE 1741: < 0:87 mJy; SIMP 0136: < 0:66 mJy. At 8 hours of integration per target to achieve these limits, we find that systematic and detailed study of this class of object at LOFAR frequencies will require a substantial dedication of resources

Hubble Space Telescope Astrometry of the Procyon System

The nearby star Procyon is a visual binary containing the F5 IV-V subgiant Procyon A, orbited in a 40.84 yr period by the faint DQZ white dwarf Procyon B. Using images obtained over two decades with the Hubble Space Telescope, and historical measurements back to the 19th century, we have determined precise orbital elements. Combined with measurements of the parallax and the motion of the A component, these elements yield dynamical masses of 1.478 +/- 0.012 Msun and 0.592 +/- 0.006 Msun for A and B, respectively. The mass of Procyon A agrees well with theoretical predictions based on asteroseismology and its temperature and luminosity. Use of a standard core-overshoot model agrees best for a surprisingly high amount of core overshoot. Under these modeling assumptions, Procyon A's age is ~2.7 Gyr. Procyon B's location in the H-R diagram is in excellent agreement with theoretical cooling tracks for white dwarfs of its dynamical mass. Its position in the mass-radius plane is also consistent with theory, assuming a carbon-oxygen core and a helium-dominated atmosphere. Its progenitor's mass was 1.9-2.2 Msun, depending on its amount of core overshoot. Several astrophysical puzzles remain. In the progenitor system, the stars at periastron were separated by only ~5 AU, which might have led to tidal interactions and even mass transfer; yet there is no direct evidence that these have occurred. Moreover the orbital eccentricity has remained high (~0.40). The mass of Procyon B is somewhat lower than anticipated from the initial-to-final-mass relation seen in open clusters. The presence of heavy elements in its atmosphere requires ongoing accretion, but the place of origin is uncertain.Comment: Accepted by Astrophysical Journa

Hubble Space Telescope Spectroscopy of the Balmer lines in Sirius B

Sirius B is the nearest and brightest of all white dwarfs, but it is very difficult to observe at visible wavelengths due to the overwhelming scattered light contribution from Sirius A. However, from space we can take advantage of the superb spatial resolution of the Hubble Space Telescope to resolve the A and B components. Since the closest approach in 1993, the separation between the two stars has become increasingly favourable and we have recently been able to obtain a spectrum of the complete Balmer line series for Sirius B using HST?s Space Telescope Imaging Spectrograph (STIS). The quality of the STIS spectra greatly exceed that of previous ground-based spectra, and can be used to provide an important determination of the stellar temperature (Teff = 25193K) and gravity (log g = 8.556). In addition we have obtained a new, more accurate, gravitational red-shift of 80.42 +/- 4.83 km s-1 for Sirius B. Combining these results with the photometric data and the Hipparcos parallax we obtain new determinations of the stellar mass for comparison with the theoretical mass-radius relation. However, there are some disparities between the results obtained independently from log g and the gravitational redshift which may arise from flux losses in the narrow 50x0.2arcsec slit. Combining our measurements of Teff and log g with the Wood (1995) evolutionary mass-radius relation we get a best estimate for the white dwarf mass of 0.978 M. Within the overall uncertainties, this is in agreement with a mass of 1.02 M obtained by matching our new gravitational red-shift to the theoretical M/R relation.Comment: 11 pages, 6 figures, accepted for publication in the Monthly Notices of the Royal Astronomical Societ

Stellar archaeology with Gaia: the Galactic white dwarf population

Gaia will identify several 1e5 white dwarfs, most of which will be in the solar neighborhood at distances of a few hundred parsecs. Ground-based optical follow-up spectroscopy of this sample of stellar remnants is essential to unlock the enormous scientific potential it holds for our understanding of stellar evolution, and the Galactic formation history of both stars and planets.Comment: Summary of a talk at the 'Multi-Object Spectroscopy in the Next Decade' conference in La Palma, March 2015, to be published in ASP Conference Series (editors Ian Skillen & Scott Trager

Observations of the pulsating subdwarf B star Feige 48: Constraints on evolution and companions

Since pulsating subdwarf B (sdBV or EC14026) stars were first discovered (Kilkenny et al, 1997), observational efforts have tried to realize their potential for constraining the interior physics of extreme horizontal branch (EHB) stars. Difficulties encountered along the way include uncertain mode identifications and a lack of stable pulsation mode properties. Here we report on Feige 48, an sdBV star for which follow-up observations have been obtained spanning more than four years, which shows some stable pulsation modes. We resolve the temporal spectrum into five stable pulsation periods in the range 340 to 380 seconds with amplitudes less than 1%, and two additional periods that appear in one dataset each. The three largest amplitude periodicities are nearly equally spaced, and we explore the consequences of identifying them as a rotationally split l=1 triplet by consulting with a representative stellar model. The general stability of the pulsation amplitudes and phases allows us to use the pulsation phases to constrain the timescale of evolution for this sdBV star. Additionally, we are able to place interesting limits on any stellar or planetary companion to Feige 48.Comment: accepted for publication in MNRA

