Abstract
The electrosynthesis of formate from CO
2
can mitigate environmental issues while providing an economically valuable product. Although stannic oxide is a good catalytic material for formate ...production, a metallic phase is formed under high reduction overpotentials, reducing its activity. Here, using a fluorine-doped tin oxide catalyst, a high Faradaic efficiency for formate (95% at 100 mA cm
−2
) and a maximum partial current density of 330 mA cm
−2
(at 400 mA cm
−2
) is achieved for the electroreduction of CO
2
. Furthermore, the formate selectivity (≈90%) is nearly constant over 7 days of operation at a current density of 100 mA cm
−2
.
In-situ/operando
spectroscopies reveal that the fluorine dopant plays a critical role in maintaining the high oxidation state of Sn, leading to enhanced durability at high current densities. First-principle calculation also suggests that the fluorine-doped tin oxide surface could provide a thermodynamically stable environment to form HCOO* intermediate than tin oxide surface. These findings suggest a simple and efficient approach for designing active and durable electrocatalysts for the electrosynthesis of formate from CO
2
.
Understanding brain function requires monitoring local and global brain dynamics. Two-photon imaging of the brain across mesoscopic scales has presented trade-offs between imaging area and ...acquisition speed. We describe a flexible cellular resolution two-photon microscope capable of simultaneous video rate acquisition of four independently targetable brain regions spanning an approximate five-millimeter field of view. With this system, we demonstrate the ability to measure calcium activity across mouse sensorimotor cortex at behaviorally relevant timescales.
The conventional view posits that E3 ligases function primarily through conjugating ubiquitin (Ub) to their substrate molecules. We report here that RIPLET, an essential E3 ligase in antiviral ...immunity, promotes the antiviral signaling activity of the viral RNA receptor RIG-I through both Ub-dependent and -independent manners. RIPLET uses its dimeric structure and a bivalent binding mode to preferentially recognize and ubiquitinate RIG-I pre-oligomerized on dsRNA. In addition, RIPLET can cross-bridge RIG-I filaments on longer dsRNAs, inducing aggregate-like RIG-I assemblies. The consequent receptor clustering synergizes with the Ub-dependent mechanism to amplify RIG-I-mediated antiviral signaling in an RNA-length dependent manner. These observations show the unexpected role of an E3 ligase as a co-receptor that directly participates in receptor oligomerization and ligand discrimination. It also highlights a previously unrecognized mechanism by which the innate immune system measures foreign nucleic acid length, a common criterion for self versus non-self nucleic acid discrimination.
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•RIPLET, not TRIM25, is the obligatory ubiquitin E3 ligase for RIG-I•RIPLET recognizes pre-assembled RIG-I oligomers on dsRNA and ubiquitinates RIG-I•RIPLET can cross-bridge RIG-I filaments formed on longer dsRNA•The two binding modes synergize for length dependent dsRNA discrimination by RIG-I
The E3 ligase RIPLET activates RIG-I via dual ubiquitin-dependent and -independent mechanisms that together work to discriminate the length of dsRNA sensed by RIG-I.
Abstract Background The long-term prognosis of patients with variant angina presenting with aborted sudden cardiac death (ASCD) is unknown. Objectives The purpose of this study was to evaluate the ...long-term mortality and ventricular tachyarrhythmic events of variant angina with and without ASCD. Methods Between March 1996 and September 2014, 188 patients with variant angina with ASCD and 1,844 patients with variant angina without ASCD were retrospectively enrolled from 13 heart centers in South Korea. The primary endpoint was cardiac death. Results Predictors of ASCD manifestation included age (odd ratio OR: 0.980 by 1 year increase; 95% confidence interval CI: 0.96 to 1.00; p = 0.013), hypertension (OR: 0.51; 95% CI: 0.37 to 0.70; p < 0.001), hyperlipidemia (OR: 0.38; 95% CI: 0.25 to 0.58; p < 0.001), family history of sudden cardiac death (OR: 3.67; 95% CI: 1.27 to 10.6; p = 0.016), multivessel spasm (OR: 2.06; 95% CI: 1.33 to 3.19; p = 0.001), and left anterior descending artery spasm (OR: 1.40; 95% CI: 1.02 to 1.92; p = 0.04). Over a median follow-up of 7.5 years, the incidence of cardiac death was significantly higher in ASCD patients (24.1 per 1,000 patient-years vs. 2.7 per 1,000 patient-years; adjusted hazard ratio HR: 7.26; 95% CI: 4.21 to 12.5; p < 0.001). Death from any cause also occurred more frequently in ASCD patients (27.5 per 1,000 patient-years vs. 9.6 per 1,000 patient-years; adjusted HR: 3.00; 95% CI: 1.92 to 4.67; p < 0.001). The incidence rate of recurrent ventricular tachyarrhythmia in ASCD patients was 32.4 per 1,000 patient-years, and the composite of cardiac death and ventricular tachyarrhythmia was 44.9 per 1,000 patient-years. A total of 24 ASCD patients received implantable cardioverter-defibrillators (ICDs). There was a nonsignificant trend of a lower rate of cardiac death in patients with ICDs than those without ICDs (p = 0.15). Conclusions The prognosis of patients with variant angina with ASCD was worse than other patients with variant angina. In addition, our findings supported ICDs in these high-risk patients as a secondary prevention because current multiple vasodilator therapy appeared to be less optimal.
The potential benefits and risks of the use of dual antiplatelet therapy beyond a 12-month period in patients receiving drug-eluting stents have not been clearly established.
In two trials, we ...randomly assigned a total of 2701 patients who had received drug-eluting stents and had been free of major adverse cardiac or cerebrovascular events and major bleeding for a period of at least 12 months to receive clopidogrel plus aspirin or aspirin alone. The primary end point was a composite of myocardial infarction or death from cardiac causes. Data from the two trials were merged for analysis.
The median duration of follow-up was 19.2 months. The cumulative risk of the primary outcome at 2 years was 1.8% with dual antiplatelet therapy, as compared with 1.2% with aspirin monotherapy (hazard ratio, 1.65; 95% confidence interval CI, 0.80 to 3.36; P=0.17). The individual risks of myocardial infarction, stroke, stent thrombosis, need for repeat revascularization, major bleeding, and death from any cause did not differ significantly between the two groups. However, in the dual-therapy group as compared with the aspirin-alone group, there was a nonsignificant increase in the composite risk of myocardial infarction, stroke, or death from any cause (hazard ratio, 1.73; 95% CI, 0.99 to 3.00; P=0.051) and in the composite risk of myocardial infarction, stroke, or death from cardiac causes (hazard ratio, 1.84; 95% CI, 0.99 to 3.45; P=0.06).
The use of dual antiplatelet therapy for a period longer than 12 months in patients who had received drug-eluting stents was not significantly more effective than aspirin monotherapy in reducing the rate of myocardial infarction or death from cardiac causes. These findings should be confirmed or refuted through larger, randomized clinical trials with longer-term follow-up. (ClinicalTrials.gov numbers, NCT00484926 and NCT00590174.)
There are conflicting data regarding the benefit of intravascular ultrasound (IVUS)–guided percutaneous coronary intervention (PCI) over angiography-guided PCI. Since the last meta-analysis was ...published, several new studies have been reported. We performed a comprehensive meta-analysis to evaluate the clinical impact of IVUS-guided PCI with drug-eluting stent compared with conventional angiography-guided PCI. This meta-analysis included 26,503 patients from 3 randomized and 14 observational studies; 12,499 patients underwent IVUS-guided PCI and 14,004 underwent angiography-guided PCI. Main outcome measures were total mortality, myocardial infarction (MI), stent thrombosis, and target lesion revascularization (TLR). IVUS-guided PCI was significantly associated with more stents, longer stents, and larger stents. Regarding clinical outcomes, IVUS-guided PCI was associated with a significantly lower risk of TLR (odds ratio OR 0.81, 95% confidence interval CI 0.66 to 1.00, p = 0.046). In addition, the risk of death (OR 0.61, 95% CI 0.48 to 0.79, p <0.001), MI (OR 0.57, 95% CI 0.44 to 0.75, p <0.001), and stent thrombosis (OR 0.59, 95% CI 0.47 to 0.75, p <0.001) were also decreased. In conclusion, our meta-analysis demonstrated that IVUS-guided PCI was associated with lower risk of death, MI, TLR, and stent thrombosis after drug-eluting stent implantation.
Most trials comparing percutaneous coronary intervention (PCI) with coronary-artery bypass grafting (CABG) have not made use of second-generation drug-eluting stents.
We conducted a randomized ...noninferiority trial at 27 centers in East Asia. We planned to randomly assign 1776 patients with multivessel coronary artery disease to PCI with everolimus-eluting stents or to CABG. The primary end point was a composite of death, myocardial infarction, or target-vessel revascularization at 2 years after randomization. Event rates during longer-term follow-up were also compared between groups.
After the enrollment of 880 patients (438 patients randomly assigned to the PCI group and 442 randomly assigned to the CABG group), the study was terminated early owing to slow enrollment. At 2 years, the primary end point had occurred in 11.0% of the patients in the PCI group and in 7.9% of those in the CABG group (absolute risk difference, 3.1 percentage points; 95% confidence interval CI, -0.8 to 6.9; P=0.32 for noninferiority). At longer-term follow-up (median, 4.6 years), the primary end point had occurred in 15.3% of the patients in the PCI group and in 10.6% of those in the CABG group (hazard ratio, 1.47; 95% CI, 1.01 to 2.13; P=0.04). No significant differences were seen between the two groups in the occurrence of a composite safety end point of death, myocardial infarction, or stroke. However, the rates of any repeat revascularization and spontaneous myocardial infarction were significantly higher after PCI than after CABG.
Among patients with multivessel coronary artery disease, the rate of major adverse cardiovascular events was higher among those who had undergone PCI with the use of everolimus-eluting stents than among those who had undergone CABG. (Funded by CardioVascular Research Foundation and others; BEST ClinicalTrials.gov number, NCT00997828.).
Oncogenic Ras mutants, frequently detected in human cancers, are high-priority anticancer drug targets. However, direct inhibition of oncogenic Ras mutants with small molecules has been extremely ...challenging. Here we report the development of a human IgG1 format antibody, RT11, which internalizes into the cytosol of living cells and selectively binds to the activated GTP-bound form of various oncogenic Ras mutants to block the interactions with effector proteins, thereby suppressing downstream signalling and exerting anti-proliferative effects in a variety of tumour cells harbouring oncogenic Ras mutants. When systemically administered, an RT11 variant with an additional tumour-associated integrin binding moiety for tumour tissue targeting significantly inhibits the in vivo growth of oncogenic Ras-mutated tumour xenografts in mice, but not wild-type Ras-harbouring tumours. Our results demonstrate the feasibility of developing therapeutic antibodies for direct targeting of cytosolic proteins that are inaccessible using current antibody technology.
Objectives The goal of this study was to identify clinical and lesion-specific local factors affecting visual-functional mismatch. Background Although lesion severity determined by coronary ...angiography has not been well correlated with physiological significance, the mechanism of the discordance remains poorly understood. Methods The authors assessed quantitative coronary angiography, intravascular ultrasound (IVUS), and fractional flow reserve (FFR) in a prospective cohort of 1,000 patients with 1,129 coronary lesions. Three-dimensional computational simulation studies were performed. Results Lesions with angiographic diameter stenosis (DS) ≥50% and FFR >0.80 (“mismatches”) were seen in 57% of non–left main lesions and in 35% of the left main lesions, respectively (p = 0.032). Conversely, among the lesions with DS <50% and FFR <0.80 (“reverse mismatches”) 16% were found in the non–left main lesions and 40% in the left main lesions (p < 0.001). The independent predictors for mismatch were advanced age, non–left anterior descending artery location, absence of plaque rupture, short lesion length, large minimal lumen area, smaller plaque burden, and greater minimal lumen diameter. Conversely, reverse mismatch was independently associated with younger age, left anterior descending artery location, the presence of plaque rupture, a smaller minimal lumen area, and larger plaque burden. In a computational simulation study, FFR was influenced by DS, lesion length, different lesion shape, plaque eccentricity, surface roughness, and various shapes of plaque rupture. Conclusions There were high frequencies of visual-functional mismatch between angiography and FFR. The discrepancy was related to the clinical and lesion-specific factors frequently unrecognizable by angiography, thus suggesting that coronary angiography cannot accurately predict FFR. (Natural History of FFR-Guided Deferred Coronary Lesions IRIS FFR-DEFER; NCT01366404 )
Spatiotemporal control of gene expression or labeling is a valuable strategy for identifying functions of genes within complex neural circuits. Here, we develop a highly light-sensitive and efficient ...photoactivatable Flp recombinase (PA-Flp) that is suitable for genetic manipulation in vivo. The highly light-sensitive property of PA-Flp is ideal for activation in deep mouse brain regions by illumination with a noninvasive light-emitting diode. In addition, PA-Flp can be extended to the Cre-lox system through a viral vector as Flp-dependent Cre expression platform, thereby activating both Flp and Cre. Finally, we demonstrate that PA-Flp-dependent, Cre-mediated Ca
3.1 silencing in the medial septum increases object-exploration behavior in mice. Thus, PA-Flp is a noninvasive, highly efficient, and easy-to-use optogenetic module that offers a side-effect-free and expandable genetic manipulation tool for neuroscience research.
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