A chalcone synthase-like bacterial protein catalyzes heterocyclic c-ring cleavage of naringenin to alter bioactivity against nuclear receptors in colonic epithelial cells

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Spatial and temporal melt variability at Helheim Glacier, East Greenland, and its effect on ice dynamics

This is the publisher's version, also available electronically from "http://onlinelibrary.wiley.com".[1] Understanding the behavior of large outlet glaciers draining the Greenland Ice Sheet is critical for assessing the impact of climate change on sea level rise. The flow of marine-terminating outlet glaciers is partly governed by calving-related processes taking place at the terminus but is also influenced by the drainage of surface runoff to the bed through moulins, cracks, and other pathways. To investigate the extent of the latter effect, we develop a distributed surface-energy-balance model for Helheim Glacier, East Greenland, to calculate surface melt and thereby estimate runoff. The model is driven by data from an automatic weather station operated on the glacier during the summers of 2007 and 2008, and calibrated with independent measurements of ablation. Modeled melt varies over the deployment period by as much as 68% relative to the mean, with melt rates approximately 77% higher on the lower reaches of the glacier trunk than on the upper glacier. We compare melt variations during the summer season to estimates of surface velocity derived from global positioning system surveys. Near the front of the glacier, there is a significant correlation (on >95% levels) between variations in runoff (estimated from surface melt) and variations in velocity, with a 1 day delay in velocity relative to melt. Although the velocity changes are small compared to accelerations previously observed following some calving events, our findings suggest that the flow speed of Helheim Glacier is sensitive to changes in runoff. The response is most significant in the heavily crevassed, fast-moving region near the calving front. The delay in the peak of the cross-correlation function implies a transit time of 12–36 h for surface runoff to reach the bed

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

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 hospitalization2–4 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

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

Investigation of tumour suppressor microRNA-424(322)/503 in the regulation of mammary epithelial cell stemness and metabolism

Ph. D. Thesis.Mammary glands are composed of heterogeneous cells that coordinate remodelling throughout a woman’s lifetime. Molecular networks underlying changes in the normal mammary gland become increasingly complicated upon malignant transformation. Part of the complexity is due to breast cancer cells that adopt features similar to embryonic stem cells. In relation to more differentiated cells within a tumour bulk, stem-like cells are self-renewing and highly adaptable. Cellular metabolism largely influences the promotion and maintenance of stemness in breast cancer. The specific events, and the mechanisms by which they are controlled, require further exploration. MicroRNAs (miRNAs) are noncoding RNA molecules that regulate gene expression through translational repression of target messenger RNAs. The genomic region of tumour suppressive miR-424(322)/503 is deleted in a subset of primary breast tumours, and knockout mice form invasive carcinomas. The mechanisms by which loss of this miRNA cluster contributes to tumorigenesis are undefined. The current PhD thesis investigated the acquisition of stemness and metabolic reprogramming upon loss of miR-424(322)/503. Knockout and knockdown of miR-424/503 in MCF-10A cells was achieved using CRISPR and miRNA inhibitors, respectively. Stemness was determined by relative expression of pluripotency transcription factors, and mammosphere formation. Metabolism was investigated using a Seahorse XF Analyser and quantifying relative activity of metabolic enzymes. To identify targets, computational algorithms and gene expression tools were applied. Reduction of miR-424(322)/503 in mammary epithelial cells increased the expression of stemness markers and mammosphere formation. Mitochondrial respiration and glycolysis were enhanced in cells with reduced or deleted miR-424(322)/503. Depletion of miR-424(322)/503 impaired pyruvate oxidation, rendering cells dependent on glutamine to maintain high rates of oxygen consumption. Mechanistically, miR-424(322)/503 regulated pluripotency and metabolism via direct targeting of zinc finger protein 217 (ZNF217). Repression of the transcription factor was sufficient to reverse the stem-like and metabolic phenotypes. The current thesis revealed previously unknown roles for miR-424(322)/503 and ZNF217 in regulating the metabolism of mammary epithelial cells. Correlations and mechanisms discovered here offer insight into the major phenotype of knockout mice - breast tumorigenesis. If repression of ZNF217 and/or glutamine deprivation impairs the ability of cells to transform and progress into mammary tumours in vivo, these vulnerabilities may establish an efficient strategy for targeting stemness in miR-424(322)/503-negative/low breast tumours.The JGW Patterson Foundation, The Academy of Medical Sciences at Newcastle University

Sudden increase in tidal response linked to calving and acceleration at a large Greenland outlet glacier

This is the publisher's version, also available electronically from "http://onlinelibrary.wiley.com/".[1] Large calving events at Greenland's largest outlet glaciers are associated with glacial earthquakes and near-instantaneous increases in glacier flow speed. At some glaciers and ice streams, flow is also modulated in a regular way by ocean tidal forcing at the terminus. At Helheim Glacier, analysis of geodetic data shows decimeter-level periodic position variations in response to tidal forcing. However, we also observe transient increases of more than 100% in the glacier's responsiveness to such tidal forcing following glacial-earthquake calving events. The timing and amplitude of the changes correlate strongly with the step-like increases in glacier speed and longitudinal strain rate associated with glacial earthquakes. The enhanced response to the ocean tides may be explained by a temporary disruption of the subglacial drainage system and a concomitant reduction of the friction at the ice-bedrock interface, and suggests a new means by which geodetic data may be used to infer glacier properties

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease