Constraints on Quasar Lifetimes and Beaming from the HeII Lyman-alpha Forest

We show that comparisons of HeII Lyman-alpha forest lines of sight to nearby quasar populations can strongly constrain the lifetimes and emission geometry of quasars. By comparing the HeII and HI Lyman-alpha forests along a particular line of sight, one can trace fluctuations in the hardness of the radiation field (which are driven by fluctuations in the HeII ionization rate). Because this high-energy background is highly variable - thanks to the rarity of the bright quasars that dominate it and the relatively short attenuation lengths of these photons - it is straightforward to associate features in the radiation field with their source quasars. Here we quantify how finite lifetimes and beamed emission geometries affect these expectations. Finite lifetimes induce a time delay that displaces the observed radiation peak relative to the quasar. For beamed emission, geometry dictates that sources invisible to the observer can still create a peak in the radiation field. We show that both these models produce substantial populations of "bare" peaks (without an associated quasar) for reasonable parameter values (lifetimes ~10^6-10^8 yr and beaming angles <90 degrees). A comparison to existing quasar surveys along two HeII Lyman-alpha forest lines of sight rules out isotropic emission and infinite lifetime at high confidence; they can be accommodated either by moderate beaming or lifetimes ~10^7-10^8 yr. We also show that the distribution of radial displacements between peaks and their quasars can unambiguously distinguish these two models, although larger statistical samples are needed.Comment: submitted to ApJ, 8 pages, 2 figure

HeII Reionization and its Effect on the IGM

Observations of the intergalactic medium (IGM) suggest that quasars reionize HeII in the IGM at z ~ 3. We have run a set of 190 and 430 comoving Mpc simulations of HeII being reionized by quasars to develop an understanding of the nature of HeII reionization and its potential impact on observables. We find that HeII reionization heats regions in the IGM by as much as 25,000 K above the temperature that is expected otherwise, with the volume-averaged temperature increasing by ~ 12,000 K and with large temperature fluctuations on ~ 50 Mpc scales. Much of the heating occurs far from QSOs by hard photons. We find a temperature-density equation of state of gamma -1 ~ 0.3 during HeII reionization, but with a wide dispersion in this relation having sigma ~ 10^4 K. HeII reionization by the observed population of quasars cannot produce an inverted relation (gamma - 1 < 0). Our simulations are consistent with the observed evolution in the mean transmission of the HeII Ly-alpha forest. We argue that the heat input due to HeII reionization is unable to cause the observed depression at z = 3.2 in the HI Ly-alpha forest opacity as has been suggested. We investigate how uncertainties in the properties of QSOs and of HeII Lyman-limit systems influence our predictions.Comment: 19 pages, 15 figures, plus 9 pages of Appendix. accepted by Ap

FIRST-2MASS Red Quasars: Transitional Objects Emerging from the Dust

We present a sample of 120 dust-reddened quasars identified by matching radio sources detected at 1.4 GHz in the FIRST survey with the near-infrared 2MASS catalog and color-selecting red sources. Optical and/or near-infrared spectroscopy provide broad wavelength sampling of their spectral energy distributions that we use to determine their reddening, characterized by E(B-V). We demonstrate that the reddening in these quasars is best-described by SMC-like dust. This sample spans a wide range in redshift and reddening (0.1 < z < 3, 0.1 < E(B-V) < 1.5), which we use to investigate the possible correlation of luminosity with reddening. At every redshift, dust-reddened quasars are intrinsically the most luminous quasars. We interpret this result in the context of merger-driven quasar/galaxy co-evolution where these reddened quasars are revealing an emergent phase during which the heavily obscured quasar is shedding its cocoon of dust prior to becoming a "normal" blue quasar. When correcting for extinction, we find that, depending on how the parent population is defined, these red quasars make up < 15-20% of the luminous quasar population. We estimate, based on the fraction of objects in this phase, that its duration is 15-20% as long as the unobscured, blue quasar phase.Comment: 21 pages, 17 figures plus a spectral atlas. Accepted for publication in the Astrophysical Journa

The impact of control strategies and behavioural changes on the elimination of Ebola from Lofa County, Liberia.

