The ultralow-frequency (ULF) electromagnetic anomaly has been considered one of the earthquake precursory signals with the potential for short-term prediction. As such, effectively detecting ULF ...anomalies is important for mitigating earthquake disasters. Given the comprehensive coverage of geomagnetic networks in Japan, the 2011 Tohoku-Oki earthquake (M9.0) provided a tremendous opportunity for investigating the characteristics and mechanisms of ULF anomalies. Previous studies reporting detections of ULF anomalies triggered by the Tohoku-Oki earthquake have been questioned on the grounds of insufficient reliability due to technological limitations. In this study, we employ a multireference station data-quality-weighted method to detect the ULF anomaly. Comparison with traditional single-reference station method demonstrates the robustness of our detection results. A statistical test also indicates that the ULF anomaly appearing approximately two months before the earthquake was driven by physical processes. Geomagnetic storm analysis further rules solar activity as the cause of the anomaly. The spatial distribution of the anomaly amplitude reveals a decrease in the anomaly energy with increasing epicentral distance, implying a strong association between the anomaly and the earthquake. Our study is helpful for understanding the possible connection between the ULF electromagnetic precursors and the seismogenic processes of strong earthquakes, which contributes to achieving the ultimate goal of short-term earthquake prediction.
Seismic electric signals (SESs) are essential short-term precursors of earthquakes. Accurate and efficient detection of SESs is significant to short-term predictions of earthquakes. However, SESs are ...usually disturbed by various noises and are thus difficult to recognize. Although conventional techniques have made substantial efforts in improving the SES detection accuracy, the success rates of SES detection at certain stations are still less satisfactory due to the complexity and diversity of noises. In this study, we apply deep learning to extract SESs and develop a novel deep learning network based on geoelectric field characteristics by combining the long short-term memory (LSTM) blocks with an autoencoder structure and a time-step attention module. The detection results of both synthetic and real data demonstrate that our proposed network yields superior performance in detecting embedded SESs in the presence of severe noise interference compared with traditional methods and several well-known networks. Moreover, our novel network shows the excellent ability of massive data processing, generalization, and migration, which can process one day's worth of data in only milliseconds, adapt to SESs whose durations and amplitudes are different from those of the training set and be easily transferred to newly acquired data. The proposed novel method can provide more efficient and accurate detection results, which will broaden the data availability of hazard mitigation based on SESs.
The use of nicotinic acid to treat dyslipidemia is limited by induction of a “flushing” response, mediated in part by the interaction of prostaglandin D2 (PGD2) with its G-protein coupled receptor, ...DP1 (Ptgdr). The impact of DP1 blockade (genetic or pharmacologic) was assessed in experimental murine models of atherosclerosis. In Ptgdr−/−ApoE−/− mice versus ApoE−/− mice, both fed a high-fat diet, aortic cholesterol content was modestly higher (1.3- to 1.5-fold, P < 0.05) in Ptgdr−/−ApoE−/− mice at 16 and 24 weeks of age, but not at 32 weeks. In multiple ApoE−/− mouse studies, a DP1-specific antagonist, L-655, generally had a neutral to beneficial effect on aortic lipids in the presence or absence of nicotinic acid treatment. In a separate study, a modest increase in some atherosclerotic measures was observed with L-655 treatment in Ldlr−/− mice fed a high-fat diet for 8 weeks; however, this effect was not sustained for 16 or 24 weeks. In the same study, treatment with nicotinic acid alone generally decreased plasma and/or aortic lipids, and addition of L-655 did not negate those beneficial effects. These studies demonstrate that inhibition of DP1, with or without nicotinic acid treatment, does not lead to consistent or sustained effects on plaque burden in mouse atherosclerotic models.
Human placenta thioredoxin reductase (HP-TR) in the presence of NADPH-catalyzed reduction of (15S)-hydroperoxy-(5Z),(8Z),11(Z),13(E)-eicosatetraenoic acid ((15S)-HPETE) into the corresponding alcohol ...((15S)-HETE). Incubation of 50 nM HP-TR and 0.5 mM NADPH with 300 μM 15-HPETE for 5 min resulted in formation of 16.5 μM 15-HETE. After 60 min, 74.7 μM 15-HPETE was reduced. The rate of the reduction of 15-HPETE by the HP-TR/NADPH peroxidase system was increased 8-fold by the presence of 2.5 μM selenocystine, a diselenide amino acid. In this case, 15-HPETE was catalytically reduced by the selenol amino acid, selenocysteine, generated from the diselenide by the HP-TR/NADPH system. To a smaller extent, selenodiglutathione or human thioredoxin also potentiated the reduction of 15-HPETE by HP-TR. Hydrogen peroxide and 15-HPETE were reduced at approximately the same rate by HP-TR, thioredoxin, and selenocystine. In contrast, t-butyl hydroperoxide was reduced at a 10-fold lower rate. Our data suggest two novel pathways for the reduction and detoxification of lipid hydroperoxides, hydrogen peroxide, and organic hydroperoxides, i.e. the human thioredoxin reductase-dependent pathway and a coupled reduction in the presence of selenols or selenide resulting from the reduction of selenocystine or selenodiglutathione.
With expanding biomarker discovery efforts and increasing costs of drug development, it is critical to maximize the value of mass-limited clinical samples. The main limitation of available methods is ...the inability to isolate and analyze, from a single sample, molecules requiring incompatible extraction methods. Thus, we developed a novel semiautomated method for tissue processing and tissue milling and division (TMAD).
We used a SilverHawk atherectomy catheter to collect atherosclerotic plaques from patients requiring peripheral atherectomy. Tissue preservation by flash freezing was compared with immersion in RNAlater®, and tissue grinding by traditional mortar and pestle was compared with TMAD. Comparators were protein, RNA, and lipid yield and quality. Reproducibility of analyte yield from aliquots of the same tissue sample processed by TMAD was also measured.
The quantity and quality of biomarkers extracted from tissue prepared by TMAD was at least as good as that extracted from tissue stored and prepared by traditional means. TMAD enabled parallel analysis of gene expression (quantitative reverse-transcription PCR, microarray), protein composition (ELISA), and lipid content (biochemical assay) from as little as 20 mg of tissue. The mean correlation was r = 0.97 in molecular composition (RNA, protein, or lipid) between aliquots of individual samples generated by TMAD. We also demonstrated that it is feasible to use TMAD in a large-scale clinical study setting.
The TMAD methodology described here enables semiautomated, high-throughput sampling of small amounts of heterogeneous tissue specimens by multiple analytical techniques with generally improved quality of recovered biomolecules.
The geoelectric data contain important anomalous information for short-term earthquake prediction. Timely and accurate identification of seismic electric anomalies is important for disaster ...prevention. However, identifying anomalies is challenging due to the huge volumes of data and noise disturbance. In this study, we develop a real-time automatic search engine (RASE) that incorporates an unsupervised convolutional denoising network (UCN) module and a supervised LSTM network (SLN) prediction module to automatically search for important anomalous signals in real-time. Experiments demonstrate that the RASE provides excellent detection accuracy and efficiency for synthetic and field data, which takes only dozens of seconds for a common PC to provide accurate detection results for data collected over a 24-hour period. The RASE has excellent flexibility and developability, as its internal modules can be adapted by more suitable technologies for better performance in various application scenarios. Comparison of multiple module combinations shows that the RASE configured with UCN and SLN has the highest detection accuracy. Our proposed search engine can reduce the human labor required for complex and repetitive detection work and fully realize the potential of geoelectric field observation in earthquake monitoring and disaster prevention.
