Search

We study the broadband emission of Mrk 501 using multiwavelength observations from 2017 to 2020 performed with a multitude of instruments, involving, among others, MAGIC, Fermi's Large Area Telescope (LAT), NuSTAR, Swift, GASP-WEBT, and the Owens Valley Radio Observatory. Mrk 501 showed an extremely low broadband activity, which may help to unravel its baseline emission. Nonetheless, significant flux variations are detected at all wave bands, with the highest occurring at X-rays and very-high-energy (VHE) γ -rays. A significant correlation (>3 σ ) between X-rays and VHE γ -rays is measured, supporting leptonic scenarios to explain the variable parts of the emission, also during low activity. This is further supported when we extend our data from 2008 to 2020, and identify, for the first time, significant correlations between the Swift X-Ray Telescope and Fermi-LAT. We additionally find correlations between high-energy γ -rays and radio, with the radio lagging by more than 100 days, placing the γ -ray emission zone upstream of the radio-bright regions in the jet. Furthermore, Mrk 501 showed a historically low activity in X-rays and VHE γ -rays from mid-2017 to mid-2019 with a stable VHE flux (>0.2 TeV) of 5% the emission of the Crab Nebula. The broadband spectral energy distribution (SED) of this 2 yr long low state, the potential baseline emission of Mrk 501, can be characterized with one-zone leptonic models, and with (lepto)-hadronic models fulfilling neutrino flux constraints from IceCube. We explore the time evolution of the SED toward the low state, revealing that the stable baseline emission may be ascribed to a standing shock, and the variable emission to an additional expanding or traveling shock.

Simões, Levy et al. use a combination of experiments and models to study how Drosophila flies steer away from dangerous heat. They discover that flies use small temperature differences between the antennae to turn clear of thermal danger; they also demonstrate that heat avoidance, a simple innate behavior, contains unexpected plasticity.

Cancer-associated fibroblast (CAF), an activated type of fibroblast, is a major stromal cell that contributes to tumor initiation and development in the tumor microenvironment (TME). We previously reported that fractionated radiation rather than acute radiation causes progressive damage to mitochondria and increases the generation of reactive oxygen species, playing an important role in the fibroblast activation in normal tissue injury. Activated fibroblasts then become CAF by interacting with tumor cells, promoting tumor growth in vivo. We here examined the chronic radiation effect on fibroblast activation. Acute radiation (<2.5 Gy) did not increase alpha-Smooth muscle actin, a CAF marker expression in healthy human cells, whereas chronic radiation (2.5 Gy) did. It can be concluded that the induction of fibroblast activation changes across acute radiation, fractionated radiation, and chronic radiation depending on the irradiation technique. This study highlights that radiation activates fibroblasts, playing a role in radiation-related tumor development via TME formation., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Blazars are active galactic nuclei (AGN) with relativistic jets whose non-thermal radiation is extremely variable on various timescales 1-3 . This variability seems mostly random, although some quasi-periodic oscillations (QPOs), implying systematic processes, have been reported in blazars and other AGN. QPOs with timescales of days or hours are especially rare 4 in AGN and their nature is highly debated, explained by emitting plasma moving helically inside the jet 5 , plasma instabilities 6,7 or orbital motion in an accretion disc 7,8 . Here we report results of intense optical and γ-ray flux monitoring of BL Lacertae (BL Lac) during a dramatic outburst in 2020 (ref.  9 ). BL Lac, the prototype of a subclass of blazars 10 , is powered by a 1.7 × 10 8  M Sun (ref.  11 ) black hole in an elliptical galaxy (distance = 313 megaparsecs (ref.  12 )). Our observations show QPOs of optical flux and linear polarization, and γ-ray flux, with cycles as short as approximately 13 h during the highest state of the outburst. The QPO properties match the expectations of current-driven kink instabilities 6 near a recollimation shock about 5 parsecs (pc) from the black hole in the wake of an apparent superluminal feature moving down the jet. Such a kink is apparent in a microwave Very Long Baseline Array (VLBA) image., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Low-dose-rate radiation exposures and their associated cancer risk are an important concern for radiation protection today. Nevertheless, there is almost no data concerning DNA damage at dose rates below 0.1 mGy/min. In this study, we investigated the formation of DNA damage repair foci under chronic low-dose-rate irradiation relative to acute high-dose-rate irradiation and assessed the magnitude of the dose-rate effect. Four human and four mouse normal fibroblast cell models from different organs were subjected to gamma irradiation at 0.096 mGy/min or 0.81 Gy/min, and dose-response curves were established for the dose range from 0.1 to 0.8 Gy. The results indicate that prolonged low-dose-rate exposures cause modestly increased levels of DNA repair foci, with a strongly supralinear dose-response relationship, where 40-70% of the radiation effect at 1 Gy was already present at the total dose of 0.1 Gy. Thus, compared to acute irradiation, low-dose-rate exposure was 6-9 times less efficient at a total dose of 0.1 Gy, and 10-20 times less efficient at 1 Gy. Comparison between cell models revealed a certain correlation between the presence of persistent, above-background foci at 48 h after irradiation and the sensitivity to low-dose-rate radiation, suggesting that repair capacity plays an important role in the cellular response to chronic irradiation. Given the findings reported here, we propose that establishing detailed dose-response curves and accounting for the repair rates of different cell models are essential steps in elucidating dose-rate effects., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

