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Full list of authors: Acciari, V. A.; Ansoldi, S.; Antonelli, L. A.; Arbet Engels, A. ; Artero, M.; Asano, K.; Baack, D.; Babić, A.; Baquero, A.; Barres de Almeida, U.; Barrio, J. A.; Batković, I.; Becerra González, J.; Bednarek, W.; Bellizzi, L.; Bernardini, E.; Bernardos, M.; Berti, A.; Besenrieder, J.; Bhattacharyya, W.; Bigongiari, C.; Biland, A.; Blanch, O.; Bošnjak, Ž.; Busetto, G.; Carosi, R.; Ceribella, G.; Cerruti, M.; Chai, Y.; Chilingarian, A.; Cikota, S.; Colak, S. M.; Colombo, E.; Contreras, J. L.; Cortina, J.; Covino, S.; D'Amico, G.; D'Elia, V.; da Vela, P.; Dazzi, F.; de Angelis, A.; de Lotto, B.; Delfino, M.; Delgado, J.; Delgado Mendez, C.; Depaoli, D.; Pierro, F. Di; Venere, L. Di; Do Souto Espiñeira, E.; Dominis Prester, D.; Donini, A.; Dorner, D.; Doro, M.; Elsaesser, D.; Fallah Ramazani, V.; Fattorini, A.; Ferrara, G.; Fonseca, M. V.; Font, L.; Fruck, C.; Fukami, S.; García López, R. J.; Garczarczyk, M.; Gasparyan, S.; Gaug, M.; Giglietto, N.; Giordano, F.; Gliwny, P.; Godinović, N.; Green, J. G.; Green, D.; Hadasch, D.; Hahn, A.; Heckmann, L.; Herrera, J.; Hoang, J.; Hrupec, D.; Hütten, M.; Inada, T.; Inoue, S.; Ishio, K.; Iwamura, Y.; Jiménez, I.; Jormanainen, J.; Jouvin, L.; Kajiwara, Y.; Karjalainen, M.; Kerszberg, D.; Kobayashi, Y.; Kubo, H.; Kushida, J.; Lamastra, A.; Lelas, D.; Leone, F.; Lindfors, E.; Lombardi, S.; Longo, F.; López-Coto, R.; López-Moya, M.; López-Oramas, A.; Loporchio, S.; Machado de Oliveira Fraga, B.; Maggio, C.; Majumdar, P.; Makariev, M.; Mallamaci, M.; Maneva, G.; Manganaro, M.; Mannheim, K.; Maraschi, L.; Mariotti, M.; Martínez, M.; Mazin, D.; Menchiari, S.; Mender, S.; Mićanović, S.; Miceli, D.; Miener, T.; Minev, M.; Miranda, J. M.; Mirzoyan, R.; Molina, E.; Moralejo, A.; Morcuende, D.; Moreno, V.; Moretti, E.; Neustroev, V.; Nigro, C.; Nilsson, K.; Nishijima, K.; Noda, K.; Nozaki, S.; Ohtani, Y.; Oka, T.; Otero-Santos, J.; Paiano, S.; Palatiello, M.; Paneque, D.; Paoletti, R.; Paredes, J. M.; Pavletić, L.; Peñil, P.; Perennes, C.; Persic, M.; Prada Moroni, P. G.; Prandini, E.; Priyadarshi, C.; Puljak, I.; Rhode, W.; Ribó, M.; Rico, J.; Righi, C.; Rugliancich, A.; Saha, L.; Sahakyan, N.; Saito, T.; Sakurai, S.; Satalecka, K.; Saturni, F. G.; Schleicher, B.; Schmidt, K.; Schweizer, T.; Sitarek, J.; Šnidarić, I.; Sobczynska, D.; Spolon, A.; Stamerra, A.; Strom, D.; Strzys, M.; Suda, Y.; Surić, T.; Takahashi, M.; Tavecchio, F.; Temnikov, P.; Terzić, T.; Teshima, M.; Tosti, L.; Truzzi, S.; Tutone, A.; Ubach, S.; van Scherpenberg, J.; Vanzo, G.; Vazquez Acosta, M.; Ventura, S.; Verguilov, V.; Vigorito, C. F.; Vitale, V.; Vovk, I.; Will, M.; Wunderlich, C.; Zarić, D.; Bissaldi, E.; Bonnoli, G.; Cutini, S.; D'Ammando, F.; Nabizadeh, A.; Marchini, A.; Orienti, M.; MAGIC Collaboration., We report here on the first multiwavelength (MWL) campaign on the blazar TXS 1515-273, undertaken in 2019 and extending from radio to very-high-energy gamma-rays (VHE). Up until now, this blazar had not been the subject of any detailed MWL observations. It has a rather hard photon index at GeV energies and was considered a candidate extreme high-synchrotron-peaked source. MAGIC observations resulted in the first-time detection of the source in VHE with a statistical significance of 7.6σ. The average integral VHE flux of the source is 6 ± 1 per cent of the Crab nebula flux above 400 GeV. X-ray coverage was provided by Swift-XRT, XMM-Newton, and NuSTAR. The long continuous X-ray observations were separated by ∼9 h, both showing clear hour scale flares. In the XMM-Newton data, both the rise and decay time-scales are longer in the soft X-ray than in the hard X-ray band, indicating the presence of a particle cooling regime. The X-ray variability time-scales were used to constrain the size of the emission region and the strength of the magnetic field. The data allowed us to determine the synchrotron peak frequency and classify the source as a flaring high, but not extreme synchrotron-peaked object. Considering the constraints and variability patterns from the X-ray data, we model the broad-band spectral energy distribution. We applied a simple one-zone model, which could not reproduce the radio emission and the shape of the optical emission, and a two-component leptonic model with two interacting components, enabling us to reproduce the emission from radio to VHE band. © 2021 The Author(s) Published by Oxford University Press on behalf of Royal Astronomical Society., The financial support of the German BMBF, MPG, and HGF; the Italian INFN and INAF; the Swiss National Fund SNF; the ERDF under the Spanish Ministerio de Ciencia e Innovacion (MICINN) (FPA201787859-P, FPA2017-85668-P, FPA2017-82729-C6-5-R, FPA201790566-REDC, PID2019-104114RB-C31, PID2019-104114RB-C32, PID2019-105510GB-C31, PID2019-107847RB-C41, PID2019107847RB-C42, PID2019-107847RB-C44, PID2019-107988GBC22); the Indian Department of Atomic Energy; the Japanese ICRR, the University of Tokyo, JSPS, and MEXT; the Bulgarian Ministry of Education and Science, National RI Roadmap Project DO1268/16.12.2019 and the Academy of Finland grant nr. 317637 and 320045 are gratefully acknowledged. This work was also supported by the Spanish Centro de Excelencia `Severo Ochoa' SEV-20160588, SEV-2017-0709 and CEX2019-000920-S, and `Maria de Maeztu' CEX2019-000918-M, the Unidad de Excelencia `Maria de Maeztu' MDM-2015-0509-18-2 and the `la Caixa' Foundation (fellowshipLCF/BQ/PI18/11630012), by the Croatian Science Foundation (HrZZ) Project IP-2016-06-9782 and the University of Rijeka Project 13.12.1.3.02, by the DFG Collaborative Research Centers SFB823/C4 and SFB876/C3, the Polish National Research Centre grant UMO-2016/22/M/ST9/00382 and by the Brazilian MCTIC, CNPq, and FAPERJ. The Fermi-LAT Collaboration acknowledges generous ongoing support from a number of agencies and institutes that have supported both the development and the operation of the LAT as well as scientific data analysis. These include the National Aeronautics and Space Administration and the Department of Energy in the United States, theCommissariat à l'Energie Atomique and the Centre National de la Recherche Scientifique/Institut National de Physique Nucleaire et de Physique des Particules in France, the Agenzia Spaziale Italiana and the Istituto Nazionale di Fisica Nucleare in Italy, the Ministry of Education, Culture, Sports, Science and Technology (MEXT), High Energy Accelerator Research Organization (KEK) and Japan Aerospace Exploration Agency (JAXA) in Japan, and the K. A. Wallenberg Foundation, the Swedish Research Council and the Swedish National Space Board in Sweden. Additional support for science analysis during the operations phase from the following agencies is also gratefully acknowledged: the Istituto Nazionale di Astrofisica in Italy and the Centre National d'Etudes Spatiales in France.

The RASopathies are a family of clinically related disorders caused by mutations affecting genes participating in the RAS-MAPK signaling cascade. Among them, Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are allelic conditions principally associated with dominant mutations in PTPN11, which encodes the nonreceptor SH2 domain-containing protein tyrosine phosphatase SHP2. Individual PTPN11 mutations are specific to each syndrome and have opposite consequences on catalysis, but all favor SHP2's interaction with signaling partners. Here, we report on a subject with NS harboring biallelic variants in PTPN11. While the former (p.Leu261Phe) had previously been reported in NS, the latter (p.Thr357Met) is a novel change impairing catalysis. Members of the family carrying p.Thr357Met, however, did not show any obvious feature fitting NSML or within the RASopathy phenotypic spectrum. A major impact of this change on transcript processing and protein stability was excluded. These findings further support the view that NSML cannot be ascribed merely to impaired SHP2's catalytic activity and suggest that PTPN11 mutations causing this condition act through an alternative dominant mechanism.

Uterine and cervical size of Holstein dairy cows is reported among reasons for a decline in dairy cow fertility. Therefore, the objectives of this study were to (a) determine whether size of the cervix and uterus at 4 weeks postpartum impacted subsequent fertility at first service in Jersey cattle, (b) determine whether progesterone level at 4 weeks postpartum impacted cyclicity and (c) the association of the presence of corpus luteum and uterus and cervix size. Body condition scores at calving, presence of postpartum diseases, parity number and milk weights were taken from lactating Jersey dairy cows (N = 147) for 28 days postpartum. During the fourth week postpartum, a blood sample was obtained for progesterone concentration, and transrectal ultrasonography was performed by a high-resolution ultrasound machine to determine cervical and uterine horn diameter, as well as ovarian structures measurements. Correcting for parity number, BCS at calving, presence of diseases and milk yield, cows with a cervix >2.54 ± 0.63 cm and uterine horn >2.25 ± 0.59 cm were less likely to become pregnant at first service (p = .04 and p = .003, respectively). The cows with larger cervix had a trend to be less likely to have a corpus luteum present at the 4th week of lactation (p = .067). Cows with larger uterine horn size were less likely to have a corpus luteum present at the 4th week of lactation (p = .015). It is concluded that a larger cervix and/or uterus during the postpartum was associated negatively with fertility and cyclicity in Jersey cows.

Hepatocellular carcinomas (HCCs) usually arise from chronic liver disease (CLD). Precancerous cells in chronically inflamed environments may be ‘epigenetically primed’, sensitising them to oncogenic transformation. We investigated whether epigenetic priming in CLD may affect HCC outcomes by influencing the genomic and transcriptomic landscapes of HCC. Analysis of DNA methylation arrays from 10 paired CLD‐HCC identified 339 shared dysregulated CpG sites and 18 shared differentially methylated regions compared with healthy livers. These regions were associated with dysregulated expression of genes with relevance in HCC, including ubiquitin D (UBD), cytochrome P450 family 2 subfamily C member 19 (CYP2C19) and O‐6‐methylguanine‐DNA methyltransferase (MGMT). Methylation changes were recapitulated in an independent cohort of nine paired CLD‐HCC. High CLD methylation score, defined using the 124 dysregulated CpGs in CLD and HCC in both cohorts, was associated with poor survival, increased somatic genetic alterations and TP53 mutations in two independent HCC cohorts. Oncogenic transcriptional and methylation dysregulation is evident in CLD and compounded in HCC. Epigenetic priming in CLD sculpts the transcriptional landscape of HCC and creates an environment favouring the acquisition of genetic alterations, suggesting that the extent of epigenetic priming in CLD could influence disease outcome., Precancerous cells in chronically diseased livers (CLD) may be ‘epigenetically primed’, sensitising them to oncogenic transformation. We investigated whether epigenetic priming in CLD also affects hepatocellular carcinoma (HCC) outcome. We found this sculpts the HCC transcriptome, creating an environment favouring the acquisition of genetic alterations. Our DNA methylation‐based score shows the extent to which epigenetic priming occurs in CLD and influences HCC outcome.