Periodic stellar variability from almost a million NGTS light curves

We analyse 829,481 stars from the Next Generation Transit Survey (NGTS) to extract variability periods. We utilise a generalisation of the autocorrelation function (the G-ACF), which applies to irregularly sampled time series data. We extract variability periods for 16,880 stars from late-A through to mid-M spectral types and periods between 0.1 and 130 days with no assumed variability model. We find variable signals associated with a number of astrophysical phenomena, including stellar rotation, pulsations and multiple-star systems. The extracted variability periods are compared with stellar parameters taken from Gaia DR2, which allows us to identify distinct regions of variability in the Hertzsprung-Russell Diagram. We explore a sample of rotational main-sequence objects in period-colour space, in which we observe a dearth of rotation periods between 15 and 25 days. This 'bi-modality' was previously only seen in space-based data. We demonstrate that stars in sub-samples above and below the period gap appear to arise from a stellar population not significantly contaminated by excess multiple systems. We also observe a small population of long-period variable M-dwarfs, which highlight a departure from the predictions made by rotational evolution models fitted to solar-type main-sequence objects. The NGTS data spans a period and spectral type range that links previous rotation studies such as those using data from Kepler, K2 and MEarth

Neuroinflammation, autoinflammation, splenomegaly and anemia caused by bi-allelic mutations in IRAK4

We describe a novel, severe autoinflammatory syndrome characterized by neuroinflammation, systemic autoinflammation, splenomegaly, and anemia (NASA) caused by bi-allelic mutations in IRAK4. IRAK-4 is a serine/threonine kinase with a pivotal role in innate immune signaling from toll-like receptors and production of pro-inflammatory cytokines. In humans, bi-allelic mutations in IRAK4 result in IRAK-4 deficiency and increased susceptibility to pyogenic bacterial infections, but autoinflammation has never been described. We describe 5 affected patients from 2 unrelated families with compound heterozygous mutations in IRAK4 (c.C877T (p.Q293*)/c.G958T (p.D320Y); and c.A86C (p.Q29P)/c.161 + 1G>A) resulting in severe systemic autoinflammation, massive splenomegaly and severe transfusion dependent anemia and, in 3/5 cases, severe neuroinflammation and seizures. IRAK-4 protein expression was reduced in peripheral blood mononuclear cells (PBMC) in affected patients. Immunological analysis demonstrated elevated serum tumor necrosis factor (TNF), interleukin (IL) 1 beta (IL-1β), IL-6, IL-8, interferon α2a (IFN-α2a), and interferon β (IFN-β); and elevated cerebrospinal fluid (CSF) IL-6 without elevation of CSF IFN-α despite perturbed interferon gene signature. Mutations were located within the death domain (DD; p.Q29P and splice site mutation c.161 + 1G>A) and kinase domain (p.Q293*/p.D320Y) of IRAK-4. Structure-based modeling of the DD mutation p.Q29P showed alteration in the alignment of a loop within the DD with loss of contact distance and hydrogen bond interactions with IRAK-1/2 within the myddosome complex. The kinase domain mutation p.D320Y was predicted to stabilize interactions within the kinase active site. While precise mechanisms of autoinflammation in NASA remain uncertain, we speculate that loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production. Blockade of IL-6 resulted in immediate and complete amelioration of systemic autoinflammation and anemia in all 5 patients treated; however, neuroinflammation has, so far proven recalcitrant to IL-6 blockade and the janus kinase (JAK) inhibitor baricitinib, likely due to lack of central nervous system penetration of both drugs. We therefore highlight that bi-allelic mutation in IRAK4 may be associated with a severe and complex autoinflammatory and neuroinflammatory phenotype that we have called NASA (neuroinflammation, autoinflammation, splenomegaly and anemia), in addition to immunodeficiency in humans

Flow on the Internet: a longitudinal study of Internet addiction symptoms during adolescence

Internet Addiction (IA) constitutes an excessive Internet use behavior with a significant impact on the user’s well-being. Online flow describes the users’ level of being absorbed by their online activity. The present study investigated age-related, gender, and flow effects on IA in adolescence. The sample comprised 648 adolescents who were assessed twice at age 16 and 18 years. IA was assessed using the Internet Addiction Test and online flow was assessed using the Online Flow Questionnaire. A three-level hierarchical model estimated age-related, gender, and online flow effects on IA symptoms and controlled for clustered random effects. IA symptoms decreased over time (for both genders) with a slower rate in males. Online flow was associated with IA symptoms and this remained consistent over time. Findings expand upon the available literature suggesting that IA symptoms could function as a development-related manifestation at the age of 16 years, while IA-related gender differences gradually increase between 16 and 18 years. Finally, the association between online flow and IA symptoms remained stable independent of age-related effects. The study highlights individual differences and provides directions for more targeted prevention and intervention initiatives for IA

Cryotomography of budding influenza a virus reveals filaments with diverse morphologies that mostly do not bear a genome at their distal end

Influenza viruses exhibit striking variations in particle morphology between strains. Clinical isolates of influenza A virus have been shown to produce long filamentous particles while laboratory-adapted strains are predominantly spherical. However, the role of the filamentous phenotype in the influenza virus infectious cycle remains undetermined. We used cryo-electron tomography to conduct the first three-dimensional study of filamentous virus ultrastructure in particles budding from infected cells. Filaments were often longer than 10 microns and sometimes had bulbous heads at their leading ends, some of which contained tubules we attribute to M1 while none had recognisable ribonucleoprotein (RNP) and hence genome segments. Long filaments that did not have bulbs were infrequently seen to bear an ordered complement of RNPs at their distal ends. Imaging of purified virus also revealed diverse filament morphologies; short rods (bacilliform virions) and longer filaments. Bacilliform virions contained an ordered complement of RNPs while longer filamentous particles were narrower and mostly appeared to lack this feature, but often contained fibrillar material along their entire length. The important ultrastructural differences between these diverse classes of particles raise the possibility of distinct morphogenetic pathways and functions during the infectious process