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

A comparison of some range condition assessment techniques used in Southern African grasslands.

Techniques currently used to assess range condition in the grassland biome of Southern Africa are reviewed. These indices were then used to evaluate each method in terms of sensitivity, index interpretation and efficiency, bearing in mind the objectives of each technique. The weighted key species method and degradation gradient method were found to currently provide the best indices for assessing range condition, and in this article the shortcomings of the techniques are recognized and suggestions are made for the application of these methods in different vegetation types; Techniques currently used to assess range condition in the grassland biome of southern Africa are reviewed. The methods were used to calculate range condition indices from fire-climax and climatic-climax grassland data. These indices were then used to evaluate each method in terms of sensitivity (i.e. the detection of spatio-temporal differences in index), index interpretation and efficiency, bearing in mind the objectives of each technique. The Weighted Key Species Method and Degradation Gradient Method were found to currently provide the best indices for assessing range condition. Shortcomings of the techniques are recognized and suggestions are made for the application of these methods in different vegetation types.Language: EnglishKeywords: Degradation gradient method; Grasslands; Grazing gradients; Indicator species; Ordination; Range conditions; Species responses; Techniques; Vegetation; Weighted key species method; condition indices; degradation; grazing gradient; key species; range condition; range condition assessment; vegetation types; grassland; efficiency; grassland biome; southern africa; method; objectives; degradation gradient; vegetation type; botan

A weighted key species method for monitoring changes in species composition of Highland Sourveld.

The use of key species for indexing veld condition in relation to the fire/grazing impact has potential for monitoring change in the Highland Sourveld of Natal. Weightings are calculated for previously identified key species. A weighted-averages approach is used in a modified weighted key species method of indexing veld condition. Veld condition indices calculated using the method are highly correlated with rankings along a previously identified grazing gradient (r = 0, 85). Weightings are provided for indicator species that can be generally used for monitoring vegetation changes in the Highland Sourveld. The method has the advantage of being able to determine the position of a sample site on a grazing gradient, and thereby make inferences as to the grazing/burning history of the site.Language: EnglishKeywords: botany; burning; condition indices; grazing gradient; grazing history; highland sourveld; indicator species; key species; method; monitoring; natal; ordination; range condition; Range conditions; south africa; species composition; vegetation change; vegetation changes; veld conditio

An evaluation of veld condition assessment techniques in Highland Sourveld.

An evaluation of six methods used to index veld condition showed that the majority provided indices that were insensitive to long-term grazing impact. However, certain species were found to either increase or decrease in relative abundance with an increase in grazing intensity. A key species method is therefore suggested to be a potentially sensitive approach for indexing veld condition in relation to grazing management in the Highland Sourveld.Language: EnglishKeywords: grazing; grazing impact; grazing intensity; grazing management; highland sourveld; key species; method; natal; ordination; relative abundance; south africa; stocking rate; Stocking rates; tabamhlope research station; Techniques; veld condition; veld condition assessment; Veld condition

Senile Dementia of Lewy Body Type and Alzheimer Type Are Biochemically Distinct in Terms of Paired Helical Filaments and Hyperphosphorylated Tau Protein (Part 2 of 2)

We have used biochemical assays to examine cingulate and occipital cortices from age-matched cases of Alzheimer's disease (AD; n = 12), senile dementia of the Lewy body type (SDLT; n = 13), Parkinson's disease (PD; 5 non-demented cases and 7 cognitively impaired cases) and controls (n = 11) for paired helical filaments (PHFs), phosphorylated and normal tau protein and &amp;#914;/A4-protein. Whereas cingulate cortex is characterised by relatively high densities of cortical Lewy bodies in the SDLT cases and lower numbers in PD, these inclusion bodies were absent in the cingulate cortex from AD and control cases. Protease-resistant PHFs and hyperphosphorylated tau protein were found in AD and, at low levels, in a minority of SDLT cases. Qualitatively, both of these preparations were indistinguishable in SDLT from those found in AD but levels of both parameters in SDLT were less than 5% of those in AD. SDLT, PD and control groups did not differ from each other in terms of the quantity of protease-resistant PHFs or the level of hyperphosphorylated tau. Furthermore, PHF accumulation did not distinguish between PD cases with or without dementia. The levels of normal tau protein did not differ between the four groups. &amp;#914;/A4 protein levels did not distinguish between PD and control groups, between AD and SDLT groups, or between SDLT and control groups for either cingulate or occipital cortices. Thus extensive accumulation of PHFs in either neurofibrillary tangles or dystrophic neurites is not a feature of either SDLT or PD. Our findings provide molecular support for the neuropathological and clinical separation of SDLT as a form of dementia that is distinct from AD.</jats:p