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Abstract: In this Letter, we report the discovery of the highest redshift, heavily obscured, radio-loud (RL) active galactic nucleus (AGN) candidate selected using JWST NIRCam/MIRI, mid-IR, submillimeter, and radio imaging in the COSMOS-Web field. Using multifrequency radio observations and mid-IR photometry, we identify a powerful, RL, growing supermassive black hole with significant spectral steepening of the radio spectral energy distribution (f 1.28 GHz ∼ 2 mJy, q 24 μm = −1.1, α 1.28−3 GHz = − 1.2, Δα = − 0.4). In conjunction with ALMA, deep ground-based observations, ancillary space-based data, and the unprecedented resolution and sensitivity of JWST, we find no evidence of AGN contribution to the UV/optical/near-infrared (NIR) data and thus infer heavy amounts of obscuration (N H > 1023 cm−2). Using the wealth of deep UV to submillimeter photometric data, we report a singular solution photo-z of z phot = 7.7 − 0.3 + 0.4 and estimate an extremely massive host galaxy ( log M ⋆ = 11.92 ± 0.5 M ⊙ ) hosting a powerful, growing supermassive black hole​​​​​ (L Bol = 4−12x × 1046 erg s−1). This source represents the farthest known obscured RL AGN candidate, and its level of obscuration aligns with the most representative but observationally scarce population of AGN at these epochs.

Supermassive black holes in galaxy centres can grow by the accretion of gas, liberating energy that might regulate star formation on galaxy-wide scales (1-3). The nature of the gaseous fuel reservoirs that power black hole growth is nevertheless largely unconstrained by observations, and is instead routinely simplified as a smooth, spherical inflow of very hot gas (4). Recent theory (5-7) and simulations (8-10) instead predict that accretion can be dominated by a stochastic, clumpy distribution of very cold molecular clouds--a departure from the 'hot mode' accretion model--although unambiguous observational support for this prediction remains elusive. Here we report observations that reveal a cold, clumpy accretion flow towards a supermassive black hole fuel reservoir in the nucleus of the Abell 2597 Brightest Cluster Galaxy (BCG), a nearby (redshift z = 0.0821) giant elliptical galaxy surrounded by a dense halo of hot plasma (11-13). Under the right conditions, thermal instabilities produce a rain of cold clouds that fall towards the galaxy's centre (14), sustaining star formation amid a kiloparsec-scale molecular nebula that is found at its core (15). The observations show that these cold clouds also fuel black hole accretion, revealing 'shadows' cast by the molecular clouds as they move inward at about 300 kilometres per second towards the active supermassive black hole, which serves as a bright backlight. Corroborating evidence from prior observations (16) of warmer atomic gas at extremely high spatial resolution (17), along with simple arguments based on geometry and probability, indicate that these clouds are within the innermost hundred parsecs of the black hole, and falling closer towards it., We observed the Abell 2597 BCG (Fig. 1) with the Atacama Large Millimeter/submillimeter Array (ALMA), enabling us to create a three-dimensional map of both the location and motions of cold [...]

Active galactic nucleus (AGN) feedback at z∼1−3 is believed to take place in the presence of thick columns of gas and dust, leading to heavily obscured systems that are challenging to detect at optical and X‐ray wavelengths but are transparent at radio and mid‐IR (MIR) wavelengths. MIR color diagnostics using the widefield infrared space explorer (WISE) observations can identify the most luminous and heavily obscured AGNs, which are believed to represent a transient phase of rapid massive black hole growth. By combining both mid‐IR and radio diagnostics, we have identified a sample of 155 ultraluminous and obscured quasars (0.47 mJy) radio emission in the NRAO VLA Sky Survey (NVSS) and Faint Images of the Radio Sky at Twenty‐one centimeters (FIRST). High‐resolution very large array (VLA) imaging has revealed compact source morphologies on angular scales <0.2″ (1.7 kpc at z∼2) for the majority of our sources. Broadband radio spectra of the entire sample, constructed from our 10 GHz VLA observations and archival radio data show that 63% of the sample has peaked or curved spectral shapes consistent with those typically seen in young radio AGN (e.g., gigahertz peaked spectrum [GPS] and compact steep spectrum [CSS] sources). Overall, our sample is consistent with a population of recently triggered, young radio jets caught in a unique evolutionary stage in which they reside in a dense interstellar medium (ISM). [ABSTRACT FROM AUTHOR]

