Using in vitro, in vivo and patient-based approaches, we investigated the potential of circulating microRNAs (miRNAs) as surrogate biomarkers of myocardial steatosis, a hallmark of diabetic ...cardiomyopathy. We analysed the cardiomyocyte-enriched miRNA signature in serum from patients with well-controlled type 2 diabetes and with verified absence of structural heart disease or inducible ischemia, and control volunteers of the same age range and BMI (N = 86), in serum from a high-fat diet-fed murine model, and in exosomes from lipid-loaded HL-1 cardiomyocytes. Circulating miR-1 and miR-133a levels were robustly associated with myocardial steatosis in type 2 diabetes patients, independently of confounding factors in both linear and logistic regression analyses (P < 0.050 for all models). Similar to myocardial steatosis, miR-133a levels were increased in type 2 diabetes patients as compared with healthy subjects (P < 0.050). Circulating miR-1 and miR-133a levels were significantly elevated in high-fat diet-fed mice (P < 0.050), which showed higher myocardial steatosis, as compared with control animals. miR-1 and miR-133a levels were higher in exosomes released from lipid-loaded HL-1 cardiomyocytes (P < 0.050). Circulating miR-1 and miR-133a are independent predictors of myocardial steatosis. Our results highlight the value of circulating miRNAs as diagnostic tools for subclinical diabetic cardiomyopathy.
ABSTRACT
We searched for an isotropic stochastic gravitational wave background in the second data release of the International Pulsar Timing Array, a global collaboration synthesizing decadal-length ...pulsar-timing campaigns in North America, Europe, and Australia. In our reference search for a power-law strain spectrum of the form $h_c = A(f/1\, \mathrm{yr}^{-1})^{\alpha }$, we found strong evidence for a spectrally similar low-frequency stochastic process of amplitude $A = 3.8^{+6.3}_{-2.5}\times 10^{-15}$ and spectral index α = −0.5 ± 0.5, where the uncertainties represent 95 per cent credible regions, using information from the auto- and cross-correlation terms between the pulsars in the array. For a spectral index of α = −2/3, as expected from a population of inspiralling supermassive black hole binaries, the recovered amplitude is $A = 2.8^{+1.2}_{-0.8}\times 10^{-15}$. None the less, no significant evidence of the Hellings–Downs correlations that would indicate a gravitational-wave origin was found. We also analysed the constituent data from the individual pulsar timing arrays in a consistent way, and clearly demonstrate that the combined international data set is more sensitive. Furthermore, we demonstrate that this combined data set produces comparable constraints to recent single-array data sets which have more data than the constituent parts of the combination. Future international data releases will deliver increased sensitivity to gravitational wave radiation, and significantly increase the detection probability.
Abstract
Most large galaxies host supermassive black holes in their nuclei and are subject to mergers, which can produce a supermassive black hole binary (SMBHB), and hence periodic signatures due to ...orbital motion. We report unique periodic radio flux density variations in the blazar PKS 2131−021, which strongly suggest an SMBHB with an orbital separation of ∼0.001–0.01 pc. Our 45.1 yr radio light curve shows two epochs of strong sinusoidal variation with the same period and phase to within ≲2% and ∼10%, respectively, straddling a 20 yr period when this variation was absent. Our simulated light curves accurately reproduce the “red noise” of this object, and Lomb–Scargle, weighted wavelet
Z
-transform and least-squares sine-wave analyses demonstrate conclusively, at the 4.6
σ
significance level, that the periodicity in this object is not due to random fluctuations in flux density. The observed period translates to 2.082 ± 0.003 yr in the rest frame at the
z
= 1.285 redshift of PKS 2131−021. The periodic variation in PKS 2131−021 is remarkably sinusoidal. We present a model in which orbital motion, combined with the strong Doppler boosting of the approaching relativistic jet, produces a sine-wave modulation in the flux density that easily fits the observations. Given the rapidly developing field of gravitational-wave experiments with pulsar timing arrays, closer counterparts to PKS 2131−021 and searches using the techniques we have developed are strongly motivated. These results constitute a compelling demonstration that the phenomenology, not the theory, must provide the lead in this field.
