To provide a better understanding of rheological properties of mantle rocks under lithospheric conditions, we carried out a series of experiments on the creep behavior of polycrystalline olivine at ...high pressures (∼4–9 GPa), relatively low temperatures (673 ≤ T ≤ 1273 K), and anhydrous conditions, using a deformation‐DIA. Differential stress and sample displacement were monitored in situ using synchrotron X‐ray diffraction and radiography, respectively. Experimental results were fit to the low‐temperature plasticity flow law, . On the basis of this analysis, the low‐temperature plasticity of olivine deformed under anhydrous conditions is well constrained by our data with a Peierls stress of σP = 5.9 ± 0.2 GPa, a zero‐stress activation energy of Ek(0) = 320 ± 50 kJ mol−1, and AP = 1.4 × 10−7 s−1 MPa−2. Compared with published results for high‐temperature creep of olivine, a transition from low‐temperature plasticity to high‐temperature creep occurs at ∼1300 K for a strain rate of ∼10−5 s−1. For a geological strain rate of 10−14 s−1, extrapolation of our low‐temperature flow law to 873 K, the cutoff temperature for earthquakes in the mantle, yields a strength of ∼600 MPa. The low‐temperature, high‐stress flow law for olivine in this study provides a solid basis for modeling tectonic processes occurring within Earth's lithosphere.
A number of MR-derived quantitative metrics have been suggested to assess the pathophysiology of MS, but the reports about combined analyses of these metrics are scarce. Our aim was to assess the ...spatial distribution of parameters for white matter myelin and axon integrity in patients with relapsing-remitting MS by multiparametric MR imaging.
Twenty-four patients with relapsing-remitting MS and 24 age- and sex-matched controls were prospectively scanned by quantitative synthetic and 2-shell diffusion MR imaging. Synthetic MR imaging data were used to retrieve relaxometry parameters (R1 and R2 relaxation rates and proton density) and myelin volume fraction. Diffusion tensor metrics (fractional anisotropy and mean, axial, and radial diffusivity) and neurite orientation and dispersion index metrics (intracellular volume fraction, isotropic volume fraction, and orientation dispersion index) were retrieved from diffusion MR imaging data. These data were analyzed using Tract-Based Spatial Statistics.
Patients with MS showed significantly lower fractional anisotropy and myelin volume fraction and higher isotropic volume fraction in widespread white matter areas. Areas with different isotropic volume fractions were included within areas with lower fractional anisotropy. Myelin volume fraction showed no significant difference in some areas with significantly decreased fractional anisotropy in MS, including in the genu of the corpus callosum and bilateral anterior corona radiata, whereas myelin volume fraction was significantly decreased in some areas where fractional anisotropy showed no significant difference, including the bilateral posterior limb of the internal capsule, external capsule, sagittal striatum, fornix, and uncinate fasciculus.
We found differences in spatial distribution of abnormality in fractional anisotropy, isotropic volume fraction, and myelin volume fraction distribution in MS, which might be useful for characterizing white matter in patients with MS.
Summary
Background
A predisposition to exacerbations is being recognized as a distinct phenotype with “previous exacerbations” representing the strongest clinical factor associated with future ...exacerbation. Thus, to identify additional novel biomarkers associated with asthma exacerbations, “past exacerbation status” must be included as a confounding factor.
Objective
This study aimed to characterize the clinical and biomarker features associated with asthma exacerbations in severe asthma.
Methods
We evaluated clinical parameters from 105 severe asthmatics yearly for 3 years, as well as their exacerbation status. We classified the subjects into 3 groups: (i) consistent non‐exacerbators (CNE, subjects who did not experience any exacerbation over the 3‐year period); (ii) consistent frequent exacerbators (CFE, subjects with frequent exacerbation, defined as those who had 2 or more exacerbations within 1 year, throughout the 3‐year period); and (iii) intermittent exacerbators (IE). We conducted multivariate analysis for comparisons among the groups for multiple factors, including several Th2‐related biomarkers, in addition to the “past exacerbation status.”