Energetic feedback driven by the large‐scale (100's of kpc) lobes of classical radio galaxies is known to play an important role in shaping galaxy evolution. However, the prevalence of young and compact jets – and their impact on the interstellar medium – remains an open question. Multi‐epoch radio surveys with cadences of years to decades offer a promising means of identifying even faint (mJy‐level) jets that are compact and potentially young on the basis of variability. Recently, a comparison of images from the Very Large Array Sky Survey (VLASS) and the Faint Images of the Radio Sky at Twenty Centimeters (FIRST) survey has revealed a population of distant (0.2

Summary: Objectives: To evaluate the potential of the automated titre score (TS) as an alternative method to continuous flow analysis (CFA) for the prediction of the nature of anti‐D in pregnancy. Background: The 2016 revised British Society for Haematology (BSH) antenatal guidelines recommended a measurement of anti‐D concentration by CFA to ensure the detection of potential immune anti‐D. Due to high referral costs and resource pressures, uptake has been challenging for hospital laboratories. Serious Hazards of transfusion (SHOT) data have previously shown that this has contributed to missed antenatal follow ups for women with immune anti‐D and neonates affected by haemolytic disease of the fetus/newborn. Methods/Materials: In this multicentre comparative study, samples referred for CFA quantification were also tested by an ORTHO VISION automated anti‐D indirect antiglobulin test (IAT) serial dilution and then converted to TS. CFA results and history of anti‐D prophylaxis were used to categorise samples as passive or immune, with the aim of determining a potential TS cut‐off for CFA referral of at risk patients. Results: Five UK National Health Service (NHS) trusts generated a total of 196 anti‐D TS results, of which 128 were classified as passive and 68 as immune. Diagnostic testing of CFA and TS values indicated a TS cut‐off of 35 to assist in distinguishing the nature of anti‐D. Using this cut‐off, 175 (89%) results were correctly assigned into the passive or immune range, giving a specificity of 92.19% and a negative predictive value of 91.47%. Conclusion: TS in conjunction with clinical and anti‐D prophylaxis history can be used as a viable and cost‐effective alternative to CFA in a hospital laboratory setting. [ABSTRACT FROM AUTHOR]

We have performed a search over 3440 deg2 of Epoch 1 (2017–2019) of the Very Large Array Sky Survey to identify unobscured quasars in the optical (0.2 < z < 3.2) and obscured active galactic nuclei (AGNs) in the infrared that have brightened dramatically in the radio over the past one to two decades. These sources would have been previously classified as "radio-quiet" quasars based on upper limits from the Faint Images of the Radio Sky at Twenty cm survey (1993–2011), but they are now consistent with "radio-loud" quasars (). A quasi-simultaneous, multiband (∼1–18 GHz) follow-up study of 14 sources with the VLA has revealed compact sources (<0.″1 or <1 kpc) with peaked radio spectral shapes. The high-amplitude variability over decadal timescales at 1.5 GHz (100% to >2500%) but roughly steady fluxes over a few months at 3 GHz are inconsistent with extrinsic variability due to propagation effects, thus favoring an intrinsic origin. We conclude that our sources are powerful quasars hosting compact/young jets. This challenges the generally accepted idea that "radio-loudness" is a property of the quasar/AGN population that remains fixed on human timescales. Our study suggests that frequent episodes of short-lived AGN jets that do not necessarily grow to large scales may be common at high redshift. We speculate that intermittent but powerful jets on subgalactic scales could interact with the interstellar medium, possibly driving feedback capable of influencing galaxy evolution. [ABSTRACT FROM AUTHOR]

