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Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas (LUAD) and exerts tumor-promoting effects. Here, we explored miRNA profiles in ASCL1-positive LUADs and identified several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95-3p/miR-95-5p, miR-124-3p, and members of the miR-17 similar to 92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, was suppressed in ASCL1-positive LUADs. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates miR-124-3p and members of the miR-17 similar to 92 family. Integrative transcriptomic analyses identified ZFP36 ring finger protein like 1 (ZFP36L1) as a target gene of miR-124-3p, and IHC studies demonstrated that ASCL1-positive LUADs are associated with low ZFP36L1 protein levels. Cell culture studies showed that ectopic ZFP36L1 expression inhibits cell proliferation, survival, and cell-cycle progression. Moreover, ZFP36L1 negatively regulated several genes including E2F transcription factor 1 (E2F1) and snail family transcriptional repressor 1 (SNAI1). In conclusion, our study revealed that suppression of ZFP36L1 via ASCL1-regulated miR-124-3p could modulate gene expression, providing evidence that ASCL1-mediated regulation of miRNAs shapes molecular features of ASCL1-positive LUADs.Implications: Our study revealed unique miRNA profiles of ASCL1-positive LUADs and identified ASCL1-regulated miRNAs with functional relevance.

[Background] Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). [Methods] This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. [Results] Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6–1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2–2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8–3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). [Conclusions] New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.

Background Mesenchymal stromal cell (MSC) transplantation therapy is a promising therapy for stroke patients. In parallel, rehabilitation with physical exercise could ameliorate stroke-induced neurological impairment. In this study, we aimed to clarify whether combination therapy of intracerebral transplantation of human modified bone marrow-derived MSCs, SB623 cells, and voluntary exercise with running wheel (RW) could exert synergistic therapeutic effects on a rat model of ischemic stroke. Methods Wistar rats received right transient middle cerebral artery occlusion (MCAO). Voluntary exercise (Ex) groups were trained in a cage with RW from day 7 before MCAO. SB623 cells (4.0 x 10(5) cells/5 mu l) were stereotactically injected into the right striatum at day 1 after MCAO. Behavioral tests were performed at day 1, 7, and 14 after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at day 15 after MCAO for mRNA level evaluation of ischemic infarct area, endogenous neurogenesis, angiogenesis, and expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The rats were randomly assigned to one of the four groups: vehicle, Ex, SB623, and SB623 + Ex groups.ResultsSB623 + Ex group achieved significant neurological recovery in mNSS compared to the vehicle group (p < 0.05). The cerebral infarct area of SB623 + Ex group was significantly decreased compared to those in all other groups (p < 0.05). The number of BrdU/Doublecortin (Dcx) double-positive cells in the subventricular zone (SVZ) and the dentate gyrus (DG), the laminin-positive area in the ischemic boundary zone (IBZ), and the mRNA level of BDNF and VEGF in SB623 + Ex group were significantly increased compared to those in all other groups (p < 0.05). Conclusions This study suggests that combination therapy of intracerebral transplantation SB623 cells and voluntary exercise with RW achieves robust neurological recovery a

In this study, stacked graphene diodes were fabricated via direct bonding using single-crystal graphene on a SiC substrate. Switching and S-shaped negative resistance were observed in the junction electrical properties measured via the 4-terminal configuration. The high-resistance state switched to the low-resistance state after applying a maximum junction voltage of ~10 V. In the high-bias voltage region, the junction voltage decreased from the maximum junction voltage to a few volts, indicating a negative resistance. In the high-resistance state, junction conductance was nearly constant at 0.13 mS. Electrical conductance in the high-bias region was expressed using an exponential function with an exponent of −1.26. Therefore, the fabricated stacked graphene diode with a simple device structure demonstrated strong nonlinear electrical properties with negative differential conductance.

Background: Vagus nerve stimulation (VNS) exerts neuroprotective and anti-inflammatory effects in preclinical models of central nervous system disorders, including Parkinson's disease (PD). VNS setting applied for experimental models is limited into single-time or intermittent short-duration stimulation. We developed a VNS device which could deliver continuous stimulation for rats. To date, the effects of vagal afferent-or efferent-selective stimulation on PD using continuous electrical stimulation remains to be determined. Objective: To investigate the effects of continuous and selective stimulation of vagal afferent or efferent fiber on Parkinsonian rats. Methods: Rats were divided into 5 group: intact VNS, afferent VNS (left VNS in the presence of left caudal vagotomy), efferent VNS (left VNS in the presence of left rostral vagotomy), sham, vagotomy. Rats un-derwent the implantation of cuff-electrode on left vagus nerve and 6-hydroxydopamine administration into the left striatum simultaneously. Electrical stimulation was delivered just after 6-OHDA adminis-tration and continued for 14 days. In afferent VNS and efferent VNS group, the vagus nerve was dissected at distal or proximal portion of cuff-electrode to imitate the selective stimulation of afferent or efferent vagal fiber respectively. Results: Intact VNS and afferent VNS reduced the behavioral impairments in cylinder test and methamphetamine-induced rotation test, which were accompanied by reduced inflammatory glial cells in substantia nigra with the increased density of the rate limiting enzyme in locus coeruleus. In contrast, efferent VNS did not exert any therapeutic effects. Conclusion: Continuous VNS promoted neuroprotective and anti-inflammatory effect in experimental PD, highlighting the crucial role of the afferent vagal pathway in mediating these therapeutic outcomes.

