We present the first major data release of the largest single key-project in area carried out in open time with the Herschel
Space Observatory. The Herschel Astrophysical Terahertz Large Area Survey ...(H-ATLAS) is a survey of 600 deg2 in five photometric bands – 100, 160, 250, 350 and 500 μm – with the Photoconductor Array Camera and Spectrometer and Spectral and Photometric Imaging Receiver (SPIRE) cameras. In this paper and the companion Paper II, we present the survey of three fields on the celestial equator, covering a total area of 161.6 deg2 and previously observed in the Galaxy and Mass Assembly (GAMA) spectroscopic survey. This paper describes the Herschel images and catalogues of the sources detected on the SPIRE 250 μm images. The 1σ noise for source detection, including both confusion and instrumental noise, is 7.4, 9.4 and 10.2 mJy at 250, 350 and 500 μm. Our catalogue includes 120 230 sources in total, with 113 995, 46 209 and 11 011 sources detected at >4σ at 250, 350 and 500 μm. The catalogue contains detections at >3σ at 100 and 160 μm for 4650 and 5685 sources, and the typical noise at these wavelengths is 44 and 49 mJy. We include estimates of the completeness of the survey and of the effects of flux bias and also describe a novel method for determining the true source counts. The H-ATLAS source counts are very similar to the source counts from the deeper HerMES survey at 250 and 350 μm, with a small difference at 500 μm. Appendix A provides a quick start in using the released data sets, including instructions and cautions on how to use them.
The presence of ribonucleotides in genomic DNA is undesirable given their increased susceptibility to hydrolysis. Ribonuclease (RNase) H enzymes that recognize and process such embedded ...ribonucleotides are present in all domains of life. However, in unicellular organisms such as budding yeast, they are not required for viability or even efficient cellular proliferation, while in humans, RNase H2 hypomorphic mutations cause the neuroinflammatory disorder Aicardi-Goutières syndrome. Here, we report that RNase H2 is an essential enzyme in mice, required for embryonic growth from gastrulation onward. RNase H2 null embryos accumulate large numbers of single (or di-) ribonucleotides embedded in their genomic DNA (>1,000,000 per cell), resulting in genome instability and a p53-dependent DNA-damage response. Our findings establish RNase H2 as a key mammalian genome surveillance enzyme required for ribonucleotide removal and demonstrate that ribonucleotides are the most commonly occurring endogenous nucleotide base lesion in replicating cells.
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► Ribonucleotides are the most common nucleotide base lesion in the mouse genome ► RNase H2 is a key genome surveillance enzyme required for removal of nucleotides ► RNase H2 is essential for mammalian development ► Without RNase H2, cells exhibit genome instability and p53 pathway activation
DNA polymerases can incorporate more than a million ribonucleotides into replicating mouse DNA in each cell, making ribonucleotides the most abundant kind of DNA lesion. RNase H2, which removes this “damage,” has an essential role in genome surveillance and is required for embryonic development.
This paper presents the first measurement of the radio luminosity function of ‘jet-mode’ (radiatively inefficient) radio-AGN out to z = 1, in order to investigate the cosmic evolution of radio-AGN ...feedback. Eight radio source samples are combined to produce a catalogue of 211 radio-loud AGN with 0.5 < z < 1.0, which are spectroscopically classified into jet-mode and radiative-mode (radiatively efficient) AGN classes. Comparing with large samples of local radio-AGN from the Sloan Digital Sky Survey, the cosmic evolution of the radio luminosity function of each radio-AGN class is independently derived. Radiative-mode radio-AGN show an order of magnitude increase in space density out to z ≈ 1 at all luminosities, consistent with these AGN being fuelled by cold gas. In contrast, the space density of jet-mode radio-AGN decreases with increasing redshift at low radio luminosities (L
1.4 GHz ≲ 1024 W Hz−1) but increases at higher radio luminosities. Simple models are developed to explain the observed evolution. In the best-fitting models, the characteristic space density of jet-mode AGN declines with redshift in accordance with the declining space density of massive quiescent galaxies, which fuel them via cooling of gas in their hot haloes. A time delay of 1.5–2 Gyr may be present between the quenching of star formation and the onset of jet-mode radio-AGN activity. The behaviour at higher radio luminosities can be explained either by an increasing characteristic luminosity of jet-mode radio-AGN activity with redshift (roughly as (1 + z)3) or if the jet-mode radio-AGN population also includes some contribution of cold-gas-fuelled sources seen at a time when their accretion rate was low. Higher redshifts measurements would distinguish between these possibilities.