Chronic inflammation is a common denominator linking a wide range of health conditions, including tissue response to radiation exposure. This pilot study investigates whether inflammatory cytokines-interleukins IL-6, -8, -10, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor α (TNFα)-can be used as early biomarkers of radiation-induced adverse health effects in occupationally exposed individuals. The study included 33 workers externally exposed to gamma radiation from the nuclear industry with cumulated doses from 0.11 to 190 mSv and 42 non-exposed controls of comparable age and socio-economic status. IL-6, IL-8, MCP-1, TNFα and IL-10 were analyzed by enzyme-linked assay (ELISA) in blood plasma samples. Total antioxidant status (TAS) of blood plasma was determined by a colorimetric assay. The radiation-exposed and control groups measured significantly different levels of MCP-1, TNFα and IL-10. Seventy-five percent of radiation workers had either high MCP-1 levels or low IL-10 levels and 30% had all three cytokines dysregulated. Approximately 50% of workers showed upregulated antioxidant status, which appeared to compensate the pro-inflammatory cytokine shift in these individuals. In contrast, only 2% of the control subjects were found to have three dysregulated cytokines, and all of them measured within the normal TAS range. The present study may represent an important step towards the establishment of a reliable set of biomarkers for health-risk estimation in population cohorts exposed to low radiation doses., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Soluble forms of Toll-like receptors (sTLR) 2 and 4 exert negative regulatory control on membrane-bound receptor activation. The study estimates the sTLR2 and sTLR4's serum levels in type 2 diabetes (T2D) and evaluates their relationship with metabolic and inflammatory parameters., Subjects and Methods: Sixty three patients with T2D and 25 controls were enrolled. sTLR were assayed through ELISA. Inflammatory markers included Interleukin 6 (IL-6), high sensitivity C-reactive protein (hs-CRP) and tumour necrosis factor α., Results: Analysis demonstrated lower sTLR2 level in T2D than in control subjects (1.15 ± 0.65 versus 1.44 ± 0.60 ng/ml, p = .019) while sTLR4 level remained similar (0.09 ± 0.16 versus 0.07 ± 0.12 ng/ml, p > .05) despite higher IL-6 (2.65 ± 2.46 versus 1.44 ± 0.22 pg/ml, p = .005) and hs-CRP (2.79 ± 2.89 versus 0.70 ± 0.89 mg/l, p < .001) concentrations. Neither sTLR correlated with BMI, HbA1c, plasma glucose and analysed cytokines (p > .05)., Conclusion: The sTLR2 serum level in T2D patients was reduced despite elevated inflammatory parameters.

Background: Interleukin-18 (IL-18) is an inflammatory cytokine found to be elevated in obesity, metabolic syndrome and type 2 diabetes (T2D) as a part of the chronic low-grade inflammatory process in these states. The aim of the study was to evaluate the interleukin level in patients with latent autoimmune diabetes of the adults (LADA) in comparison to that in T2D subjects., Materials and Methods: IL-18 was analyzed through enzyme-linked immunosorbent assay in 76 participants with T2D and 24 with LADA and 14 control subjects. Evaluation was also carried out in body mass index (BMI)- and glycemic control-matched diabetic patients., Results: The serum concentration of IL-18 was higher in patients with T2D (389.04 ± 203.44 pg/mL) and LADA (327.04 ± 144.48 pg/mL) than that in control subjects (219.88 ± 91.03 pg/mL), P  < 0.05. However, it was not significantly different between both diabetic groups ( P  = 0.255) despite higher IL-6 (4.78 ± 5.84 vs 1.79 ± 0.96 pg/mL, P  < 0.001) and hs-CRP (2.60 ± 1.70 vs 1.29 ± 1.20 mg/L, P  = 0.002) level in T2D patients. The results were persistent in BMI-matched subjects with diabetes (IL-18 = 403.48 ± 226.32 vs 329.30 ± 146.30 pg/mL, respectively for T2D and LADA, P  = 0.391). The correlations in T2D group concerning HDL cholesterol ( r  = -0.377, P  = 0.001), postprandial glucose ( r  = 0.244, P  = 0.043), IL-6 ( r  = 0.398, P  < 0.001) and hs-CRP ( r  = 0.427, P  = 0.001) were not confirmed in LADA and control subjects., Conclusion: The IL-18 serum level was higher in T2D and LADA than that in control subjects, but did not differ between both diabetic groups, even when they were BMI matched. Correlations with lipid, glycemic and inflammatory parameters were present in T2D only., (© 2018 The authors.)