The Ebola epidemic in West Africa was stopped by an enormous concerted effort of local communities and national and international organizations. It is not clear, however, how much the public health response and behavioural changes in affected communities, respectively, contributed to ending the outbreak. Here, we analyse the epidemic in Lofa County, Liberia, lasting from March to November 2014, by reporting a comprehensive time line of events and estimating the time-varying transmission intensity using a mathematical model of Ebola transmission. Model fits to the epidemic show an alternation of peaks and troughs in transmission, consistent with highly heterogeneous spread. This is combined with an overall decline in the reproduction number of Ebola transmission from early August, coinciding with an expansion of the local Ebola treatment centre. We estimate that healthcare seeking approximately doubled over the course of the outbreak, and that isolation of those seeking healthcare reduced their reproduction number by 62% (mean estimate, 95% credible interval (CI) 59-66). Both expansion of bed availability and improved healthcare seeking contributed to ending the epidemic, highlighting the importance of community engagement alongside clinical intervention.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'

Calibration of myocardial T2 and T1 against iron concentration.

BACKGROUND: The assessment of myocardial iron using T2* cardiovascular magnetic resonance (CMR) has been validated and calibrated, and is in clinical use. However, there is very limited data assessing the relaxation parameters T1 and T2 for measurement of human myocardial iron. METHODS: Twelve hearts were examined from transfusion-dependent patients: 11 with end-stage heart failure, either following death (n=7) or cardiac transplantation (n=4), and 1 heart from a patient who died from a stroke with no cardiac iron loading. Ex-vivo R1 and R2 measurements (R1=1/T1 and R2=1/T2) at 1.5 Tesla were compared with myocardial iron concentration measured using inductively coupled plasma atomic emission spectroscopy. RESULTS: From a single myocardial slice in formalin which was repeatedly examined, a modest decrease in T2 was observed with time, from mean (± SD) 23.7 ± 0.93 ms at baseline (13 days after death and formalin fixation) to 18.5 ± 1.41 ms at day 566 (p<0.001). Raw T2 values were therefore adjusted to correct for this fall over time. Myocardial R2 was correlated with iron concentration [Fe] (R2 0.566, p<0.001), but the correlation was stronger between LnR2 and Ln[Fe] (R2 0.790, p<0.001). The relation was [Fe] = 5081•(T2)-2.22 between T2 (ms) and myocardial iron (mg/g dry weight). Analysis of T1 proved challenging with a dichotomous distribution of T1, with very short T1 (mean 72.3 ± 25.8 ms) that was independent of iron concentration in all hearts stored in formalin for greater than 12 months. In the remaining hearts stored for <10 weeks prior to scanning, LnR1 and iron concentration were correlated but with marked scatter (R2 0.517, p<0.001). A linear relationship was present between T1 and T2 in the hearts stored for a short period (R2 0.657, p<0.001). CONCLUSION: Myocardial T2 correlates well with myocardial iron concentration, which raises the possibility that T2 may provide additive information to T2* for patients with myocardial siderosis. However, ex-vivo T1 measurements are less reliable due to the severe chemical effects of formalin on T1 shortening, and therefore T1 calibration may only be practical from in-vivo human studies

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Living Under Coronavirus and Injecting Drugs in Bristol (LUCID-B): a qualitative study of experiences of COVID-19 among people who inject drugs