Hendra virus (HeV) is one of the two prototypical members of the Henipavirus genus of paramyxoviruses, which are designated biosafety level 4 (BSL-4) organisms due to the high mortality rate of Nipah ...virus (NiV) and HeV in humans. Paramyxovirus cell entry is mediated by the fusion protein, F, in response to binding of a host receptor by the attachment protein. During posttranslational processing, the fusion peptide of F is released and, upon receptor-induced triggering, inserts into the host cell membrane. As F undergoes a dramatic refolding from its prefusion to postfusion conformation, the fusion peptide brings the host and viral membranes together, allowing entry of the viral RNA. Here, we present the crystal structure of the prefusion form of the HeV F ectodomain. The structure shows very high similarity to the structure of prefusion parainfluenza virus 5 (PIV5) F, with the main structural differences in the membrane distal apical loops and the fusion peptide cleavage loop. Functional assays of mutants show that the apical loop can tolerate perturbation in length and surface residues without loss of function, except for residues involved in the stability and conservation of the F protein fold. Structure-based disulfide mutants were designed to anchor the fusion peptide to conformationally invariant residues of the F head. Two mutants were identified that inhibit F-mediated fusion by stabilizing F in its prefusion conformation.
Contractile dysfunction is underdiagnosed in early stages of diabetic cardiomyopathy. We evaluated the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers of subclinical cardiac ...abnormalities in type 2 diabetes. Forty-eight men with well-controlled type 2 diabetes and 12 healthy age-matched volunteers were enrolled in the study. Left ventricular (LV) parameters were measured by magnetic resonance imaging. A panel of lncRNAs was quantified in serum by RT-qPCR. No differences in expression levels of lncRNAs were observed between type 2 diabetes patients and healthy volunteers. In patients with type 2 diabetes, long intergenic non-coding RNA predicting cardiac remodeling (LIPCAR) was inversely associated with diastolic function, measured as E/A peak flow (P < 0.050 for all linear models). LIPCAR was positively associated with grade I diastolic dysfunction (P < 0.050 for all logistic models). Myocardial infarction-associated transcript (MIAT) and smooth muscle and endothelial cell-enriched migration/differentiation-associated long noncoding RNA (SENCR) were directly associated with LV mass to LV end-diastolic volume ratio, a marker of cardiac remodelling (P < 0.050 for all linear models). These findings were validated in a sample of 30 patients with well-controlled type 2 diabetes. LncRNAs are independent predictors of diastolic function and remodelling in patients with type 2 diabetes.
The storage of triglyceride (TG) droplets in nonadipose tissues is called ectopic fat storage. Ectopic fat is associated with insulin resistance and type 2 diabetes mellitus (T2DM). Not the ...triglycerides per se but the accumulation of intermediates of lipid metabolism in organs, such as the liver, skeletal muscle, and heart seem to disrupt metabolic processes and impair organ function. We describe the mechanisms of ectopic fat depositions in the liver, skeletal muscle, and in and around the heart and the consequences for each organs function. In addition, we systematically reviewed the literature for the effects of diet-induced weight loss and exercise on ectopic fat depositions.
Lake isotope records can be used to assess the spatial coherency of Late Quaternary climate change across the circum-Mediterranean region. We place modern and palaeo-data within a simple conceptual ...lake response model to show that the isotope hydrology of most Mediterranean lakes has been influenced strongly by water balance, even in those systems that are chemically dilute (i.e. freshwater).
δ
18O data on biogenic and endogenic carbonates from 24 lake basins are used to reconstruct multi-millennial-scale trends since the LGM. While it is difficult to make direct comparisons between lake records in terms of single climatic parameters, coherent regional isotopic trends can be identified. During glacial times Mediterranean lakes deposited carbonates isotopically heavier in
δ
18O compared to the Holocene, partly due to source area effects. Isotopic enrichment was most marked during intervals corresponding to the H1 and Younger Dryas events, confirming that Late Pleistocene cold stages in the North Atlantic region were marked by aridity around much of the Mediterranean. Almost all Mediterranean lake records shifted to more depleted isotopic values during the Last Glacial–Interglacial Transition (LGIT). This shift is the reverse of the trend which characterised the same transition in lakes from northern and central Europe, and suggests that temperature changes were not an important direct driver of Mediterranean lake isotopic records over glacial–interglacial timescales. In the early Holocene, many lakes in the eastern part of the region were more depleted isotopically than in recent millennia. This corresponds with marine sapropel formation, both chronologically and geographically, and implies that increases in local rainfall contributed significantly to the creation of a freshwater lid and anoxia in the East Mediterranean Sea. In contrast, no such pattern is currently apparent from lake isotope records from the West Mediterranean, suggesting a possible NW–SE contrast in climate history during the Holocene.
