In this paper, a method for generating samples of a fully non-stationary zero-mean Gaussian process, having a target acceleration time-history as one of its own samples, is presented. The proposed ...method requires the following steps: i) divide the time axis of the target accelerogram in contiguous time intervals in which a uniformly modulated process is introduced as the product of a deterministic modulating function per a stationary zero-mean Gaussian sub-process, whose power spectral density (PSD) function is filtered by two Butterworth filters; ii) estimate, in the various time intervals, the parameters of modulating functions by least-square fitting the expected energy of the proposed model to the energy of the target accelerogram; iii) estimate the parameters of the PSD function of the stationary sub-process, once the occurrences of maxima and of zero-level up-crossings of the target accelerogram, in the various intervals, are counted; iv) obtain the evolutionary spectral representation of the fully non-stationary process by adding the various contribution evaluated in the various intervals.
•The generation of artificial accelerograms consistent with real seismic records is addressed.•Main characteristics of target accelerograms are used to define fully non-stationary processes.•The target accelerogram is considered a sample of the fully non-stationary process.•The proposed method is suitable for selecting input motion for dynamic analyses of structural and geotechnical systems.•The proposed procedure is characterised by accuracy and computational efficiency.
Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to ...SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.
Cardiovascular disease (CVD) is the most common cause of death in industrialized countries. One underlying cause is atherosclerosis, which is a systemic disease characterized by plaques of retained ...lipids, inflammatory cells, apoptotic cells, calcium and extracellular matrix (ECM) proteins in the arterial wall. The biologic composition of an atherosclerotic plaque determines whether the plaque is more or less vulnerable, that is prone to rupture or erosion. Here, the ECM and tissue repair play an important role in plaque stability, vulnerability and progression. This review will focus on ECM remodelling in atherosclerotic plaques, with focus on how ECM biomarkers might predict plaque vulnerability and outcome.
Abdominal aortic aneurysm (AAA) is a complex disease which is incompletely accounted for. Basement membrane (BM) Collagen IV (COL4A1/A2) is abundant in the artery wall, and several lines of evidence ...indicate a protective role of baseline COL4A1/A2 in AAA development. Using Col4a1/a2 hemizygous knockout mice (Col4a1/a2
, 129Svj background) we show that partial Col4a1/a2 deficiency augmented AAA formation. Although unchallenged aortas were morphometrically and biomechanically unaffected by genotype, explorative proteomic analyses of aortas revealed a clear reduction in BM components and contractile vascular smooth muscle cell (VSMC) proteins, suggesting a central effect of the BM in maintaining VSMCs in the contractile phenotype. These findings were translated to human arteries by showing that COL4A1/A2 correlated to BM proteins and VSMC markers in non-lesioned internal mammary arteries obtained from coronary artery bypass procedures. Moreover, in human AAA tissue, MYH11 (VSMC marker) was depleted in areas of reduced COL4 as assessed by immunohistochemistry. Finally, circulating COL4A1 degradation fragments correlated with AAA progression in the largest Danish AAA cohort, suggesting COL4A1/A2 proteolysis to be an important feature of AAA formation. In sum, we identify COL4A1/A2 as a critical regulator of VSMC phenotype and a protective factor in AAA formation.
Background:Collagen type IV and laminin are the main constituents of basement membranes (BMs). Epitopes on these molecules are targeted in various autoimmune diseases, systemic lupus erythematosus ...(SLE) in particular. Accelerated large vessel disease is a well-recognized cause of premature cardiovascular morbidity and mortality in SLE. Novel tools for quantification of soluble MMP-derived fragments of collagen type IV (C4M) and laminin (LG1M) have emerged as promising biomarkers for BM remodeling in atherosclerosis.Objectives:To study serum levels of collagen type IV and laminin metabolites in patients with SLE and in healthy controls. And to search for associations with disease activity, organ damage and cardiovascular comorbidity.Methods:One hundred and six SLE patients without and 20 with previous CVD events were included (1). One hundred and twenty male and female blood donors aged 20-65 years served as healthy reference. Disease activity (SLEDAI) and damage (SLICC) scores were