Cystatins as calpain inhibitors: Engineered chicken cystatin- and stefin B-kininogen domain 2 hybrids support a cystatin-like mode of interaction with the catalytic subunit of μ-calpain

Within the cystatin superfamily, only kininogen domain 2 (KD2) is able to inhibit μ- and m-calpain. In an attempt to elucidate the structural requirements of cystatins for calpain inhibition, we constructed recombinant hybrids of human stefin B (an intracellular family 1 cystatin) with KD2 and Delta L110 deletion mutants of chicken cystatin-KD2 hybrids. Substitution of the N-terminal contact region of stefin B by the corresponding KD2 sequence resulted in a calpain inhibitor of K-i = 188 nM. Deletion of L110, which forms a beta -bulge in family 1 and 2 cystatins but is lacking in KD2, improved inhibition of mu -calpain 4- to 8-fold. All engineered cystatins were temporary inhibitors of calpain due to slow substrate-like cleavage of a single peptide bond corresponding to Gly9-Ala10 in chicken cystatin. Biomolecular interaction analysis revealed that, unlike calpastatin, the cystatin-type inhibitors do not bind to the calmodulin-like domain of the small subunit of calpain, and their interaction with the mu -calpain heterodimer is completely prevented by a synthetic peptide comprising subdomain B of calpastatin domain 1. Based on these results we propose that (i) cystatin-type calpain inhibitors interact with the active site of the catalytic domain of calpain in a similar cystatin-like mode as with papain and (ii) the potential for calpain inhibition is due to specific subsites within the papain-binding regions of the general cystatin fold

Women's knowledge of maternal danger signs during pregnancy: Findings from a cross-sectional survey in Papua New Guinea

© 2019 Objective: To explore knowledge of pregnancy related danger signs among women attending antenatal clinics in Papua New Guinea. Design: Cross-sectional survey undertaken as part of a wider integrated health and demographic survey. Setting: Three sites in Papua New Guinea: Hiri District (Central Province), Karkar (Madang Province) and Asaro (Eastern Highlands Province). Participants: 482 women aged 15–44 years. Findings: Almost all (95.2%; 459/482) women attended for antenatal care at least once; 68.2% attended four or more times. Among women who attended the antenatal clinic, 53.6% (246/459) reported receiving information about danger signs in pregnancy from a health worker. Of these 60.2% (148/246) could recall at least one danger sign. In addition, 16.4% (35/213) of women who did not receive information from the antenatal clinic reported pregnancy related danger signs. Among the 183 women who reported danger signs, 47.5% (87/183) reported fever; 39.3% (72/183) reported vaginal bleeding and 36.6% (67/183) reported swelling of the face, legs and arms. Women who reported receiving information at the antenatal clinic were significantly more likely know any danger signs, compared with women who did not receive information at the antenatal clinic (OR 7.68 (95%CI: 4.93, 11.96); p = <0.001). Knowledge of danger signs was significantly associated with secondary school education, compared with none or only primary education (OR 3.08 (95% CI: 2.06, 4.61); p = <0.001). Conclusions and implications for practice: Every antenatal clinic visit should be used opportunistically to provide women with information about key danger signs during pregnancy and childbirth. Recognising maternal danger signs, together with the importance of seeking early transfer to the health facility and the importance of attending for a health facility birth are critical to improving outcomes for mothers and babies especially in low income settings such as Papua New Guinea

Chiral magnetization textures stabilized by the Dzyaloshinskii-Moriya interaction during spin-orbit torque switching

We study the effect of the Dzyaloshinskii-Moriya interaction (DMI) on current-induced magnetic switching of a perpendicularly magnetized heavy-metal/ferromagnet/oxide trilayer both experimentally and through micromagnetic simulations. We report the generation of stable helical magnetization stripes for a sufficiently large DMI strength in the switching region, giving rise to intermediate states in the magnetization confirming the essential role of the DMI on switching processes. We compare the simulation and experimental results to a macrospin model, showing the need for a micromagnetic approach. The influence of the temperature on the switching is also discussed.Comment: Includes corrected acknowledgements and clarification of simulation parameter

Emission pathways to achieve 2.0°C and 1.5°C climate targets

We investigated the feasibilities of 2.0°C and 1.5°C climate targets by considering the abatement potentials of a full suite of greenhouse gases, pollutants, and aerosols. We revised the inter-temporal dynamic optimization model DICE-2013R by introducing three features as follows. First, we applied a new marginal abatement cost curve derived under moderate assumptions regarding future socioeconomic development—the Shared Socioeconomic Pathways 2 (SSP2) scenario. Second, we addressed emission abatement for not only industrial CO2 but also land-use CO2, CH4, N2O, halogenated gases, CO, volatile organic compounds, SOx, NOx, black carbon and organic carbon. Third, we improved the treatment of the non-CO2 components in the climate module based on MAGICC 6.0. We obtained the following findings: (1) It is important to address the individual emissions in an analysis of low stabilization scenarios because abating land-use CO2, non-CO2 and aerosol emissions also contributes to maintaining a low level of radiative forcing and substantially affects the climate costs. (2) The 2.0°C target can be efficiently reached under the assumptions of the SSP2 scenario. (3) The 1.5°C target can be met with early deep cuts under the assumption of a temperature overshoot, and it will triple the carbon price and double the mitigation cost compared with the 2.0°C case

Electron-phonon relaxation and excited electron distribution in zinc oxide and anatase

We propose a first-principle method for evaluations of the time-dependent electron distribution function of excited electrons in the conduction band of semiconductors. The method takes into account the excitations of electrons by external source and the relaxation to the bottom of conduction band via electron-phonon coupling. The methods permits calculations of the non-equilibrium electron distribution function, the quasi-stationary distribution function with steady-in-time source of light, the time of setting of the quasi-stationary distribution and the time of energy loss via relaxation to the bottom of conduction band. The actual calculations have been performed for titanium dioxide in the anatase structure and zinc oxide in the wurtzite structure. We find that the quasi-stationary electron distribution function for ZnO is a fermi-like curve that rises linearly with increasing excitation energy whereas the analogous curve for anatase consists of a main peak and a shoulder. The calculations demonstrate that the relaxation of excited electrons and the setting of the quasi-stationary distribution occur within the time no more than 500 fsec for ZnO and 100 fsec for anatase. We also discuss the applicability of the effective phonon model with energy-independent electron-phonon transition probability. We find that the model only reproduces the trends in changing of the characteristic times whereas the precision of such calculations is not high. The rate of energy transfer to phonons at the quasi-stationary electron distribution also have been evaluated and the effect of this transfer on the photocatalyses has been discussed. We found that for ZnO this rate is about 5 times less than in anatase.Comment: 21 p., 9 figure

Tpeak-Tend, Tpeak-Tend/QT ratio and Tpeak-Tend dispersion for risk stratification in Brugada Syndrome:A systematic review and meta-analysis

Background: Brugada syndrome is an ion channelopathy that predisposes affected subjects to ventricular tachycardia/fibrillation (VT/VF), potentially leading to sudden cardiac death (SCD). Tpeak-Tend intervals, (Tpeak-Tend)/QT ratio and Tpeak-Tend dispersion have been proposed for risk stratification, but their predictive values in Brugada syndrome have been challenged recently. Methods: A systematic review and meta-analysis was conducted to examine their values in predicting arrhythmic and mortality outcomes in Brugada Syndrome. PubMed and Embase databases were searched until 1 May 2018, identifying 29 and 57 studies. Results: Nine studies involving 1740 subjects (mean age 45 years old, 80% male, mean follow-up duration was 68 ± 27 months) were included. The mean Tpeak-Tend interval was 98.9 ms (95% CI: 90.5-107.2 ms) for patients with adverse events (ventricular arrhythmias or SCD) compared to 87.7 ms (95% CI: 80.5-94.9 ms) for those without such events, with a mean difference of 11.9 ms (95% CI: 3.6-20.2 ms, P = 0.005; I2 = 86%). Higher (Tpeak-Tend)/QT ratios (mean difference = 0.019, 95% CI: 0.003-0.036, P = 0.024; I2 = 74%) and Tpeak-Tend dispersion (mean difference = 7.8 ms, 95% CI: 2.1-13.4 ms, P = 0.007; I2 = 80%) were observed for the event-positive group. Conclusion: Tpeak-Tend interval, (Tpeak-Tend)/QT ratio and Tpeak-Tend dispersion were higher in high-risk than low-risk Brugada subjects, and thus offer incremental value for risk stratification

Observation of Coherently Coupled Cation Spin Dynamics in an Insulating Ferrimagnetic Oxide

Many technologically useful magnetic oxides are ferrimagnetic insulators, which consist of chemically distinct cations. Here, we examine the spin dynamics of different magnetic cations in ferrimagnetic NiZnAl-ferrite (Ni$_{0.65}$Zn$_{0.35}$Al$_{0.8}$Fe$_{1.2}$O$_4$) under continuous microwave excitation. Specifically, we employ time-resolved x-ray ferromagnetic resonance to separately probe Fe$^{2+/3+}$ and Ni$^{2+}$ cations on different sublattice sites. Our results show that the precessing cation moments retain a rigid, collinear configuration to within $\approx$2$^\circ$. Moreover, the effective spin relaxation is identical to within $<$10% for all magnetic cations in the ferrite. We thus validate the oft-assumed ``ferromagnetic-like'' dynamics in resonantly driven ferrimagnetic oxides, where the magnetic moments from different cations precess as a coherent, collective magnetization

Room temperature chiral magnetic skyrmion in ultrathin magnetic nanostructures

Magnetic skyrmions are chiral spin structures with a whirling configuration. Their topological properties, nanometer size and the fact that they can be moved by small current densities have opened a new paradigm for the manipulation of magnetisation at the nanoscale. To date, chiral skyrmion structures have been experimentally demonstrated only in bulk materials and in epitaxial ultrathin films and under external magnetic field or at low temperature. Here, we report on the observation of stable skyrmions in sputtered ultrathin Pt/Co/MgO nanostructures, at room temperature and zero applied magnetic field. We use high lateral resolution X-ray magnetic circular dichroism microscopy to image their chiral N\'eel internal structure which we explain as due to the large strength of the Dzyaloshinskii-Moriya interaction as revealed by spin wave spectroscopy measurements. Our results are substantiated by micromagnetic simulations and numerical models, which allow the identification of the physical mechanisms governing the size and stability of the skyrmions.Comment: Submitted version. Extended version to appear in Nature Nanotechnolog