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We present a comprehensive multi-messenger study of NGC 1068, the prototype Seyfert II galaxy associated with high-energy neutrinos following a detection by the IceCube Neutrino Observatory. Various aspects of the source, including its nuclear activity, jet, outflow and starburst region, are analysed in detail using a multi-wavelength approach and relevant luminosities are derived. We then explore its γ-ray and neutrino emissions and investigate the potential mechanisms underlying these phenomena and their relations with the different astrophysical components to try to understand which is responsible for the IceCube neutrinos. By first using simple order-of-magnitude arguments and then applying specific theoretical models, we infer that only the region close to the accretion disk around the supermassive black hole has the right density of both the X-ray photons needed to provide the targets for protons to sustain neutrino production and the optical/infrared photons required to absorb the associated, but unobserved, γ-rays. We conclude by highlighting ongoing efforts to constrain a possible broad connection between neutrinos and active galactic nuclei, as well as future synergies between astronomical and neutrino facilities. Observations of the galaxy NGC 1068 in different wavebands are brought together in a multi-messenger case study, exploring the potential origin and mechanisms responsible for the recently detected neutrino emission from this source.

Bursting at high redshift Two groups present redshift determinations and other spectroscopic data for the γ-ray burst GRB 090423 — now the earliest and most distant astronomical object known. Salvaterra et al . report its initial detection with the Swift satellite on 23 April 2009, and a redshift determination with the Telescopio Nazionale Galileo on La Palma 14 hours after the burst, obtaining z ≈ 8.1. Tanvir et al . used the United Kingdom Infrared Telescope, Hawaii, from about 20 minutes after the burst and arrive at z ≈ 8.2. The previous highest redshift known for any object was z = 6.96 for a Lyman-α emitting galaxy. These measurements imply that massive stars were being produced and were dying as γ-ray bursts as early as about 600 million years after the Big Bang, and that their properties are very similar to those stars producing γ-ray bursts 10 billion years later. Long-duration γ-ray bursts (GRBs), thought to result from the explosions of certain massive stars, are bright enough that some of them should be observable out to redshifts of z > 20. So far, the highest redshift measured for any object has been z = 6.96, for a Lyman-α emitting galaxy. Here, and in an accompanying paper, GRB 090423 is reported to lie at a redshift of z ≈ 8.2, implying that massive stars were being produced and dying as GRBs approximately 620 million years after the Big Bang. Gamma-ray bursts (GRBs) are produced by rare types of massive stellar explosion. Their rapidly fading afterglows are often bright enough at optical wavelengths that they are detectable at cosmological distances. Hitherto, the highest known redshift for a GRB was z = 6.7 (ref. 1 ), for GRB 080913, and for a galaxy was z = 6.96 (ref. 2 ). Here we report observations of GRB 090423 and the near-infrared spectroscopic measurement of its redshift, z = . This burst happened when the Universe was only about 4 per cent of its current age 3 . Its properties are similar to those of GRBs observed at low/intermediate redshifts, suggesting that the mechanisms and progenitors that gave rise to this burst about 600,000,000 years after the Big Bang are not markedly different from those producing GRBs about 10,000,000,000 years later.

In Archaea, the importance of the proteasome system for basic biological processes is only poorly understood. Proteasomes were partially purified from Halobacterium by native gradient density ultracentrifugation. The peptidase activity profiles showed that the 20S proteasome accumulation is altered depending on the physiological state of the cells. The amount of active 20S particles increases in Halobacterium cells as a response to thermal and low salt stresses. In the same conditions, Northern experiments showed a positive transcriptional regulation of the alpha and beta proteasome subunits as well as of the two proteasome regulatory ATPases, PANA and PANB. Co-immunoprecipitation experiments demonstrated the existence of a physical interaction between the two P roteasome A ctivating N ucleotidase (PAN) proteins in cell extracts. Thus, a direct regulation occurs on the PAN–proteasome components to adjust the protein degradation activity to growth and environmental constraints. These results also indicate that, in extreme halophiles, proteasome mediated proteolysis is an important aspect of low salt stress response. The tri-peptide vinyl sulfone inhibitor NLVS was used in cell cultures to study the in vivo function of proteasome in Halobacterium. The chemical inhibition of proteasomes was measured in the cellular extracts. It has no effect on cell growth and mortality under normal growth conditions as well as under heat shock conditions. These results suggest that the PAN activators or other proteases compensate for loss of proteasome activity in stress conditions.