Results
Thirty‐nine subjects were classified as CNE, 15 as CFE, and 51 as IE. Frequent exacerbations in the previous year predicted exacerbations for the following year (P < .001). Among the several Th2‐related biomarkers, only FeNO was associated with exacerbation status. When we analysed the data after the second visit, the impact of FeNO on predicting future exacerbation remained significant, even after considering the exacerbation status during the first year (P < .05).
Conclusions and Clinical Relevance
Measurement of FeNO has a significant potential to predict future asthma exacerbation, which is independent of the “past exacerbation history.”
Blood flow in an intracranial stent cannot be visualized with 3D time-of-flight MR angiography owing to magnetic susceptibility and radiofrequency shielding. As a novel follow-up tool after ...stent-assisted coil embolization, we applied MRA by using a Silent Scan algorithm that contains an ultrashort TE combined with an arterial spin-labeling technique (Silent MRA). The purpose of this study was to determine whether Silent MRA could visualize flow in an intracranial stent placed in the anterior circulation.
Nine patients treated with stent-assisted coil embolization for anterior circulation aneurysms underwent MRAs (Silent MRA and TOF MRA) and x-ray digital subtraction angiography. MRAs were performed in the same session on a 3T unit. Two neuroradiologists independently reviewed the MRA images and subjectively scored flow in a stent as 1 (not visible) to 4 (excellent) by referring to the latest x-ray digital subtraction angiography image as a criterion standard.
Both observers gave MRA higher scores than TOF MRA for flow in a stent in all cases. The mean score for Silent MRA was 3.44 ± 0.53, and for TOF MRA, it was 1.44 ± 0.46 (P < .001).
Silent MRA was able to visualize flow in an intracranial stent more effectively than TOF MRA. Silent MRA might be useful for follow-up imaging after stent-assisted coil embolization, though these study results may be only preliminary due to some limitations.
Abstract
Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such ...high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment.
Summary
Background
Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. The phenotypes that have clinical features of both asthma and COPD are still incompletely ...understood.
Objective
To clarify the best discriminators of the asthma‐COPD overlap phenotype from asthma and COPD subgroups using a clustering approach.
Methods
This study assessed pathophysiological parameters, including mRNA expression levels of T helper cell‐related transcription factors, namely TBX21 (Th1), GATA3 (Th2), RORC (Th17) and FOXP3 (Treg), in peripheral blood mononuclear cells in asthma patients (n=152) and in COPD patients (n=50). Clusters were determined using k‐means clustering. Exacerbations of asthma and COPD were recorded during the 1‐year follow‐up period.
Results
The cluster analysis revealed four biological clusters: cluster 1, predominantly patients with COPD; cluster 2, patients with an asthma‐COPD overlap phenotype; cluster 3, patients with non‐atopic and late‐onset asthma; and cluster 4, patients with early‐onset atopic asthma. Hazard ratios for exacerbation were 2.5 (95% confidence interval CI, 1.1‐5.6) in cluster 1 and 2.3 (95% CI, 1.0‐5.0) in cluster 2 compared with patients in other clusters. Cluster 2 was discriminated from other clusters by total serum IgE level ≥310 IU/mL, blood eosinophil counts ≥280 cells/μL, a higher ratio of TBX21/GATA3, FEV1/FVC ratio <0.67 and smoking ≥10 pack‐years with an area under the curve of 0.94 (95% CI, 0.90‐0.98) in the receiver operating characteristic analysis.
Conclusions and Clinical Relevance
The asthma‐COPD overlap phenotype was characterized by peripheral blood eosinophilia and higher levels of IgE despite the Th2‐low endotype.
