Crystallographic studies of the Escherichia coli quinol-fumarate reductase with inhibitors bound to the quinol-binding site

The quinol-fumarate reductase (QFR) respiratory complex of Escherichia coli is a four-subunit integral-membrane complex that catalyzes the final step of anaerobic respiration when fumarate is the terminal electron acceptor. The membrane-soluble redox-active molecule menaquinol (MQH(2)) transfers electrons to QFR by binding directly to the membrane-spanning region. The crystal structure of QFR contains two quinone species, presumably MQH(2), bound to the transmembrane-spanning region. The binding sites for the two quinone molecules are termed Q(P) and Q(D), indicating their positions proximal Q(P)) or distal (Q(D)) to the site of fumarate reduction in the hydrophilic flavoprotein and iron-sulfur protein subunits. It has not been established whether both of these sites are mechanistically significant. Co-crystallization studies of the E. coli QFR with the known quinol-binding site inhibitors 2-heptyl-4-hydroxyquinoline-N-oxide and 2-[1-(p-chlorophenyl)ethyl] 4,6-dinitrophenol establish that both inhibitors block the binding of MQH(2) at the Q(P) site. In the structures with the inhibitor bound at Q(P), no density is observed at Q(D), which suggests that the occupancy of this site can vary and argues against a structurally obligatory role for quinol binding to Q(D). A comparison of the Q(P) site of the E. coli enzyme with quinone-binding sites in other respiratory enzymes shows that an acidic residue is structurally conserved. This acidic residue, Glu-C29, in the E. coli enzyme may act as a proton shuttle from the quinol during enzyme turnover

Highlighting the hidden dangers of a ‘weak’ opioid:Deaths following use of dihydrocodeine in England (2001–2020)

BackgroundDihydrocodeine (DHC) is considered a ‘weak’ opioid, but there is evidence of its increasing misuse in overdose deaths. This research aims to analyse trends in DHC-related deaths in England relevant to source and dose of DHC, and decedent demographics.MethodsCases from England reported to the National Programme on Substance Abuse Deaths (NPSAD) where DHC was identified at post-mortem and/or implicated in death between 2001 and 2020 were extracted for analysis.Results2071 DHC-related deaths were identified. The greatest number of deaths involved illicitly obtained DHC and a significant increase in these deaths was recorded over time (r = 0.5, p = 0.03). However, there was a concurrent decline in the implication rate of DHC in causing death (r = −0.6, p &lt; 0.01). Fatalities were primarily due to accidental overdose (64.8%) and misuse was highly prevalent in combination with additional central nervous system depressants (95.3%), namely illicit heroin/morphine and diazepam. In contrast, when DHC was obtained over-the-counter (OTC) suicide mortality accounted for almost half of the deaths (42.5%). Differences in polysubstance use were also identified, with less heroin/morphine and benzodiazepine co-detection, but increased OTC codeine co-detection.ConclusionsDHC misuse in England is increasing. The pharmacological consideration of DHC as a ‘weak’ opioid may be misinterpreted by users, leading to accidental overdosing. There is an urgent need to understand increasing polypharmacy in overdose deaths. Additionally, suicides involving DHC is a potential cause for concern and a review of OTC opioid-paracetamol preparations is necessary to determine whether the benefits of these medications continue to outweigh the risks of intentional overdose.</p

Comparing cover crop research in farmer-led and researcher-led experiments in the Western Corn Belt

