Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

The role of nitrogen and in-crop lucerne suppression for increasing cereal performance in companion cropping systems

Abstract Five field experiments located at four sites (Burraja, Grogan, North Boorhaman and Roseworthy) across south eastern Australia compared cereal grain yields in the presence of lucerne (companion cropping) and absence of lucerne (cereal monoculture). Top-dressed nitrogen (N) was applied to subplots at Burraja, Grogan and North Boorhaman, while in-crop lucerne suppression was applied to plots at Burraja and two separate, but adjacent experiments at Roseworthy, to determine if these management strategies could improve cereal performance in the presence of lucerne. In addition annual lucerne and cereal biomass was measured at North Boorhaman from a companion crop and compared with both a lucerne and cereal monoculture. Over the three years and four sites, cereals growing with lucerne yielded between 19% and 57% less (P<0.05) grain than cereals growing alone. There was no main treatment by top-dressed N interaction at all sites, indicating that applying N to cereals irrespective of whether they were growing with or without lucerne, resulted in same yield responses. Top-dressing N at North Boorhaman in 2003 and 2005 resulted in a 14% and 40% respectively, increase (P<0.05) in grain yield across all cereal crops. The absence of a response at Burraja and Grogan was probably due to sub-optimal growing season rainfall. In-crop lucerne suppression did not increase grain yields at either Burraja or Roseworthy, but in some seasons reduced (P<0.05) cereal grain contamination by lucerne pods and flowers. Companion cropping increased (P<0.05) total (cereal and lucerne) annual biomass production by 20-41%, compared with the lucerne monoculture, and 16% more (P<0.05) than the cereal monoculture. Demonstrating that while grain yield reductions reduce the attractiveness of companion cropping, this practice does offer other advantages in terms of improved yearly water use and quality out-of-season feed supply that cereal monocultures can not deliver. Key words Inter-cropping, companion cropping, grain yield reduction, in-crop lucerne suppression, top-dressed nitrogen, lucerne, wheat, barley. Introduction Lucerne companion cropping (also known as inter-cropping or over-cropping) involves sowing an annual crop directly into an existing lucerne stand. In comparison with conventional cropping systems, companion cropping promotes greater utilisation of rainfall by maintaining a perennial plant throughout the year, and therefore reducing the risk of excess rainfall leaking below the root zone and contributing to the harmful effects of dryland salinity

The role of nitrogen and in-crop lucerne suppression for increasing cereal performance in companion cropping systems

Five field experiments located at four sites (Burraja, Grogan, North Boorhaman and Roseworthy) across south eastern Australia compared cereal grain yields in the presence of lucerne (companion cropping) and absence of lucerne (cereal monoculture). Top-dressed nitrogen (N) was applied to subplots at Burraja, Grogan and North Boorhaman, while in-crop lucerne suppression was applied to plots at Burraja and two separate, but adjacent experiments at Roseworthy, to determine if these management strategies could improve cereal performance in the presence of lucerne. In addition annual lucerne and cereal biomass was measured at North Boorhaman from a companion crop and compared with both a lucerne and cereal monoculture. Over the three years and four sites, cereals growing with lucerne yielded between 19% and 57% less (P<0.05) grain than cereals growing alone. There was no main treatment by top-dressed N interaction at all sites, indicating that applying N to cereals irrespective of whether they were growing with or without lucerne, resulted in same yield responses. Top-dressing N at North Boorhaman in 2003 and 2005 resulted in a 14% and 40% respectively, increase (P<0.05) in grain yield across all cereal crops. The absence of a response at Burraja and Grogan was probably due to sub-optimal growing season rainfall. In-crop lucerne suppression did not increase grain yields at either Burraja or Roseworthy, but in some seasons reduced (P<0.05) cereal grain contamination by lucerne pods and flowers. Companion cropping increased (P<0.05) total (cereal and lucerne) annual biomass production by 20-41%, compared with the lucerne monoculture, and 16% more (P<0.05) than the cereal monoculture. Demonstrating that while grain yield reductions reduce the attractiveness of companion cropping, this practice does offer other advantages in terms of improved yearly water use and quality out-of-season feed supply that cereal monocultures can not deliver.Rob Harris, Tim Clune, Mark Peoples, Antony Swan, William Bellotti and Wen Che

