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Abstract Self-organized structure formation in magnetically confined plasmas is one of the most attractive subjects in modern experimental physics. Nonequilibrium media are known to often exhibit phenomena that cannot be predicted by superposition of linear theories. One representative example of such phenomena is the hydrogen isotope effect in fusion plasmas, where the larger the mass of the hydrogen isotope fuel is the better the plasma confinement becomes, contrary to what simple scaling models anticipate. In this article, threshold condition of a plasma structure formation is shown to have a strong hydrogen isotope effect. To investigate the underlying mechanism of this isotope effect, the electrostatic potential is directly measured by a heavy ion beam probe. It is elucidated that the core electrostatic potential transition occurs with less input power normalized by plasma density in plasmas with larger isotope mass across the structure formation. This observation is suggestive of the isotope effect in the radial electric field structure formation.

Ultraviolet (UV) irradiation offers an effective and convenient method for the disinfection of pathogenic microorganisms. However, UV irradiation causes protein and/or DNA damage; therefore, further insight into the performance of different UV wavelengths and their applications is needed to reduce risks to the human body. In this paper, we determined the efficacy of UV inactivation of the SARS-CoV-2 omicron BA.2 and BA.5 variants in a liquid suspension at various UV wavelengths by the 50% tissue culture infection dose (TCID 50 ) method and quantitative polymerase chain reaction (qPCR) assay. The inactivation efficacy of 220 nm light, which is considered safe for the human body, was approximately the same as that of health hazardous 260 nm light for both BA.2 and BA.5. Based on the inactivation rate constants determined by the TCID 50 and qPCR methods versus the UV wavelength, the action spectra were determined, and BA.2 and BA.5 showed almost the same spectra. This result suggests that both variants have the same UV inactivation characteristics., (© 2023. The Author(s).)

Understanding the tumor microenvironment (TME) and anti-tumor immune responses in gastric cancer are required for precision immune-oncology. Taking advantage of next-generation sequencing technology, the feasibility and reliability of transcriptome-based TME analysis were investigated. TME of 30 surgically resected gastric cancer tissues was analyzed by RNA-Seq, immunohistochemistry (IHC) and flow cytometry (FCM). RNA-Seq of bulk gastric cancer tissues was computationally analyzed to evaluate TME. Computationally analyzed immune cell composition was validated by comparison with cell densities established by IHC and FCM from the same tumor tissue. Immune cell infiltration and cellular function were also validated with IHC and FCM. Cell proliferation and cell death in the tumor as assessed by RNA-Seq and IHC were compared. Computational tools and gene set analysis for quantifying CD8 + T cells, regulatory T cells and B cells, T cell infiltration and functional status, and cell proliferation and cell death status yielded an excellent correlation with IHC and FCM data. Using these validated transcriptome-based analyses, the immunological status of gastric cancer could be classified into immune-rich and immune-poor subtypes. Transcriptome-based TME analysis is feasible and is valuable for further understanding the immunological status of gastric cancer., (© 2022. The Author(s).)

Self-organized structure formation in magnetically confined plasmas is one of the most attractive subjects in modern experimental physics. Nonequilibrium media are known to often exhibit phenomena that cannot be predicted by superposition of linear theories. One representative example of such phenomena is the hydrogen isotope effect in fusion plasmas, where the larger the mass of the hydrogen isotope fuel is the better the plasma confinement becomes, contrary to what simple scaling models anticipate. In this article, threshold condition of a plasma structure formation is shown to have a strong hydrogen isotope effect. To investigate the underlying mechanism of this isotope effect, the electrostatic potential is directly measured by a heavy ion beam probe. It is elucidated that the core electrostatic potential transition occurs with less input power normalized by plasma density in plasmas with larger isotope mass across the structure formation. This observation is suggestive of the isotope effect in the radial electric field structure formation., (© 2022. The Author(s).)

The isotope effect, which has been a long-standing mystery in the turbulent magnetically confined plasmas, is the phenomena that the plasma generated with heavier hydrogen isotope show a mitigated transport. This is on the contrary to what is predicted with the simple scaling theory, in which the heavier ions easily diffuse because of its larger gyro-radius. Thanks to the newly developed analysis method and a comprehensive parameter scan experiment in the steady-state plasmas in the Large Helical Device (LHD), the isotope effect was clearly observed in the self-organized internal transport barrier (ITB) structure for the first time. Comparing the ITB intensity in deuterium (D) and hydrogen (H) plasmas, two distinct hydrogen isotope effects are found: stronger ITB is formed in D plasmas and a significant edge confinement degradation accompanied by the ITB formation emerges in H plasmas. This observation sheds light on a new aspect of the turbulent plasmas regarding how the basic properties of the fluid material affect the turbulent structure formation in the open-system.

