Topological Defect Formation in a Phase Transition with Tunable Order.

The Kibble-Zurek mechanism (KZM) describes the nonequilibrium dynamics and topological defect formation in systems undergoing second-order phase transitions. KZM has found applications in fields such as cosmology and condensed matter physics. However, it is generally not suitable for describing first-order phase transitions. It has been demonstrated that transitions in systems like superconductors or charged superfluids, typically classified as second order, can exhibit weakly first-order characteristics when the influence of fluctuations is taken into account. Moreover, the order of the phase transition (i.e., the extent to which it becomes first rather than second order) can be tuned. We explore quench-induced formation of topological defects in such tunable phase transitions and propose that their density can be predicted by combining KZM with nucleation theory.

Nonadiabatic transitions during a passage near a critical point.

The passage through a critical point of a many-body quantum system leads to abundant nonadiabatic excitations. Here, we explore a regime, in which the critical point is not crossed although the system is passing slowly very close to it. We show that the leading exponent for the excitation probability can then be obtained by standard arguments of the Dykhne formula, but the exponential prefactor is no longer simple and behaves as a power law on the characteristic transition rate. We derive this prefactor for the nonlinear Landau-Zener model by adjusting Dykhne's approach. Then, we introduce an exactly solvable model of the transition near a critical point in the Stark ladder. We derive the number of excitations for it without approximations and find qualitatively similar results for the excitation scaling.

Changes in the Quality of Life of Patients with Left Ventricular Assist Device and their Caregivers in Japan: Retrospective Observational Study.

Left ventricular assist devices (LVAD) improve quality of life (QOL) in many patients with end-stage severe heart failure, but not in some patients. In addition, the burden on caregivers is expected to increase after LVAD patients are discharged. Our study aimed to investigate the impact of LVAD on the QOL of patients and caregivers. Thirty-two LVAD patients were assessed for changes in QOL, mental status, and activity level using the Euro QOL (EQ-5D-5L), Short Form 12 (SF-12), Minnesota Living with Heart Failure Questionnaire, Hospital Anxiety and Depression Scale (HADS), and Frenchay Activities Index. Twenty-four caregivers were assessed for changes in QOL, mental status, and burden of care using the EQ-5D-5L, SF-12, HADS, and Burden Index of Caregiver (BIC-11). The LVAD patients and caregivers responded contemporaneously regarding two points: pre-and post-LVAD. Patients' physical and mental QOL was significantly improved, but not social QOL and activity level. Caregivers' QOL and burden of care did not change, and anxiety was reduced (p = 0.028). The patients were divided into two groups based on whether EQ-5D-5L was improved: twelve patients in the unimproved group (UG) and twenty patients in the improved group (IG). In the UG, 50% had LVAD-related strokes (p = 0.001, IG: 0%), and their social QOL decreased (p = 0.023). The activity levels improved in the IG. Multi-dimensional analyses on the QOL in LVAD patients yielded mixed results. Anticipated benefits derived from LVAD therapy may be limited by LVAD-related complications such as stroke that negatively impacts on the QOL.

Anderson Localization of Composite Particles.

We investigate the effect of coupling between translational and internal degrees of freedom of composite quantum particles on their localization in a random potential. We show that entanglement between the two degrees of freedom weakens localization due to the upper bound imposed on the inverse participation ratio by purity of a quantum state. We perform numerical calculations for a two-particle system bound by a harmonic force in a 1D disordered lattice and a rigid rotor in a 2D disordered lattice. We illustrate that the coupling has a dramatic effect on localization properties, even with a small number of internal states participating in quantum dynamics.

Effect of AceK (acesulfame potassium) on brain function under dietary restriction in mice.

People preferably take zero or low-calorie beverages and foods with artificial sweeteners even though it has been recently suggested that long-term artificial sweetener use affects physiological functions. In addition, a lower body weight was considered to be more healthful, but an abnormally low body weight caused by an excessive diet has been reported to cause health problems. Acesulfame potassium (AceK) is one of the most commonly used for foods and beverages because of its resistance to thermal degradation and marked sweetness. However, the combined effect of AceK and a low body weight on the physiological functions remains unknown. Here, we investigated the effect of long-term AceK fluid intake on the cognitive function under dietary restriction. We administered AceK to mice fed a low carbohydrate (LC) diet for 4 weeks, and behavioral assays were then performed for a week. The mice fed the LC diet with AceK treatment for 4 weeks showed an increase in water intake and a decrease in short-term and object cognitive memories in the Y-maze and novel object recognition tests, respectively. Mice were sacrificed after behavioral tests to measure glucose levels. The glucose levels in the frontal cortex were significantly decreased in mice fed the LC diet with AceK treatment in comparison with mice fed the LC diet alone, although there was no significant difference in the plasma glucose levels. These results suggest that the combination of long-term AceK intake and the LC diet affects the cognitive function through the reduction of cortical glucose levels.