We present the results of deep Chandra and XMM–Newton observations of a complex merging galaxy cluster Abell 2256 (A2256) that hosts a spectacular radio relic (RR). The temperature and metallicity maps show clear evidence of a merger between the western subcluster (SC) and the primary cluster (PC). We detect five X-ray surface brightness edges. Three of them near the cluster centre are cold fronts (CFs): CF1 is associated with the infalling SC; CF2 is located in the east of the PC; and CF3 is located to the west of the PC core. The other two edges at cluster outskirts are shock fronts (SFs): SF1 near the RR in the NW has Mach numbers derived from the temperature and the density jumps, respectively, of M T = 1.62 ± 0.12 and M ρ = 1.23 ± 0.06; SF2 in the SE has M T = 1.54 ± 0.05 and M ρ = 1.16 ± 0.13. In the region of the RR, there is no evidence for the correlation between X-ray and radio substructures, from which we estimate an upper limit for the inverse-Compton emission, and therefore set a lower limit on the magnetic field (∼ 450 kpc from PC centre) of B > 1.0 μG for a single power-law electron spectrum or B > 0.4 μG for a broken power-law electron spectrum. We propose a merger scenario including a PC, an SC, and a group. Our merger scenario accounts for the X-ray edges, diffuse radio features, and galaxy kinematics, as well as projection effects. [ABSTRACT FROM AUTHOR]

We present a multiwavelength investigation of the radio galaxy population in the galaxy cluster MOO J1506+5137 at z = 1.09 ± 0.03, which in previous work we identified as having multiple complex radio sources. The combined data set used in this work includes data from the Low-Frequency Array Two-meter Sky Survey, NSF's Karl G. Jansky Very Large Array, the Robert C. Byrd Green Bank Telescope, the Spitzer Space Telescope, and the Dark Energy Camera Legacy Survey. We find that there are five radio sources, which are all located within 500 kpc (∼1′) of the cluster center and have radio luminosities P1.4 GHz > 1.6 × 1024 W Hz−1. The typical host galaxies are among the highest stellar mass galaxies in the cluster. The exceptional radio activity among the massive galaxy population appears to be linked to the dynamical state of the cluster. The galaxy distribution suggests an ongoing merger, with a subgroup found to the northwest of the main cluster. Furthermore, two of the five sources are classified as bent-tail sources, with one being a potential wide-angle tail/hybrid morphology radio source, indicating a dynamic environment. The cluster also lies in a region of the mass–richness plane occupied by other merging clusters in the Massive and Distant Clusters of WISE Survey. The data suggest that during the merger phase, radio activity can be dramatically enhanced, which would contribute to the observed trend of increased radio activity in clusters with increasing redshift. [ABSTRACT FROM AUTHOR]

This paper describes the statistical property of Jupiter's millisecond burst (S‐burst) beaming for Io‐related decametric (Io‐DAM) sources from a ground‐based radio telescope network. To do so, we performed simultaneous observations of Jovian Io‐DAM S‐bursts from 15 January through 4 May 2016 for a total of nine events using several radio telescopes. These radio telescopes include the Long Wavelength Array station One (LWA1) in the United States, Nançay Decameter Array (NDA) in France, and three large radio telescopes (UTR2, URAN2, and URAN3) in Ukraine. We conducted a cross‐correlation analysis of the S‐burst spectrograms in a frequency range of 10.5 to 33 MHz over effective baselines of up to 8,950 km. We found that the beaming of the S‐bursts is formed on the flashlight‐like structure within an east‐west beam width of 2.75" for Io‐A/C, 2.63" for Io‐A', and 2.75" for Io‐B/D. In parallel, the flashlight‐like beam was completely filled because the results from all usable pairs of telescopes supported this model. Hence, these beam widths directly correspond to the minimum cone thickness where a radio source emanates over large solid angles from the same direction of Jupiter, as opposed to a localized radio source emitting over small solid angles along active magnetic flux tubes that are tied to Io's orbital motion in Jupiter's rotation frame (beacon‐like structure). Additionally, this cross‐correlation technique shows a practical benefit of producing statistical profiles of S‐bursts. Plain Language Summary: In our solar system, Jupiter is second only to the Sun in its intensity as a radio source. One of the radio sources tied to Jovian auroras dominates at the decameter wavelength, exhibiting fine structures (called S‐bursts) in a timescale of milliseconds. While spacecraft equipped with a low‐frequency radio system is insufficient to capture S‐bursts in a broad frequency bandwidth and a long‐term period, Earth‐based radio telescopes offer high‐resolution observations of Jovian S‐bursts. Using five world‐class large radio telescopes in the United States, France, and Ukraine, we performed the common S‐burst observation campaign in 2016. We found that S‐burst beaming is wide enough to cover the maximum baseline of 8,950 km between radio telescopes in the United States and Ukraine. This result provides a nature of Jovian S‐burst beaming lasting on the order of the milliseconds. Key Points: S‐burst long baseline analysis was performed using five powerful radio telescopes on the groundStatistics of nine Io‐related events show that S‐burst beam is formed by a flashlight‐like beam structureThe cross‐correlation analysis can isolate the S‐burst frequency‐dependent distributions from those of the other emissions [ABSTRACT FROM AUTHOR]