Methane biogenesis in methanogens is mediated by methyl-coenzyme M reductase, an enzyme that is also responsible for the utilization of methane through anaerobic methane oxidation. The enzyme uses an ...ancillary factor called coenzyme Fsub.430, a nickel-containing modified tetrapyrrole that promotes catalysis through a methyl radical/Ni(ii)-thiolate intermediate. However, it is unclear how coenzyme Fsub.430 is synthesized from the common primogenitor uroporphyrinogen iii, incorporating 11 steric centres into the macrocycle, although the pathway must involve chelation, amidation, macrocyclic ring reduction, lactamization and carbocyclic ring formation. Here we identify the proteins that catalyse the biosynthesis of coenzyme Fsub.430 from sirohydrochlorin, termed CfbACfbE, and demonstrate their activity. The research completes our understanding of how the repertoire of tetrapyrrole-based pigments are constructed, permitting the development of recombinant systems to use these metalloprosthetic groups more widely.
The earliest environmental criticism took its inspiration from the Romantic poets and their immersion in the natural world. Today the “romanticising” of nature has come to be viewed with suspicion. ...Written by one of the leading ecocritics writing today, Reclaiming Romanticism rediscovers the importance of the European Romantic tradition to the ways that writers and critics engage with the environment in the Anthropocene era. Exploring the work of such poets as Wordsworth, Shelley and Clare, the book discovers a rich vein of Romantic ecomaterialism and brings these canonical poets into dialogue with contemporary American, Canadian and Australian poets and artists. Kate Rigby demonstrates the ways in which Romantic ecopoetics responds to postcolonial challenges and environmental peril to offer a collaborative artistic practice for an era of human-non-human cohabitation and kinship.
Anaesthesiologists and non-anaesthesiologist sedationists have a limited set of available i.v. hypnotics, further reduced by the withdrawal of thiopental in the USA and its near disappearance in ...Europe. Meanwhile, demand for sedation increases and new clinical groups are using what traditionally are anaesthesiologists' drugs. Improved understanding of the determinants of perioperative morbidity and mortality has spotlighted hypotension as a potent cause of patient harm, and practice must be adjusted to respect this. High-dose propofol sedation may be harmful, and a critical reappraisal of drug choices and doses is needed. The development of remimazolam, initially for procedural sedation, allows reconsideration of benzodiazepines as the hypnotic component of a general anaesthetic even if their characterisation as i.v. anaesthetics is questionable. Early data suggest that a combination of remimazolam and remifentanil can induce and maintain anaesthesia. Further work is needed to define use cases for this technique and to determine the impact on patient outcomes.
Background
Existing PK models of propofol include sparse data from very obese patients. The aim of this study was to develop a PK model based on standardised surgical conditions and spanning from ...normal‐weight up to, and including, a high number of very obese patients.
Methods
Adult patients scheduled for laparoscopic cholecystectomy or bariatric surgery were studied. Anaesthesia was induced with propofol 2 mg/kg adjusted body weight over 2 min followed by 6 mg/kg/h adjusted body weight over 30 min. For the remainder of the operation anaesthesia was maintained with sevoflurane. Remifentanil was dosed according to clinical need. Eight arterial samples were drawn in a randomised block sampling regimen over a span of 24 h. Time‐concentration data were analysed by population PK modelling using non‐linear mixed‐effects modelling.
Results
Four hundred and seventy four serum propofol concentrations were collected from 69 patients aged 19–60 years with a BMI 21.6–67.3 kg/m2. Twenty one patients had a BMI above 50 kg/m2. A 3‐compartment PK model was produced wherein three different body weight descriptors and sex were included as covariates in the final model. Total body weight was found to be a covariate for clearance and Q3; lean body weight for V1, V2 and Q2; predicted normal weight for V3 and sex for V1. The fixed allometric exponent of 0.75 applied to all clearance parameters improved the performance of the model. Accuracy and precision were 1.4% and 21.7% respectively in post‐hoc performance evaluation.
Conclusion
We have developed a new PK model of propofol that is suitable for all adult weight classes. Specifically, it is based on data from an unprecedented number of individuals with very high BMI.
Rapid, accurate assessment of the yield of a large-scale urban explosion will assist in implementing emergency response plans, will facilitate better estimates of areas at risk of high damage and ...casualties, and will provide policy makers and the public with more accurate information about the event. On 4 August 2020, an explosion occurred in the Port of Beirut, Lebanon. Shortly afterwards, a number of videos were posted to social media showing the moment of detonation and propagation of the resulting blast wave. In this article, we present a method to rapidly calculate explosive yield based on analysis of 16 videos with a clear line-of-sight to the explosion. The time of arrival of the blast is estimated at 38 distinct positions, and the results are correlated with well-known empirical laws in order to estimate explosive yield. The best estimate and reasonable upper limit of the 2020 Beirut explosion determined from this method are 0.50 kt TNT and 1.12 kt TNT, respectively.
Aicardi–Goutières syndrome (AGS) provides a monogenic model of nucleic acid‐mediated inflammation relevant to the pathogenesis of systemic autoimmunity. Mutations that impair ribonuclease (RNase) H2 ...enzyme function are the most frequent cause of this autoinflammatory disorder of childhood and are also associated with systemic lupus erythematosus. Reduced processing of either RNA:DNA hybrid or genome‐embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid‐sensing pathway. Here, we establish Rnaseh2bA174T/A174T knock‐in mice as a subclinical model of disease, identifying significant interferon‐stimulated gene (ISG) transcript upregulation that recapitulates the ISG signature seen in AGS patients. The inflammatory response is dependent on the nucleic acid sensor cyclic GMP‐AMP synthase (cGAS) and its adaptor STING and is associated with reduced cellular ribonucleotide excision repair activity and increased DNA damage. This suggests that cGAS/STING is a key nucleic acid‐sensing pathway relevant to AGS, providing additional insight into disease pathogenesis relevant to the development of therapeutics for this childhood‐onset interferonopathy and adult systemic autoimmune disorders.
Synopsis
Mutations in the RNase H2 enzyme complex are the most frequent cause of the autoinflammatory condition Aicardi–Goutières syndrome (AGS). It is thought that nucleic acid sensing is responsible for initiating inflammation; however, the nature of the nucleic acid‐sensing pathway has not been determined. Here, we establish that:
Rnaseh2bA174T/A174T mice upregulate interferon‐stimulated genes (ISG) in tissues.
ISG response is dependent on the nucleic acid sensor cyclic GMP‐AMP synthase (cGAS) and its adaptor STING.
ISG induction is associated with reduced ribonucleotide excision repair (RER) activity and increased DNA damage.
A new mouse model reveals the key nucleic acid‐sensing and signalling pathway in autoinflammatory Aicardi–Goutières syndrome caused by RNase H2 mutations.
Ubiquinone (also known as coenzyme Q) is a ubiquitous lipid-soluble redox cofactor that is an essential component of electron transfer chains. Eleven genes have been implicated in bacterial ...ubiquinone biosynthesis, including ubiX and ubiD, which are responsible for decarboxylation of the 3-octaprenyl-4-hydroxybenzoate precursor. Despite structural and biochemical characterization of UbiX as a flavin mononucleotide (FMN)-binding protein, no decarboxylase activity has been detected. Here we report that UbiX produces a novel flavin-derived cofactor required for the decarboxylase activity of UbiD. UbiX acts as a flavin prenyltransferase, linking a dimethylallyl moiety to the flavin N5 and C6 atoms. This adds a fourth non-aromatic ring to the flavin isoalloxazine group. In contrast to other prenyltransferases, UbiX is metal-independent and requires dimethylallyl-monophosphate as substrate. Kinetic crystallography reveals that the prenyltransferase mechanism of UbiX resembles that of the terpene synthases. The active site environment is dominated by π systems, which assist phosphate-C1' bond breakage following FMN reduction, leading to formation of the N5-C1' bond. UbiX then acts as a chaperone for adduct reorientation, via transient carbocation species, leading ultimately to formation of the dimethylallyl C3'-C6 bond. Our findings establish the mechanism for formation of a new flavin-derived cofactor, extending both flavin and terpenoid biochemical repertoires.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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