The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Timing of Complete Revascularization with Multivessel PCI for Myocardial Infarction.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI) with multivessel coronary artery disease, the time at which complete revascularization of nonculprit lesions should be performed remains unknown. METHODS: We performed an international, open-label, randomized, noninferiority trial at 37 sites in Europe. Patients in a hemodynamically stable condition who had STEMI and multivessel coronary artery disease were randomly assigned to undergo immediate multivessel percutaneous coronary intervention (PCI; immediate group) or PCI of the culprit lesion followed by staged multivessel PCI of nonculprit lesions within 19 to 45 days after the index procedure (staged group). The primary end point was a composite of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year after randomization. The percentages of patients with a primary or secondary end-point event are provided as Kaplan-Meier estimates at 6 months and at 1 year. RESULTS: We assigned 418 patients to undergo immediate multivessel PCI and 422 to undergo staged multivessel PCI. A primary end-point event occurred in 35 patients (8.5%) in the immediate group as compared with 68 patients (16.3%) in the staged group (risk ratio, 0.52; 95% confidence interval, 0.38 to 0.72; P<0.001 for noninferiority and P<0.001 for superiority). Nonfatal myocardial infarction and unplanned ischemia-driven revascularization occurred in 8 patients (2.0%) and 17 patients (4.1%), respectively, in the immediate group and in 22 patients (5.3%) and 39 patients (9.3%), respectively, in the staged group. The risk of death from any cause, the risk of stroke, and the risk of hospitalization for heart failure appeared to be similar in the two groups. A total of 104 patients in the immediate group and 145 patients in the staged group had a serious adverse event. CONCLUSIONS: Among patients in hemodynamically stable condition with STEMI and multivessel coronary artery disease, immediate multivessel PCI was noninferior to staged multivessel PCI with respect to the risk of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year. (Supported by Boston Scientific; MULTISTARS AMI ClinicalTrials.gov number, NCT03135275.).

Constraining nonlinear time series modeling with the metabolic theory of ecology.

Forecasting the response of ecological systems to environmental change is a critical challenge for sustainable management. The metabolic theory of ecology (MTE) posits scaling of biological rates with temperature, but it has had limited application to population dynamic forecasting. Here we use the temperature dependence of the MTE to constrain empirical dynamic modeling (EDM), an equation-free nonlinear machine learning approach for forecasting. By rescaling time with temperature and modeling dynamics on a "metabolic time step," our method (MTE-EDM) improved forecast accuracy in 18 of 19 empirical ectotherm time series (by 19% on average), with the largest gains in more seasonal environments. MTE-EDM assumes that temperature affects only the rate, rather than the form, of population dynamics, and that interacting species have approximately similar temperature dependence. A review of laboratory studies suggests these assumptions are reasonable, at least approximately, though not for all ecological systems. Our approach highlights how to combine modern data-driven forecasting techniques with ecological theory and mechanistic understanding to predict the response of complex ecosystems to temperature variability and trends.

Angiography after Out-of-Hospital Cardiac Arrest without ST-Segment Elevation.

BACKGROUND: Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest. However, the benefits of early coronary angiography and revascularization in resuscitated patients without electrocardiographic evidence of ST-segment elevation are unclear. METHODS: In this multicenter trial, we randomly assigned 554 patients with successfully resuscitated out-of-hospital cardiac arrest of possible coronary origin to undergo either immediate coronary angiography (immediate-angiography group) or initial intensive care assessment with delayed or selective angiography (delayed-angiography group). All the patients had no evidence of ST-segment elevation on postresuscitation electrocardiography. The primary end point was death from any cause at 30 days. Secondary end points included a composite of death from any cause or severe neurologic deficit at 30 days. RESULTS: A total of 530 of 554 patients (95.7%) were included in the primary analysis. At 30 days, 143 of 265 patients (54.0%) in the immediate-angiography group and 122 of 265 patients (46.0%) in the delayed-angiography group had died (hazard ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.63; P = 0.06). The composite of death or severe neurologic deficit occurred more frequently in the immediate-angiography group (in 164 of 255 patients [64.3%]) than in the delayed-angiography group (in 138 of 248 patients [55.6%]), for a relative risk of 1.16 (95% CI, 1.00 to 1.34). Values for peak troponin release and for the incidence of moderate or severe bleeding, stroke, and renal-replacement therapy were similar in the two groups. CONCLUSIONS: Among patients with resuscitated out-of-hospital cardiac arrest without ST-segment elevation, a strategy of performing immediate angiography provided no benefit over a delayed or selective strategy with respect to the 30-day risk of death from any cause. (Funded by the German Center for Cardiovascular Research; TOMAHAWK ClinicalTrials.gov number, NCT02750462.).

Left ventricular hypertrophy as a risk factor for accelerated brain aging: Results from the Study of Health in Pomerania.

Previous studies provided evidence for the importance of cardiac structure abnormalities, in particular greater left ventricular (LV) mass, for brain aging, but longitudinal studies are lacking to date. We included 926 individuals (median age 48 years; 53% women) from the TREND cohort of the Study of Health in Pomerania (SHIP) without reduced ejection fraction or a history of myocardial infarction. LV mass index (LVMI) was determined by echocardiography at baseline. Brain morphometric measurements were derived from magnetic resonance images at baseline and 7-year follow-up. Direct effects of baseline LVMI on brain morphometry at follow-up were estimated using linear regression models with adjustment for baseline brain morphometry. At baseline, median LVMI was 40 g/m2.7 and 241 individuals (26%) met the criterion of LV hypertrophy. After correction for multiple testing, baseline LVMI was directly associated with reduced global cortical thickness and increased cortical brain age at follow-up independent from hypertension and blood pressure. Exposure-outcome relations were nonlinear and significantly stronger in the upper half of the exposure distribution. Specifically, an increase in baseline LVMI from the 50% quantile to the 95% quantile was associated additional 2.7 years (95% confidence interval = [1.5 years, 3.8 years]) of cortical brain age at follow-up. Additional regional analyses yielded bilateral effects on multiple frontal cortical regions. Our findings highlight the role of cardiac structure in brain aging. LVMI constitutes an easily measurable marker that might help to identify persons at risk for cognitive impairment and dementia.

Association of aortic diameters and mortality in the general population-an MRI-based study.

BACKGROUND: Increased diameters of the aorta are associated with increased mortality risk. In the present analyses, we assessed whether aortic diameters are associated with cardiovascular and all-cause mortality in community-dwelling individuals free of known cardiovascular disease (CVD). METHODS: MRI-derived vascular parameters of the thoracic and abdominal aorta from 2668 participants (median age = 53 years; 51.1% women) of the population-based SHIP-START-2 and SHIP-TREND-0 cohorts without CVD were analyzed. Age- and sex-adjusted, as well as multivariable-adjusted Cox-proportional hazard models, were used to estimate associations of diameters of six different aortic segments to mortality. RESULTS: Over a median follow-up time of 10.6 years (IQR: 8.7; 12.4), a total of 188 participants (126 men and 62 women) died, of which 38 deaths were due to CVD. In unadjusted models, mortality rates were higher in participants with aortic diameters above the median compared to below the median for all investigated aortic sections (all log-rank p < 0.001). In multivariable-adjusted models, the diameters of the ascending thoracic aorta (HR = 1.34 95% CI: 1.04; 1.72, p = 0.022) and of the infrarenal aorta (HR = 3.75 95% CI: 1.06; 13.3, p = 0.040), modeled continuously, were associated with greater cardiovascular mortality. The diameter of the subphrenic aorta was associated with higher cardiovascular mortality only in the age and sex-adjusted model (HR = 3.65 95% CI: 1.01; 13.3, p = 0.049). None of the investigated aortic segments were associated with all-cause mortality. CONCLUSION: Non-indexed diameters of the ascending thoracic and infrarenal aorta were associated with higher cardiovascular mortality but not with all-cause mortality in a population sample free of clinically overt CVD at baseline. CLINICAL RELEVANCE STATEMENT: Increased aortic diameter is associated with cardiovascular mortality and can help to identify high-risk patients. KEY POINTS: Increased aortic diameter is associated with mortality. Non-indexed diameters of the ascending and infrarenal aorta are associated with cardiovascular mortality but not all-cause mortality. Aortic diameter measurements support the estimate of cardiovascular mortality.

Body surface scan anthropometrics are associated with grip strength in the general population.

BACKGROUND AND AIM: Body shape and anthropometrics are well-known risk factors for cardiovascular diseases (CVD) and mortality. Hand-grip strength (HGS) is also a meaningful marker of health and a promising predictor of CVD and mortality. There is a lack of studies that have systematically investigated associations between body shape and anthropometrics with HGS. In a population-based study, we investigated if anthropometric markers derived from 3D body scanning are related to HGS. METHODS AND RESULTS: We used the data of 1,599 individuals aged 36 to 93 years, who participated in the Study of Health in Pomerania. A total of 87 anthropometric markers, determined by a 3D body scanner, were included in the analysis. Anthropometric measurements were standardized and used as exposure variables. HGS was measured with a hand dynamometer and used as outcome. Sex-stratified linear regression models adjusted for age and height were used to relate standardized anthropometrics and HGS. Anthropometric markers were ranked according to -log-p-values. In men, left and right forearm circumference, left arm length to neck (C7), left forearm length, and forearm-fingertip length were most strongly related to HGS. In women, right forearm circumference, forearm-fingertip length, shoulder breadth, left forearm circumference, and right wrist circumference showed the most significant associations with HGS. The final prediction models contained 13 anthropometric markers in males (R2=0.54) and eight anthropometric markers in females (R2=0.37). CONCLUSIONS: The identified parameters may help estimate HGS in the clinical setting. However, studies in clinical settings are essential to validating our findings.

Associations between 47 anthropometric markers derived from a body scanner and relative fat-free mass in a population-based study.

BACKGROUND: Low relative fat free mass (FFM) is associated with a greater risk of chronic diseases and mortality. Unfortunately, FFM is currently not being measured regularly to allow for individuals therapy. OBJECTIVE: One reason why FFM is not being used may be related to additional equipment and resources, thus we aimed to identify easily accessible anthropometric markers related with FFM. MATERIALS AND METHODS: We analyzed data of 1,593 individuals (784 women; 49.2%, age range 28-88 years) enrolled in the population-based Study of Health in Pomerania (SHIP-TREND 1). Forty-seven anthropometric markers were derived from a 3D optical body-scanner. FFM was assessed by bioelectrical impedance analysis (FFMBIA) or air displacement plethysmography (FFMADP). In sex-stratified linear regression models, FFM was regressed on anthropometric measurements adjusted for body height and age. Anthropometric markers were ranked according to the coefficient of determination (R2) derived from these regression models. RESULTS: Circumferences of high hip, belly, middle hip, waist and high waist showed the strongest inverse associations with FFM. These relations were stronger in females than in males. Associations of anthropometric markers with FFMAPD were greater compared to FFMBIA. CONCLUSION: Anthropometric measures were more strongly associated with FFMADP compared to FFMBIA. Anthropometric markers like circumferences of the high or middle hip, belly or waist may be appropriate surrogates for FFM to aid in individualized therapy. Given that the identified markers are representative of visceral adipose tissue, the connection between whole body strength as surrogate for FFM and fat mass should be explored in more detail.

Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

Integrative Analyses of Circulating Proteins and Metabolites Reveal Sex Differences in the Associations with Cardiac Function among DCM Patients.

Dilated cardiomyopathy (DCM) is characterized by reduced left ventricular ejection fraction (LVEF) and left or biventricular dilatation. We evaluated sex-specific associations of circulating proteins and metabolites with structural and functional heart parameters in DCM. Plasma samples (297 men, 71 women) were analyzed for proteins using Olink assays (targeted analysis) or LC-MS/MS (untargeted analysis), and for metabolites using LC MS/MS (Biocrates AbsoluteIDQ p180 Kit). Associations of proteins (n = 571) or metabolites (n = 163) with LVEF, measured left ventricular end diastolic diameter (LVEDDmeasured), and the dilation percentage of LVEDD from the norm (LVEDDacc. to HENRY) were examined in combined and sex-specific regression models. To disclose protein-metabolite relations, correlation analyses were performed. Associations between proteins, metabolites and LVEF were restricted to men, while associations with LVEDD were absent in both sexes. Significant metabolites were validated in a second independent DCM cohort (93 men). Integrative analyses demonstrated close relations between altered proteins and metabolites involved in lipid metabolism, inflammation, and endothelial dysfunction with declining LVEF, with kynurenine as the most prominent finding. In DCM, the loss of cardiac function was reflected by circulating proteins and metabolites with sex-specific differences. Our integrative approach demonstrated that concurrently assessing specific proteins and metabolites might help us to gain insights into the alterations associated with DCM.

Intermittent instability is widespread in plankton communities.

Chaotic dynamics appear to be prevalent in short-lived organisms including plankton and may limit long-term predictability. However, few studies have explored how dynamical stability varies through time, across space and at different taxonomic resolutions. Using plankton time series data from 17 lakes and 4 marine sites, we found seasonal patterns of local instability in many species, that short-term predictability was related to local instability, and that local instability occurred most often in the spring, associated with periods of high growth. Taxonomic aggregates were more stable and more predictable than finer groupings. Across sites, higher latitude locations had higher Lyapunov exponents and greater seasonality in local instability, but only at coarser taxonomic resolution. Overall, these results suggest that prediction accuracy, sensitivity to change and management efficacy may be greater at certain times of year and that prediction will be more feasible for taxonomic aggregates.

The Impact of Molecular Subtyping on Pathological Staging of Pancreatic Cancer.

BACKGROUND: The long-term outcomes following surgical resection for pancreatic ductal adenocarcinoma (PDAC) remains poor, with only 20% of patients surviving 5 years after pancreatectomy. Patient selection for surgery remains suboptimal largely due to the absence of consideration of aggressive tumor biology. OBJECTIVE: The aim of this study was to evaluate traditional staging criteria for PDAC in the setting of molecular subtypes. METHODS: Clinicopathological data were obtained for 5 independent cohorts of consecutive unselected patients, totaling n = 1298, including n = 442 that underwent molecular subtyping. The main outcome measure was disease-specific survival following surgical resection for PDAC stratified according to the American Joint Commission for Cancer (TNM) staging criteria, margin status, and molecular subtype. RESULTS: TNM staging criteria and margin status confers prognostic value only in tumors with classical pancreatic subtype. Patients with tumors that are of squamous subtype, have a poor outcome irrespective of favorable traditional pathological staging [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, P = 0.032]. Margin status has no impact on survival in the squamous subtype (16.0 vs 12.1 months, P = 0.374). There were no differences in molecular subtype or gene expression of tumors with positive resection margin status. CONCLUSIONS: Aggressive tumor biology as measured by molecular subtype predicts poor outcome following pancreatectomy for PDAC and should be utilized to inform patient selection for surgery.

Three segment ligation of a 104 kDa multi-domain protein by SrtA and OaAEP1.

NMR spectroscopy is an excellent tool for studying protein structure and dynamics which provides a deeper understanding of biological function. As the size of the biomolecule of interest increases, it can become advantageous to dilute the number of observed signals in the NMR spectrum to decrease spectral overlap and increase resolution. One way to limit the number of resonances in the NMR data is by selectively labeling a smaller domain within the larger macromolecule, a process called segmental isotopic labeling. Many examples of segmental isotopic labeling have been described where two segments of a protein are ligated together by chemical or enzymatic means, but there are far fewer descriptions of a three or more segment ligation reaction. Herein, we describe an enzymatic segmental labeling scheme that combines the widely used Sortase A and more recently described OaAEP1 for a two site ligation strategy. In preparation to study proposed long-range allostery in the 104 kDa DNA damage repair protein Rad50, we ligated side-chain methyl group labeled Zn Hook domain between two long segments of otherwise unlabeled P.furiosus Rad50. Enzymatic activity data demonstrated that the scars resulting from the ligation reactions did not affect Rad50 function within the Mre11-Rad50 DNA double strand break repair complex. Finally, methyl-based NMR spectroscopy confirmed the formation of the full-length ligated protein. Our strategy highlights the strengths of OaAEP1 for segmental labeling, namely faster reaction times and a smaller recognition sequence, and provides a straightforward template for using these two enzymes in multisite segmental labeling reactions.

Carotid intima-media thickness and atherosclerotic plaques are associated with renal function decline: a 14-year longitudinal population-based study.

BACKGROUND: Chronic kidney disease (CKD) leads to increased morbidity and mortality. The underlying causes of CKD are often similar to those of atherosclerosis. We investigated whether carotid atherosclerotic parameters are associated with renal function decline. METHODS: Within the population-based Study of Health in Pomerania (SHIP), Germany, 2904 subjects were observed over 14 years. The carotid intima-media thickness (cIMT) as well as carotid plaques were measured by standardized B-mode ultrasound protocol. CKD is defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and albuminuria as urinary albumin-creatinine ratio (ACR) ≥30 mg/g. eGFR was calculated by the full age spectrum (FAS) equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Mixed models were applied to associate carotid parameters with change in renal function longitudinally and adjusted for confounding. RESULTS: The age range of the study sample was 25-86 years with a median of 54 years at baseline. In longitudinal analyses, subjects with high cIMT and the presence of plaques at baseline showed a greater decrease in eGFR (cIMT: FAS-eGFR: P < .001, CKD-EPI-eGFR: P < .001; plaques: FAS-eGFR: P < .001, CKD-EPI-eGFR: n.s.) as well as an increased risk of developing CKD during the follow-up (cIMT: FAS-eGFR: P = .001, CKD-EPI-eGFR: P = .04; plaques: FAS-eGFR: P = .008, CKD-EPI-eGFR: P = .001). There was no association between atherosclerotic parameters and the risk of developing albuminuria. CONCLUSIONS: cIMT and carotid plaques are associated with renal function decline as well as CKD in a population-based sample. Furthermore, the FAS equation adapts best to this study population.

A new approach for clinical translation of infrared spectroscopy: exploitation of the signature of glioblastoma for general brain tumor recognition.

PURPOSE: Infrared (IR) spectroscopy has the potential for tumor delineation in neurosurgery. Previous research showed that IR spectra of brain tumors are generally characterized by reduced lipid-related and increased protein-related bands. Therefore, we propose the exploitation of these common spectral changes for brain tumor recognition. METHODS: Attenuated total reflection IR spectroscopy was performed on fresh specimens of 790 patients within minutes after resection. Using principal component analysis and linear discriminant analysis, a classification model was developed on a subset of glioblastoma (n = 135) and non-neoplastic brain (n = 27) specimens, and then applied to classify the IR spectra of several types of brain tumors. RESULTS: The model correctly classified 82% (517/628) of specimens as "tumor" or "non-tumor", respectively. While the sensitivity was limited for infiltrative glioma, this approach recognized GBM (86%), other types of primary brain tumors (92%) and brain metastases (92%) with high accuracy and all non-tumor samples were correctly identified. CONCLUSION: The concept of differentiation of brain tumors from non-tumor brain based on a common spectroscopic tumor signature will accelerate clinical translation of infrared spectroscopy and related technologies. The surgeon could use a single instrument to detect a variety of brain tumor types intraoperatively in future clinical settings. Our data suggests that this would be associated with some risk of missing infiltrative regions or tumors, but not with the risk of removing non-tumor brain.

Topographic Mapping of the Primary Sensory Cortex Using Intraoperative Optical Imaging and Tactile Irritation.

The determination of exact tumor boundaries within eloquent brain regions is essential to maximize the extent of resection. Recent studies showed that intraoperative optical imaging (IOI) combined with median nerve stimulation is a helpful tool for visualization of the primary sensory cortex (PSC). In this technical note, we describe a novel approach of using IOI with painless tactile irritation to demonstrate the feasibility of topographic mapping of different body regions within the PSC. In addition, we compared the IOI results with preoperative functional MRI (fMRI) findings. In five patients with tumors located near the PSC who received tumor removal, IOI with tactile irritation of different body parts and fMRI was applied. We showed that tactile irritation of the hand in local and general anesthesia leads to reliable changes of cerebral blood volume during IOI. Hereby, we observed comparable IOI activation maps regarding the median nerve stimulation, fMRI and tactile irritation of the hand. The tactile irritation of different body areas revealed a plausible topographic distribution along the PSC. With this approach, IOI is also suitable for awake surgeries, since the tactile irritation is painless compared with median nerve stimulation and is congruent to fMRI findings. Further studies are ongoing to standardize this method to enable a broad application within the neurosurgical community.

Low-grade inflammation is associated with a heterogeneous lipoprotein subclass profile in an apparently healthy population sample.

BACKGROUND AND AIMS: Prevention measures for cardiovascular diseases (CVD) have shifted their focus from lipoproteins to the immune system. However, low-grade inflammation and dyslipidemia are tightly entangled. The objective of this study was to assess the relations between a broad panel of inflammatory biomarkers and lipoprotein subclass parameters. METHODS: We utilized data from the population-based Study of Health in Pomerania (SHIP-TREND, n = 403). Plasma concentrations of 37 inflammatory markers were measured by a bead-based assay. Furthermore, we employed nuclear magnetic resonance spectroscopy to measure total cholesterol, total triglycerides, total phospholipids as well as the fractional concentrations of cholesterol, triglycerides, phospholipids, ApoA1, ApoA2 and ApoB in all major lipoprotein subclasses. Associations between inflammatory biomarkers and lipoprotein subclasses were analyzed by adjusted linear regression models. RESULTS: APRIL, BAFF, TWEAK, sCD30, Pentraxin-3, sTNFR1, sTNFR2, Osteocalcin, Chitinase 3-like 1, IFN-alpha2, IFN-gamma, IL-11, IL-12p40, IL-29, IL-32, IL-35, TSLP, MMP1 and MMP2 were related with lipoprotein subclass components, forming two distinct clusters. APRIL had inverse relations to HDL-C (total and subclasses) and HDL Apo-A1 and Apo-A2 content. MMP-2 was inversely related to VLDL-C (total and subclasses), IDL-C as well as LDL5/6-C and VLDL-TG, IDL-TG, total triglycerides as well as LDL5/5-TG and HDL4-TG. Additionally, we identified a cluster of cytokines linked to the Th1-immune response, which were associated with an atherogenic lipoprotein profile. CONCLUSION: Our findings expand the existing knowledge of inflammation-lipoprotein interactions, many of which are suggested to be involved in the pathogeneses of chronic non-communicable diseases. The results of our study support the use of immunomodulatory substances for the treatment and possibly prevention of CVD.