We present a comprehensive multi-messenger study of NGC 1068, the prototype Seyfert II galaxy recently associated with high-energy IceCube neutrinos. Various aspects of the source, including its nuclear activity, jet, outflow, and starburst region, are analyzed in detail using a multi-wavelength approach and relevant luminosities are derived. We then explore its gamma-ray and neutrino emissions and investigate potential mechanisms underlying these phenomena and their relations with the different astrophysical components to try to understand which one is responsible for the IceCube neutrinos. By first using simple order-of-magnitude arguments and then applying specific theoretical models, we infer that only the region close to the accretion disc around the supermassive black hole has both the right density of X-ray photons needed to provide the targets for protons to sustain neutrino production and of optical/infrared photons required to absorb the associated but unobserved gamma rays. We conclude by highlighting ongoing efforts to constrain a possible broad connection between neutrinos and active galactic nuclei, as well as future synergies between astronomical and neutrino facilities.

Twelve populations of Escherichia coli evolved in and adapted to a glucose-limited environment from a common ancestor. We used two-dimensional protein electrophoresis to compare two evolved clones, isolated from independently derived populations after 20,000 generations. Exceptional parallelism was detected. We compared the observed changes in protein expression profiles with previously characterized global transcription profiles of the same clones; this is the first time such a comparison has been made in an evolutionary context where these changes are often quite subtle. The two methodologies exhibited some remarkable similarities that highlighted two different levels of parallel regulatory changes that were beneficial during the evolution experiment. First, at the higher level, both methods revealed extensive parallel changes in the same global regulatory network, reflecting the involvement of beneficial mutations in genes that control the ppGpp regulon. Second, both methods detected expression changes of identical gene sets that reflected parallel changes at a lower level of gene regulation. The protein profiles led to the discovery of beneficial mutations affecting the malT gene, with strong genetic parallelism across independently evolved populations. Functional and evolutionary analyses of these mutations revealed parallel phenotypic decreases in the maltose regulon expression and a high level of polymorphism at this locus in the evolved populations.

Intermediate- or low-risk patients with severe aortic stenosis were excluded from earlier transcatheter aortic valve implantation (TAVI) clinical trials; however, they are already being treated by TAVI despite a lack of data regarding the safety and efficacy in these patients. We aimed to assess the safety and efficacy of TAVI in patients at intermediate or low risk. Patients undergoing TAVI during 2008 to 2014 were included into a shared database (n = 1,327). Procedural outcomes were adjudicated according to Valve Academic Research Consortium 2 definitions. Patients were stratified according to their Society of Thoracic Surgeons (STS) score into 3 groups: high (STS ≥8, n = 223, 17%), intermediate (STS 4 to 8; n = 496, 38%), or low risk (STS <4; n = 576, 45%). Low-risk patients were significantly younger and more likely to be men compared to intermediate- and high-risk patients. Baseline characteristics differed significantly between the groups with a gradual increase in the rates of previous bypass surgery, stroke, peripheral vascular disease, renal failure, lung disease, and frailty scores, from low to high risk groups. Compared with intermediate- and high-risk patients, low-risk patients were more likely to undergo TAVI through the transfemoral route (81% vs 88% vs 95%, p <0.001) and under conscious sedation (69% vs 72% vs 81%, <0.001). There were no significant differences in the rates of procedural complications apart from acute kidney injury (19% vs 17% vs 13%, p = 0.03) and stroke rates (4.5% vs 2% vs 2.3%, p = 0.1). Short- and long-term mortality rates were significantly higher for intermediate- (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2 to 2.9) and high-risk patients (HR 4.1, 95% CI 2.7 to 6.4) than low-risk patients also after multivariate adjustment (HR 1.6, 95% CI 1 to 2.6 and HR 2.7, 95% CI 1.7 to 4.5, respectively; all p <0.05). In conclusion, TAVI for intermediate- and low-risk patients is safe and associated with improved outcome compared with high-risk patients.

Although transcatheter aortic valve implantation (TAVI) for severe aortic stenosis is becoming an established technique, the impact of gender-related differences remains unclear. Two hundred twenty-four consecutive patients undergoing TAVI were prospectively followed up in a tertiary medical center. The primary end point of the present study was all-cause mortality at 2 years of follow-up. Interaction-term analysis was used to identify gender-specific predictors of mortality after TAVI. Fifty-seven percent of the study patients were women. Age was similar (82 ± 7 years). Compared with men, women had a lower frequency of coronary artery disease (CAD) and a higher baseline left ventricular ejection fraction (LVEF). The cumulative probability of all-cause mortality was significantly lower among women (8.6%) compared with men (26.8%; log-rank p value <0.001). A lower baseline LVEF (<45%) was associated with a significant, more than fourfold (p = 0.0019 and 0.048, respectively), increase in mortality risk among both men and women (p value for gender-by-LVEF interaction = 0.87). In contrast, the risk associated with the presence of previous CAD was shown to be gender related. Thus, in women, CAD was associated with a pronounced >14-fold increase in mortality risk, whereas in men, CAD was not associated with a significant mortality risk (p value for gender-by-LVEF interaction = 0.01). In conclusion, our findings suggest that risk assessment before TAVI should consider gender-specific differences in survival and risk factors.