Theoretical studies have predicted that interactions between magnetic skyrmions and antiskyrmions give rise to various properties, such as unique arrangements, pair annihilation, topological transformation, and rectilinear and trochoidal motions that do not appear in only skyrmions or antiskyrmions. Recently, experimental studies have discovered that a Heusler material with the anisotropic Dzyaloshinskii–Moriya interaction shows a coexisting phase at 268 K and in-plane magnetic field-induced topological transformation of elliptical skyrmions and square-shaped antiskyrmions. Therefore, experimentally observing the coexisting phase and the topological transformation could be promising for developing skyrmion–antiskyrmion-based spintronics. However, such interactions and the detailed transformation mechanism remain unrevealed and unclear, respectively. Using Lorentz transmission electron microscopy experiments and micromagnetic simulations, we comprehensively study the properties in a coexisting phase of skyrmions and antiskyrmions in a Heusler material, Mn1.3Pt1.0Pd0.1Sn. Control of dipolar interaction (the sample thickness) allows us to realize a room-temperature coexisting phase. We find that the topological transformation occurs stochastically rather than deterministically, which can be explained by considering the magnetic point group and the direction of an in-plane magnetic field. We further observe isotropic long-range repulsive interaction between skyrmions and antiskyrmions in contrast to the conventional thought of the relative-position- and helicity-dependent short-range pairwise interactions, and deformation of skyrmions and antiskyrmions depending on the distance between them. Our simulations show that the deformation exerts significant influence on the magnetic energies and the energy landscape, contributing to the interaction. Our results provide insight into coexisting phases of skyrmions and antiskyrmions and a guide for developing skyrmion–antiskyrmi

BackgroundActivating mutations of the KRAS occurs in >90% of pancreatic ductal adenocarcinoma (PDAC) cases. However, direct pharmacological targeting of the activated KRAS protein has been challenging. We previously reported that KR12, a DNA-alkylating pyrrole-imidazole polyamide designed to recognize the KRAS G12D/V mutation, showed an anti-tumor effect in colorectal cancer. In this study, we evaluated the anti-tumor effect of KR12 in PDAC.MethodsKR12 was synthesized by an automated peptide synthesizer PSSM-8 and tested for anti-tumor effect in PDAC mouse models.ResultKR12 inhibited tumor growth in a spontaneous PDAC mouse model, although the anti-tumor activity appeared to be limited in a human PDAC xenograft model. We developed a pyrrole-imidazole polyamide screening process based on the hypothesis that genetic elements otherwise unaffected by KR12 could exert attenuating effects on KRAS-suppression-resistant PDAC. We identified RAD51 as a potential therapeutic target in human PDAC cells. A RAD51 inhibitor showed an inhibitory effect on cell growth and affected the cytotoxic activity of KR12 in PDAC cells.ConclusionThese data suggested that the simultaneous inhibition of RAD51 and mutant KRAS blockage would be an important therapeutic strategy for PDAC.

This study investigates energy harvesting by a deionized (DI) water droplet flow on an epitaxial graphene film on a SiC substrate. We obtain an epitaxial single-crystal graphene film by annealing a 4H-SiC substrate. Energy harvesting of the solution droplet flow on the graphene surface has been investigated by using NaCl or HCl solutions. This study validates the voltage generated from the DI water flow on the epitaxial graphene film. The maximum generated voltage was as high as 100 mV, which was a quite large value compared with the previous reports. Furthermore, we measure the dependence of flow direction on electrode configuration. The generated voltages are independent of the electrode configuration, indicating that the DI water flow direction is not influenced by the voltage generation for the single-crystal epitaxial graphene film. Based on these results, the origin of the voltage generation on the epitaxial graphene film is not only an outcome of the fluctuation of the electrical-double layer, resulting in the breaking of the uniform balance of the surface charges, but also other factors such as the charges in the DI water or frictional electrification. In addition, the buffer layer has no effect on the epitaxial graphene film on the SiC substrate.

Following Getzler’s idea from the geometric viewpoint as to symbol calculus on a spin manifold, we introduce a new symbol calculus of H-pseudodifferential operators on a contact Riemannian manifold with contact distribution H. An explicit formula for the top grading part of the symbol of the composite of H-differential operators is presented.

The interruption of cerebral blood flow leads to ischemic cell death and results in ischemic stroke. Although ischemic stroke is one of the most important causes of long-term disability and mortality, limited treatments are available for functional recovery. Therefore, extensive research has been conducted to identify novel treatments. Neurogenesis is regarded as a fundamental mechanism of neural plasticity. Therefore, therapeutic strategies targeting neurogenesis are thought to be promising. Basic research has found that therapeutic intervention including cell therapy, rehabilitation, and pharmacotherapy increased neurogenesis and was accompanied by functional recovery after ischemic stroke. In this review, we consolidated the current knowledge of the relationship between neurogenesis and treatment for ischemic stroke. It revealed that many treatments for ischemic stroke, including clinical and preclinical ones, have enhanced brain repair and functional recovery post-stroke along with neurogenesis. However, the intricate mechanisms of neurogenesis and its impact on stroke recovery remain areas of extensive research, with numerous factors and pathways involved. Understanding neurogenesis will lead to more effective stroke treatments, benefiting not only stroke patients but also those with other neurological disorders. Further research is essential to bridge the gap between preclinical discoveries and clinical implementation.

Theoretical studies have predicted that interactions between magnetic skyrmions and antiskyrmions give rise to various properties, such as unique arrangements, pair annihilation, topological transformation, and rectilinear and trochoidal motions that do not appear in only skyrmions or antiskyrmions. Recently, experimental studies have discovered that a Heusler material with the anisotropic Dzyaloshinskii–Moriya interaction shows a coexisting phase at 268 K and in-plane magnetic field-induced topological transformation of elliptical skyrmions and square-shaped antiskyrmions. Therefore, experimentally observing the coexisting phase and the topological transformation could be promising for developing skyrmion–antiskyrmion-based spintronics. However, such interactions and the detailed transformation mechanism remain unrevealed and unclear, respectively. Using Lorentz transmission electron microscopy experiments and micromagnetic simulations, we comprehensively study the properties in a coexisting phase of skyrmions and antiskyrmions in a Heusler material, Mn1.3Pt1.0Pd0.1Sn. Control of dipolar interaction (the sample thickness) allows us to realize a room-temperature coexisting phase. We find that the topological transformation occurs stochastically rather than deterministically, which can be explained by considering the magnetic point group and the direction of an in-plane magnetic field. We further observe isotropic long-range repulsive interaction between skyrmions and antiskyrmions in contrast to the conventional thought of the relative-position- and helicity-dependent short-range pairwise interactions, and deformation of skyrmions and antiskyrmions depending on the distance between them. Our simulations show that the deformation exerts significant influence on the magnetic energies and the energy landscape, contributing to the interaction. Our results provide insight into coexisting phases of skyrmions and antiskyrmions and a guide for developing skyrmion–antiskyrmi

Background: Vagus nerve stimulation (VNS) exerts neuroprotective and anti-inflammatory effects in preclinical models of central nervous system disorders, including Parkinson's disease (PD). VNS setting applied for experimental models is limited into single-time or intermittent short-duration stimulation. We developed a VNS device which could deliver continuous stimulation for rats. To date, the effects of vagal afferent-or efferent-selective stimulation on PD using continuous electrical stimulation remains to be determined. Objective: To investigate the effects of continuous and selective stimulation of vagal afferent or efferent fiber on Parkinsonian rats. Methods: Rats were divided into 5 group: intact VNS, afferent VNS (left VNS in the presence of left caudal vagotomy), efferent VNS (left VNS in the presence of left rostral vagotomy), sham, vagotomy. Rats un-derwent the implantation of cuff-electrode on left vagus nerve and 6-hydroxydopamine administration into the left striatum simultaneously. Electrical stimulation was delivered just after 6-OHDA adminis-tration and continued for 14 days. In afferent VNS and efferent VNS group, the vagus nerve was dissected at distal or proximal portion of cuff-electrode to imitate the selective stimulation of afferent or efferent vagal fiber respectively. Results: Intact VNS and afferent VNS reduced the behavioral impairments in cylinder test and methamphetamine-induced rotation test, which were accompanied by reduced inflammatory glial cells in substantia nigra with the increased density of the rate limiting enzyme in locus coeruleus. In contrast, efferent VNS did not exert any therapeutic effects. Conclusion: Continuous VNS promoted neuroprotective and anti-inflammatory effect in experimental PD, highlighting the crucial role of the afferent vagal pathway in mediating these therapeutic outcomes.

In this study, stacked graphene diodes were fabricated via direct bonding using single-crystal graphene on a SiC substrate. Switching and S-shaped negative resistance were observed in the junction electrical properties measured via the 4-terminal configuration. The high-resistance state switched to the low-resistance state after applying a maximum junction voltage of ~10 V. In the high-bias voltage region, the junction voltage decreased from the maximum junction voltage to a few volts, indicating a negative resistance. In the high-resistance state, junction conductance was nearly constant at 0.13 mS. Electrical conductance in the high-bias region was expressed using an exponential function with an exponent of −1.26. Therefore, the fabricated stacked graphene diode with a simple device structure demonstrated strong nonlinear electrical properties with negative differential conductance.

This study investigates energy harvesting by a deionized (DI) water droplet flow on an epitaxial graphene film on a SiC substrate. We obtain an epitaxial single-crystal graphene film by annealing a 4H-SiC substrate. Energy harvesting of the solution droplet flow on the graphene surface has been investigated by using NaCl or HCl solutions. This study validates the voltage generated from the DI water flow on the epitaxial graphene film. The maximum generated voltage was as high as 100 mV, which was a quite large value compared with the previous reports. Furthermore, we measure the dependence of flow direction on electrode configuration. The generated voltages are independent of the electrode configuration, indicating that the DI water flow direction is not influenced by the voltage generation for the single-crystal epitaxial graphene film. Based on these results, the origin of the voltage generation on the epitaxial graphene film is not only an outcome of the fluctuation of the electrical-double layer, resulting in the breaking of the uniform balance of the surface charges, but also other factors such as the charges in the DI water or frictional electrification. In addition, the buffer layer has no effect on the epitaxial graphene film on the SiC substrate.

One way of expressing an environmental sound is using vocal imitations, which involve the process of replicating or mimicking the rhythm and pitch of sounds by voice. We can effectively express the features of environmental sounds, such as rhythm and pitch, using vocal imitations, which cannot be expressed by conventional input information, such as sound event labels, images, or texts, in an environmental sound synthesis model. In this paper, we propose a framework for environmental sound synthesis from vocal imitations and sound event labels based on a framework of a vector quantized encoder and the Tacotron2 decoder. Using vocal imitations is expected to control the pitch and rhythm of the synthesized sound, which only sound event labels cannot control. Our objective and subjective experimental results show that vocal imitations effectively control the pitch and rhythm of synthesized sounds., Comment: Submitted to ICASSP2024

Data movement is a key bottleneck in terms of both performance and energy efficiency in modern HPC systems. The NEC SX-series supercomputers have a long history of accelerating memory-intensive HPC applications by providing sufficient memory bandwidth to applications. In this paper, we analyze the performance of a prototype SX-Aurora TSUBASA supercomputer equipped with the brand-new Vector Engine (VE30) processor. VE30 is the first major update to the Vector Engine processor series, and offers significantly improved memory access performance due to its renewed memory subsystem. Moreover, it introduces new instructions and incorporates architectural advancements tailored for accelerating memory-intensive applications. Using standard benchmarks, we demonstrate that VE30 considerably outperforms other processors in both performance and efficiency of memory-intensive applications. We also evaluate VE30 using applications including SPEChpc, and show that VE30 can run real-world applications with high performance. Finally, we discuss performance tuning techniques to obtain maximum performance from VE30., Comment: This paper has been accepted at ISC 2023

Project Based Learning (PBL) is a teaching and learning method in which students actively solve real-world problems and gain knowledge and skills. The teaching experiences, materials, and methods for PBL have diversity and are not shared with universities. We present the Faculty Development (FD) camp for PBL, in order to share them. The FD camp provides the place of discussing the PBL to the participants, in order to solve subjects of PBL. We hold three FD camps with Open Space Technology (OST), which is a simple way to run productive meetings. Evaluations in questionnaires show that most of the participants have good impressions in the FD camp with OST. We mainly learn that the contribution of the FD camp is to build the facultycommunity.

The far-infrared emission properties of epitaxial graphene on SiC obtained by current injection were investigated using an infrared camera and Fourier-transform infrared spectroscopy. The radiation directivity from the graphene emitter was observed in the directions perpendicular to the surface and edge of the sample. The emission energy density from the graphene edge was larger than that from the graphene surface in all directions. The maximum measured temperature change at 0.4 W for the edge emission was 76.1 K for a tilt angle of 50° and that for the surface emission was 54.1 K for 0°. A blackbody-like emission spectrum with a constant peak wavelength of 10.0 µm, regardless of the applied electrical power, was observed for both the surface and edge. A far-infrared light emitter was successfully realized using single-crystal graphene on SiC.