calculated. Coronary artery calcification (CAC) was studied by CT scan and expressed as Agatston score. Carotid intima-media thickness (IMT) was measured by ultrasound (LOGIQ E9, GE Healthcare). In either subgroup atherosclerosis was defined as Agatston > 99 U and/or IMT>1 mm and/or presence of plaque. C4M and LG1M were measured by competitive ELISAs (2).Results:Patient characteristics are presented in Table 1. Overall, C4M and LG1M were significantly increased in the entire SLE cohort vs. healthy controls (35.7 ± 17.5 vs. 22.3 ± 9.4 ng/mL, p<0.0001 and 20.9 ± 21.1 vs. 9.7 ± 8.0 ng/mL, p<0.0001, respectively) (Fig 1). Highly significant positive correlations were detected between C4M and LG1M in the entire SLE cohort and in the healthy control group (Fig 2).In terms of CVD and atherosclerosis LG1M was significantly higher in SLE patients with manifest CVD vs. those without (34.47 ± 41.22 vs. 18.34 ± 13.55, p=0.0015) and in those with atherosclerosis by imaging (25.53 ± 28.12 vs 17.53 ± 13.35, p=0.036). There were no associations between C4M and CVD or atherosclerosis. There was a weak association between LG1M and SLICC (r=0.22, p=0.01), but not with SLEDAI. Details on associations with other CVD risk factors and specific organ involvement will be presented.Table 1Characteristics for SLE patients with and without CVDPatients characteristicsAll (126)SLE + CVD (20)SLE without CVD (106)pFemales, no. (%)113 (89)18 (90)95 (89)0.95Age, yrs., mean ± SD50.6± 14.454.8 ± 15.346.8± 14.10.15Disease duration, yrs., mean ± SD13.9 ± 9.319.0± 11.313.0± 11.30.007SLEDAI, median, range4 (0-14)4 (0-10)4 (0-14)0.717SLICC, median, range1 (0-11)3 (1-11)1 (0-10)0.0001Atherosclerosis, no. (%)53 (42)14 (70)39 (37)0.0006LG1M (ng/ml), mean ± SD20.9± 21.234.5± 41.218.3 ± 13.60.0015C4M (ng/ml), mean ± SD35.7 ± 17.538.1± 20.635.3± 16.90.518Conclusion:Serological levels of collagen type IV and laminin biomarkers were elevated and interrelated in an unstratified SLE population. Moreover, LG1M but not C4M was significantly elevated in SLE patients with previous CVD events and in those with atherosclerosis by imaging. These findings indicate that LG1M may serve as a serological marker for SLE-related large vessel disease. However, additional extravascular sites of increased basement membrane remodeling may contribute to the abnormal biomarker pattern.References:1Kay SD, Poulsen MK, Diederichsen AC, Voss A. J Rheumatol 2016;43:315–222Sand JM, Larsen L, Hogaboam C et al. PLoS One 2013;8:e84934Kay SD and Genovese F contributed equally to this work.Figure 1.Levels of C4M and LG1M in serum of patients with SLE and healthy controls; graphs are presented as box and whiskers plot (in the style of Tukey). Statistical significance: ***p<0.0001.Figure 2.Correlation plots (Spearman r) of C4M and LG1M in SLE patients and healthy controls.Disclosure of Interests:Susan Due Kay: None declared, Federica Genovese Shareholder of: Own Nordic Bioscience stocks, Employee of: Nordic Bioscience, Anne Sofie Siebuhr Employee of: Nordic Bioscience, Morten Karsdal Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee at Nordic Bioscience A/S., Anne Voss: None declared, Peter Junker: None declared
Background
Rupture of atherosclerotic plaques is the major cause of acute cardiovascular events. The biomarker PRO‐C6 measuring Endotrophin, a matrikine of collagen type VI, may provide valuable ...information detecting subjects in need of intensified strategies for secondary prevention.
Objective
In this study, we evaluate endotrophin in human atherosclerotic plaques and circulating levels of PRO‐C6 in patients with atherosclerosis, to determine the predictive potential of the biomarker.
Methods
Sections from the stenotic human carotid plaques were stained with the PRO‐C6 antibody. PRO‐C6 was measured in serum of patients enrolled in the Carotid Plaque Imagining Project (CPIP) (discovery cohort, n = 577) and the innovative medicines initiative surrogate markers for micro‐ and macrovascular hard end‐points for innovative diabetes tools (IMI‐SUMMIT, validation cohort, n = 1,378). Median follow‐up was 43 months. Kaplan–Meier curves and log‐rank tests were performed in the discovery cohort. Cox proportional hazard regression analysis (HR with 95% CI) was used in the discovery cohort and binary logistic regression (OR with 95% CI) in the validation cohort.
Results
PRO‐C6 was localized in the core and shoulder of the atherosclerotic plaque. In the discovery cohort, PRO‐C6 independently predicted future cardiovascular events (HR 1.089 95% CI 1.019 −1.164, p = 0.01), cardiovascular death (HR 1.118 95% CI 1.008 −1.241, p = 0.04) and all‐cause death (HR 1.087 95% CI 1.008 −1.172, p = 0.03). In the validation cohort, PRO‐C6 predicted future cardiovascular events (OR 1.063 95% CI 1.011 −1.117, p = 0.017).
Conclusion
PRO‐C6 is present in the atherosclerotic plaque and associated with future cardiovascular events, cardiovascular death and all‐cause mortality in two large prospective cohorts.
Highlights • In rats, we evaluated the impact of mild TBI on conditioned fear. • Conditioned fear was implemented using a conditioned suppression procedure. • Mild TBI was produced through multiple ...blast overpressure exposures. • Mild TBI blunted the expression of a conditioned fear while not delaying extinction. • Results are relevant to a possible relationship between mTBI and PTSD.
There is a need for precision medicine and an unspoken promise of an optimal approach for identification of the right patients for value-based medicine based on big data. However, there may be a ...misconception that measurement of proteins is more valuable than measurement of fewer selected biomarkers. In population-based research, variation may be somewhat eliminated by quantity. However, this fascination of numbers may limit the attention to and understanding of the single. This review highlights that protein measurements (with collagens as examples) may mean different things depending on the targeted epitope – formation or degradation of tissues, and even signaling potential of proteins.
PubMed was searched for collagen, neo-epitope, biomarkers. Results: Ample examples of assays with specific epitopes, either pathological such as HbA1c, or domain specific such as pro-peptides, which total protein arrays would not have identified were evident.
We suggest that big data may be considered as the funnel of data points, in which most important parameters will be selected. If the technical precision is low or the biological accuracy is limited, and we include suboptimal quality of biomarkers, disguised as big data, we may not be able to fulfill the promise of helping patients searching for the optimal treatment. Alternatively, if the technical precision of the total protein quantification is high, but we miss the functional domains with the most considerable biological meaning, we miss the most important and valuable information of a given protein. This review highlights that measurements of the same protein in different ways may provide completely different meanings. We need to understand the pathological importance of each epitope quantified to maximize protein measurements.
Objective
Atherosclerosis is characterized by accumulation of lipids, cells and extracellular matrix (ECM) proteins in the arterial wall. Collagen type I (COL1), a component of the arterial ECM, is ...cleaved by matrix metalloproteinases (MMPs) and known to be remodelled in atherosclerosis. We explored whether the MMP‐mediated COL1 biomarker, C1M, was associated with cardiovascular events, cardiovascular mortality and all‐cause mortality in a large prospective cohort of patients with known atherosclerosis.
Methods
Serum from 787 patients who underwent a carotid endarterectomy was included. Circulating levels of C1M were measured in serum. A total of 473 patients were followed for 6 years after surgery. Associations between C1M and incidence of cardiovascular events, cardiovascular mortality and all‐cause mortality were assessed by Kaplan–Meier curves and Cox regression analysis.
Results
A total of 101 (21.4%) patients suffered from nonfatal cardiovascular events during the follow‐up period, and 64 (13.5%) patients died. Of these, 39 (60.9%) died from cardiovascular diseases. Patients with C1M levels above the median were significantly associated with cardiovascular events, cardiovascular mortality and all‐cause mortality (P < 0.001, P = 0.004 and P < 0.001, respectively). C1M was included in the final model for prediction of cardiovascular events (HR 2.15, 95% CI 1.40–3.32, P = 0.001), cardiovascular mortality (HR 2.20, 95% CI 1.07–4.51, P = 0.031) and all‐cause mortality (HR 2.98 95% CI 1.67–5.33, P = < 0.001).
Conclusions
In patients with atherosclerotic carotid lesions, high levels of C1M predicted cardiovascular events, cardiovascular mortality and all‐cause mortality. These findings emphasize the importance of remodelling mechanisms in atherosclerosis that are now becoming more and more explored.
Fibrotic diseases may be described as a disease of the extracellular matrix, where the balance between matrix formation and degradation has been shifted leading to an accumulation of matrix. ...Currently a fit for purpose model and readily available approach are adapted when doing cell cultures, which may not reflect physiology and pathophysiology optimally. The aim of this review is to draw special attention to the similarities and differences of current state of the art in vitro and ex vivo models, with special focus on the proteins, cell–cell interactions, and correct matrix composition, which may be a better representative of in vivo conditions in a disease where the extracellular matrix is the central player.
We reviewed current literature with emphasis on the role of the extracellular matrix in health and disease, different fibrotic disease models, and highlighting the importance of this when looking at translational science.
To further our fibrotic research one paramount problem is to fundamentally understand the core of the disease, the production and degradation of the extracellular matrix. For a surprisingly long time the ECM has been underestimated until recently, with the discovery that the ECM may control cell phenotype through cell–matrix interactions. This highlights the need of a native ECM when investigating pathways and response to potential therapy. Clearly, both in vitro and in vivo models provide fit to purpose benefits, but in particular for the fibrosis field we may ask, do single cell cultures in monolayers recapitulate the complicated ECM environment controlling cell fate?
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