Gamma-ray bursts (GRBs) are produced by rare types of massive stellar explosion. Their rapidly fading afterglows are often bright enough at optical wavelengths that they are detectable at cosmological distances. Hitherto, the highest known redshift for a GRB was z = 6.7 (ref. 1), for GRB 080913, and for a galaxy was z = 6.96 (ref. 2). Here we report observations of GRB 090423 and the near-infrared spectroscopic measurement of its redshift, z = 8.1(-0.3)(+0.1). This burst happened when the Universe was only about 4 per cent of its current age. Its properties are similar to those of GRBs observed at low/intermediate redshifts, suggesting that the mechanisms and progenitors that gave rise to this burst about 600,000,000 years after the Big Bang are not markedly different from those producing GRBs about 10,000,000,000 years later.

Choked jets (CJ) have attracted particular attention as potential sources of high-energy cosmic neutrinos. Testing this hypothesis is challenging because of the missing gamma-ray counterpart, hence the identification of other electromagnetic (EM) signatures is crucial. A CJ source is expected harbouring in core-collapse supernovae (CCSNe) with extended H envelopes, releasing ultraviolet (UV) and optical emission for a few days. The UV band will be visible with an unprecedentedly large field of view by the future satellite ULTRASAT, for which we investigate the detection prospects in relation to the CJ visibility in the optical band with the currently operating telescope ZTF. ULTRASAT will be able to double the volume of sky currently visible by ZTF for the same emitting sources (sample of observed Type II SNe enlarged by 60%). As these sources can produce neutrinos via hadronic/photohadronic interactions in CJ, we investigate how neutrino observations by existing Cherenkov high-energy neutrino telescopes (IceCube and KM3NeT) can be used in association with EM signals coming from shock breakout (SBO) events. For optimized multimessenger detections, the delay between neutrino produced at SBO (during the jet propagation inside the stellar envelope) and ULTRASAT observations should be of around 4(5) days, with a follow-up by instruments like ZTF about one week after. Fewer than 1% of the CCSNe from red supergiant stars detectable with ULTRASAT might host a CJ and release TeV neutrinos. EM and neutrino detections, if accompanied by photometric and spectroscopic follow-up with evidence for a relativistic jet launched by the central engine, would suggest CCSNe harbouring choked jets as main contributors to the cosmic diffuse neutrino flux.

Although previous retrospective studies have suggested the clinical benefits of clopidogrel pretreatment in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI), the antiplatelet effect of thienopyridines during a narrow door-to-balloon time frame has not been evaluated. Seventy-nine consecutive patients with STEMI were treated with either 600 mg of clopidogrel (n = 49) or 60 mg of prasugrel (n = 30) loading on admission. All patients underwent PPCI with a door-to-balloon time of 48 ± 20 minutes. Adenosine diphosphate (ADP)–induced platelet aggregation (PA) was determined by light transmission aggregometry before thienopyridine loading, at PPCI, and after 72 hours. Baseline ADP-induced PA was comparable in clopidogrel- and prasugrel-treated patients (79 ± 10% vs 76 ± 9%, p = 0.2). Although ADP-induced PA was reduced significantly in both clopidogrel- and prasugrel-treated patients (p <0.01 for both), it was significantly lesser in prasugrel-treated patients (63 ± 18% vs 74 ± 12%, p = 0.002). Yet, <50% of the prasugrel-treated patients achieved adequate platelet inhibition (ADP-induced PA <70%) at PPCI. Prasugrel-treated patients, compared with clopidogrel-treated patients, were more likely to have Thrombolysis In Myocardial Infarction myocardial perfusion grade of ≥2 (79% vs 49%, p = 0.01), lower Thrombolysis In Myocardial Infarction frame count (10.2 ± 5.7 vs 13.6 ± 7.2, p = 0.03), and a numerically greater incidence of early ST-segment resolution >50% (26 of 30 [87%] vs 35 of 49 [71%], p = 0.1), suggesting better myocardial reperfusion. In conclusion, overall, prasugrel compared with clopidogrel pretreatment resulted in greater platelet inhibition at PPCI, but even with prasugrel, only <50% of the patients achieved early adequate platelet response.