We report the results of a series of three-dimensional (3D) simulations of the deflagration phase of the gravitationally confined detonation mechanism for Type Ia supernovae. In this mechanism, ...ignition occurs at one or several off-center points, resulting in a burning bubble of hot ash that rises rapidly, breaks through the surface of the star, and collides at a point opposite the breakout on the stellar surface. We find that detonation conditions are robustly reached in our 3D simulations for a range of initial conditions and resolutions. Detonation conditions are achieved as the result of an inwardly directed jet that is produced by the compression of unburnt surface material when the surface flow collides with itself. A high-velocity outwardly directed jet is also produced. The initial conditions explored in this paper lead to conditions at detonation that can be expected to produce large amounts of super(56)Ni and small amounts of intermediate-mass elements. These particular simulations are therefore relevant only to high-luminosity Type Ia supernovae. Recent observations of Type Ia supernovae imply a compositional structure that is qualitatively consistent with that expected from these simulations.
Nipah virus is an emergent paramyxovirus that causes deadly encephalitis and respiratory infections in humans. Two glycoproteins coordinate the infection of host cells, an attachment protein (G), ...which binds to cell surface receptors, and a fusion (F) protein, which carries out the process of virus-cell membrane fusion. The G protein binds to ephrin B2/3 receptors, inducing G conformational changes that trigger F protein refolding. Using an optical approach based on second harmonic generation, we show that monomeric and dimeric receptors activate distinct conformational changes in G. The monomeric receptor-induced changes are not detected by conformation-sensitive monoclonal antibodies or through electron microscopy analysis of G:ephrinB2 complexes. However, hydrogen/deuterium exchange experiments confirm the second harmonic generation observations and reveal allosteric changes in the G receptor binding and F-activating stalk domains, providing insights into the pathway of receptor-activated virus entry.Nipah virus causes encephalitis in humans. Here the authors use a multidisciplinary approach to study the binding of the viral attachment protein G to its host receptor ephrinB2 and show that monomeric and dimeric receptors activate distinct conformational changes in G and discuss implications for receptor-activated virus entry.
Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures and thiazolidinediones (TZDs) increase this risk. TZDs stimulate the expression of sclerostin, a negative regulator ...of bone formation, in vitro. Abnormal sclerostin production may, therefore, be involved in the pathogenesis of increased bone fragility in patients with T2DM treated with TZDs.
We measured serum sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and carboxy-terminal cross-linking telopeptide of type I collagen (CTX) in 71 men with T2DM treated with either pioglitazone (PIO) (30 mg once daily) or metformin (MET) (1000 mg twice daily). Baseline values of sclerostin and P1NP were compared with those of 30 healthy male controls.
Compared with healthy controls, patients with T2DM had significantly higher serum sclerostin levels (59.9 vs 45.2 pg/ml, P<0.001) but similar serum P1NP levels (33.6 vs 36.0 ng /ml, P=0.39). After 24 weeks of treatment, serum sclerostin levels increased by 11% in PIO-treated patients and decreased by 1.8% in MET-treated patients (P=0.018). Changes in serum sclerostin were significantly correlated with changes in serum CTX in all patients (r=0.36, P=0.002) and in PIO-treated patients (r=0.39, P=0.020), but not in MET-treated patients (r=0.17, P=0.31).
Men with T2DM have higher serum sclerostin levels than healthy controls, and these levels further increase after treatment with PIO, which is also associated with increased serum CTX. These findings suggest that increased sclerostin production may be involved in the pathogenesis of increased skeletal fragility in patients with T2DM in general and may specifically contribute to the detrimental effect of TZDs on bone.
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