We present results from the deep Chandra observation (105 ks), together with new Giant Metrewave Radio Telescope and Very Large Array data of the AGN outburst in the radio-loud galaxy group 3C 88. The system shows a prominent X-ray cavity on the eastern side with a diameter of ∼50 kpc at ∼28 kpc from the nucleus. The total enthalpy of the cavity is 3.8 × 1058 erg and the average power required to inflate the X-ray bubble is ∼ 2.0 × 1043 erg s−1. From surface brightness profiles, we detect a shock with a Mach number of M  = 1.4 ± 0.2, consistent with the value obtained from temperature jump. The shock energy is estimated to be 1.9 × 1059 erg. The size and total enthalpy of the cavity in 3C 88 are the largest known in galaxy groups, as well as the shock energy. The eastern X-ray cavity is not aligned with the radio jet axis. This factor, combined with the radio morphology, strongly suggests jet reorientation in the last tens of million years. The bright rim and arm features surrounding the cavity show metallicity enhancement, suggesting they originated as high metallicity gas from the group centre, lifted by the rising X-ray bubbles. Our Chandra study of 3C 88 also reveals that galaxy groups with powerful radio AGN can have high cavity power, although deep X-ray observations are typically required to confirm the cavities in galaxy groups. [ABSTRACT FROM AUTHOR]

As part of an on-going study of radio transients in Epoch 1 (2017–2019) of the Very Large Array Sky Survey (VLASS), we have discovered a sample of 0.2 < z < 3.2 active galactic nuclei (AGN) selected in the optical/infrared that have recently brightened dramatically in the radio. These sources would have previously been classified as radio-quiet based on upper limits from the Faint Images of the Radio Sky at Twenty-centimeters (FIRST; 1993-2011) survey; however, they are now consistent with radio-loud quasars. We present a quasi-simultaneous, multi-band (1–18 GHz) VLA follow-up campaign of our sample of AGN with extreme radio variability. We conclude that the radio properties are most consistent with AGN that have recently launched jets within the past few decades, potentially making them among the youngest radio AGN known. [ABSTRACT FROM AUTHOR]

We present a 66 ks Chandra X-ray observation of the galaxy cluster RXJ0334.2-0111. This deep observation revealed a unique bow shock system associated with a wide angle tail (WAT) radio galaxy and several intriguing substructures. The temperature across the bow shock jumps by a factor of ~1.5 (from 4.1 to 6.2 keV), and is consistent with the Mach number M = 1.6+0.5-0.3. A second inner surface brightness edge is a cold front that marks the border between infalling subcluster cool core and the intracluster medium of the main cluster. The temperature across the cold front increases from 1.3+0.3-0.8 to 6.2+0.6-0.6 keV. We find an overpressurized region ~250 kpc east of the cold front that is named 'the eastern extension (EE)'. The EE may be a part of the third subcluster in the ongoing merger. We also find a tail shaped feature that originates near the bow shock and may extend up to a distance of ~1 Mpc. This feature is also likely overpressurized. The luminous FR-I radio galaxy, 3C89, appears to be the cD galaxy of the infalling subcluster. We estimated 3C89's jet power from jet bending and the possible interaction between the X-ray gas and the radio lobes. A comparison between the shock standoff distance and the Mach number for all known shock front/cold front combinations suggests that the core is continuously shrinking in size by stripping. [ABSTRACT FROM AUTHOR]

