Gene and metabolite expression dependence on body mass index in human myocardium

Funding Van Geest Foundation, Leicester NIHR Biomedical Research Centre, British Heart Foundation CH/12/1/29419, AA18/3/34220. Competing interests Mrs. Kumar, Prof. Murphy and Dr Woźniak received a grant from Zimmer Biomet. Dr Murphy also received grants from Terumo and Baxter. The remaining authors have disclosed that they do not have any potential conflicts of interest.Peer reviewedPublisher PD

Investigating reproductive development in Brachypodium distachyon focussing on the YABBY family of transcription factors

Brachypodium, as a sister to the core pooids containing wheat, barley, oats and rye, represents a good model and point of comparison for the study of development and evolution in temperate cereals. Using a comparative cellular developmental and transcriptomic approach, we investigated regulation of key stages in grain development. This was achieved by generating a transcriptome incorporating several distinct developmental stages of Brachypodium grains; pre-anthesis ovaries, young grain (1-3 DAA), mid-length grain (3-8 DAA), full-length (8-15 DAA) and mature grain (15-24 DAA), mature grain (without embryo), germinating grains and seedlings stage. By looking at the differential expression of genes through grain development we identified clusters that coincide with the initiation of key developmental stages, such as the initiation of endosperm proliferation, cellularisation and differentiation, as well as the activation of specific metabolic pathways, such as starch and protein biosynthesis. Focus was given to members of the YABBY gene family that have an established role in promoting abaxial cell fate and as master regulators of reproductive development in eudicots, but with less clarity in grass species. Using Brachypodium as the model plant for cereal crops, the orthologues of YABBY genes in grasses were identified and subjected to detailed phylogenetic, expression and functional analyses using Bayesian Interference (BI) analyses, RT-PCR, transcriptomics, mRNA in situ hybridization (ISH) and RNAi. Based on several analyses, YABBY6 was suggested as a novel candidate of transcription factors regulating seed development in Brachypodium. Metadata from Chapter 2 were used to extract similar expression genes of YABBY family members and potential motifs regulated in polarity networks involving YABBY genes were suggested

Vascular smooth muscle cell senescence accelerates medin aggregation via small extracellular vesicle secretion and extracellular matrix reorganization

Vascular amyloidosis, caused when peptide monomers aggregate into insoluble amyloid, is a prevalent age‐associated pathology. Aortic medial amyloid (AMA) is the most common human amyloid and is composed of medin, a 50‐amino acid peptide. Emerging evidence has implicated extracellular vesicles (EVs) as mediators of pathological amyloid accumulation in the extracellular matrix (ECM). To determine the mechanisms of AMA formation with age, we explored the impact of vascular smooth muscle cell (VSMC) senescence, EV secretion, and ECM remodeling on medin accumulation. Medin was detected in EVs secreted from primary VSMCs. Small, round medin aggregates colocalized with EV markers in decellularized ECM in vitro and medin was shown on the surface of EVs deposited in the ECM. Decreasing EV secretion with an inhibitor attenuated aggregation and deposition of medin in the ECM. Medin accumulation in the aortic wall of human subjects was strongly correlated with age and VSMC senescence increased EV secretion, increased EV medin loading and triggered deposition of fibril‐like medin. Proteomic analysis showed VSMC senescence induced changes in EV cargo and ECM composition, which led to enhanced EV‐ECM binding and accelerated medin aggregation. Abundance of the proteoglycan, HSPG2, was increased in the senescent ECM and colocalized with EVs and medin. Isolated EVs selectively bound to HSPG2 in the ECM and its knock‐down decreased formation of fibril‐like medin structures. These data identify VSMC‐derived EVs and HSPG2 in the ECM as key mediators of medin accumulation, contributing to age‐associated AMA development

Runx2 (Runt-Related Transcription Factor 2) Links the DNA Damage Response to Osteogenic Reprogramming and Apoptosis of Vascular Smooth Muscle Cells

Objective: The development of ectopic vascular calcification is strongly linked with organismal aging, which is primarily caused by the accumulation of DNA damage over time. As Runx2 (Runt-related transcription factor 2) has been identified as a regulator of vascular smooth muscle cell osteogenic transition, a key component of vascular calcification, we examined the relationship between DNA damage and Runx2 activation. Approach and Results: We found genotoxic stress-stimulated Runx2 accumulation and transactivation of its osteogenic target genes, leading to enhanced calcification. Inhibition of DNA damage signaling attenuated this response. Runx2 localized to sites of DNA damage and participated in DNA repair by regulating phosphorylation events on histone H2AX, with exogenous expression of Runx2 resulting in unrepaired DNA damage and increased apoptosis. Mechanistically, Runx2 was PARylated in response to genotoxic stress, and inhibition of this modification disrupted its localization at DNA lesions and reduced its binding to osteogenic gene promoters. Conclusions: These data identify Runx2 as a novel component of the DNA damage response, coupling DNA damage signaling to both osteogenic gene transcription and apoptosis and providing a mechanism for accelerated mineralization in aging and chronic disease

Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: a network meta-analysis

BackgroundPatient blood management (PBM) interventions aim to improve clinical outcomes by reducing bleeding and transfusion. We assessed whether existing evidence supports the routine use of combinations of these interventions during and after major surgery.MethodsFive systematic reviews and a National Institute of Health and Care Excellence health economic review of trials of common PBM interventions enrolling participants of any age undergoing surgery were updated. The last search was on June 1, 2019. Studies in trauma, burns, gastrointestinal haemorrhage, gynaecology, dentistry, or critical care were excluded. The co-primary outcomes were: risk of receiving red cell transfusion and 30-day or hospital all-cause mortality. Treatment effects were estimated using random-effects models and risk ratios (RR) with 95% confidence intervals (CIs). Heterogeneity assessments used I2. Network meta-analyses used a frequentist approach. The protocol was registered prospectively (PROSPERO CRD42018085730).ResultsSearches identified 393 eligible randomised controlled trials enrolling 54 917 participants. PBM interventions resulted in a reduction in exposure to red cell transfusion (RR=0.60; 95% CI 0.57, 0.63; I2=77%), but had no statistically significant treatment effect on 30-day or hospital mortality (RR=0.93; 95% CI 0.81, 1.07; I2=0%). Treatment effects were consistent across multiple secondary outcomes, sub-groups and sensitivity analyses that considered clinical setting, type of intervention, and trial quality. Network meta-analysis did not demonstrate additive benefits from the use of multiple interventions. No trial demonstrated that PBM was cost-effective.ConclusionsIn randomised trials, PBM interventions do not have important clinical benefits beyond reducing bleeding and transfusion in people undergoing major surgery.</p