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.     

Development of gap sensing system for narrow gap laser welding

Narrow gap welding with an oscillation laser beam is one of the effective processes for thick plate welding. To put this welding process into practical manufacturing, a groove-sensing system using image processing for narrow gap welding with an oscillation laser beam is used. This developed system uses still images of the weld zone taken by a coaxial CMOS camera. It can recognize the position of the groove wall by analysing the brightness distribution in the still image. It can then control the oscillation width and the laser-irradiated area by calculating the groove width and the groove centre position. Some narrow gap welding experiments were performed to evaluate the performance of the developed system. The results revealed that the developed system is effective for narrow gap welding with an oscillation laser beam. Using this system, the narrow gap groove can be welded even if the groove width has changed during the welding process.     

High-speed melt spinning of bicomponent fibers: Mechanism of fiber structure development in poly(ethylene terephthalate)/polypropylene system

High-speed bicomponent spinning of poly(ethylene terephthalate)(PET)(core) and poly-propylene (PP) (sheath) was carried out and the structure development in the individual components, PET and PP, was investigated. The orientation and crystallinity development in the PET component was enhanced as compared to that of the single-component spinning while the PP component remained in a low orientation state and had a pseudohexagonal crystal structure even at high take-up speeds. To clarify the mutual interaction between the two components in bicomponent spinning, a semiquantitative numerical simulation was performed. The simulation results obtained using the Newtonian fluid model showed that the solidification stress in the PET component was enhanced while that of the PP component was decreased in comparison with the corresponding single-component spinning. This is due to the difference in the temperature dependence of their elongational viscosity. Simulation with an upper-convected Maxwell model as the constitutive equation suggested that significant stress relaxation of the PP component can occur in the spinline if the PET component solidifies earlier than does PP. Based on the structural characterization results, and the simulation results, it was concluded that the difference in the activation energy of the elongational viscosity and solidification temperature between the two polymers are the main factors influencing the mutual interaction in the bicomponent spinning process. © 1996 John Wiley & Sons, Inc.     

Therapeutic Targets and Emerging Treatments in Advanced Chondrosarcoma

Simple SummaryChondrosarcomas develop chemoresistance to standard anticancer drugs, making it difficult to control unresectable or metastatic chondrosarcomas. To improve the clinical outcomes of chondrosarcoma, new treatment approaches, such as molecule-targeting agents and immunotherapy, are needed. Recent research has revealed promising biomarkers and therapeutic targets for chondrosarcoma. In addition, several molecule-targeting agents have shown favorable antitumor activities in several clinical studies in patients with advanced sarcomas, including chondrosarcoma. This review summarizes recent basic studies on biomarkers and therapeutic targets and recent clinical studies on treating chondrosarcomas.AbstractDue to resistance to standard anticancer agents, it is difficult to control the disease progression in patients with metastatic or unresectable chondrosarcoma. Novel therapeutic approaches, such as molecule-targeting drugs and immunotherapy, are required to improve clinical outcomes in patients with advanced chondrosarcoma. Recent studies have suggested several promising biomarkers and therapeutic targets for chondrosarcoma, including IDH1/2 and COL2A1. Several molecule-targeting agents and immunotherapies have shown favorable antitumor activity in clinical studies in patients with advanced chondrosarcomas. This review summarizes recent basic studies on biomarkers and molecular targets and recent clinical studies on the treatment of chondrosarcomas.