We present results from deep Chandra X-ray observations of the galaxy group NGC 5813. This system shows three pairs of collinear cavities, with each pair associated with an elliptical AGN outburst shock. Due to the relatively regular morphology of this system, and the unique unambiguous detection of three distinct AGN outburst shocks, it is particularly well-suited for the study of AGN feedback and the AGN outburst history. We find that the mean kinetic power is roughly the same for each outburst, and that the total energy associated with the youngest outburst is significantly lower than that of the previous outbursts. This implies that the mean AGN jet power has remained stable for at least 50 Myr, and that the youngest outburst is ongoing. We find that the mean shock heating rate balances the local radiative cooling rate at each shock front, suggesting that AGN outburst shock heating alone is sufficient to offset cooling and establish AGN/ICM feedback within at least the central 30 kpc. Finally, we find non-zero shock front widths that are too large to be explained by particle diffusion, but are instead consistent with arising from broadening of the shock fronts due to propagation through a turbulent ICM with a mean turbulent speed of ~ 70 km s−1. [ABSTRACT FROM PUBLISHER]

Cool cores of some galaxy clusters exhibit faint radio “minihalos.” Their origin is unclear, and their study has been limited by their small number. We undertook a systematic search for minihalos in a large sample of X-ray luminous clusters with high-quality radio data. In this article, we report four new minihalos (A 478, ZwCl 3146, RXJ 1532.9+3021, and A 2204) and five candidates found in the reanalyzed archival Very Large Array observations. The radio luminosities of our minihalos and candidates are in the range of 1023-25 W Hz–1 at 1.4 GHz, which is consistent with these types of radio sources. Their sizes (40-160 kpc in radius) are somewhat smaller than those of previously known minihalos. We combine our new detections with previously known minihalos, obtaining a total sample of 21 objects, and briefly compare the cluster radio properties to the average X-ray temperature and the total masses estimated from Planck. We find that nearly all clusters hosting minihalos are hot and massive. Beyond that, there is no clear correlation between the minihalo radio power and cluster temperature or mass (in contrast with the giant radio halos found in cluster mergers, whose radio luminosity correlates with the cluster mass). Chandra X-ray images indicate gas sloshing in the cool cores of most of our clusters, with minihalos contained within the sloshing regions in many of them. This supports the hypothesis that radio-emitting electrons are reaccelerated by sloshing. Advection of relativistic electrons by the sloshing gas may also play a role in the formation of the less extended minihalos. [ABSTRACT FROM AUTHOR]

Excess morbidity in people with enduring mental illness is well known. The promotion of healthier lifestyles and physical health monitoring has started to receive more attention in recent years. Despite this, the British Society for Disability and Oral Health (BSDH) has highlighted extensive unmet needs for inpatients with mental illness who have poor levels of oral health and hygiene compounded by restricted access to dental services. An audit cycle of oral health and hygiene was completed at Heather Close Recovery Unit (HCRU), Mansfield in 2009 and 2010, with the aims to improve the oral healthcare of the patients at HCRU and to develop the multidisciplinary team's ability to promote, monitor and enable patients to look after their dental health. A total of 59 people were helped to fill in the questionnaire during two audit runs. Improvement in access to toothbrushes increased from 68% to 86%. There is also an improvement in knowledge of basic oral hygiene practice from 55% to 61%. The ideally recommended practice of brushing teeth twice daily increased from 29% to 38% in our patients. There was a little improvement in the number of patients registered with the dentist since the last audit. We believe that prevention and early intervention are keys to addressing dental health problems in psychiatric patients. The improvement in oral/dental healthcare of patients with chronic mental illness should be seen as part of the holistic recovery package. Effective liaison with community preventive dentistry teams can play a vital role in educating mental health practitioners and patients. [ABSTRACT FROM AUTHOR]

The Long Wavelength Array (LWA) will be a new multipurpose radio telescope operating in the frequency range 10-88 MHz. Upon completion, the LWA will consist of 53 phased array "stations" distributed over a region about 400 km in diameter in the state of New Mexico. Each station will consist of 256 pairs of dipole-type antennas whose signals are formed into beams, with outputs transported to a central location for high-resolution aperture synthesis imaging. The resulting image sensitivity is estimated to be a few millijanskys (5σ, 8 MHz, two polarizations, 1 h, zenith) in 20-80 MHz; with resolution and field of view of (8", 8°) and (2", 2°) at 20 and 80 MHz, respectively. Notable engineering features of the instrument, demonstrated in this paper, include Galactic-noise limited active antennas and direct sampling digitization of the entire tuning range. This paper also summarizes the LWA science goals, specifications, and analysis leading to top-level design decisions. [ABSTRACT FROM AUTHOR]

We present VLA Low-band Ionosphere and Transient Experiment (VLITE) 338 MHz observations of the galaxy cluster CL 0838+1948. We combine the VLITE data with Giant Metrewave Radio Telescope 610 MHz observations and survey data. The central galaxy hosts a 250 kpc source whose emission is dominated by two large lobes at low frequencies. At higher frequencies, a pair of smaller lobes (∼30 kpc) is detected within the galaxy optical envelope. The observed morphology is consistent with a restarted radio galaxy. The outer lobes have a spectral index α out = 1.6 , indicating that they are old, whereas the inner lobes have α inn = 0.6 , typical for an active source. Spectral modeling confirms that the outer emission is a dying source whose nuclear activity switched off not more than 110 Myr ago. Using archival Chandra X-ray data, we compare the radio and hot gas emission. We find that the active radio source is contained within the innermost and X-ray brightest region, possibly a galactic corona. Alternatively, it could be the remnant of a larger cool core whose outer layers have been heated by the former epoch of activity that has generated the outer lobes. [ABSTRACT FROM AUTHOR]

Recently, we have developed a model of airway inflammation in a CFTR knockout mouse utilizing Aspergillus fumigatus crude protein extract (Af-cpe) to mimic allergic bronchopulmonary aspergillosis (ABPA) , an unusual IgE-mediated hypersensitivity syndrome seen in up to 15% of cystic fibrosis (CF) patients and rarely elsewhere. We hypothesized that replacement of CFTR via targeted gene delivery to airway epithelium would correct aberrant epithelial cytokine signaling and ameliorate the ABPA phenotype in CFTR-deficient (CFTR 489X − /−, FABP-hCFTR + / +) mice. CFTR knockout mice underwent intra-tracheal (IT) delivery of recombinant adeno-associated virus serotype 5 (rAAV5Δ-264CFTR) or rAAV5-GFP at 2.58 × 1012 viral genomes/mouse. All mice were then sensitized with two serial injections (200 µg) of crude Af antigen via the intra-peritoneal (IP) route. Untreated mice were sensitized without virus exposure. Challenges were performed 2 weeks after final sensitization, using a 0.25% solution containing Aspergillus fumigatus crude protein extract delivered by inhalation on three consecutive days. The rAAV5Δ-264CFTR-treated mice had lower total serum IgE levels (172513 ng/ml ± 1312) than rAAV5-GFP controls (26 892 ng/ml ± 3715) ( p = 0.037) and non-treated, sensitized controls (24 816 ± 4219 ng/ml). Serum IgG1 levels also were lower in mice receiving the CFTR vector. Interestingly, splenocytes from rAAV5Δ-264CFTR-treated mice secreted less IL-13, INFg, TNFa, RANTES and GM-CSF after ConA stimulation. Gene therapy with rAAV5Δ-264CFTR attenuated the hyper-IgE response in this reproducible CF mouse model of ABPA, with systemic effects also evident in the cytokine response of stimulated splenocytes. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We present deep Giant Metrewave Radio Telescope (GMRT) radio observations at 240, 330, and 610 MHz of the complex radio source at the center of the NGC 1407 galaxy group. Previous GMRT observations at 240 MHz revealed faint, diffuse emission enclosing the central twin-jet radio galaxy. This has been interpreted as an indication of two possible radio outbursts occurring at different times. Both the inner double and diffuse components are detected in the new GMRT images at high levels of significance. Combining the GMRT observations with archival Very Large Array data at 1.4 and 4.9 GHz, we derive the total spectrum of both components. The inner double has a spectral index α = 0.7, typical for active, extended radio galaxies, whereas the spectrum of the large-scale emission is very steep, with α = 1.8 between 240 MHz and 1.4 GHz. The radiative age of the large-scale component is very long, ∼300 Myr, compared to ∼30 Myr estimated for the central double, confirming that the diffuse component was generated during a former cycle of activity of the central galaxy. The current activity have so far released an energy which is nearly one order of magnitude lower than that associated with the former outburst. The group x-ray emission in the Chandra and XMM-Newton images and extended radio emission show a similar swept-back morphology. We speculate that the two structures are both affected by the motion of the group core, perhaps due to the core sloshing in response to a recent encounter with the nearby elliptical galaxy NGC 1400. [ABSTRACT FROM AUTHOR]

The search for diffuse non-thermal, inverse Compton (IC) emission from galaxy clusters at hard X-ray energies has been underway for many years, with most detections being either of low significance or controversial. In this work, we investigate 14-195 keV spectra from the Swift Burst Alert Telescope (BAT) all-sky survey for evidence of non-thermal excess emission above the exponentially decreasing tail of thermal emission in the flux-limited HIFLUGCS sample. To account for the thermal contribution at BAT energies, XMM-Newton EPIC spectra are extracted from coincident spatial regions so that both thermal and non-thermal spectral components can be determined simultaneously. We find marginally significant IC components in six clusters, though after closer inspection and consideration of systematic errors we are unable to claim a clear detection in any of them. The spectra of all clusters are also summed to enhance a cumulative non-thermal signal not quite detectable in individual clusters. After constructing a model based on single-temperature fits to the XMM-Newton data alone, we see no significant excess emission above that predicted by the thermal model determined at soft energies. This result also holds for the summed spectra of various subgroups, except for the subsample of clusters with diffuse radio emission. For clusters hosting a diffuse radio halo, a relic, or a mini-halo, non-thermal emission is initially detected at the ∼5σ confidence level—driven by clusters with mini-halos—but modeling and systematic uncertainties ultimately degrade this significance. In individual clusters, the non-thermal pressure of relativistic electrons is limited to ≲ 10% of the thermal electron pressure, with stricter limits for the more massive clusters, indicating that these electrons are likely not dynamically important in the central regions of clusters. [ABSTRACT FROM AUTHOR]

Abstract: Gene transfer into pancreatic cells in vivo could be of immense therapeutic benefit in cases of type 1 diabetes (T1D) through the production of molecules capable of interrupting the progression of autoimmunity or promoting regeneration of insulin-secreting β cells. We adapted a clinically relevant surgical technique (endoscopic retrograde cholangiopancreatography) to deliver rAAV encoding human α1-antitrypsin (approved gene symbol SERPINA1) to the pancreas of 3-week-old Fisher 344 rats and C57BL/6 mice. We compared natural as well as bioengineered serotypes of rAAV (rAAV1, rAAV2/Apo (B. R. Burkhardt et al., 2003, Ann. N. Y. Acad. Sci. 1005, 237–241) [1], rAAV8) as well as different promoters (chicken β-actin, human insulin) for their expression in vivo. Rats injected with rAAV1 showed the highest hAAT expression (week 2, rAAV1/CB-AT, 579 ± 457 ng/ml). In mice, rAAV8 vector delivered the highest serum concentration of hAAT (week 2, rAAV8/CB-AT, 19 ± 6 μg/ml). The chicken β-actin promoter provided the highest expression in both rodent experiments. Immunohistochemical staining indicated transduction primarily of pancreatic acinar cells with either the rAAV1/CB-AT vector in the rat or the rAAV8/CB-AT vector in the mouse. This study demonstrates that rAAV vectors can be designed to deliver therapeutic genes efficiently to the pancreas and achieve high levels of gene expression and may be useful in treating pancreatic disorders, including T1D. [Copyright &y& Elsevier]