Cover crops can mitigate soil degradation and nutrient loss and can be used to achieve continuous living cover in cropping systems, although their adoption in the Western Corn Belt of the United States remains low. It is increasingly recognized that cover crop integration into corn (Zea mays L.)-based crop rotations is complex, requiring site and operation specific management. In this review, we compared on-farm, farmer-led field scale trials to researcher-led trials carried out in small plots on University of Nebraska-Lincoln experiment stations. Although there is a range of cover crop research conducted in the state, there is no synthesis of the scope and key results of such eorts. Common cover crop challenges and goals in the state are similar to those reported nationwide; challenges include adequate planting timing, associated costs, and weather, while a top goal of cover crop use is to improve soil health. Farmer-led trials most frequently compared a cover crop to a no-cover crop control, likely reflecting a desire to test a basic design determining site-specific performance. Both researcher-led and farmer-led trials included designs testing cash crop planting timing, while some portion of farmer-led trials tested cover crop seeding rates, which are directly related to reported cover crop challenges. Farmer-led trials were carried out on a greater variety of soils, including sandy soils, whereas sandy soils were absent from researcher-led trials. More than half of farmer- led experiments were conducted on fields with slopes of 6–17% while most researcher-led experiments were conducted on fields with slopes of \u3c1%. Mean cover crop biomass production was 600 kg/ha in farmer-led and 2,000 kg/ha in researcher-led trials. Crop yields were not significantly aected by cover crops in either farmer-led or researcher-led trials. Such comparisons demonstrate that in some instances, cover crop research is addressing challenges, and in some instances, it could be expanded. This synthesis expands our knowledge base in a way that can promote co-learning between dierent scales of experiments, and ultimately, reduce risks associated with cover crop management and further promote continuous living cover of agricultural landscapes

Patient experience of gastrointestinal endoscopy: Informing the development of the Newcastle ENDOPREM

Background Measuring patient experience is important for evaluating the quality of patient care, identifying aspects requiring improvement and optimising patient outcomes. Patient Reported Experience Measures (PREMs) should, ideally, be patient derived, however no such PREMs for gastrointestinal (GI) endoscopy exist. This study explored the experiences of patients undergoing GI endoscopy and CT colonography (CTC) in order to: identify aspects of care important to them; determine whether the same themes are relevant across investigative modalities; develop the framework for a GI endoscopy PREM. Methods Patients aged ≥18 years who had undergone oesophagogastroduodenoscopy (OGD), colonoscopy or CTC for symptoms or surveillance (but not within the national bowel cancer screening programme) in one hospital were invited to participate in semi-structured interviews. Recruitment continued until data saturation. Inductive thematic analysis was undertaken. Results 35 patients were interviewed (15 OGD, 10 colonoscopy, 10 CTC). Most patients described their experience chronologically, and five ‘procedural stages’ were evident: before attending for the test; preparing for the test; at the hospital, before the test; during the test; after the test. Six themes were identified: anxiety; expectations; choice & control; communication & information; comfort; embarrassment & dignity. These were present for all three procedures but not all procedure stages. Some themes were inter-related (eg, expectations & anxiety; communication & anxiety). Conclusion We identified six key themes encapsulating patient experience of GI procedures and these themes were evident for all procedures and across multiple procedure stages. These findings will be used to inform the development of the Newcastle ENDOPREM™

The Spiderweb galaxy: a forming massive cluster galaxy at z~2

We present a deep image of the radio galaxy MRC 1138-262 taken with the Hubble Space Telescope (HST) at a redshift of z = 2.2. The galaxy is known to have properties of a cD galaxy progenitor and be surrounded by a 3 Mpc-sized structure, identified with a protocluster. The morphology shown on the new deep HST/ACS image is reminiscent of a spider's web. More than 10 individual clumpy features are observed, apparently star-forming satellite galaxies in the process of merging with the progenitor of a dominant cluster galaxy 11 Gyr ago. There is an extended emission component, implying that star formation was occurring over a 50 times 40 kpc region at a rate of more than 100 M_sun/yr. A striking feature of the newly named ``Spiderweb galaxy'' is the presence of several faint linear galaxies within the merging structure. The dense environments and fast galaxy motions at the centres of protoclusters may stimulate the formation of these structures, which dominate the faint resolved galaxy populations in the Hubble Ultra Deep Field. The new image provides a unique testbed for simulations of forming dominant cluster galaxies.Comment: 5 pages, 2 figures (reduced to grayscale); ApJ Letter

Towards country-specific nitrous oxide emission factors for manures applied to arable and grassland soils in the UK