Aims SB623 cells are human bone marrow stromal cells transfected with Notch1 intracellular domain. In this study, we examined potential regenerative mechanisms underlying stereotaxic transplantation of SB623 cells in rats with experimental acute ischemic stroke. Methods We prepared control group, empty capsule (EC) group, SB623 cell group (SB623), and encapsulated SB623 cell (eSB623) group. Transient middle cerebral artery occlusion (MCAO) was performed on day 0, and 24 h after MCAO, stroke rats received transplantation into the envisioned ischemic penumbra. Modified neurological severity score (mNSS) was evaluated, and histological evaluations were performed. Results In the mNSS, SB623 and eSB623 groups showed significant improvement compared to the other groups. Histological analysis revealed that the infarction area in SB623 and eSB623 groups was reduced. In the eSB623 group, robust cell viability and neurogenesis were detected in the subventricular zone that increased significantly compared to all other groups. Conclusion SB623 cells with or without encapsulation showed therapeutic effects on ischemic stroke. Encapsulated SB623 cells showed enhanced neurogenesis and increased viability inside the capsules. This study reveals the mechanism of secretory function of transplanted SB623 cells, but not cell-cell interaction as primarily mediating the cells' functional benefits in ischemic stroke.

Clarifying the adsorption characteristics of biomolecules on graphene surfaces is critical for the development of field-effect transistor (FET)-based biosensors for detecting pH, DNA, proteins, and other biomarkers. Although there are many reports on biomolecule detection using graphene FETs, the detection mechanism has not yet been clarified. In this study, the adsorption behavior and electron transfer characteristics of 20 proteinogenic amino acids on graphene field-effect transistors are investigated. Large single-crystal graphene films were epitaxially grown on SiC substrates by a resist-free metal stencil mask lithography process then patterned by air plasma etching to form FET devices. Amino acids with different charge conditions (positive or negative charge) were introduced onto the epitaxial graphene surface in solution. The charge neutral points of the drain current vs gate voltage curves shifted in the negative gate voltage direction after the introduction of all amino acids, regardless of the type of amino acid and its charge condition. These amino acid adsorption characteristics agree well with previously reported protein adsorption characteristics on epitaxial graphene surfaces, indicating that the adsorption of proteins in the liquid phase occurs by electron doping to the graphene surface. These results indicate that non-specific protein binding always leads to electron doping of epitaxial graphene FETs.

Nagase T., Todai M., Wang P., et al. Design and development of (Ti, Zr, Hf)-Al based medium entropy alloys and high entropy alloys. Materials Chemistry and Physics, 276, 125409. https://doi.org/10.1016/j.matchemphys.2021.125409., The design and development of TiZrHfAl medium entropy alloy (MEA), and the TiZrHfAlNb0.2 and TiZrHfAlV0.2 high entropy alloys (HEAs) is described. The combination of 4th subgroup elements (Ti, Zr, and Hf) with Al is discussed based on the periodic table and taxonomy of HEAs. The alloys were designed using alloy parameters for HEAs, predicted ground state diagrams from the Materials Project, and the calculation of phase diagrams (CALPHAD). Rapid solidification was effective to suppress the formation of intermetallic compounds, resulting in BCC/B2 phase formation. Significant differences in the constituent phases and Vickers hardness between ingots and melt-spun ribbons were found among the TiZrHfAl MEA, TiZrHfAlNb0.2, and TiZrHfAlV0.2 HEAs.

Aims SB623 cells are human bone marrow stromal cells transfected with Notch1 intracellular domain. In this study, we examined potential regenerative mechanisms underlying stereotaxic transplantation of SB623 cells in rats with experimental acute ischemic stroke. Methods We prepared control group, empty capsule (EC) group, SB623 cell group (SB623), and encapsulated SB623 cell (eSB623) group. Transient middle cerebral artery occlusion (MCAO) was performed on day 0, and 24 h after MCAO, stroke rats received transplantation into the envisioned ischemic penumbra. Modified neurological severity score (mNSS) was evaluated, and histological evaluations were performed. Results In the mNSS, SB623 and eSB623 groups showed significant improvement compared to the other groups. Histological analysis revealed that the infarction area in SB623 and eSB623 groups was reduced. In the eSB623 group, robust cell viability and neurogenesis were detected in the subventricular zone that increased significantly compared to all other groups. Conclusion SB623 cells with or without encapsulation showed therapeutic effects on ischemic stroke. Encapsulated SB623 cells showed enhanced neurogenesis and increased viability inside the capsules. This study reveals the mechanism of secretory function of transplanted SB623 cells, but not cell-cell interaction as primarily mediating the cells' functional benefits in ischemic stroke.

Clarifying the adsorption characteristics of biomolecules on graphene surfaces is critical for the development of field-effect transistor (FET)-based biosensors for detecting pH, DNA, proteins, and other biomarkers. Although there are many reports on biomolecule detection using graphene FETs, the detection mechanism has not yet been clarified. In this study, the adsorption behavior and electron transfer characteristics of 20 proteinogenic amino acids on graphene field-effect transistors are investigated. Large single-crystal graphene films were epitaxially grown on SiC substrates by a resist-free metal stencil mask lithography process then patterned by air plasma etching to form FET devices. Amino acids with different charge conditions (positive or negative charge) were introduced onto the epitaxial graphene surface in solution. The charge neutral points of the drain current vs gate voltage curves shifted in the negative gate voltage direction after the introduction of all amino acids, regardless of the type of amino acid and its charge condition. These amino acid adsorption characteristics agree well with previously reported protein adsorption characteristics on epitaxial graphene surfaces, indicating that the adsorption of proteins in the liquid phase occurs by electron doping to the graphene surface. These results indicate that non-specific protein binding always leads to electron doping of epitaxial graphene FETs.

Nagase T., Todai M., Wang P., et al. Design and development of (Ti, Zr, Hf)-Al based medium entropy alloys and high entropy alloys. Materials Chemistry and Physics, 276, 125409. https://doi.org/10.1016/j.matchemphys.2021.125409., The design and development of TiZrHfAl medium entropy alloy (MEA), and the TiZrHfAlNb0.2 and TiZrHfAlV0.2 high entropy alloys (HEAs) is described. The combination of 4th subgroup elements (Ti, Zr, and Hf) with Al is discussed based on the periodic table and taxonomy of HEAs. The alloys were designed using alloy parameters for HEAs, predicted ground state diagrams from the Materials Project, and the calculation of phase diagrams (CALPHAD). Rapid solidification was effective to suppress the formation of intermetallic compounds, resulting in BCC/B2 phase formation. Significant differences in the constituent phases and Vickers hardness between ingots and melt-spun ribbons were found among the TiZrHfAl MEA, TiZrHfAlNb0.2, and TiZrHfAlV0.2 HEAs.

The characteristics of the seafloor environment of the harvesting grounds of the kelp, Saccharina longissima, were evaluated by spatial analysis using a geographic information system (GIS) in the Pacific coastal area of eastern Hokkaido. The kelp harvesting grounds were formed in water depths ranging from 1.2 m to 9.6 m, slopes ranging from 0° to 16.3°, bottom substrate (coarseness score) ranging from 1.82 to 3.00, bottom current velocities ranging from 0.7 cm/s to 116.4 cm/s, and a maximum slope of 37.6°. These values include the viable environmental conditions for the kelp. The kelp growth parameters estimated from kelp measurement data before the harvesting season were positively related to the bottom current velocity. This suggests that the bottom current velocity has a significant effect on kelp growth. The 58 harvesting grounds were classified into two categories based on their growth: those with high kelp growth and those with low kelp growth. Based on a decision tree model, the differences between the two harvesting ground categories were explained by the bottom current velocity, maximum slope, and bottom substrate. In addition, their specific environmental conditions were also quantified. The quantified environmental conditions were also used to create a potential map for the kelp growth in the harvesting grounds. This study provides an understanding of the environmental characteristics of the kelp harvesting grounds, as well as a procedure for mapping the kelp growth potential, thus contributing to the sustainable use of the kelp resources through kelp harvesting ground management and maintenance.

PURPOSE: This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS: Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS: Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION: Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

Sleep is generally viewed as a period of recovery, but how the supply of cerebral blood flow (CBF) changes across sleep/wake states has remained unclear. Here, we directly observe red blood cells (RBCs) within capillaries, where the actual substance exchange between the blood and neurons/glia occurs, by two-photon microscopy. Across multiple cortical areas, average capillary CBF is largely increased during rapid eye movement (REM) sleep, whereas it does not differ between periods of active wakefulness and non-REM sleep. Capillary RBC flow during REM sleep is further elevated following REM sleep deprivation, suggesting that capillary CBF reflects REM sleep pressure. At the molecular level, signaling via adenosine A2a receptors is crucial; in A2a-KO mice, capillary CBF upsurge during REM sleep is dampened, and effects of REM sleep pressure are abolished. These results provide evidence regarding the dynamics of capillary CBF across sleep/wake states and insights to the underlying mechanisms.

軽水炉においては、冷却系配管破断等による冷却材喪失事故(LOCA)時にも炉心の冷却可能な形状を維持し放射性核分裂生成物の周辺への放出を抑制するために、非常用炉心冷却系(ECCS)が設置されている。ECCSの設計上の機能及び性能を評価し、評価結果が十分な安全余裕を有することを確認するために、「軽水型動力炉の非常用炉心冷却系の性能評価指針」が定められている。同指針に規定されている基準は1975年に定められた後、1981年に当時の最新知見を参考に見直しが行われている。その後、軽水炉においては燃料の高燃焼度化及びそれに必要な被覆管材料の改良や設計変更が進められたが、それに対応した指針の見直しは行われていない。一方、高燃焼度燃料のLOCA時挙動や高燃焼度燃料への現行指針の適用性に関する多くの技術的な知見が取得されてきている。本報告においては、我が国における指針の制定経緯及び技術的根拠を確認しつつ、国内外におけるLOCA時燃料挙動に係る最新の技術的知見を取りまとめる。また、同指針を高燃焼度燃料に適用することの妥当性に関する見解を述べる。, Each light-water reactor (LWR) is equipped with the Emergency Core Cooling System (ECCS) to maintain the coolability of the reactor core and to suppress the release of radioactive fission products to the environment even in a loss-of-coolant accident (LOCA) caused by breaks in the reactor coolant pressure boundary. The acceptance criteria for ECCS have been established in order to evaluate the ECCS performance and confirm the sufficient safety margin in the evaluation. The limits defined in the criteria were determined in 1975 and reviewed based on state-of-the-art knowledge in 1981. Though the fuel burnup extension and necessary improvements of cladding materials and fuel design have been conducted, the criteria have not been reviewed since then. Meanwhile, much technical knowledge has been accumulated regarding the behavior of high-burnup fuel during LOCAs and the applicability of the criteria to the high-burnup fuel. This report provides a comprehensive review of the history and technical bases of the current criteria and summarizes state-of-the-art technical findings regarding the fuel behavior during LOCAs. The applicability of the current criteria to the high-burnup fuel is also discussed., 著者所属: 日本原子力研究開発機構(JAEA), JAEA-Review 2020-076

To reveal the infrared absorption causes in the wavelength region between electronic and lattice absorptions, we measured the temperature dependence of the absorption coefficient of $p$-type low-resistivity ($\sim 10^2~{\rm \Omega cm}$) CdZnTe crystals. We measured the absorption coefficients of CdZnTe crystals in four-wavelength bands ($\lambda=6.45$, 10.6, 11.6, 15.1$~\mu$m) over the temperature range of $T=8.6-300$ K with an originally developed system. The CdZnTe absorption coefficient was measured to be $\alpha=0.3-0.5$ ${\rm cm^{-1}}$ at $T=300$ K and $\alpha=0.4-0.9$ ${\rm cm^{-1}}$ at $T=8.6$ K in the investigated wavelength range. With an absorption model based on transitions of free holes and holes trapped at an acceptor level, we conclude that the absorption due to free holes at $T=150-300$ K and that due to trapped-holes at $T<50$ K are dominant absorption causes in CdZnTe. We also discuss a method to predict the CdZnTe absorption coefficient at cryogenic temperature based on the room-temperature resistivity., Comment: Accepted for publication in Journal of Electronic Material, 30 pages, 6 figures, 5 tables