Abstract: α1-Antitrypsin (AAT) deficiency is a single-gene disorder in which a mutation in the AAT (approved symbol SERPINA1) gene (PI*Z) leads to misfolding of the protein, loss of the protective antiprotease effect of AAT for the lungs, and a toxic effect on hepatocytes. Optimal therapy for AAT deficiency will require a high percentage of hepatocyte transduction to be effective for liver and lung disease. Recently, rAAV genomes pseudotyped with capsids from serotypes 7 and 8 showed efficient hepatic transduction. We hypothesized that upon portal vein injection to target hepatocytes, serotype 8 would better transduce target cells and therefore express hAAT in both a greater percentage of cells and greater amounts. AAV2 and pseudotyped vectors for serotypes 1, 5, and 8 carrying the human AAT transgene were injected at 1 × 1010 particle doses into C57Bl/6 mice. Circulating hAAT from AAV2/8-injected animals showed a 2-log advantage over AAV2 and 3-log increase over AAV2/1 and 5 for the 24-week study. Most significantly, up to 40% of total liver cells stained positive for the transgene in AAV2/8 subjects while remaining primarily episomal. Therefore, pseudotyped AAV8 provides a vehicle to infect a high percentage of hepatocytes stably and thereby express therapeutic molecules to modify AAT PiZ transcripts. [Copyright &y& Elsevier]

Mouse antithymocyte globulin (mATG) prevents, as well as reverses, type 1 diabetes in NOD mice, through mechanisms involving modulation of the immunoregulatory activities of T lymphocytes. Dendritic cells (DC) play a pivotal role in the generation of T cell responses, including those relevant to the autoreactive T cells enabling type 1 diabetes. As Abs against DC are likely generated during production of mATG, we examined the impact of this preparation on the phenotype and function of DC to elucidate novel mechanisms underlying its beneficial activities. In vivo, mATG treatment transiently induced the trafficking of mature CD8(-) predominant DC into the pancreatic lymph node of NOD mice. Splenic DC from mATG-treated mice also exhibited a more mature phenotype characterized by reduced CD8 expression and increased IL-10 production. The resultant DC possessed a potent capacity to induce Th2 responses when cultured ex vivo with diabetogenic CD4(+) T cells obtained from BDC2.5 TCR transgenic mice. Cotransfer of these Th2-deviated CD4(+) T cells with splenic cells from newly diabetic NOD mice into NOD.RAG(-/-) mice significantly delayed the onset of diabetes. These studies suggest the alteration of DC profile and function by mATG may skew the Th1/Th2 balance in vivo and through such actions, represent an additional novel mechanism by which this agent provides its beneficial activities.

Infections with respiratory pathogens such as respiratory syncytial virus and rhinovirus have been associated with the development of long-term chronic airway disease. To better understand the events responsible for this clinical outcome, a rodent model of virus-induced chronic airway disease has been characterized. Upon infection with Sendai virus (parainfluenza virus type-1), Brown Norway (BN) rats develop an asthma-like clinical syndrome, while Fischer 344 (F344) rats fully recover. Our previous studies demonstrated that after infection, tumor necrosis factor-alpha (TNF-alpha) expression is substantially higher in BN rats compared to F344 rats, and this may at least partially mediate the virus-induced airway abnormalities. To investigate the underlying mechanism(s) for the increased TNF-alpha expression, the role of nuclear factor-kappaB (NF-kappaB), an important regulator of TNF-alpha gene transcription, was examined. Supershift electrophoretic mobility shift assays (EMSAs) indicate that normal F344 rats predominantly express the p65 subunit of NF-kappaB in the lungs, and virus infection temporarily increases expression of the p50 subunit. In contrast, normal BN rats have higher expression of the p50 subunit in the pulmonary tract. Upon infection, p50-subunit expression in BN rats increases to levels higher than those observed in virus-infected F344 rats. Interestingly, treatment of infected BN rats with dexamethasone at doses known to prevent virus-induced airway abnormalities increases pulmonary expression of the p65 subunit, and decreases TNF-alpha mRNA levels in the lungs. Furthermore, direct inhibition of TNF-alpha also increases pulmonary expression of p65 in virus-infected BN, but not F344, rats. Taken together, these results suggest that differential expression of NF-kappaB subunits may play an important role in the development of post-viral chronic airway abnormalities.

The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.