Hidden similarities in the dynamics of a weakly synchronous marine metapopulation.

Populations of many marine species are only weakly synchronous, despite coupling through larval dispersal and exposure to synchronous environmental drivers. Although this is often attributed to observation noise, factors including local environmental differences, spatially variable dynamics, and chaos might also reduce or eliminate metapopulation synchrony. To differentiate spatially variable dynamics from similar dynamics driven by spatially variable environments, we applied hierarchical delay embedding. A unique output of this approach, the "dynamic correlation," quantifies similarity in intrinsic dynamics of populations, independently of whether their abundance is correlated through time. We applied these methods to 17 populations of blue crab (Callinectes sapidus) along the US Atlantic coast and found that their intrinsic dynamics were broadly similar despite largely independent fluctuations in abundance. The weight of evidence suggests that the latitudinal gradient in temperature, filtered through a unimodal response curve, is sufficient to decouple crab populations. As unimodal thermal performance is ubiquitous in ectotherms, we suggest that this may be a general explanation for the weak synchrony observed at large distances in many marine species, although additional studies are needed to test this hypothesis.

Fast behavioral feedbacks make ecosystems sensitive to pace and not just magnitude of anthropogenic environmental change.

Anthropogenic environmental change is altering the behavior of animals in ecosystems around the world. Although behavior typically occurs on much faster timescales than demography, it can nevertheless influence demographic processes. Here, we use detailed data on behavior and empirical estimates of demography from a coral reef ecosystem to develop a coupled behavioral-demographic ecosystem model. Analysis of the model reveals that behavior and demography feed back on one another to determine how the ecosystem responds to anthropogenic forcing. In particular, an empirically observed feedback between the density and foraging behavior of herbivorous fish leads to alternative stable ecosystem states of coral population persistence or collapse (and complete algal dominance). This feedback makes the ecosystem more prone to coral collapse under fishing pressure but also more prone to recovery as fishing is reduced. Moreover, because of the behavioral feedback, the response of the ecosystem to changes in fishing pressure depends not only on the magnitude of changes in fishing but also on the pace at which changes are imposed. For example, quickly increasing fishing to a given level can collapse an ecosystem that would persist under more gradual change. Our results reveal conditions under which the pace and not just the magnitude of external forcing can dictate the response of ecosystems to environmental change. More generally, our multiscale behavioral-demographic framework demonstrates how high-resolution behavioral data can be incorporated into ecological models to better understand how ecosystems will respond to perturbations.

Ancestral genetic variation in phenotypic plasticity underlies rapid evolutionary changes in resurrected populations of waterfleas.

The role of phenotypic plasticity in adaptive evolution has been debated for decades. This is because the strength of natural selection is dependent on the direction and magnitude of phenotypic responses to environmental signals. Therefore, the connection between plasticity and adaptation will depend on the patterns of plasticity harbored by ancestral populations before a change in the environment. Yet few studies have directly assessed ancestral variation in plasticity and tracked phenotypic changes over time. Here we resurrected historic propagules of Daphnia spanning multiple species and lakes in Wisconsin following the invasion and proliferation of a novel predator (spiny waterflea, Bythotrephes longimanus). This approach revealed extensive genetic variation in predator-induced plasticity in ancestral populations of Daphnia It is unlikely that the standing patterns of plasticity shielded Daphnia from selection to permit long-term coexistence with a novel predator. Instead, this variation in plasticity provided the raw materials for Bythotrephes-mediated selection to drive rapid shifts in Daphnia behavior and life history. Surprisingly, there was little evidence for the evolution of trait plasticity as genetic variation in plasticity was maintained in the face of a novel predator. Such results provide insight into the link between plasticity and adaptation and highlight the importance of quantifying genetic variation in plasticity when evaluating the drivers of evolutionary change in the wild.