Cumulative impact assessments of multiple host species loss from plant diseases show disproportionate reductions in associated biodiversity

Funding Information: This work was funded by BBSRC grant Protecting Oak Ecosystems (PuRpOsE): BB/N022831/1 with additional funding from the Scottish Government's Rural and Environment Research and Analysis Directorate 2016–2021 strategic research programme. The authors thank Nick Hodgetts for collating the lists of the bryophyte species associated with ash and oak, Ralph Harmer for conducting some of the site visits and the site owners for allowing us access to the sites. Katharine Preedy provided statistical advice. Steve Albon and Robin Pakeman kindly provided comments to improve earlier drafts.Peer reviewe

Cumulative impact assessments of multiple host species loss from plant diseases show disproportionate reductions in associated biodiversity

Non-native plant pests and pathogens are increasing exponentially, causing extirpation of foundation species. The impact of large-scale declines in a single host on associated biodiversity is widely documented. However, the impact of multiple host loss on biodiversity and whether these impacts are multiplicative has not been assessed. Ecological theory suggests that systems with greater functional redundancy (alternative hosts) will be more resilient to the loss of sympatric hosts. We test this theory and show its importance in relation to pest/pathogen impact assessments. We assessed the potential impact on biodiversity of the loss of two widely occurring sympatric European tree species, Fraxinus excelsior and Quercus petraea/robur, both of which are currently threatened by a range of pests and pathogens. At the UK scale, the total number of associated species at risk of extirpation from plant diseases affecting these two sympatric hosts is greater than the sum of the associated species at risk from declines in either host alone. F. excelsior hosts 45 obligate species (species only found on that host) and Q. petraea/robur hosts 326. However, a decline in both these trees would impact 512 associated species, across multiple taxon groups, a 38% increase. Assessments at a local scale, 24 mixed F. excelsior–Q. petraea/robur woodlands revealed that these impacts may be even greater due to a lack of functional redundancy. Only 21% of sites were able to provide functional redundancy for F. excelsior and Q. petraea/robur associated species which can use other tree species. In most woodlands, the tree species required to provide functional redundancy were not present, although the site conditions were often suitable for them to grow. Synthesis. Understanding of functional redundancy should be applied to assessments of pests/pathogens impact on biodiversity. In risk assessments, higher impact scores should be given to pests/pathogens affecting hosts occurring with other host plant species already impacted by pests/pathogens. Current pest/pathogen risk assessment approaches that ignore the cumulative, cascading effects shown in this study may allow an insidious, mostly overlooked, driver of biodiversity loss to continue.Biotechnology and Biological Sciences Research Council, Grant/Award Number: BB/N022831/1; Rural and Environment Science and Analytical Services Division.info:eu-repo/semantics/publishedVersio

Assessing similarity to primary tissue and cortical layer identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics

Induced pluripotent stem cell (iPSC)-derived cortical neurons potentially present a powerful new model to understand corticogenesis and neurological disease. Previous work has established that differentiation protocols can produce cortical neurons, but little has been done to characterize these at cellular resolution. In particular, it is unclear to what extent in vitro two-dimensional, relatively disordered culture conditions recapitulate the development of in vivo cortical layer identity. Single-cell multiplex reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to interrogate the expression of genes previously implicated in cortical layer or phenotypic identity in individual cells. Totally, 93.6% of single cells derived from iPSCs expressed genes indicative of neuronal identity. High proportions of single neurons derived from iPSCs expressed glutamatergic receptors and synaptic genes. And, 68.4% of iPSC-derived neurons expressing at least one layer marker could be assigned to a laminar identity using canonical cortical layer marker genes. We compared single-cell RNA-seq of our iPSC-derived neurons to available single-cell RNA-seq data from human fetal and adult brain and found that iPSC-derived cortical neurons closely resembled primary fetal brain cells. Unexpectedly, a subpopulation of iPSC-derived neurons co-expressed canonical fetal deep and upper cortical layer markers. However, this appeared to be concordant with data from primary cells. Our results therefore provide reassurance that iPSC-derived cortical neurons are highly similar to primary cortical neurons at the level of single cells but suggest that current layer markers, although effective, may not be able to disambiguate cortical layer identity in all cells

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

Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer

Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.M.G., A.Woolston, L.J.B., and B.G. were supported by CRUK, a charitable donation from Tim Morgan, Cancer Genetics UK and the Constance Travis Trust. G.S. was funded by an Institute of Cancer PhD Studentship, R.G.E. by a Spanish Society of Medical Oncology (FSEOM) grant for Translational Research in Reference Centers. The study was also supported by the ICR/RMH NIHR Biomedical Research Center for Cancer, by the CRUK Immunotherapy Accelerator (ICR/RMH, UCL) and by a Wellcome Trust Strategic Grant (105104/Z/14/Z)

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