The importance of in-crop lucerne suppression and nitrogen for cereal companion crops in south-eastern Australia

Five field experiments located at four sites across south-eastern Australia found cereal grain yields were less in the presence of lucerne (companion cropping) than in the absence of lucerne (cereal monoculture). Top-dressed nitrogen (N) and in-crop lucerne suppression, generally did not enhance cereal crop yields in the presence of lucerne compared with cereals growing in monoculture. Grain yield reductions from cereals growing with lucerne were found at four of the five sites, with reductions ranging from 16 to 26% compared with cereals growing in monoculture. In regard to cereal production, there was no main treatment by top-dressed N interaction at all sites, indicating that applying N to cereals irrespective of whether they were growing with or without lucerne, resulted in the same yield responses. With favourable growing seasons (decile > 6) and low available soil N levels, top-dressing N resulted in a 31% and a 0.8 unit increase in grain yield and grain protein, respectively, across all cereal crops and years. However, the absence of a grain yield response to top-dressed N at one site was due to excessive cereal biomass production from N application, causing extensive crop lodging in 2003, and decile 2 growing season rainfall in 2004. At another site, high available soil N levels and low growing season rainfall (decile 3) resulted in a 12% decline in grain yield across all cereal crops and years in response to top-dressing N. We therefore conclude that N application to cereals growing with lucerne can increase cereal grain yields, but only when accompanied by favourable growing season rainfall and low available soil N levels. In-crop lucerne suppression was effective at reducing cereal grain contamination by lucerne pods and flowers in companion crops, but was less effective under dry seasonal conditions, demonstrating that soil moisture will affect herbicide efficacy and the effectiveness of this practice. Economic analyses of companion cropping based on grain yields alone, will not be adequate without an assessment of summer lucerne production, until such data exists across a range of environments, it would be premature to conclude whether and or where this practice has commercial merit

Sheep grazing on crop residues do not reduce crop yields in no-till, controlled traffic farming systems in an equi-seasonal rainfall environment

In southern Australia, the majority of farms combine a sheep enterprise with a cropping enterprise to form a mixed farming business. Crops are grown in sequence with pastures, and sheep graze vegetative juvenile crops and crop stubble residues after harvest. Recently, growers practicing no-till, controlled traffic cropping became concerned that grazing livestock would damage soil and reduce soil water capture, crop yield and profitability. Sheep grazing on stubbles remove residue cover and compact surface soil, but there is little published research on potential impacts on subsequent crop performance. Two experiments were conducted in high (Temora) and low (Condobolin) rainfall environments from 2009 to 2013 to determine whether sheep grazing crops during the vegetative phase and/or stubbles after harvest damaged soil, reduced soil water capture and storage or affected the performance of subsequent crops. Sheep grazing on stubbles did not reduce crop yields provided summer weeds were controlled with herbicides and at least 70% stubble cover (2–3 t/ha cereal stubble) was maintained on the soil surface. Sheep grazing on stubble increased soil strength and bulk density and reduced water infiltration rates, but rarely to levels that were detrimental to soil water capture, crop growth or grain yield. Where reduced infiltration rates did reduce soil water capture, it was due to removal of cover by grazing rather than compaction. Grazing of vegetative crops in winter when soils were generally wet further increased soil strength compared to grazing stubbles alone, but not to an extent that was detrimental to plant growth. Yield effects from grazing crops in winter were not due to soil physical effects, but to differences in plant growth in response to defoliation. Grazing of both stubbles and crops increased the availability of soil mineral N to subsequent crops which increased grain yield and protein in some seasons. The results from these experiments provide strong evidence that livestock can be retained within modern conservation cropping systems without compromising crop performance, and continue to provide the production and business risk benefits for which they have been historically valued

The role of nitrogen and in-crop lucerne suppression for increasing cereal performance in companion cropping systems

Five field experiments located at four sites (Burraja, Grogan, North Boorhaman and Roseworthy) across south eastern Australia compared cereal grain yields in the presence of lucerne (companion cropping) and absence of lucerne (cereal monoculture). Top-dressed nitrogen (N) was applied to subplots at Burraja, Grogan and North Boorhaman, while in-crop lucerne suppression was applied to plots at Burraja and two separate, but adjacent experiments at Roseworthy, to determine if these management strategies could improve cereal performance in the presence of lucerne. In addition annual lucerne and cereal biomass was measured at North Boorhaman from a companion crop and compared with both a lucerne and cereal monoculture. Over the three years and four sites, cereals growing with lucerne yielded between 19% and 57% less (P<0.05) grain than cereals growing alone. There was no main treatment by top-dressed N interaction at all sites, indicating that applying N to cereals irrespective of whether they were growing with or without lucerne, resulted in same yield responses. Top-dressing N at North Boorhaman in 2003 and 2005 resulted in a 14% and 40% respectively, increase (P<0.05) in grain yield across all cereal crops. The absence of a response at Burraja and Grogan was probably due to sub-optimal growing season rainfall. In-crop lucerne suppression did not increase grain yields at either Burraja or Roseworthy, but in some seasons reduced (P<0.05) cereal grain contamination by lucerne pods and flowers. Companion cropping increased (P<0.05) total (cereal and lucerne) annual biomass production by 20-41%, compared with the lucerne monoculture, and 16% more (P<0.05) than the cereal monoculture. Demonstrating that while grain yield reductions reduce the attractiveness of companion cropping, this practice does offer other advantages in terms of improved yearly water use and quality out-of-season feed supply that cereal monocultures can not deliver

Not all hERG pore domain mutations have a severe phenotype: G584s has an inactivation gating defect with mild phenotype compared to G572s, which has a dominant negative trafficking defect and a severe phenotype

Distinct Phenotypes in hERG Pore Domain Mutations. Introduction: Mutations in the pore domain of the human ether-a-go-go-related gene (hERG) potassium channel are associated with higher risk of sudden death. However, in many kindreds clinical presentation is variable, making it hard to predict risk. We hypothesized that in vitro phenotyping of the intrinsic severity of individual mutations can assist with risk stratification. Methods and Results: We analyzed 2 hERG pore domain mutations, G572S and G584S. Similar to 90% of hERG missense mutations, G572S-hERG subunits did not traffic to the plasma membrane but could coassemble with WT subunits and resulted in a dominant negative suppression of hERG current density. The G584S-hERG subunits traffic normally but have abnormal inactivation gating. Computer models of human ventricular myocyte action potentials (AP), incorporating Markov models of the hERG mutants, indicate that G572S-hERG channels would cause more severe AP prolongation than that seen with G584ShERG channels. Conclusions: hERG-G572S and -G584S are 2 pore domain mutations that involve the same change in sidechain but have very different in vitro phenotypes; G572S causes a dominant negative trafficking defect, whereas G584S is the first hERG missense mutation where the cause of disease can be exclusively attributed to enhanced inactivation. The G572S mutation is intrinsically more severe than the G584S mutation, consistent with the overall clinical presentation in the 2 small kindreds studied here. Further investigation, involving a larger number of cohorts, to test the hypothesis that in vitro phenotyping of the intrinsic severity of a given mutation will assist with risk stratification is therefore warranted

Soil mineral nitrogen benefits derived from legumes and comparisons of the apparent recovery of legume or fertiliser nitrogen by wheat

Nitrogen (N) contributed by legumes is an important component of N supply to subsequent cereal crops, yet few Australian grain-growers routinely monitor soil mineral N before applying N fertiliser. Soil and crop N data from 16 dryland experiments conducted in eastern Australia from 1989–2016 were examined to explore the possibility of developing simple predictive relationships to assist farmer decision-making. In each experiment, legume crops were harvested for grain or brown-manured (BM, terminated before maturity with herbicide), and wheat, barley or canola were grown. Soil mineral N measured immediately before sowing wheat in the following year was significantly higher (