Purpose Radiation exposure, besides the risk of cancer, may also increase the risk of non-cancer diseases, including cardiovascular disease (CVD). This study investigates whether the soluble form of the ST2 receptor (sST2), an emerging prognostic marker in patients with CVD, can be used to monitor the CVD risk in individuals occupationally exposed to radiation. Materials and methods sST2 in blood plasma from 69 individuals, 45 workers from the nuclear industry and 24 controls, was analyzed using enzyme-linked assay (ELISA). Total antioxidant status (TAS) of blood plasma and levels of reactive oxygen species (ROS) in lymphocytes were determined by colorimetric and fluorescence assays. Results The data suggest a 5-fold increase in the number of subjects with sST2 levels above the clinical threshold and a 10-fold increase in the number of subjects with TAS levels outside the reference range in the exposed group when compared to the group of non-exposed individuals. The strongest up-regulation of TAS was measured in the group of younger workers with cumulative doses not exceeding 50 mSv. Conclusion The present study may represent an initial step towards the establishment of sST2 as a biomarker for CVD risk estimation in the context of radiation exposure.

Neuronally coexpressed ELAV/Hu proteins comprise a family of highly related RNA binding proteins which bind to very similar cognate sequences. How this redundancy is linked to in vivo function and how gene-specific regulation is achieved have not been clear. Analysis of mutants in Drosophila ELAV/Hu family proteins ELAV, FNE, and RBP9 and of genetic interactions among them indicates that they have mostly independent roles in neuronal development and function but have converging roles in the regulation of synaptic plasticity. Conversely, ELAV, FNE, RBP9, and human HuR bind ELAV target RNA in vitro with similar affinities. Likewise, all can regulate alternative splicing of ELAV target genes in nonneuronal wing disc cells and substitute for ELAV in eye development upon artificially increased expression; they can also substantially restore ELAV's biological functions when expressed under the control of the elav gene. Furthermore, ELAV-related Sex-lethal can regulate ELAV targets, and ELAV/Hu proteins can interfere with sexual differentiation. An ancient relationship to Sex-lethal is revealed by gonadal expression of RBP9, providing a maternal fail-safe for dosage compensation. Our results indicate that highly related ELAV/Hu RNA binding proteins select targets for mRNA processing through alteration of their expression levels and subcellular localization but only minimally by altered RNA binding specificity., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

ELAV (embryonic lethal/abnormal visual system)/Hu proteins comprise a family of highly related neuronal RBPs (RNA-binding proteins) involved in many aspects of mRNA processing. Although they bind to highly similar short sequence motifs, they have acquired diverse functions suggesting that cellular signalling is important for their functional diversification. Indeed, ELAV/Hu proteins harbour many phosphorylatable amino acids. In the present article, we review our current knowledge about phosphorylation of ELAV/Hu proteins and how phosphorylation affects cellular localization of ELAV/Hu proteins and their binding to RNA.

The protein coding sequence of most eukaryotic genes (exons) is interrupted by non-coding parts (introns), which are excised in a process termed splicing. To generate a mature messenger RNA (mRNA) hundreds of combinatorial protein-protein and RNA-protein interactions are required to splice out often very large introns with high fidelity and accuracy. Inherent to splicing is the use of alternative splice sites generating immense proteomic diversity from a limited number of genes. In humans, alternative splicing is a major mode of regulating gene expression, occurs in over 90% of genes and is particularly abundant in the brain. Only recently, it has been recognized that the complexity of the splicing process makes it susceptible to interference by various xenobiotics. These compounds include antineoplastic substances, commonly used drugs and food supplements and cause a spectrum of effects ranging from deleterious inhibition of general splicing to highly specific modifications of alternative splicing affecting only certain genes. Alterations in splicing have been implicated in numerous diseases such as cancer and neurodegeneration. Splicing regulation plays an important role in the execution of programmed cell death. The switch between anti- and pro-apoptotic isoforms by alternative splice site selection and misregulation of a number of splicing factors impacts on cell survival and disease. Here, our current knowledge is summarized on compounds interfering with general and alternative splicing and of the current methodology to study changes in these processes relevant to the field of toxicology and future risk assessments., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The study aimed to differentiate the factors triggering porphyria cutanea tarda, paying special attention to the presumed role of hepatitis C virus infection. In a representative Bulgarian contingent, HCV-antibodies were identified using ELISA II and immunoblot. Seropositivity was significantly higher (p < 0.01) in the sporadic form (36 out of 57 patients; 63.2%) compared with the familiar form (4 out of 20 subjects; 20%). Alcohol abuse was the most common factor preceding the expression of open porphyria both in the sporadic and the familiar forms. In 10 sporadic cases, no precipitating factors were observed, except for the fact that they were anti-HCV positive. In another 2 anti-HCV positive patients, porphyria cutanea tarda was preceded by blood transfusions. Renewed consumption of alcohol after successful treatment was a common reason for relapse, but relapses were most frequent in anti-HCV positive patients (35 relapses in 12 patients), in whom other promoting factors were absent. Analysis of triggering factors shows that most probably hepatitis C virus infection could contribute to the expression of porphyria cutanea tarda and the association of both diseases is not coincidental.