Thiarubrine production in roots and root cultures of Ambrosia chamissonis

Ambrosia chamissonis (Asteraceae) provides antibiotic sulphur heterocyclic polyynes known as thiarubrines and thiophenes. They occur in all parts of the plant, especially in the roots and can be visualized in hand sections. Methods were developed for their isolation, purification and quantification. Plants were collected from various locations in B.C. and found to have different thiarubrine profiles. A new thiarubrine (3-(1-propyny1)-6-(6-hydroxyhex-3-yn-1yny1)-1,2-dithiacyclohexadiene) and thiophene (2-(1-propyny1)-6-(6-hydroxyhex-3-yn-1yny1)-thiophene) were identified from roots and root cultures. Transgenic and non-transgenic root cultures were generated and shown to produce the same compounds as occur in natural roots. Quantitative chemical profiles of the cultured roots matched those of roots which had little secondary growth. Elicitation, with fungal preparations, did not enhance the over-all thiarubrine concentration, but the content of a more fungicidal thiarubrine was enhanced at the expense of a less active, but predominant thiarubrine. Administration of biosynthetic precursors did not have any effect on thiarubrine production. Antibiotic testing indicated that the thiarubrines are toxic against a number of fungi and, to a lesser degree, bacteria.Science, Faculty ofBotany, Department ofGraduat

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

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization 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