Nitrous oxide (N2O) emission factors (EFs) were calculated from measurements of emissions from livestock manures applied to UK arable crops and grassland as part of a wider research programme to reduce uncertainty in the UK national agricultural N2O inventory and to enhance regional inventory reporting through increased understanding of processes and factors controlling emissions. Field studies were undertaken between 2011 and 2013 at 3 arable and 3 grassland sites in the UK. Nitrous oxide emissions were measured following the autumn and spring application of different manures (pig slurry, cattle slurry, cattle farmyard manure (FYM), pig FYM, poultry layer manure, and broiler litter) at typical rates, using representative manure application and soil incorporation methods. In addition, ammonia emissions and nitrate leaching losses (1 site on a light sandy soil) were measured to calculate indirect N2O losses. IPCC comparable, direct N2O EFs ranged from −0.05 to 2.30% of total nitrogen applied, with the variability driven by a range of factors including differences in manure composition, application method, incorporation and climatic conditions. When data from the autumn applications were pooled, the mean N2O EF from poultry manure (1.52%) was found to be greater (P < 0.001) than from FYM (0.37%) and slurry (0.72%), with no difference found (P = 0.784) in the EF for bandspread compared with surface broadcast slurry application, and no effect (P = 0.328) of the nitrification inhibitor, Dicyandiamide (DCD). For the spring applications, the mean N2O EF for bandspread slurry (0.56%) was greater (P = 0.028) than from surface broadcast slurry (0.31%), but there were no differences (P = 0.212) in the mean N2O EFs from poultry manure (0.52%), slurry (0.44%), and FYM (0.22%). The study did confirm, however, that DCD reduced N2O emissions from slurries applied in the spring by 45%. EF data from this project have been used in the derivation of robust Tier 2 country specific EFs for inclusion in the UK national agriculture greenhouse gas inventory

Domestic Cooking and Food Skills: A Review

Domestic cooking skills (CS) and food skills (FS) encompass multiple components, yet there is a lack of consensus on their constituent parts, inter-relatedness or measurement, leading to limited empirical support for their role in influencing dietary quality. This review assessed the measurement of CS and FS in adults (>16 years); critically examining study designs, psychometric properties of measures, theoretical basis and associations of CS/FS with diet. Electronic databases (PsychInfo), published reports and systematic reviews on cooking and home food preparation interventions (Rees et al. 2012 ; Reicks et al. 2014 ) provided 834 articles of which 26 met the inclusion criteria. Multiple CS/FS measures were identified across three study designs: qualitative; cross-sectional; and dietary interventions; conducted from 1998-2013. Most measures were not theory-based, limited psychometric data was available, with little consistency of items or scales used for CS/FS measurements. Some positive associations between CS/FS and FV intake were reported; though lasting dietary changes were uncommon. The role of psycho-social (e.g., gender, attitudes) and external factors (e.g. food availability) on CS/FS is discussed. A conceptual framework of CS/FS components is presented for future measurement facilitation, which highlights the role for CS/FS on food-related behaviour and dietary quality. This will aid future dietary intervention design

Overturning circulation, nutrient limitation, and warming in the Glacial North Pacific

This work was funded by NERC grant NE/N011716/1 to J.W.B.R., a NERC studentship to B.T., and NSF grant OPP 1643445 to I.E. A.R. acknowledges support from NSF grant 1736771.Although the Pacific Ocean is a major reservoir of heat and CO2, and thus an important component of the global climate system, its circulation under different climatic conditions is poorly understood. Here, we present evidence that during the Last Glacial Maximum (LGM), the North Pacific was better ventilated at intermediate depths and had surface waters with lower nutrients, higher salinity, and warmer temperatures compared to today. Modeling shows that this pattern is well explained by enhanced Pacific meridional overturning circulation (PMOC), which brings warm, salty, and nutrient-poor subtropical waters to high latitudes. Enhanced PMOC at the LGM would have lowered atmospheric CO2—in part through synergy with the Southern Ocean—and supported an equable regional climate, which may have aided human habitability in Beringia, and migration from Asia to North America.Publisher PDFPeer reviewe