The pathophysiology of non-pulmonary vein (PV) triggers of atrial fibrillation (AF) is unclear. We hypothesized that left atrial non-PV (LANPV) triggers are associated with atrial tissue degeneration. This study analyzed 431 patients that underwent catheter ablation (mean age 62 yrs, 303 men, 255 paroxysmal AF [pAF] patients). Clinical and electrophysiological characteristics of non-PV trigger were analyzed. Fifty non-PV triggers in 40 patients (9.3%) were documented; LANPV triggers were the most prevalent (n = 19, 38%). LANPV triggers were correlated with non-paroxysmal AF (non-pAF) (OR 3.31, p = 0.04) whereas right atrial non-PV (RANPV) triggers (n = 14) and SVC triggers (n = 17) were not. The voltage at the LANPV sites during SR was 0.3 ± 0.16 mV (p < 0.001 vs. control site). Low-voltage areas (LVAs) in the LA were significantly greater in non-pAF compared to pAF (14.2% vs. 5.8%, p < 0.01). RANPV trigger sites had preserved voltage (0.74 ± 0.48 mV). Long-term outcomes of patients with non-PV triggers treated with tailored targeting strategies were not significantly inferior to those without non-PV triggers. In conclusion, non-PV triggers arise from the LA with degeneration, which may have an important role in AF persistence. A trigger-oriented, patient-tailored ablation strategy considering LA voltage map may be feasible and effective in persistent/recurrent AF.

Cell-penetrating peptides (CPPs) including arginine-rich peptides are attracting a lot of attention due to their potential as a novel intracellular drug delivery tool without substantial toxicity. On the other hand, disease-associated arginine-rich CPPs, such as poly-PR and poly-GR translated from C9orf72 gene, also efficiently enter neuronal cells and then kill them. Although both non-harmful CPPs and harmful poly-PR/GR penetrate the plasma membrane using same arginine residues, little is known about the factors which determine the toxicity of the pathogenic CPPs. Here, we show that poly-PR and poly-GR, but not other Arg-rich CPPs, specifically distributed to nucleolus via interaction with RNA. Importantly, C9orf72-dipeptides, but not other Arg-rich CPPs, caused inhibition of protein translation and cell death. Raising extracellular pH enhanced the cell penetration of poly-PR. The repeat number of (PR) affected the secondary structure and determined the intracellular delivery rate and neurotoxicity, and enforced intracellular delivery of non-penetrating short poly-PR peptide caused cell death, suggesting that modulation of extracellular environment to inhibit the uptake of Arg-rich dipeptides might be a drug target against poly-PR/GR-mediated neurotoxicity.

Amino acids participate directly and indirectly in many important biochemical functions in the brain. We focused on one amino acid metabolic enzyme, L-amino acid oxidase (LAO), and investigated the importance of LAO in brain function using LAO1 knockout (KO) mice. Compared to wild-type mice, LAO1 KO mice exhibited impaired fear learning and memory function in a passive avoidance test. This impairment in LAO1 KO mice coincided with significantly reduced hippocampal acetylcholine levels compared to wild-type mice, while treatment with donepezil, a reversible acetylcholine esterase inhibitor, inhibited this reduction. Metabolomic analysis revealed that knocking out LAO1 affected amino acid metabolism (mainly of phenylalanine [Phe]) in the hippocampus. Specifically, Phe levels were elevated in LAO1 KO mice, while phenylpyruvic acid (metabolite of Phe produced largely by LAO) levels were reduced. Moreover, knocking out LAO1 decreased hippocampal mRNA levels of pyruvate kinase, the enzymatic activity of which is known to be inhibited by Phe. Based on our findings, we propose that LAO1 KO mice exhibited impaired fear learning and memory owing to low hippocampal acetylcholine levels. Furthermore, we speculate that hippocampal Phe metabolism is an important physiological mechanism related to glycolysis and may underlie cognitive impairments, including those observed in Alzheimer's disease.

To facilitate the optimization of cancer immunotherapy lacking immune-related adverse events, we performed TCR repertoire analysis of tumor-infiltrating CD8 + T-cells in B16 melanoma-bearing mice receiving anti-PD-1, anti-CTLA-4, anti-4-1BB, anti-CD4 or a combination of anti-PD-1 and 4-1BB antibodies. Although CD8 + T-cells in the tumor were activated and expanded to a greater or lesser extent by these therapies, tumor growth suppression was achieved only by anti-PD-1, anti-PD-1/4-1BB combined, or by anti-CD4 treatment, but not by anti-CTLA-4 or anti-4-1BB monotherapy. Increased CD8 + T cell effector function and TCR diversity with enrichment of certain TCR clonotypes in the tumor was associated with anti-tumor effects. In contrast, polyclonal activation of T-cells in the periphery was associated with tissue damage. Thus, optimal combination therapy increases TCR diversity with extended activation of selective CD8 + T-cells specifically in the tumor but not in the periphery. Incorporation of the concept of evenness for the TCR diversity is proposed.