In an attempt to understand the applicability of various animal models to dyslipidemia in humans and to identify improved preclinical models for target discovery and validation for dyslipidemia, we ...measured comprehensive plasma lipid profiles in 24 models. These included five mouse strains, six other nonprimate species, and four nonhuman primate (NHP) species, and both healthy animals and animals with metabolic disorders. Dyslipidemic humans were assessed by the same measures. Plasma lipoprotein profiles, eight major plasma lipid fractions, and FA compositions within these lipid fractions were compared both qualitatively and quantitatively across the species. Given the importance of statins in decreasing plasma low-density lipoprotein cholesterol for treatment of dyslipidemia in humans, the responses of these measures to simvastatin treatment were also assessed for each species and compared with dyslipidemic humans. NHPs, followed by dog, were the models that demonstrated closest overall match to dyslipidemic humans. For the subset of the dyslipidemic population with high plasma triglyceride levels, the data also pointed to hamster and db/db mouse as representative models for practical use in target validation. Most traditional models, including rabbit, Zucker diabetic fatty rat, and the majority of mouse models, did not demonstrate overall similarity to dyslipidemic humans in this study.
GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists ...are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut. Here we describe how GPR40 AgoPAMs stimulate both insulin and incretin secretion in vivo over time in diabetic GK rats. We also describe effects of AgoPAMs in vivo to lower glucose and body weight beyond what is seen with partial GPR40 agonists in both the acute and chronic setting. Further comparisons of the glucose lowering profile of AgoPAMs suggest these compounds may possess greater glucose control even in the presence of elevated glucagon secretion, an unexpected feature observed with both acute and chronic treatment with AgoPAMs. Together these studies highlight the complexity of GPR40 pharmacology and the potential additional benefits AgoPAMs may possess above partial agonists for the diabetic patient.
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Spironolactone (SPL), a mineralocorticoid receptor (MR) antagonist is used for the treatment of hypertension and heart failure, acting through competitive binding of aldosterone (aldo), ...which has been shown to induce sustained increases in plasma renin activity (PRA) and aldo concentration (PAC) in the treated patients. In the present study, our goal was to evaluate SPL effect on blood pressure (BP) and renal function in hypertensive rat models with high vs. low PRA/PAC. Plasma/urine chemistry and BP was monitored in Dahl salt sensitive rats fed with low vs. high salt diet (LSD vs. HSD) before and after administration of SPL (100mg/kg/day) or placebo premixed in feed for 4 weeks. Compared to LSD, HSD for 3 weeks reduced PRA and suppressed PAC to unmeasurable levels. Following the 4 week chronic administration of SPL, animals fed LSD showed acute increase in Na+ excretion (2 fold), decrease in K+ excretion (Δ0.05mmol/mg), and sustained elevation of PAC/urinary aldo (3 fold) with no significant effect on PRA; animals fed HSD only exhibited acute decrease in K+ excretion (Δ0.04mmol/mg) with no effect on Na+ excretion and PRA/PAC. Interestingly animals fed LSD vs. HSD exhibited equivalent BP lowering (LSD, 155±4 vs. 143±3mmHg; HSD, 193±9 vs. 180±5mmHg, P<0.05 placebo vs. SPL). In conclusion, MR antagonism with SPL at the tested dose exhibits comparable BP lowering efficacy in hypertensive rats regardless of PRA/PRC levels.
Human plasma glutathione peroxidase (GSH-Px) is a distinct extracellular selenoenzyme that detoxifies hydroperoxides when
used with GSH in high (mM) non-physiological concentrations. We have ...discovered that NADPH and human thioredoxin reductase
(TR) by itself or with thioredoxin (Trx) are efficient electron donors to this human plasma peroxidase. Incubation of 0.05
microM TR with 0.25 microM GSH-Px, in a system free from GSH, resulted in reduction of t-butyl hydroperoxide. Addition of
Trx, 2.5 and 5 microM, respectively, further increased the rate of the reaction. These data were obtained using an assay measuring
the oxidation of NADPH. A direct assay demonstrated the formation of cumyl alcohol from cumene hydroperoxide in this GSH-independent
peroxidase reaction. Incubation of 0.25 microM GSH-Px with a low concentration of GSH (10 microM), representing the upper
level in plasma, plus excess glutathione reductase and NADPH did not result in any reduction of t-butyl hydroperoxide. However,
after addition of 2.5 microM human glutaredoxin, a linear peroxidase reaction started. The results suggest that extracellular
TR, Trx, or glutaredoxin are reductants for the selenium-dependent peroxidase rather than GSH.
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