Declined asparagine synthetase mRNA expression and enhanced sensitivity to asparaginase in HL-60 cells committed to monocytic differentiation.

During 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced differentiation of human promyelocytic leukemia HL-60 cells toward maturing monocytes/macrophages, asparagine synthetase (ASNS) mRNA expression declined time and dose-dependently. The effect of TPA was inhibited by inhibitors for PKC and MEK 1/2, but not by those for JNK and p38 MAPK. Combination treatment with TPA and asparaginase synergistically enhanced the growth retardation accompanied by apoptotic cell death characterized by internucleosomal DNA fragmentation. These data suggest the possible involvement of MEK1/2 MAPK in the inhibitory effect of TPA on ASNS mRNA expression and that the induction of the down-regulation of ASNS (via MEK1/2 activation) may be a new strategy for the treatment of leukemia blast cells.

Tumor-specificity and type of cell death induced by vitamin K2 derivatives and prenylalcohols.

Fourteen vitamin K2 (menaquinone (MK)-n, n = 1-14) and ten prenylalcohol derivatives (n = 1-10) with different numbers (n) of isoprenyl groups in the side chains were investigated for their cytotoxicity against nine human tumor cell lines and three human normal oral cells. Among the vitamin K2 derivatives, MK-2 (n = 2) showed the greatest cytotoxicity, followed by MK-1 (n = 1) and MK-3 (n = 3). MK-1, MK-2 and MK-3 showed the highest tumor-specific index (TS= > 2.0, 2.0 and > 1.7, respectively). Among the prenylalcohols, geranylgeraniol (GG) (n = 4) showed the highest cytotoxicity, followed by farnesol (n = 3) and geranylfarnesol (GF) (n = 3). GG showed the highest tumor-specificity (TS = 1.8), followed by farnesol (TS = > 1.4), GF (TS= > < 1.3). However, the tumor-specificity of MK-2 and GG was much lower than that of conventional chemotherapeutic agents. The human leukemic cell lines were the most sensitive, whereas the human glioblastoma cell lines were the most resistant to MK-2 and GG. MK-2 did not induce internucleosomal DNA fragmentation in either the human promyelocytic leukemia HL-60 or the human squamous cell carcinoma HSC-4 cell lines. GG induced marginal internucleosomal DNA fragmentation in the HL-60 cells, but not in the HSC-4 cells. Both MK-2 and GG did not induce the formation of autophagosomes, nor did they clearly change the intracellular concentration of three polyamines. Electron spin resonance (ESR) spectroscopy showed that only MK-1 (n = 1), as well as GGF (n = 7) and GFF (n = 8) which had lower cytotoxicity, produced radicals, suggesting the lack of connection between cytotoxicity and radical production. The present study demonstrates that the presence of 1,4-naphtoquinone structure (including alpha,beta-unsaturated ketones) in vitamin K2 derivatives confers on them the ability to induce non-apoptotic cell death.

Induction of cell death by combination treatment with cisplatin and 5-fluorouracil in a human oral squamous cell carcinoma cell line.

The possible apoptosis-inducing activity of several sequential treatments of cisplatin (CDDP) and 5-fluorouracil (5-FU) against the human oral squamous cell carcinoma HSC-2 cell line was investigated. The following three combination treatments (CT) were used: simultaneous treatment with CDDP and 5-FU (for 72 hours) (CT-1), CDDP treatment (24 hours) followed by 5-FU treatment (48 hours) (CT-2) and 5-FU treatment (24 hours) followed by CDDP treatment (48 hours) (CT-3). CT-1 produced the highest cytotoxicity, followed by CT-3 and CT-2. No treatment induced any detectable internucleosomal DNA fragmentation, and caspase-3,-8 and -9 were activated to a much lesser extent than that attained using actinomycin D. High-performance liquid chromatography analysis demonstrated that 5-FU, as well as CT-1 and CT-2, preferentially reduced the intracellular concentration of putrescine. These results suggest that simultaneous treatment with CDDP and 5-FU induces lower level of apoptotic cell death in HSC-2 cells.

Tumor-specificity and type of cell death induced by phenoxazines.

Phenoxazines have shown diverse biological activities, but tumor-specific cytotoxic activity has not been investigated. A total of 24 phenoxazine derivatives (WM1-24) was investigated for their relative cytotoxicity against human tumor cell lines vs. normal cells. WM7 and WM8 showed the highest tumor-specificity index of 4.3 and 4.8, respectively. Considerable difference in drug-sensitivity was found among these tumor cell lines. Human promyelocytic leukemia HL-60 cells showed the highest sensitivity to both WM7 and WM8, followed by human oral squamous cell carcinoma (HSC-2, HSC-3, HSC-4), and human gingival fibroblast (HGF), pulp cell (HPC) and periodontal ligament fibroblast (HPLF) were the most resistant. WM7 and WM8 induced little or no internucleosomal DNA fragmentation, and activated caspase-3 in HSC-2, HSC-4 and human glioblastoma T98G cells. These compounds failed to induce autophagic cell death, as judged by acridine orange and microtubule-associated protein 1 light chain 3 (LC3)-GFP assays. These results suggested that the higher cytotoxicity of WM7 and WM8 are derived from the positively-charged quaternary nitrogen substituents on the phenoxazine ring and the electron density of nitrogen at N12, and that inhibition of autophagy is not always coupled with apoptosis induction.

Re-evaluation of tumor-specific cytotoxicity of mitomycin C, bleomycin and peplomycin.

Three antitumor antibiotics, mitomycin C, bleomycin sulfate and peplomycin sulfate, were compared for their tumor-specific cytotoxicity, using human oral squamous cell lines (HSC-2, HSC-3, HSC-4, Ca9-22 and NA), human promyelocytic leukemic cell line HL-60 and human normal oral cell types (gingival fibroblast HGF, pulp cell HPC and periodontal ligament fibroblast HPLF). Among these three compounds, mitomycin C showed the highest tumor-specificity, due to its higher cytotoxic activity against human oral tumor cell lines than bleomycin and peplomycin. However, there was considerable variation of drug sensitivity among the six tumor cell lines. Mitomycin C induced internucleosomal DNA fragmentation and caspase-3, -8 and -9 activation in HL-60 cells only after 24 h. On the other hand, mitomycin C induced no clear-cut DNA fragmentation in HCS-2 cells, although it activated caspase-3, -8 and -9 to a slightly higher extent. Western blot analysis demonstrated that mitomycin C did not induce any apparent change in the intracellular concentration of anti-apoptotic protein (Bcl-2) and pro-apoptotic proteins (Bax, Bad). Electron microscopy of mitomycin C-treated HL-60 cells showed intact mitochondria (as regards to integrity and size) and cell surface microvilli, without production of an apoptotic body or autophagosome, at an early stage after treatment. The present study suggests the incomplete induction of apoptosis or the induction of another type of cell death by mitomycin C treatment.

Changes in fluoride sensitivity during in vitro senescence of normal human oral cells.

We have previously reported that sodium fluoride (NaF) showed slightly higher cytotoxicity against human oral tumor cell lines than normal human oral cells. Possible changes in the NaF sensitivity of three normal human oral cell types (gingival fibroblast HGF, pulp cell HPC, periodontal ligament fibroblast HPLF) during in vitro ageing were investigated in the present study. When these cells were subcultured at 1:4 split ratio every week, their saturation density declined with increasing population doubling level (PDL), and they ceased to divide when they reached 20 PDL. Mitochondrial function, evaluated by MTT stainability per cell basis, was elevated at the terminal phase. NaF dose-dependently reduced the viable cell number, but did not show any beneficial (growth promoting) effect (so-called "hormesis") at lower concentrations. NaF produced large DNA fragments, without induction of internucleosomal DNA fragmentation, possibly due to weak activation of caspases -3, -8 and -9. Higher concentrations of NaF were required to reduce the number of viable senescent cells than younger cells, indicating that cells become resistant to cytotoxicity of NaF with in vitro ageing.

Molecular requirements of lignin-carbohydrate complexes for expression of unique biological activities.

Lignins are major cell wall components formed by the dehydrogenative polymerization of three monolignols, p-coumaryl, coniferyl and sinapyl alcohols. We prepared lignin-carbohydrate complexes (Fr. VI and Fr. VII) from pine cones by acid and ethanol precipitation, and investigated which part of these molecules is essential for expression of biological activities. They showed potent antiviral activity upon direct interaction with the virus. The antiviral activity of Frs. VI and VII required the higher-order structure of polyphenols without polysaccharides. Pretreatment of mice with Fr. VI or VII induced higher antiparasite activity than those of natural and chemically modified antitumor polysaccharides. Fr. VI or VII at higher concentrations enhanced the radical intensity and cytotoxic activity of vitamin C, whereas tannins counteracted the effect of vitamin C. Fr. VI at lower concentrations enhanced the O2(-)-scavenging activity of vitamin C. Frs. VI and VII stimulated mouse macrophage-like cells Raw 264.7 to produce nitric oxide (NO), citrulline (CIT) and asparagine (ASN), via the enhanced expression of iNOS and ASN synthetase, whereas phenylpropenoid monomers and polymers inhibited NO/CIT/ASN production. These data suggest that the polymerized structure of phenylpropenoids in lignin-carbohydrate complexes is required for the induction of antiviral activity, and that the higher-order structure of phenylpropenoid polymers and polysaccharides is required for immunopotentiation, including macrophage activation.

Induction of tumor-specific cytotoxicity and apoptosis by doxorubicin.

Doxorubicin (adriamycin), an anthracycline antibiotic, showed higher cytotoxic activity against human tumor cell lines (oral squamous cell carcinoma HSC-2, HSC-3, submandibular gland carcinoma HSG, promyelocytic leukemia HL-60) than against normal human cells (gingival fibroblast HGF, pulp cell HPC, periodontal ligament fibroblast HPLF). Doxorubicin activated caspases 3, 8 and 9 in both HSC-2 and HL-60 cells, but induced internucleosomal DNA fragmentation only in HL-60 cells. Western blot analysis showed that doxorubicin did not significantly change the intracellular concentration of Bcl-2, Bax and Bad in HL-60 cells. Real-time PCR analysis showed that HPC cells expressed the highest amount of mdr1 mRNA, followed by HSC-2 > HGF > HSC-3 > HPLF > HSG > HL-60. ESR spectroscopy showed that doxorubicin produced no discernible radical under alkaline conditions (pH 7.4 to 10.5) except at pH 12.5, and it did not scavenge O2-, NO and DPPH radicals. The present study demonstrates that doxorubicin induces the tumor-specific cytotoxicity and some, but not all, apoptosis markers possibly by a radical-independent mechanism, and that mdr1 expression in the tumor cells is not related to the tumor specificity of doxorubicin.

Adult-onset idiopathic hypogonadotropic hypogonadism due to isolated pituitary gonadotropin deficiency.

A 25-year-old Japanese man with adult-onset idiopathic hypogonadotropic hypogonadism is reported. He had been delivered normally, had normal puberty, and experienced erectile dysfunction at age 24 years. Brain MRI revealed no abnormal findings and endocrinological data supported the diagnosis of isolated gonadotropin deficiency. Although most patients with idiopathic hypogonadotropic hypogonadism have a hypothalamic dysfunction, the lesion in this case may be considered to be in the pituitary since repetitive GnRH loading failed to increase serum LH and FSH.

Comparison of cytotoxicity and radical scavenging activity between tea extracts and Chinese medicines.

Three hot water extracts of black tea, green tea and powdered green tea and five Chinese medicines (Shosaiko-tou, Orengedoku-tou, Goshuyu-tou, Choto-san, Keishininjinn-tou) were investigated for their ability to modify nitric oxide (NO) production by lipopolysaccharide (LPS)-stimulated mouse macrophage-like Raw 264.7 cells, and for their cytotoxicity, radical intensity and scavenging activity. All eight materials significantly reduced the extracellular concentration of NO in the LPS-stimulated Raw 264.7 cells. ESR spectroscopy shows that tea extracts, which had higher cytotoxicity, generated higher amounts of radicals, and more efficiently scavenged O2- (generated by hypoxanthine-xanthine oxidase reaction), hydroxyl radical (generated by Fenton reaction) and NO (generated by 1-hydroxyl-2-oxo-3-(N-3-methyl-3-aminopropyl)-3-methyl-1-triazene) than Chinese medicines. Close association between the radical intensity and radical scavenging activity suggests their bimodal (anti-oxidant and pro-oxidant) action. Pretreatment of mice with tea extracts significantly reduced the lethality of Escherichia coli-infection. All tea extracts showed no apparent anti-HIV activity. The present study demonstrates, for the first time, several attractive features of tea extracts in comparison with Chinese medicines, suggesting the possible application of the tea extracts for radical-mediated diseases.

Effects of isoflavones from Sophora species on the growth and activation of a mouse macrophage-like cell line.

We investigated the effect of eleven isoflavones on the growth and activation of mouse macrophage-like Raw 264.7 cells. The study of structure-activity relationship suggests that both hydrophilic (hydroxyl) and hydrophobic (prenyl) groups within isoflavone molecules are the determinants for the induction of cytotoxic activity. When hydrophobicity was assessed by octanol-water partition coefficient (log P), the maximum cytotoxic activity was observed at a log P value above 2.5. All isoflavones did not significantly stimulate the nitric oxide (NO) production by Raw 264.7 cells, but reduced the NO production by lipopolysaccharide (LPS)-stimulated Raw 264.7 cells, at cytotoxic concentrations. Amino acid analysis in the culture medium demonstrated that isoflavones significantly inhibited the LPS-stimulated production of citrulline and asparagine. Isoflavones inhibited the LPS-stimulated NO production more efficiently than citrulline and asparagine production, possibly due to their NO scavenging activity. These data suggest that the inhibiton of LPS action by isoflavones may be coupled with their cytotoxic activity.

Diverse biological activities of fermented pine seed shell extract.

Intraperitoneal administration of fermented pine seed shell extract (PSSE) (up to 2 g/kg) induced no apparent acute toxicity to mice. Pretreatment of mice with PSSE protected them from the lethality of Escherichia coli infection. PSSE showed a very weak cytotoxic activity against both normal and tumor cells and no anti-HIV activity, but stimulated the mouse macrophage-like Raw 264.7 cells to produce nitric oxide (NO) and citrulline. ESR spectroscopy showed that PSSE produced no detectable radicals, but effectively scavenged O2- (generated by the hypoxanthine-xanthine oxidase reaction), hydroxyl radical (generated by the Fenton reaction) and NO (generated by NOC-7). Comparison of PSSE with other natural products, such as polyphenols and vitamins, further confirmed the close association between radical intensity and radical scavenging activity, suggesting the bimodal action of natural products. Although the biological activities of PSSE were relatively lower than those of other natural products, the present study suggests the possible medicinal efficacy of PSSE.

Stimulation of arginine consumption and asparagine production in LPS-activated macrophages.

Changes in amino acid utilization during lipopolysaccharide (LPS)-induced activation of mouse macrophage-like cells Raw264.7 were investigated. Amino acids in the medium and cell fractions were extracted by 5% trichloroacetic acid and quantitated by amino acid analyzer. Glutamine was utilized by cells at the highest rate, followed by serine and arginine, a precursor of nitric oxide (NO). When Raw264.7 cells were incubated with 10 or 100 ng/mL LPS, the consumption of arginine and the production of citrulline, nitric oxide (NO) and asparagine were significantly increased. The intracellular amino acid concentration was not significantly changed. These data suggest that arginine consumption and asparagine production might be possible markers of macrophage activation.

Effects of prenylflavanones from Sophora species on growth and activation of mouse macrophage-like cell line.

We investigated the effect of 2 flavanones and 8 chemically-defined prenylflavanones on the growth and activation of mouse macrophage-like Raw 264.7 cells. Amino acid analysis in the culture medium demonstrated the rapid consumption of serine and glutamine by Raw264.7 cells, suggesting the necessity to supplement these amino acids for the prolonged culture. Naringenin and hesperetin showed little or no cytotoxic activity. However, addition of the isoprenyl group (sophoraflavanone B, euchrestaflavanone A) or the lavandulyl and hydroxyl group (sophoraflavanone G) significantly enhanced the cytotoxic activity. The cytotoxic activity of these compounds was significantly influenced by both log P value and ionization potential. These compounds slightly, but significantly, reduced both nitric oxide (NO) and tumor necrosis factor (TNF) production by lipopolysaccharide (LPS)-stimulated Raw 264.7 cells, regardless of their cytotoxic activity. These data suggest that the macrophage inhibitory effect of prenylflavanones might not be related to their cytotoxic activity.

Effect of lignins and their precursors on nitric oxide, citrulline and asparagine production by mouse macrophage-like Raw 264.7 cells.

Lignins, tannins and flavonoids are commonly found polyphenols. Among these polyphenols, lignins, polymers of phenylpropenoids complexed with polysaccharides, were the least cytotoxic and most potently stimulated the production of nitric oxide (NO), citrulline and asparagine by mouse macrophage-like Raw 264.7 cells. The maximum production of these substances reached the level attained by lipopolysaccharide (LPS). However, epigallocatechin gallate, phenylpropenoid monomers (ferulic acid, caffeic acid) and gallic acid (component unit of tannin) were inactive. These data suggest that the macrophage-stimulation activity of polyphenols depends, at least in part, on their molecular weight or structural configuration. There was a positive relationship between the extent of asparagine production and that of NO or citrulline. Western blot analysis demonstrated that both lignins and LPS elevated the cellular level of asparagine synthetase. The present study suggests the possible link between the stimulated asparagine production and macrophage activation.