The change in electronic structure of extremely small Rh x Cu y alloy nanoparticles (NPs) with composition variation was investigated by core-level (CL) and valence-band (VB) hard X-ray photoelectron spectroscopy. A combination of CL and VB spectra analyses confirmed that intermetallic charge transfer occurs between Rh and Cu. This is an important compensation mechanism that helps to explain the relationship between the catalytic activity and composition of Rh x Cu y alloy NPs. For monometallic Rh and Rh-rich alloy (Rh 0.77 Cu 0.23 ) NPs, the formation of Rh surface oxide with a non-integer oxidation state (Rh (3-δ)+ ) resulted in high catalytic activity. Conversely, for alloy NPs with comparable Rh:Cu ratio (Rh 0.53 Cu 0.47 and Rh 0.50 Cu 0.50 ), the decreased fraction of catalytically active Rh (3-δ)+ oxide is compensated by charge transfer from Cu to Rh. As a result, ensuring negligible change in the catalytic activities of the NPs with comparable Rh:Cu ratio to those of Rh-rich and monometallic Rh NPs.

Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effect of early reperfusion therapy for acute myocardial infarction (AMI), in which the recruitment of inflammatory monocytes plays a causative role. Here we develop bioabsorbable poly-lactic/glycolic acid (PLGA) nanoparticles incorporating irbesartan, an angiotensin II type 1 receptor blocker with a peroxisome proliferator-activated receptor (PPAR)γ agonistic effect (irbesartan-NP). In a mouse model of IR injury, intravenous PLGA nanoparticles distribute to the IR myocardium and monocytes in the blood and in the IR heart. Single intravenous treatment at the time of reperfusion with irbesartan-NP (3.0 mg kg(-1) irbesartan), but not with control nanoparticles or irbesartan solution (3.0 mg kg(-1)), inhibits the recruitment of inflammatory monocytes to the IR heart, and reduces the infarct size via PPARγ-dependent anti-inflammatory mechanisms, and ameliorates left ventricular remodeling 21 days after IR. Irbesartan-NP is a novel approach to treat myocardial IR injury in patients with AMI.

Rh is one of the most important noble metals for industrial applications. A major fraction of Rh is used as a catalyst for emission control in automotive catalytic converters because of its unparalleled activity toward NOx reduction. However, Rh is a rare and extremely expensive element; thus, the development of Rh alternative composed of abundant elements is desirable. Pd and Ru are located at the right and left of Rh in the periodic table, respectively, nevertheless this combination of elements is immiscible in the bulk state. Here, we report a Pd-Ru solid-solution-alloy nanoparticle (PdxRu1-x NP) catalyst exhibiting better NOx reduction activity than Rh. Theoretical calculations show that the electronic structure of Pd0.5Ru0.5 is similar to that of Rh, indicating that Pd0.5Ru0.5 can be regarded as a pseudo-Rh. Pd0.5Ru0.5 exhibits better activity than natural Rh, which implies promising applications not only for exhaust-gas cleaning but also for various chemical reactions.

Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effects of early reperfusion therapy for acute myocardial infarction (MI), in which mitochondrial permeability transition pore (mPTP) opening plays a critical role. Our aim was to determine whether poly-lactic/glycolic acid (PLGA) nanoparticle-mediated mitochondrial targeting of a molecule that inhibits mPTP opening, cyclosporine A (CsA), enhances CsA-induced cardioprotection. In an in vivo murine IR model, intravenously injected PLGA nanoparticles were located at the IR myocardium mitochondria. Treatment with nanoparticles incorporated with CsA (CsA-NP) at the onset of reperfusion enhanced cardioprotection against IR injury by CsA alone (as indicated by the reduced MI size at a lower CsA concentration) through the inhibition of mPTP opening. Left ventricular remodeling was ameliorated 28 days after IR, but the treatment did not affect inflammatory monocyte recruitment to the IR heart. In cultured rat cardiomyocytes in vitro, mitochondrial PLGA nanoparticle-targeting was observed after the addition of hydrogen peroxide, which represents oxidative stress during IR, and was prevented by CsA. CsA-NP can be developed as an effective mPTP opening inhibitor and may protect organs from IR injury.