Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Distribution, abundance and symbiotic effectiveness of Rhizobium leguminosarum bv. trifolii from alkaline pasture soils in South Australia

The current dissatisfaction with low productivity of annual medic (Medicago spp.) pastures has highlighted the need to seek alternative legumes to provide efficient N2 fixation in low rainfall, alkaline soil environments of southern Australia. Clover species adapted to these environments will have limited N2 fixation if effective rhizobia are not present in sufficient quantities. A survey of 61 sites was conducted across South Australia to determine the size, distribution and effectiveness of Rhizobium leguminosarum bv. trifolii (clover rhizobia) populations resident in these low rainfall, alkaline soil environments. Clover rhizobia were detected at 56 of the sites, with a median density of 230–920 rhizobia/g soil. Most rhizobial populations were poor in their capacity to fix nitrogen. Rhizobial populations from fields provided 11–89% and 10–85% of the shoot biomass of commercial reference strains when inoculated onto host legumes T. purpureum (purple clover) and T. resupinatum (persian clover), respectively. Rhizobial population size was correlated negatively to pH and the percentage of CaCO3 in the soil, and was significantly increased in the rhizospheres of naturalised clover, found at 17 sites. Management options for rhizobial populations to improve legume diversity and productivity are discussed in terms of rhizobial population dynamics and likely soil constraints to successful rhizobial colonisation

Nitrogen fixation in annual Trifolium species in alkaline soils as assessed by the 15N natural abundance method

Annual clover species such as Trifolium purpureum Loisel., T. resupinatum L., and T. alexandrinum L. are adapted to alkaline soil conditions and provide certain agronomic advantages over annual medics (Medicago spp.). Annual clovers have not been widely grown in alkaline soils in Australia, and quantifying their dinitrogen (N(2)) fixation in alkaline soils is important in understanding their potential role in mixed farming systems of southern Australia. Using the (15)N natural abundance technique, it was estimated that annual clovers fixed 101-137 kg N/ha at Roseworthy and 59-62 kg N/ha at Mallala, on Calcarosols with soil pH of 8.0 and 8.5, respectively. Species differed in the percentages of fixed N2 estimated in shoot dry matter, which was highest in T. alexandrinum (77-85%), moderate in T. resupinatum (76%), and lowest in T. purpureum (65-74%). Naturally occurring soil rhizobia (Rhizobium leguminosarum bv. trifolii) provided adequate nodulation, as inoculation with different strains of rhizobia had little influence on nodulation or N(2) fixation. These results indicate that clovers can provide a significant contribution of fixed N(2) to mixed farming systems. Examination of nodules indicated variable nodule occupancy by the inoculant rhizobia and that 69% of shoot N was fixed when clovers were nodulated by the soil populations of rhizobia. A simple model is defined to identify the potential interactions between inoculated legumes and soil rhizobia, and the options for enhancing symbiotic effectiveness are discussed

A comparison of epidural infusions of fentanyl or pethidine with bupivacaine in the management of postoperative pain

A double-blind randomised clinical trial was undertaken in 40 patients undergoing major abdominal surgery. Postoperative pain relief was provided using epidural infusions of 0.06% bupivacaine with fentanyl 4 μg.ml<sup>-1</sup> (n = 20) (group F) or with pethidine 1.5 mg.ml<sup>-1</sup> (n = 20) (group P). Postoperative pain scores using a visual analogue scale (0-100 mm) were not significantly different between the two groups. Median pain scores were 0-19 mm at all times of assessment indicating that good analgesia was provided by both regimens. There was no significant difference between the epidural infusion rates in the two groups. The side effects and effect on pulmonary function were similar in each group. Nine patients were withdrawn from the study (four from group F, five from group P) due to failure of the epidural technique or other complications. Fourteen patients, equally distributed, required a total of 24 epidural 'top-ups' by an anaesthetist because of inadequate analgesia. We demonstrated no advantage with epidural pethidine over fentanyl when used by infusion in combination with bupivacaine in the management of postoperative pain

Current matters of Bundesbank policy, particularly as they relate to European economic and monetary union

Talk given 1 Feb 1993SIGLEGBUnited Kingdo

Adaptabilidade e estabilidade de cultivares de trigo em diferentes épocas de semeadura, no Paraná

O objetivo deste trabalho foi identificar as melhores épocas de semeadura e avaliar a adaptabilidade e a estabilidade de cultivares de trigo, em duas regiões tritícolas do Paraná. Avaliou-se a produtividade de grãos de sete cultivares, em Guarapuava, e de nove, em Palotina, em quatro épocas de semeadura, em 2006, 2007 e 2008. Utilizou-se o delineamento experimental de blocos ao acaso, com quatro repetições em Guarapuava, e três em Palotina. Foram utilizadas a metodologia REML/BLUP e a dos efeitos principais dos genótipos e da interação genótipo x ambiente (GGE biplot) para a avaliação da adaptabilidade e da estabilidade das cultivares, e o métodoAMMI para a identificação das melhores épocas de semeadura. Semeaduras em julho, em Guarapuava, e em abril, em Palotina, maximizam a produtividade de grãos. As cultivares Safira, em Guarapuava, e CD 113, em Palotina, são estáveis, amplamente adaptadas e apresentam alta produtividade de grãos

ROLE OF CD1A AND HSP60 IN THE ANTITUMORAL RESPONSE OF OESOPHAGEAL CANCER.

Oesophageal cancer (OC) is one of the most common and severe forms of tumor. A wider knowledge of molecular mechanisms which lead to a normal epithelium becoming a neoplasm may reveal new strategies to improve treatment and outcome of this disease. In this review, we report recent findings concerning molecular events which take place during carcinogenesis of the oesophagus. In particular, we focus on the role of two molecules, CD1a and Hsp60, which are overexpressed in oesophageal and many other types of tumor. Both molecules may present tumor antigens and promote in situ the stimulation of an antitumoral immune activity. We suggest there is a synergistic action between these molecules. Further knowledge about their intracellular pathways and extracellular roles may help develop new antitumoral tools for OC