Y-configuration stent-assisted coil embolization is used for treating wide-neck aneurysms. Noninvasive alternatives to x-ray DSA for follow-up after Y-configuration stent-assisted coil embolization ...treatment are required. This study aimed to assess the usefulness of non-contrast-enhanced MRA by using a Silent Scan (silent MRA) for follow-up after Y-configuration stent-assisted coil embolization for basilar tip aneurysms.
Seven patients treated with Y-configuration stent-assisted coil embolization for basilar tip aneurysms underwent silent MRA, 3D TOF-MRA, and DSA. Silent MRA and 3D TOF-MRA images were obtained during the same scan session on a 3T MR imaging system. Two neuroradiologists independently reviewed both types of MRA images and subjectively scored the flow in the stents on a scale of 1 (not visible) to 5 (nearly equal to DSA) by referring to the latest DSA image as a criterion standard. Furthermore, we evaluated the visualization of the neck remnant.
In all patients, the 2 observers gave a higher score for the flow in the stents on silent MRA than on 3D TOF-MRA. The average score ± standard deviation was 4.07 ± 0.70 for silent MRA and 1.93 ± 0.80 (
< .05) for 3D TOF-MRA. Neck remnants were depicted by DSA in 5 patients. In silent MRA, neck remnants were depicted in 5 patients, and visualization was similar to DSA; however, in 3D TOF-MRA, neck remnants were depicted in only 1 patient.
Silent MRA might be useful for follow-up after Y-configuration stent-assisted coil embolization.
Antisense transcription (transcription from the opposite strand to a protein-coding or sense strand) has been ascribed roles in gene regulation involving degradation of the corresponding sense ...transcripts (RNA interference), as well as gene silencing at the chromatin level. Global transcriptome analysis provides evidence that a large proportion of the genome can produce transcripts from both strands, and that antisense transcripts commonly link neighboring "genes" in complex loci into chains of linked transcriptional units. Expression profiling reveals frequent concordant regulation of sense/antisense pairs. We present experimental evidence that perturbation of an antisense RNA can alter the expression of sense messenger RNAs, suggesting that antisense transcription contributes to control of transcriptional outputs in mammals.
Tofogliflozin, a highly selective inhibitor of sodium/glucose cotransporter 2 (SGLT2), induces urinary glucose excretion (UGE), improves hyperglycemia and reduces body weight in patients with Type 2 ...diabetes (T2D). The mechanisms of tofogliflozin on body weight reduction were investigated in detail with obese and diabetic animal models.
Diet-induced obese (DIO) rats and KKAy mice (a mouse model of diabetes with obesity) were fed diets containing tofogliflozin. Body weight, body composition, biochemical parameters and metabolic parameters were evaluated.
In DIO rats tofogliflozin was administered for 9 weeks, UGE was induced and body weight gain was attenuated. Body fat mass decreased without significant change in bone mass or lean body mass. Food consumption (FC) increased without change in energy expenditure, and deduced total calorie balance (deduced total calorie balance=FC-UGE-energy expenditure) decreased. Respiratory quotient (RQ) and plasma triglyceride (TG) level decreased, and plasma total ketone body (TKB) level increased. Moreover, plasma leptin level, adipocyte cell size and proportion of CD68-positive cells in mesenteric adipose tissue decreased. In KKAy mice, tofogliflozin was administered for 3 or 5 weeks, plasma glucose level and body weight gain decreased together with a reduction in liver weight and TG content without a reduction in body water content. Combination therapy with tofogliflozin and pioglitazone suppressed pioglitazone-induced body weight gain and reduced glycated hemoglobin level more effectively than monotherapy with either pioglitazone or tofogliflozin alone.
Body weight reduction with tofogliflozin is mainly due to calorie loss with increased UGE. In addition, tofogliflozin also induces a metabolic shift from carbohydrate oxidation to fatty acid oxidation, which may lead to prevention of fat accumulation and inflammation in adipose tissue and liver. Tofogliflozin may have the potential to prevent obesity, hepatic steatosis and improve insulin resistance as well as hyperglycemia.
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