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"Mathias, J."
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Lipidomic risk scores are independent of polygenic risk scores and can predict incidence of diabetes and cardiovascular disease in a large population cohort
Type 2 diabetes (T2D) and cardiovascular disease (CVD) represent significant disease burdens for most societies and susceptibility to these diseases is strongly influenced by diet and lifestyle. Physiological changes associated with T2D or CVD, such has high blood pressure and cholesterol and glucose levels in the blood, are often apparent prior to disease incidence. Here we integrated genetics, lipidomics, and standard clinical diagnostics to assess future T2D and CVD risk for 4,067 participants from a large prospective population-based cohort, the Malmö Diet and Cancer-Cardiovascular Cohort. By training Ridge regression-based machine learning models on the measurements obtained at baseline when the individuals were healthy, we computed several risk scores for T2D and CVD incidence during up to 23 years of follow-up. We used these scores to stratify the participants into risk groups and found that a lipidomics risk score based on the quantification of 184 plasma lipid concentrations resulted in a 168% and 84% increase of the incidence rate in the highest risk group and a 77% and 53% decrease of the incidence rate in lowest risk group for T2D and CVD, respectively, compared to the average case rates of 13.8% and 22.0%. Notably, lipidomic risk correlated only marginally with polygenic risk, indicating that the lipidome and genetic variants may constitute largely independent risk factors for T2D and CVD. Risk stratification was further improved by adding standard clinical variables to the model, resulting in a case rate of 51.0% and 53.3% in the highest risk group for T2D and CVD, respectively. The participants in the highest risk group showed significantly altered lipidome compositions affecting 167 and 157 lipid species for T2D and CVD, respectively. Our results demonstrated that a subset of individuals at high risk for developing T2D or CVD can be identified years before disease incidence. The lipidomic risk, which is derived from only one single mass spectrometric measurement that is cheap and fast, is informative and could extend traditional risk assessment based on clinical assays.
Journal Article
Revitalizing membrane rafts: new tools and insights
Key Points
Ten years ago, the lipid raft field was suffering from ambiguous methodology and imprecise nomenclature.
New high-resolution imaging methods are now giving insights into raft dynamics. Together with other studies, this has led to changes in our concept of rafts.
Rafts in plasma membranes can be characterized by three different states: dynamic nanoscale assemblies, raft platforms stabilized by oligomerization and micrometre-scale phase separation.
Lipidomics is beginning to give comprehensive views of the lipid composition of raft domains.
Three examples of roles that rafts have in cellular function are: T cell signalling, HIV assembly and membrane trafficking.
A key open issue for the field is how lipids interact with integral raft proteins.
Ten years ago, the cell biological role of lipid rafts was controversial owing to limited methodology and confusing nomenclature. Through technical advances, our concept of lipid rafts has evolved into that of dynamic nanoscale assemblies that can be stabilized to control signalling and membrane trafficking.
Ten years ago, we wrote a Review on lipid rafts and signalling in the launch issue of
Nature Reviews Molecular Cell Biology
. At the time, this field was suffering from ambiguous methodology and imprecise nomenclature. Now, new techniques are deepening our insight into the dynamics of membrane organization. Here, we discuss how the field has matured and present an evolving model in which membranes are occupied by fluctuating nanoscale assemblies of sphingolipids, cholesterol and proteins that can be stabilized into platforms that are important in signalling, viral infection and membrane trafficking.
Journal Article
Plant-derived coumarins shape the composition of an Arabidopsis synthetic root microbiome
The factors that contribute to the composition of the root microbiome and, in turn, affect plant fitness are not well understood. Recent work has highlighted a major contribution of the soil inoculum in determining the composition of the root microbiome. However, plants are known to conditionally exude a diverse array of unique secondary metabolites, that vary among species and environmental conditions and can interact with the surrounding biota. Here, we explore the role of specialized metabolites in dictating which bacteria reside in the rhizosphere. We employed a reduced synthetic community (SynCom) of Arabidopsis thaliana root-isolated bacteria to detect community shifts that occur in the absence of the secreted small-molecule phytoalexins, flavonoids, and coumarins. We find that lack of coumarin biosynthesis in f6′h1 mutant plant lines causes a shift in the root microbial community specifically under iron deficiency. We demonstrate a potential role for iron-mobilizing coumarins in sculpting the A. thaliana root bacterial community by inhibiting the proliferation of a relatively abundant Pseudomonas species via a redox-mediated mechanism. This work establishes a systematic approach enabling elucidation of specific mechanisms by which plant-derived molecules mediate microbial community composition. Our findings expand on the function of conditionally exuded specialized metabolites and suggest avenues to effectively engineer the rhizosphere with the aim of improving crop growth in iron-limited alkaline soils, which make up a third of the world’s arable soils.
Journal Article
Genome-wide association analysis of plasma lipidome identifies 495 genetic associations
The human plasma lipidome captures risk for cardiometabolic diseases. To discover new lipid-associated variants and understand the link between lipid species and cardiometabolic disorders, we perform univariate and multivariate genome-wide analyses of 179 lipid species in 7174 Finnish individuals. We fine-map the associated loci, prioritize genes, and examine their disease links in 377,277 FinnGen participants. We identify 495 genome-trait associations in 56 genetic loci including 8 novel loci, with a considerable boost provided by the multivariate analysis. For 26 loci, fine-mapping identifies variants with a high causal probability, including 14 coding variants indicating likely causal genes. A phenome-wide analysis across 953 disease endpoints reveals disease associations for 40 lipid loci. For 11 coronary artery disease risk variants, we detect strong associations with lipid species. Our study demonstrates the power of multivariate genetic analysis in correlated lipidomics data and reveals genetic links between diseases and lipid species beyond the standard lipids.
The human plasma lipidome captures risk for cardiometabolic diseases. Here, the authors perform univariate and multivariate genome-wide analyses of 179 lipid species in 7174 Finnish individuals, revealing genetic links between diseases and lipid species beyond the standard lipids HDL-Cholesterol, LDL-Cholesterol, Triglycerides, and total Cholesterol.
Journal Article
Direct observation of a few-photon phase shift induced by a single quantum emitter in a waveguide
Realizing a sensitive photon-number-dependent phase shift on a light beam is required both in classical and quantum photonics. It may lead to new applications for classical and quantum photonics machine learning or pave the way for realizing photon-photon gate operations. Nonlinear phase-shifts require efficient light-matter interaction, and recently quantum dots coupled to nanophotonic devices have enabled near-deterministic single-photon coupling. We experimentally realize an optical phase shift of 0.19
π
± 0.03 radians ( ≈ 34 degrees) using a weak coherent state interacting with a single quantum dot in a planar nanophotonic waveguide. The phase shift is probed by interferometric measurements of the light scattered from the quantum dot in the waveguide. The process is nonlinear in power, the saturation at the single-photon level and compatible with scalable photonic integrated circuitry. The work may open new prospects for realizing high-efficiency optical switching or be applied for proof-of-concept quantum machine learning or quantum simulation demonstrations.
The ability to imprint phase shifts on light lie at the basis of several classical and quantum light-based information processing primitives. Here, the authors demonstrate the phase shift of an optical field by a single quantum emitter in a waveguide, at the single photon level.
Journal Article
Flexibility of a Eukaryotic Lipidome – Insights from Yeast Lipidomics
Mass spectrometry-based shotgun lipidomics has enabled the quantitative and comprehensive assessment of cellular lipid compositions. The yeast Saccharomyces cerevisiae has proven to be a particularly valuable experimental system for studying lipid-related cellular processes. Here, by applying our shotgun lipidomics platform, we investigated the influence of a variety of commonly used growth conditions on the yeast lipidome, including glycerophospholipids, triglycerides, ergosterol as well as complex sphingolipids. This extensive dataset allowed for a quantitative description of the intrinsic flexibility of a eukaryotic lipidome, thereby providing new insights into the adjustments of lipid biosynthetic pathways. In addition, we established a baseline for future lipidomic experiments in yeast. Finally, flexibility of lipidomic features is proposed as a new parameter for the description of the physiological state of an organism.
Journal Article
Lower cerebral blood flow predicts cognitive decline in patients with vascular cognitive impairment
INTRODUCTION Chronic cerebral hypoperfusion is one of the assumed pathophysiological mechanisms underlying vascular cognitive impairment (VCI). We investigated the association between baseline cerebral blood flow (CBF) and cognitive decline after 2 years in patients with VCI and reference participants. METHODS One hundred eighty‐one participants (mean age 66.3 ± 7.4 years, 43.6% women) underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) and neuropsychological assessment at baseline and at 2‐year follow‐up. We determined the association between baseline global and lobar CBF and cognitive decline with multivariable regression analysis. RESULTS Lower global CBF at baseline was associated with more global cognitive decline in VCI and reference participants. This association was most profound in the domain of attention/psychomotor speed. Lower temporal and frontal CBF at baseline were associated with more cognitive decline in memory. DISCUSSION Our study supports the role of hypoperfusion in the pathophysiological and clinical progression of VCI. Highlights Impaired cerebral blood flow (CBF) at baseline is associated with faster cognitive decline in VCI and normal aging. Our results suggest that low CBF precedes and contributes to the development of vascular cognitive impairment. CBF determined by ASL might be used as a biomarker to monitor disease progression or treatment responses in VCI.
Journal Article
Mouse lipidomics reveals inherent flexibility of a mammalian lipidome
Lipidomics has become an indispensable method for the quantitative assessment of lipid metabolism in basic, clinical, and pharmaceutical research. It allows for the generation of information-dense datasets in a large variety of experimental setups and model organisms. Previous studies, mostly conducted in mice (
Mus musculus
), have shown a remarkable specificity of the lipid compositions of different cell types, tissues, and organs. However, a systematic analysis of the overall variation of the mouse lipidome is lacking. To fill this gap, in the present study, the effect of diet, sex, and genotype on the lipidomes of mouse tissues, organs, and bodily fluids has been investigated. Baseline quantitative lipidomes consisting of 796 individual lipid molecules belonging to 24 lipid classes are provided for 10 different sample types. Furthermore, the susceptibility of lipidomes to the tested parameters is assessed, providing insights into the organ-specific lipidomic plasticity and flexibility. This dataset provides a valuable resource for basic and pharmaceutical researchers working with murine models and complements existing proteomic and transcriptomic datasets. It will inform experimental design and facilitate interpretation of lipidomic datasets.
Journal Article
Prevalence of Depression, Anxiety and PTSD in People with Dementia: a Systematic Review and Meta-Analysis
There appears to be a link between depression/anxiety/PTSD and dementia, although the evidence is incomplete and the reason is unclear. Mental illness may cause dementia or may be prodromal or comorbid with dementia, or dementia may trigger a relapse of symptoms in individuals with a history of mental illness. This study examined the link between depression/anxiety/PTSD and dementia by evaluating the prevalence of these disorders in people with dementia, relative to their healthy peers. Existing meta-analyses have examined the prevalence of clinically-significant depression and anxiety in Alzheimer’s disease (AD), and depression in frontotemporal dementia (FTD), but have not considered vascular dementia (VaD), dementia with Lewy bodies (DLB), PTSD, or anxiety in FTD. The current meta-analysis compared the prevalence of clinically-significant depression, anxiety and PTSD in the four most common types of dementia (AD, VaD, DLB, FTD) and in unspecified dementia to that of healthy controls (PROSPERO number: CRD42017082086). PubMed, EMBASE, PsycINFO and CINAHL database searches identified 120 eligible studies. Prevalence rates were calculated for depression and anxiety in AD, VaD, DLB, FTD, unspecified dementia, and controls. PTSD data were only available for unspecified dementia. Subgroup analyses indicated that depression, but not anxiety, was more prevalent in people with dementia compared to controls; however, the anxiety analyses were probably under-powered. The results support a link between depression and dementia; however, the link between anxiety or PTSD and dementia remains unclear due to insufficient data. Longitudinal data is now needed to clarify whether depression/anxiety/PTSD may be risk factors for dementia.
Journal Article