Clustering of multivariate time series is a central problem in data mining with applications in many fields. Frequently, the clustering target is to identify groups of series generated by the same ...multivariate stochastic process. Most of the approaches to address this problem include a prior step of dimensionality reduction which may result in a loss of information or consider dissimilarity measures based on correlations and cross-correlations but ignoring the serial dependence structure. We propose a novel approach to measure dissimilarity between multivariate time series aimed at jointly capturing both cross dependence and serial dependence. Specifically, each series is characterized by a set of matrices of estimated quantile cross-spectral densities, where each matrix corresponds to a pair of quantile levels. Then the dissimilarity between every couple of series is evaluated by comparing their estimated quantile cross-spectral densities, and the pairwise dissimilarity matrix is taken as starting point to develop a partitioning around medoids algorithm. Since the quantile-based cross-spectra capture dependence in quantiles of the joint distribution, the proposed metric has a high capability to discriminate between high-level dependence structures. An extensive simulation study shows that our clustering procedure outperforms a wide range of alternative methods and exhibits robustness to noise distribution besides being computationally efficient. A real data application involving bivariate financial time series illustrates the usefulness of the proposed approach. The procedure is also applied to cluster nonstationary series from the UEA multivariate time series classification archive.
•A new measure based on quantiles to perform clustering of multivariate time series.•The measure examines simultaneously both cross-dependence and serial dependence.•The proposed measure takes advantage of the nice properties of the quantiles.•Accurate, robust and efficient clustering performance in the frequency domain.•The methodology is successfully applied to cluster time series of S&P 500.
Ionic transition‐metal complexes based on silver(I) metal core (Ag‐iTMCs) represent an appealing alternative to other iTMCs in solid‐state lighting owing to (i) their low cost and well‐known ...synthesis, (ii) the tunable bandgap, and (iii) the highly efficient photoluminescence. However, their electroluminescence behavior is barely studied. Herein, the archetypal green‐emitting Ag‐iTMCs, namely Ag(4,4′‐dimethoxy‐2,2′‐bipyridine)(Xantphos)X (X = BF4, PF6, and ClO4), are thoughtfully investigated, revealing their electroluminescent features in light‐emitting electrochemical cells (LECs). Despite optimizing device fabrication and operation, luminance of 40 cd m−2, efficacy of 0.2 cd A−1, and a very poor stability of 30 s are achieved. This outcome encourages the comprehensive study of the degradation mechanism combining electrochemical impedance spectroscopy, X‐ray diffraction, and cyclic voltammetry techniques. These results point out the irreversible formation of silver nanoclusters under operation strongly limiting the device performance. As such, LECs are further optimized by (i) changing the counterions (PF6− and ClO4−) and (ii) decoupling electron injection and exciton formation using a double‐layered architecture. The synergy of both approaches leads to a broad exciplex‐like whitish electroluminescence emission (x/y CIE of 0.40/0.44 and color rendering index of 85) with an outstanding improved stability of ≈4 orders of magnitude (>80 h) without losing brightness (35 cd m−2).
Ionic silver(I) complexes represent an emerging class of emitters for solid‐state lighting. Herein, the first in‐depth study on the electroluminescence behavior of an silver(I) complex in light‐emitting electrochemical cells is provided. While elucidating the device degradation mechanism, a successful solution to enhance the device stability from seconds to days is proposed.
The aim of this study was to assess the static posturography in dogs as a useful tool for diagnosis of lameness by means of the use of a pressure platform. For this purpose, a series of different ...parameters (pressure distribution, area of support, mean pressure, maximum pressure and statokinesiograms) were obtained from five lame dogs with unilateral elbow osteoarthritis treated with plasma rich in growth factors. Data were obtained before and 3 months after treatment, and results were compared with a control group of sound dogs of similar conformation. Significant differences were found in the above mentioned parameters between sound and lame limbs. Improvement after 3 months of treatment was also detected, demonstrating that this multi-parametric technique is an effective and reliable method for the assessment of lameness in dogs.
Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8
T lymphocytes are recruited and ...activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8
T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8
T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8
T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8
T lymphocytes in the setting of acute myocardial infarction.
In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 major mediators of ...efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction.
We generated double-deficient mice for Mertk and Mfge8 (Mertk(-/-)/Mfge8(-/-)) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk(-/-)), or Mfge8-deficient (Mfge8(-/-)) animals, Mertk(-/-)/Mfge8(-/-) mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly by cardiac Ly6C(High and Low) monocytes and macrophages. In parallel, Mertk(-/-)/Mfge8(-/-) bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis. We found that the abrogation of efferocytosis affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6C(High) and Ly6C(How) monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6C(High)/Ly6C(Low) monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre(+)/VEGFA(fl/fl) mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis.
After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the dysfunctional heart.
Abstract
Aims
The cardioprotective effects of human induced pluripotent stem cell-derived cardiovascular progenitor cells (CPC) are largely mediated by the paracrine release of extracellular vesicles ...(EV). We aimed to assess the immunological behaviour of EV-CPC, which is a prerequisite for their clinical translation.
Methods and results
Flow cytometry demonstrated that EV-CPC expressed very low levels of immune relevant molecules including HLA Class I, CD80, CD274 (PD-L1), and CD275 (ICOS-L); and moderate levels of ligands of the natural killer (NK) cell activating receptor, NKG2D. In mixed lymphocyte reactions, EV-CPC neither induced nor modulated adaptive allogeneic T cell immune responses. They also failed to induce NK cell degranulation, even at high concentrations. These in vitro effects were confirmed in vivo as repeated injections of EV-CPC did not stimulate production of immunoglobulins or affect the interferon (IFN)-γ responses from primed splenocytes. In a mouse model of chronic heart failure, intra-myocardial injections of EV-CPC, 3 weeks after myocardial infarction, decreased both the number of cardiac pro-inflammatory Ly6Chigh monocytes and circulating levels of pro-inflammatory cytokines (IL-1α, TNF-α, and IFN-γ). In a model of acute infarction, direct cardiac injection of EV-CPC 2 days after infarction reduced pro-inflammatory macrophages, Ly6Chigh monocytes, and neutrophils in heart tissue as compared to controls. EV-CPC also reduced levels of pro-inflammatory cytokines IL-1α, IL-2, and IL-6, and increased levels of the anti-inflammatory cytokine IL-10. These effects on human macrophages and monocytes were reproduced in vitro; EV-CPC reduced the number of pro-inflammatory monocytes and M1 macrophages, while increasing the number of anti-inflammatory M2 macrophages.
Conclusions
EV-CPC do not trigger an immune response either in in vitro human allogeneic models or in immunocompetent animal models. The capacity for orienting the response of monocyte/macrophages towards resolution of inflammation strengthens the clinical attractiveness of EV-CPC as an acellular therapy for cardiac repair.
Graphical Abstract
A wide range of organisms use circadian clocks to keep internal sense of daily time and regulate their behavior accordingly. Most of these clocks use intracellular genetic networks based on positive ...and negative regulatory elements. The integration of these "circuits" at the cellular level imposes strong constraints on their functioning and design. Here, we study a recently proposed model Barkai, N. & Leibler, S. (2000) Nature (London), 403, 267-268 that incorporates just the essential elements found experimentally. We show that this type of oscillator is driven mainly by two elements: the concentration of a repressor protein and the dynamics of an activator protein forming an inactive complex with the repressor. Thus, the clock does not need to rely on mRNA dynamics to oscillate, which makes it especially resistant to fluctuations. Oscillations can be present even when the time average of the number of mRNA molecules goes below one. Under some conditions, this oscillator is not only resistant to but, paradoxically, also enhanced by the intrinsic biochemical noise.
B cell depletion significantly reduces the burden of several immune-mediated diseases. However, B cell activation has been until now associated with a protection against atherosclerosis, suggesting ...that B cell-depleting therapies would enhance cardiovascular risk. We unexpectedly show that mature B cell depletion using a CD20-specific monoclonal antibody induces a significant reduction of atherosclerosis in various mouse models of the disease. This treatment preserves the production of natural and potentially protective anti-oxidized low-density lipoprotein (oxLDL) IgM autoantibodies over IgG type anti-oxLDL antibodies, and markedly reduces pathogenic T cell activation. B cell depletion diminished T cell-derived IFN-gamma secretion and enhanced production of IL-17; neutralization of the latter abrogated CD20 antibody-mediated atheroprotection. These results challenge the current paradigm that B cell activation plays an overall protective role in atherogenesis and identify new antiatherogenic strategies based on B cell modulation.
Phytoplankton is a sentinel of marine ecosystem change. Composed by many species with different life-history strategies, it rapidly responds to environment changes. An analysis of the abundance of 54 ...phytoplankton species in Galicia (NW Spain) between 1989 and 2008 to determine the main components of temporal variability in relation to climate and upwelling showed that most of this variability was stochastic, as seasonality and long term trends contributed to relatively small fractions of the series. In general, trends appeared as non linear, and species clustered in 4 groups according to the trend pattern but there was no defined pattern for diatoms, dinoflagellates or other groups. While, in general, total abundance increased, no clear trend was found for 23 species, 14 species decreased, 4 species increased during the early 1990s, and only 13 species showed a general increase through the series. In contrast, series of local environmental conditions (temperature, stratification, nutrients) and climate-related variables (atmospheric pressure indices, upwelling winds) showed a high fraction of their variability in deterministic seasonality and trends. As a result, each species responded independently to environmental and climate variability, measured by generalized additive models. Most species showed a positive relationship with nutrient concentrations but only a few showed a direct relationship with stratification and upwelling. Climate variables had only measurable effects on some species but no common response emerged. Because its adaptation to frequent disturbances, phytoplankton communities in upwelling ecosystems appear less sensitive to changes in regional climate than other communities characterized by short and well defined productive periods.
•Stochastic variability dominated phytoplankton species abundance in the Galician upwelling.•Species responses largely unrelated to taxonomical or functional groups.•Only a few species showed direct relationships with climate, stratification or upwelling intensity.•Independent response of species to nutrient inputs favored by relative climate and oceanographic stability.•Phytoplankton in upwelling ecosystems well adapted to changes in climate.
New mononuclear copper(I) and silver(I) compounds of formula Cu(Xantphos)2BF4 (1), Ag(Xantphos)2ClO4·H2O (2), Cu(tBuXantphos)(BF4) (3), Ag(tBuXantphos)ClO4 (4), and Cu(Nixantphos)Br(DMF) (5) Xantphos ...= 4,5‐Bis(diphenylphosphino)‐9,9‐dimethylxanthene, tBuXantphos = 9,9‐dimethyl‐4,5‐bis(di‐tert‐butylphosphino)xanthene, Nixantphos = 4,6‐bis(diphenylphosphino)phenoxazine have been synthesized and characterized by spectroscopic methods and X‐ray crystal structure determinations. The influence of the diverse Xantphos derivative ligands on the coordination in their copper(I) and silver(I) complexes is reported. Whereas copper(I) complexes adopt a coordination number of four, with tetrahedral (1 and 5) and square‐planar (3) geometries; silver(I) complexes display coordination numbers of four and two with tetrahedral (2) and linear (4) geometries. A remarkable feature is the coordination of the BF4– anion to the copper(I) ion in 3. In addition, compounds 2 and 5 are emitting materials with radiation bands at around 485 nm.
Copper(I) and silver(I) complexes with Xantphos derivative ligands have been synthesized. The impact of the biphosphine ligand and the metal(I) ion on the coordination geometries and photoluminescence properties is studied.
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