26 research outputs found
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
Effects of reduced salinity on the photosynthetic characteristics and intracellular DMSP concentrations of the red coralline alga, Lithothamnion glaciale
This work was conducted whilst HB was in receipt of a Natural Environment Research Council studentship (NE/H525303/1), and a Marine Alliance for Science and Technology for Scotland (MASTS) Research Fellowship, and whilst NK was in receipt of a Royal Society of Edinburgh/Scottish Government fellowship (RES 48704/1).Mid- to high-latitude fjordic coastal environments experience naturally variable salinity regimes. Climate projections suggest that freshwater input into the coastal ocean will increase in the future, exposing coastal organisms to further periods of reduced salinity. This study investigated the effect of low salinity on Lithothamnion glaciale, a red coralline alga found in mid- to high-latitude fjordic regions, during a 21-day experiment. Specific measurements included: the intracellular concentration of dimethylsulphoniopropionate (DMSP, an algal secondary metabolite and major precursor to the climatically active gas dimethylsulphide), pigment composition and photosynthetic characteristics. No significant difference in intracellular DMSP concentrations was observed between treatments, suggesting that the primary function for DMSP in L. glaciale is not as a compatible solute, perhaps favouring an antioxidant role. Photosynthetic parameters (including pigment composition) exhibited a mixed response, suggesting some degree of photosynthetic resilience to reduced salinity. This study provides evidence of intracellular mechanisms adopted by L. glaciale in response to reduced salinity. This has significant implications for the survival of L. glaciale under a projected freshening scenario and provides organism-level detail to ecosystem-level projected changes should lower-salinity conditions become more frequent and more intense in the future.Publisher PDFPeer reviewe
Gene expression signature: a powerful approach for drug discovery in diabetes
Type 2 diabetes (T2D) is increasing in prevalence at an alarming rate around the world. Much effort has gone into the discovery and design of antidiabetic drugs; however, those already available are unable to combat the underlying causes of the disease and instead only moderate the symptoms. The reason for this is that T2D is a complex disease, and attempts to target one biological pathway are insufficient to combat the full extent of the disease. Additionally, the underlying pathophysiology of this disease is yet to be fully elucidated making it difficult to design drugs that target the mechanisms involved. Therefore, the approach of designing new drugs aimed at a specific molecular target is not optimal and a more expansive, unbiased approach is required. In this review, we will look at the current state of diabetes treatments and how these target the disease symptoms but are unable to combat the underlying causes. We will also review how the technique of gene expression signatures (GESs) has been used successfully for other complex diseases and how this may be applied as a powerful tool for the discovery of new drugs for T2D
Red coralline algae as a source of marine biogenic dimethylsulphoniopropionate
The biogenic gas dimethylsulphide (DMS), derived from dimethylsulphoniopropionate (DMSP), plays an important role in the Earth’s albedo, and thus climate regulation, through the formation of aerosols and cloud condensation nuclei. It is estimated that biogenic sources of DMS contribute 42% (mean) of the atmospheric sulphur burden and, significantly, >90% of that contribution is derived from marine sources. Phytoplankton, macroalgae and corals are thought to be the main producers of marine biogenic DMSP. Red coralline algae (known as maerl or rhodoliths) cover extensive areas of seabed, yet despite their widespread global distribution, maerl-forming coralline algae have received little or no attention regarding their DMSP productivity. In the present study we report for the first time the occurrence of DMSP in 2 species of maerl. DMSP concentrations were found to average 1914 nmol g–1 for soft tissue and estimated to be 637 µmol m–2 for maerl beds. In incubation experiments, maerl led to a dissolved DMSP (DMSPd) increase at a rate of 57.4 to 767.6 nmol m–2 d–1 in surrounding seawater, indicating that maerl contributes to DMSPd concentrations in the adjacent water column. Results show that maerl beds are a previously undiscovered source of DMSP in the marine environment. Further study is warranted to assess the significance of maerl as a source of DMSP and the role coralline algae may play in the biogenic sulphur cycle
The effect of chronic and acute low pH on the intracellular DMSP production and epithelial cell morphology of red coralline algae
The release of dimethylsulphoniopropionate (DMSP) by marine algae has major impacts on the global sulphur cycle and
may influence local climate through the formation of dimethylsulphide (DMS). However, the effect of global change on DMSP/DMS (DMS(P)) production by algae is not well understood. This study examined the effect of low pH on DMS(P) production and epithelial cell morphology of the free-living red coralline alga Lithothamnion glaciale. Three pH treatments were used in the 80-day experiment: (1) current pH level (8.18, control), (2) low, chronic pH representing a 2100 ocean acidification (OA) scenario (7.70) and (3) low, acute pH (7.75, with a 3-day spike to 6.47), representing acute variable conditions that might be associated with leaks from carbon capture and storage infrastructure, at CO2 vent sites or in areas of upwelling. DMS(P) production was not significantly enhanced under low, stable pH conditions, indicating that red coralline algae may have some resilience to OA. However, intracellular and water column DMS(P) concentrations were significantly higher than the control when pH was acutely spiked. Cracks were observed between the cell walls of the algal skeleton in both low pH treatments. It is proposed that this structural change may cause membrane damage that allows DMS(P) to leak from the cells into the water column, with subsequent implications for the cycling of DMS(P) in coralline algae habitats