Epithelial-mesenchymal transition (EMT) is a cellular process during which epithelial cells acquire mesenchymal phenotypes. Cancer cells undergo EMT to acquire malignant features and TGF-beta is a key regulator of EMT. Here, we demonstrate for the first time that TGF-beta could elicit EMT in a mouse lung adenocarcinoma cell line. TGF-beta signaling activation led to cell morphological changes corresponding to EMT and enhanced the expression of mesenchymal markers and EMT-associated transcription factors in CMT64 lung cancer cells. RNA-sequencing analyses revealed that TGF-beta increases expression of Tead transcription factors and an array of Tead2 target genes. TGF-beta stimulation also resulted in alternative splicing of several genes including Cd44, tight junction protein 1 (Tjp1), and Cortactin (Cttn). In parallel with EMT, TGF-beta enhanced cell growth of CMT64 cells and promoted tumor formation in a syngeneic transplantation model. Of clinical importance, the expression of TGF-beta-induced genes identified in CMT64 cells correlated with EMT gene signatures in human lung adenocarcinoma tissue samples. Furthermore, TGF-beta-induced gene enrichment was related to poor prognosis, underscoring the tumor-promoting role of TGF-beta signaling in lung adenocarcinoma. Our cellular and syngeneic transplantation model would provide a simple and useful experimental tool to study the significance of TGF-beta signaling and EMT.

Epithelial-mesenchymal transition (EMT) is a cellular process during which epithelial cells acquire mesenchymal phenotypes. Cancer cells undergo EMT to acquire malignant features and TGF-beta is a key regulator of EMT. Here, we demonstrate for the first time that TGF-beta could elicit EMT in a mouse lung adenocarcinoma cell line. TGF-beta signaling activation led to cell morphological changes corresponding to EMT and enhanced the expression of mesenchymal markers and EMT-associated transcription factors in CMT64 lung cancer cells. RNA-sequencing analyses revealed that TGF-beta increases expression of Tead transcription factors and an array of Tead2 target genes. TGF-beta stimulation also resulted in alternative splicing of several genes including Cd44, tight junction protein 1 (Tjp1), and Cortactin (Cttn). In parallel with EMT, TGF-beta enhanced cell growth of CMT64 cells and promoted tumor formation in a syngeneic transplantation model. Of clinical importance, the expression of TGF-beta-induced genes identified in CMT64 cells correlated with EMT gene signatures in human lung adenocarcinoma tissue samples. Furthermore, TGF-beta-induced gene enrichment was related to poor prognosis, underscoring the tumor-promoting role of TGF-beta signaling in lung adenocarcinoma. Our cellular and syngeneic transplantation model would provide a simple and useful experimental tool to study the significance of TGF-beta signaling and EMT.

Epithelial-mesenchymal transition (EMT) is a cellular process during which epithelial cells acquire mesenchymal phenotypes. Cancer cells undergo EMT to acquire malignant features and TGF-beta is a key regulator of EMT. Here, we demonstrate for the first time that TGF-beta could elicit EMT in a mouse lung adenocarcinoma cell line. TGF-beta signaling activation led to cell morphological changes corresponding to EMT and enhanced the expression of mesenchymal markers and EMT-associated transcription factors in CMT64 lung cancer cells. RNA-sequencing analyses revealed that TGF-beta increases expression of Tead transcription factors and an array of Tead2 target genes. TGF-beta stimulation also resulted in alternative splicing of several genes including Cd44, tight junction protein 1 (Tjp1), and Cortactin (Cttn). In parallel with EMT, TGF-beta enhanced cell growth of CMT64 cells and promoted tumor formation in a syngeneic transplantation model. Of clinical importance, the expression of TGF-beta-induced genes identified in CMT64 cells correlated with EMT gene signatures in human lung adenocarcinoma tissue samples. Furthermore, TGF-beta-induced gene enrichment was related to poor prognosis, underscoring the tumor-promoting role of TGF-beta signaling in lung adenocarcinoma. Our cellular and syngeneic transplantation model would provide a simple and useful experimental tool to study the significance of TGF-beta signaling and EMT.

We experimentally demonstrate the observation of a frequency-shift dynamics at a temporal boundary in the terahertz (THz) region relying on a scheme that controls the structural dispersion of a metal-semiconductor waveguide. Ultrafast structural-dispersion switching is achieved within a subpicosecond timescale by illuminating a waveguide surface with an optical pump pulse during the propagation of a THz pulse in the waveguide. Owing to the relatively high conversion efficiency, up to 23%, under the condition that the frequency shift is sufficiently larger than the bandwidth of the incident pulse, the rapid variation of the THz frequency around the temporal boundary is directly observed in the time domain., source:https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.127.053902

Two types of vertically stacked graphene junction diodes were fabricated in this study. Samples of single-crystal graphene measuring 100 mm2 were epitaxially grown on SiC substrate using the thermal decomposition method and were bonded using the direct bonding technique. The direct-bonded stacked junction diode exhibited nonlinear current-voltage characteristics and acted as a far-infrared emitter. Fowler-Nordheim tunneling phenomena with a strong nonlinear behavior was observed in the tunneling diode with a thin insulative layer (air gap or structured water). By using simple device-assembly processes, vertically stacked graphene diodes with new functions were successfully fabricated.

Thermal desorption of the structured water layer on graphene was observed in this study via electrical conductivity measurements. Specifically, a structured water layer was formed on the graphene surface via deionized water treatment, following which we examined the thermal desorption process of the layer using sheet resistance measurements. The water molecules acting as a p-type dopant were strongly adsorbed on graphene, forming a solid layer. Consequently, the layer was completely removed from the graphene surface at 300⁡°C. The thermal desorption spectrum of the structured water layer on graphene was quantitatively obtained by converting the measured sheet resistance to carrier density change.

Objectives. The aim of this study was to elucidate the clinicopathological features of ovarian granulosa cell tu-mors (GCTs) and to identify the prognostic factors. Methods. The Japanese Society of Gynecologic Oncology (JSGO) conducted an observational retrospective co-hort study of women with GCTs enrolled in the Gynecological Tumor Registry of the Japan Society of Obstetrics and Gynecology (JSOG) between 2002 and 2015. Clinicopathological features, including lymph node metastasis, were evaluated. In addition, we performed a prognostic analysis of patients between 2002 and 2011 for whom survival data were available. Kaplan-Meier and multivariate Cox proportional hazards analyses were performed. Results. We identified 1426 patients with GCTs. Of the 222 patients who underwent lymph node dissection, 10 (4.5%) had lymph node metastasis. The incidence of lymph node metastasis in patients with pT1, pT2, and pT3 was 2.1%, 13.3%, and 26.7%, respectively (p < 0.001). Prognostic analysis was performed on 674 patients. In the multivariate Cox regression analysis, residual disease after initial surgery (hazard ratio (HR) = 10.39, 95% confidence interval (CI) = 3.15-34.29) and lymph node metastasis (HR = 5.58, 95% CI = 1.62-19.19) were independent risk factors for cancer-specific survival. Conclusions. In the initial surgery for GCTs, lymph node dissection can be omitted if the operative finding is pT1. In cases of pT2 or higher, lymph node dissection should be considered. Debulking is critical for achieving no gross residual tumor at the end of the surgery. (c) 2021 Elsevier Inc. All rights reserved.

Iijima Y., Nagase T., Matsugaki A., et al. Design and development of Ti–Zr–Hf–Nb–Ta–Mo high-entropy alloys for metallic biomaterials. Materials and Design, 202, 109548. https://doi.org/10.1016/j.matdes.2021.109548., Applying empirical alloy parameters (including Mo equivalent), the predicted ground state diagram, and thermodynamic calculations, noble nonequiatomic Ti–Zr–Hf–Nb–Ta–Mo high-entropy alloys for metallic biomaterials (BioHEAs) were designed and newly developed. It is found that the Moeq and valence electron concentration (VEC) parameters are useful for alloy design involving BCC structure formation in bio medium-entropy alloys and BioHEAs. Finally, we find a Ti28.33Zr28.33Hf28.33Nb6.74Ta6.74Mo1.55 (at.%) BioHEA that exhibits biocompatibility comparable to that of CP–Ti, higher mechanical strength than CP–Ti, and an appreciable room-temperature tensile ductility. The current findings pave the way for new Ti–Zr–Hf–Nb–Ta–Mo BioHEAs development and are applicable for another BioHEA alloys system.

Ishimoto T., Ozasa R., Nakano K., et al. Development of TiNbTaZrMo bio-high entropy alloy (BioHEA) super-solid solution by selective laser melting, and its improved mechanical property and biocompatibility. Scripta Materialia, 194, 113658. https://doi.org/10.1016/j.scriptamat.2020.113658., BioHEAs, specifically designed high entropy alloy (HEA) systems for biomedical applications, represent a new era for biometals. However, recent challenges are (1) the poor shape customizability, and (2) the inevitable severe segregation due to the intrinsic fact that HEA is an ultra-multicomponent alloy system. To achieve shape customization and suppression of elemental segregation simultaneously, we used an extremely high cooling rate (~107 K/s) of the selective laser melting (SLM) process. We, for the first time, developed pre-alloyed Ti1.4Nb0.6Ta0.6Zr1.4Mo0.6 BioHEA powders and SLM-built parts with low porosity, customizable shape, excellent yield stress, and good biocompatibility. The SLM-built specimens showed drastically suppressed elemental segregation compared to the cast counterpart, representing realization of a super-solid solution. As a result, the 0.2% proof stress reached 1690 ± 78 MPa, which is significantly higher than that of cast Ti1.4Nb0.6Ta0.6Zr1.4Mo0.6 (1140 MPa). The SLM-built Ti1.4Nb0.6Ta0.6Zr1.4Mo0.6 BioHEA is promising as a next-generation metallic material for biomedical applications.

PIK3CA is the most frequently mutated oncogene in cervical cancer, and somatic mutations in the PIK3CA gene result in increased activity of PI3K. In cervical cancer, the E545K mutation in PIK3CA leads to elevated cell proliferation and reduced apoptosis. In the present study, we designed and synthesized a novel pyrrole-imidazole polyamide-seco-CBI conjugate, P3AE5K, to target the PIK3CA gene bearing the E545K mutation, rendered possible by nuclear access and the unique sequence specificity of pyrrole-imidazole polyamides. P3AE5K interacted with double-stranded DNA of the coding region containing the E545K mutation. When compared with conventional PI3K inhibitors, P3AE5K demonstrated strong cytotoxicity in E545K-positive cervical cancer cells at lower concentrations. PIK3CA mutant cells exposed to P3AE5K exhibited reduced expression levels of PIK3CA mRNA and protein, and subsequent apoptotic cell death. Moreover, P3AE5K significantly decreased the tumor growth in mouse xenograft models derived from PIK3CA mutant cells. Overall, the present data strongly suggest that the alkylating pyrrole-imidazole polyamide P3AE5K should be a promising new drug candidate targeting a constitutively activating mutation of PIK3CA in cervical cancer.

Anaplastic lymphoma kinase (ALK) aberration is related to high-risk neuroblastomas and is an important therapeutic target. As acquired resistance to ALK tyrosine kinase inhibitors is inevitable, novel anti-ALK drug development is necessary in order to overcome potential drug resistance against ATP-competitive kinase inhibitors. In this study, to overcome ALK inhibitor resistance, we examined the growth inhibition effects of newly developed ALK-targeting pyrrole-imidazole polyamide CCC-003, which was designed to directly bind and alkylate DNA within the F1174L-mutated ALK gene. CCC-003 suppressed cell proliferation in ALK-mutated neuroblastoma cells. The expression of total and phosphorylated ALK was downregulated by CCC-003 treatment but not by treatment with a mismatch polyamide without any binding motif within the ALK gene region. CCC-003 preferentially bound to the DNA sequence with the F1174L mutation and significantly suppressed tumor progression in a human neuroblastoma xenograft mouse model. Our data suggest that the specific binding of CCC-003 to mutated DNA within the ALK gene exerts its anti-tumor activity through a mode of action that is distinct from those of other ALK inhibitors. In summary, our current study provides evidence for the potential of pyrrole-imidazole polyamide ALK inhibitor CCC-003 for the treatment of neuroblastoma thus offering a possible solution to the problem of tyrosine kinase inhibitor resistance.

Epithelial-mesenchymal transition (EMT) is a cellular process during which epithelial cells acquire mesenchymal phenotypes. Cancer cells undergo EMT to acquire malignant features and TGF-beta is a key regulator of EMT. Here, we demonstrate for the first time that TGF-beta could elicit EMT in a mouse lung adenocarcinoma cell line. TGF-beta signaling activation led to cell morphological changes corresponding to EMT and enhanced the expression of mesenchymal markers and EMT-associated transcription factors in CMT64 lung cancer cells. RNA-sequencing analyses revealed that TGF-beta increases expression of Tead transcription factors and an array of Tead2 target genes. TGF-beta stimulation also resulted in alternative splicing of several genes including Cd44, tight junction protein 1 (Tjp1), and Cortactin (Cttn). In parallel with EMT, TGF-beta enhanced cell growth of CMT64 cells and promoted tumor formation in a syngeneic transplantation model. Of clinical importance, the expression of TGF-beta-induced genes identified in CMT64 cells correlated with EMT gene signatures in human lung adenocarcinoma tissue samples. Furthermore, TGF-beta-induced gene enrichment was related to poor prognosis, underscoring the tumor-promoting role of TGF-beta signaling in lung adenocarcinoma. Our cellular and syngeneic transplantation model would provide a simple and useful experimental tool to study the significance of TGF-beta signaling and EMT.

Objectives. The aim of this study was to elucidate the clinicopathological features of ovarian granulosa cell tu-mors (GCTs) and to identify the prognostic factors. Methods. The Japanese Society of Gynecologic Oncology (JSGO) conducted an observational retrospective co-hort study of women with GCTs enrolled in the Gynecological Tumor Registry of the Japan Society of Obstetrics and Gynecology (JSOG) between 2002 and 2015. Clinicopathological features, including lymph node metastasis, were evaluated. In addition, we performed a prognostic analysis of patients between 2002 and 2011 for whom survival data were available. Kaplan-Meier and multivariate Cox proportional hazards analyses were performed. Results. We identified 1426 patients with GCTs. Of the 222 patients who underwent lymph node dissection, 10 (4.5%) had lymph node metastasis. The incidence of lymph node metastasis in patients with pT1, pT2, and pT3 was 2.1%, 13.3%, and 26.7%, respectively (p < 0.001). Prognostic analysis was performed on 674 patients. In the multivariate Cox regression analysis, residual disease after initial surgery (hazard ratio (HR) = 10.39, 95% confidence interval (CI) = 3.15-34.29) and lymph node metastasis (HR = 5.58, 95% CI = 1.62-19.19) were independent risk factors for cancer-specific survival. Conclusions. In the initial surgery for GCTs, lymph node dissection can be omitted if the operative finding is pT1. In cases of pT2 or higher, lymph node dissection should be considered. Debulking is critical for achieving no gross residual tumor at the end of the surgery. (c) 2021 Elsevier Inc. All rights reserved.

Iijima Y., Nagase T., Matsugaki A., et al. Design and development of Ti–Zr–Hf–Nb–Ta–Mo high-entropy alloys for metallic biomaterials. Materials and Design, 202, 109548. https://doi.org/10.1016/j.matdes.2021.109548., Applying empirical alloy parameters (including Mo equivalent), the predicted ground state diagram, and thermodynamic calculations, noble nonequiatomic Ti–Zr–Hf–Nb–Ta–Mo high-entropy alloys for metallic biomaterials (BioHEAs) were designed and newly developed. It is found that the Moeq and valence electron concentration (VEC) parameters are useful for alloy design involving BCC structure formation in bio medium-entropy alloys and BioHEAs. Finally, we find a Ti28.33Zr28.33Hf28.33Nb6.74Ta6.74Mo1.55 (at.%) BioHEA that exhibits biocompatibility comparable to that of CP–Ti, higher mechanical strength than CP–Ti, and an appreciable room-temperature tensile ductility. The current findings pave the way for new Ti–Zr–Hf–Nb–Ta–Mo BioHEAs development and are applicable for another BioHEA alloys system.

Ishimoto T., Ozasa R., Nakano K., et al. Development of TiNbTaZrMo bio-high entropy alloy (BioHEA) super-solid solution by selective laser melting, and its improved mechanical property and biocompatibility. Scripta Materialia, 194, 113658. https://doi.org/10.1016/j.scriptamat.2020.113658., BioHEAs, specifically designed high entropy alloy (HEA) systems for biomedical applications, represent a new era for biometals. However, recent challenges are (1) the poor shape customizability, and (2) the inevitable severe segregation due to the intrinsic fact that HEA is an ultra-multicomponent alloy system. To achieve shape customization and suppression of elemental segregation simultaneously, we used an extremely high cooling rate (~107 K/s) of the selective laser melting (SLM) process. We, for the first time, developed pre-alloyed Ti1.4Nb0.6Ta0.6Zr1.4Mo0.6 BioHEA powders and SLM-built parts with low porosity, customizable shape, excellent yield stress, and good biocompatibility. The SLM-built specimens showed drastically suppressed elemental segregation compared to the cast counterpart, representing realization of a super-solid solution. As a result, the 0.2% proof stress reached 1690 ± 78 MPa, which is significantly higher than that of cast Ti1.4Nb0.6Ta0.6Zr1.4Mo0.6 (1140 MPa). The SLM-built Ti1.4Nb0.6Ta0.6Zr1.4Mo0.6 BioHEA is promising as a next-generation metallic material for biomedical applications.