BACKGROUND: : People who inject drugs (PWID) are a high-risk group for COVID-19 transmission and serious health consequences. Restrictions imposed in the UK in response to the pandemic led to rapid health and housing service alterations. We aimed to examine PWID experiences of: 1) challenges relating to the COVID-19 public health measures; 2) changes to opioid substitution therapy (OST) and harm reduction services; and 3) perceived effects of COVID-19 on drug use patterns and risk behaviour. METHODS: : Telephone semi-structured interviews were conducted with 28 PWID in Bristol, Southwest of England. Analysis followed a reflexive thematic analysis. RESULTS: : Concern about COVID-19 and adherence to public health guidance varied. Efforts made by services to continue providing support during the pandemic were appreciated and some changes were preferred, such as less frequent OST collection, relaxation of supervised consumption and needle and syringe programmes (NSP) home delivery. However, remote forms of contact were highlighted as less beneficial and more difficult to engage with than in-person contact. Public health guidance advising people to ‘stay home’ led to increased isolation, boredom, and time to ruminate which impacted negatively on mental health. Lockdown restrictions directly impacted on sources of income and routine. Changes in drug use were explained as a consequence of isolation and fewer interactions with peers, problems accessing drugs, reduced drug purity and reduced financial resources. CONCLUSION: : This study captures the significant impacts and challenges of the COVID-19 pandemic on the lives of PWID. While rapid adaptations to service delivery to help mitigate the risks of COVID-19 were appreciated and some changes such as relaxation of supervised daily OST consumption were viewed positively, barriers to access need further attention. Going forwards there may be opportunities to harness the positive aspects of some changes to services

Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor

Glucocorticoid (GC) receptors (GRs) have profound anti-survival effects on human small cell lung cancer (SCLC). To explore the basis of these effects, protein partners for GRs were sought using a yeast two-hybrid screen. We discovered a novel gene, FAM33A, subsequently identified as a SKA1 partner and involved in mitosis, and so renamed Ska2. We produced an anti-peptide antibody that specifically recognized full-length human SKA2 to measure expression in human cell lines and tissues. There was a wide variation in expression across multiple cell lines, but none was detected in the liver cell line HepG2. A xenograft model of human SCLC had intense staining and archival tissue revealed SKA2 in several human lung and breast tumours. SKA2 was found in the cytoplasm, where it co-localized with GR, but nuclear expression of SKA2 was seen in breast tumours. SKA2 overexpression increased GC transactivation in HepG2 cells while SKA2 knockdown in A549 human lung epithelial cells decreased transactivation and prevented dexamethasone inhibition of proliferation. GC treatment decreased SKA2 protein levels in A549 cells, as did Staurosporine, phorbol ester and trichostatin A; all agents that inhibit cell proliferation. Overexpression of SKA2 potentiated the proliferative response to IGF-I exposure, and knockdown with shRNA caused cells to arrest in mitosis. SKA2 has recently been identified in HeLa S3 cells as part of a complex, which is critical for spindle checkpoint silencing and exit from mitosis. Our new data show involvement in cell proliferation and GC signalling, with implications for understanding how GCs impact on cell fate

Wind and shipping influences on sea currents around an inshore fish farm in a heavily contested Mediterranean embayment

Marine aquaculture expansion will continue to be challenged by a lack of space in areas of the marine domain that can support aquaculture, due to competition from other maritime activities vying for the same spaces. This research attempts to characterise those natural and anthropogenic forces that influence and drive sea currents measured over a 16-month period around a nearshore fish farm located within a busy multiple-use bay in the central Mediterranean Sea. Evidence from a concomitant two-year-long meteorological dataset reveals the occurrence of variable winds that result in a dominant and perpetual forcing on near-surface current magnitude and direction. The correlation coefficient between wind and sea currents decreases with increasing depth and hourly time lag. Moreover, the observed water level variations were more related to meteorological forcing factors than to tidal influences recorded at the mouth of the bay. However, intermittently observed water current values could not be exclusively explained by atmospheric forcing variables when the relationship between in-situ measurements and sea current values predicted by the hydrodynamic-wave model (Marine Forecasting System) was analysed. Consequently, this lack of correlation spurred further analysis, which revealed that relevant water current disturbances, particularly in near-surface sea currents, corresponded to 131 different Automatic Identification System (AIS) records of vessels. These vessels included bunkering barges, pilot boats and dredging vessels operating and navigating within a 650 m radius from the fish farm and during a 10-min window. This study thus provides evidence for natural and anthropogenically-derived influences on local fish farm-scale hydrodynamics that have important implications for the effective and sustainable development of aquaculture within a marine spatial context, especially in congested, multi-use environments

Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition

Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression