A procedure to analyze surface profiles of the protein molecules visualized by quick-freeze deep-etch replica electron microscopy

Quick-freeze deep-etch replica electron microscopy gives high contrast snapshots of individual protein molecules under physiological conditions in vitro or in situ. The images show delicate internal pattern, possibly reflecting the rotary-shadowed surface profile of the molecule. As a step to build the new system for the "Structural analysis of single molecules", we propose a procedure to quantitatively characterize the structural property of individual molecules; e.g. conformational type and precise view-angle of the molecules, if the crystallographic structure of the target molecule is available. This paper presents a framework to determine the observed face of the protein molecule by analyzing the surface profile of individual molecules visualized in freeze-replica specimens. A comprehensive set of rotary-shadowed views of the protein molecule was artificially generated from the available atomic coordinates using light-rendering software. Exploiting new mathematical morphology-based image filter, characteristic features were extracted from each image and stored as template. Similar features were extracted from the true replica image and the most likely projection angle and the conformation of the observed particle were determined by quantitative comparison with a set of archived images. The performance and the robustness of the procedure were examined with myosin head structure in defined configuration for actual application.     

Effect of the dilation caused by helium bubbles on edge dislocation motion in α-iron: molecular dynamics simulation

Various types of nanometric defects such as voids and helium (He) bubbles produced by high-energy neutron irradiations are known to degrade the mechanical properties of irradiated materials. In this study, we have evaluated the obstacle strength of He bubbles to the mobility of an edge dislocation in α-iron for 2 and 4 nm bubbles with He-to-vacancy (He/V) ratios ranging from 0 to 1 at 300 and 500 K, by molecular dynamics simulation. Results showed that as the He/V ratio increases, the obstacle strength needed for the release of a dislocation from the bubble becomes stronger up to a moderate He/V ratio (0.6 and 0.4 for 2 and 4 nm bubbles, respectively, at both temperatures), and a further increase in the He/V ratio leads to weakening of the obstacle strength. For He/V = 1, the obstacle strengths are 10–30% weaker than those at moderate He/V ratios depending on the bubble size and temperature. The extent of obstacle strength was found to be correlated with the dilation caused by He bubbles depending on the bubble size, He/V ratio, and temperature.     

Analysis of spatial smoothing effect of short‐term fluctuation of global solar radiation based on data including quantization error

Photovoltaic (PV) systems are attracting attention as one of the promising countermeasures against global warming and the environmental issues. However, the generation output from PV systems is generally unstable and unpredictable. Therefore, large penetration of PV systems may cause some serious impacts on power system operation, such as load frequency control, voltage regulation, etc. Estimation of the influences of PV system installation is becoming important, but it requires simultaneous multipoint solar radiation measurements. The Japan Meteorological Business Support Center has provided 1‐minute meteorological data observed in Japan, but its solar radiation data includes quantization errors. This paper proposes a regeneration method for solar radiation data including quantization errors. It also analyzes the spatial smoothing effect of global solar radiation fluctuations. © 2012 Wiley Periodicals, Inc. Electr Eng Jpn, 180(3): 55–63, 2012; Published online in Wiley Online Library ( wileyonlinelibrary.com ). DOI 10.1002/eej.21274     

Towards the improvement of thermal efficiency in lignite‐fired power generation: Concerning the utilization of Polish lignite deposits in state‐of‐the‐art IGCC technology

Integrated coal Gasification Combined Cycle (IGCC) is the most advanced technology for coal‐fired power generation. The two‐stage entrained flow gasification process allows for the use of a wide range of coal, as long as the gasification temperature is above the ash melting point of a used fuel. In this gasification technology, lignite, which often has a low ash melting point, can be preferably utilized. However, ash fluidity is also another importance, because the behaviour of molten slag can diminish a stable ash discharge from a gasifier. As the eligibility of coal ash properties is a considerable factor, water physically and chemically kept in lignite (30 – 60% in mass) attributes to deteriorating gasification efficiency, because it causes significant heat loss and increasing oxygen consumption. Developing a thermal evaporative lignite drying method will be a necessary attempt to apply lignite to the coal gasification process. For those preceded objectives, coal and ash properties and drying characteristics of several grades of Polish lignite, extracted from Belchatow and Turow deposits, have been experimentally investigated in a preliminary study evaluating the applicability and consideration for its utilization in state‐of‐the‐art clean coal technology, IGCC. This paper particularly discusses the eligibility of Polish lignite from the perspective of the fusibility and fluidity of ash melts and the fundamental drying kinetics of lignite in superheated steam in the light of water removal. The viscosity of ash melts is measured at high temperature up to 1700 °C. In the drying tests, the significant influence of structural issues, because of the provenance and origin of lignite on the drying characteristics, was found by applying the method of sensitivity analysis of physical propensity. This paper concludes that the investigated Polish lignite has characteristics favourable for utilization in IGCC technology, once the precautions related to its high moisture have been carefully addressed. Copyright © 2016 John Wiley & Sons, Ltd.     

Characteristics of hydrogen-assisted intergranular fatigue crack growth in interstitial-free steel: role of plastic strain localization

The behavior of intergranular fatigue crack growth in an interstitial-free (IF) steel in a hydrogen environment was investigated at different frequencies. Focusing on the plastic strain localization, we observed details of the striation-like feature on the intergranular fracture surface, slip behavior around microvoids, and crystallographic orientation gradient underneath the fracture surface. It was determined that the intergranular fatigue crack growth mechanism in the IF steel is microvoid formation at the crack tip and subsequent coalescence with the crack. Moreover, it was found that the grain boundaries, acting as propagation paths, suffer from pre-damage arising from plastic strain localization near the grain boundaries even before the main crack propagates to a certain location. Therefore, fatigue cracks in a hydrogen environment easily propagate to the grain boundaries. The frequency dependence of fatigue crack growth in the hydrogen environment is significantly smaller than that in a low carbon steel, probably because of the frequency dependence of the pre-damage evolution behavior.     

Development of Selective TGR5 Ligands Based on the 5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalene Skeleton

TGR5, a G-protein-coupled receptor (GPCR), plays an important role in several physiological functions. TGR5 activation through bile acids induces an increase in energy expenditure. Therefore, synthetic TGR5 ligands could be useful for the treatment of obesity or dyslipidemia. In this study, we designed and synthesized a set of TGR5 ligands with a 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (TMN) skeleton, and evaluated their TGR5 agonistic activity. We also investigated the selectivity of the synthesized compounds for TGR5 relative to the farnesoid X receptor (FXR) and retinoic acid receptor (RAR). Our results show that compound 4 b [N-(2-chlorophenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxamide] exhibited potent TGR5 agonist activity with an IC₅₀ value of 8.4 nM without significant cytotoxicity. In addition, compound 4 b showed only slight agonistic activity toward FXR and RAR at 1 μM treatment. These data indicate that compound 4 b is a selective TGR5 agonist, and could be a promising therapeutic agent for dyslipidemia.     

Application of multiple sensory evaluations to produce fermented beverages made from sole whey using Kluyveromyces marxianus

Various fermented whey-based beverages have been developed to reduce waste. However, approaches to increase the preference of whey-based beverages are required because of the low sensory acceptability of whey. Here, we identified the better starting material (whey type), between raw whey (RW) and demineralised whey (DMW), and determined the optimal initial concentration using multiple sensory evaluations to develop acceptable fermented beverages made from sole whey with pure cultured Kluyveromyces marxianus (i.e. without additional ingredients and processing methods). Acceptance tests showed that fermented beverages made from DMW were superior to RW as the starting material. The amounts of ethanol produced were 5.0%, 7.6% and 9.5% v/v from the different initial DMW concentrations of 10%, 15% and 20% w/v, respectively. We observed a significant positive correlation (r_s = 0.32, P < 0.05) between the assessment attributes, strength of taste as alcohol beverage and overall acceptability, indicating that higher concentrations of DMW yielded a more desirable product.     

Emerging Immunotherapy for Acute Myeloid Leukemia

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11–67% CR rates with 13–78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10–36% CR rates with 7–24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.     

Inhibitory Effect of 8‐Halogenated 7‐Deaza‐2′‐deoxyguanosine Triphosphates on Human 8‐Oxo‐2′‐deoxyguanosine Triphosphatase,hMTH1, Activities

hMTH1 (8‐oxo‐2′‐deoxyguanine triphosphatase) hydrolyzes oxidized nucleoside triphosphates; its presence is non‐essential for survival of normal cells but is required for survival of cancer cells. In this study, 8‐halogenated‐7‐deaza‐2′‐deoxyguanosine triphosphate (8‐halogenated‐7‐deazadGTP) derivatives were synthesized. Interestingly, these triphosphates were poor substrates for hMTH1, but exhibited strong competitive inhibition against hMTH1 at nanomolar levels. This inhibitory effect is attributed to slower rate of hydrolysis, possibly arising from enzyme structural changes, specifically different stacking interactions with 8‐halogenated‐7‐deazadGTP. This is the first example of using nucleotide derivatives to inhibit hMTH1, thus demonstrating their potential as antitumor agents.