Generation of thermofield double states and critical ground states with a quantum computer.

Finite-temperature phases of many-body quantum systems are fundamental to phenomena ranging from condensed-matter physics to cosmology, yet they are generally difficult to simulate. Using an ion trap quantum computer and protocols motivated by the quantum approximate optimization algorithm (QAOA), we generate nontrivial thermal quantum states of the transverse-field Ising model (TFIM) by preparing thermofield double states at a variety of temperatures. We also prepare the critical state of the TFIM at zero temperature using quantum-classical hybrid optimization. The entanglement structure of thermofield double and critical states plays a key role in the study of black holes, and our work simulates such nontrivial structures on a quantum computer. Moreover, we find that the variational quantum circuits exhibit noise thresholds above which the lowest-depth QAOA circuits provide the best results.

Identification of specifically reduced Th2 cell subsets in allergic rhinitis patients after sublingual immunotherapy.

BACKGROUND: Although Th2 cells are well known to play important roles in allergic diseases including allergic rhinitis (AR), the factors that induce and sustain the pathogenesis of AR remain unclear. The recent development of sublingual immunotherapy (SLIT) is expected to allow changes to the underlying pathogenesis of AR. However, which Th2 cell subsets are important in house dust mite-induced AR (HDM-AR), the influence of SLIT on the pathogenic Th2 cells, and the association of Th2 cell subsets with SLIT efficacy have not been clarified. METHODS: The cytokine production and frequency of HDM-reactive T-cell subsets in peripheral blood mononuclear cells (PBMCs) were evaluated using flow cytometry in 89 HDM-AR patients (placebo [n = 43] and HDM 300 IR [n = 46]) who participated in a placebo-controlled study of SLIT with HDM tablets. All patients provided samples both before treatment as a baseline and at the end of the 52-week study. The PBMCs were stained with CellTrace™ Violet (CTV) before culture with HDM extract, and HDM-reactive T cells were detected as the proliferated cells with diminished CTV. RESULTS: HDM-reactive IL-5+ IL-13+ CD27- CD161+ CD4+ cells and ST2+ CD45RO+ CD4+ cells were observed in the peripheral blood from each patient with HDM-AR; these cells significantly decreased after SLIT in the group treated with active tablets. HDM-reactive ST2+ CD45RO+ CD4+ cells were significantly lower in active-responders. CONCLUSION: Allergen-reactive ST2+ CD45RO+ CD4+ cells or those combined with IL-5+ IL-13+ CD27- CD161+ CD4+ cells may be useful as markers indicating the successful treatment of SLIT. These cells may play a crucial role in the pathogenesis of AR as pathogenic memory Th2 cells.

Magnetic stimulation and movement-related cortical activity for acute stroke with hemiparesis.

BACKGROUND AND PURPOSE: This double-blind, randomized, placebo-controlled study investigated the beneficial effects of repetitive transcranial magnetic stimulation (rTMS) to patients with motor paresis in acute subcortical stroke on functional recovery and electrophysiological measures. METHODS: Twenty patients with acute stroke were randomized into real rTMS (n = 10) or sham (n = 10) groups. Patients received five daily sessions of rTMS with 1200 pulses at 1 Hz for 20 min or sham stimulation over the contralesional motor cortex. Movement-related cortical potential MRCP, consisting of the Bereitschaftpotential, negative slope (NS') and motor potential (MP), was recorded during self-paced wrist extension of the affected limb associated with assessment of the Fugl-Meyer assessment (FMA) of the upper extremity, the pegboard test and the grip strength before and after the rTMS session. RESULTS: Real rTMS improved the FMA and pegboard test scores compared to the sham group in the affected hand. This improvement was associated with increases in the MP and NS' over the front-central sites in the ipsilesional hemisphere, whereas the sham group did not show significant changes in MRCP components by rTMS. CONCLUSIONS: Our findings suggest that low-frequency rTMS to the contralesional motor cortex facilitates functional recovery of paretic limbs in acute stroke patients through enhancing the the neuronal activity of ipsilesional motor and pre-motor areas.

Circular chromosome formation in a fission yeast mutant defective in two ATM homologues.

Telomeres, found at chromosomal ends, are essential for stable maintenance of linear chromosomes in eukaryotes. The ATM family of genes, including budding yeast TEL1 (refs 1,2), fission yeast rad3+ (ref. 3) and human ATM (ref. 4), have been reported to be involved in telomere length regulation, although the significance of the telomere phenotypes observed with the mutated genes remains elusive. We have cloned tel1+, another fission yeast ATM homologue, and found that a tel1rad3 double mutant lost all telomeric DNA sequences. Thus, the ATM homologues are essential in telomere maintenance. The mutant grew poorly and formed irregular-shaped colonies, probably due to chromosome instability, however, during prolonged culture of the double mutant, cells forming normal round-shaped colonies arose at a relatively high frequency. All three chromosomes in these derivative cells were circular and lacked telomeric sequences. To our knowledge, this is the first report of eukaryotic cells whose chromosomes are all circular. Upon meiosis, these derivative cells produced few viable spores. Therefore, the exclusively circular genome lacking telomeric sequences is proficient for mitotic growth, but does not permit meiosis.

A monoclonal antibody (8H3) that binds to rat T lineage cells and augments in vitro proliferative responses.

A murine monoclonal antibody, designated 8H3, recognizes a cell surface antigen expressed exclusively on rat T lineage cells. 8H3 antibody immunoprecipitated 180-, 120-, and 90-kD components from rat thymocytes as well as splenic T cells under nonreducing conditions. 8H3 antibody specifically inhibited the binding of thymocytes to fibronectin. Furthermore, binding of rat thymocytes to immobilized synthetic peptide Gly-Arg-Gly-Asp-Ser-Pro-Cys-BSA was inhibited by 8H3 antibody as was Gly-Arg-Gly-Asp-Ser-Pro-Cys, but not by Gly-Arg-Ala-Asp-Ser-Pro-Lys or Gly-Arg-Gly-Glu-Ser-Pro. Crosslinking of 8H3 antigen on double-negative thymocytes and adult thymocytes, as well as splenic T lymphocytes by 8H3 antibody and F(ab')2 fragments of goat antibodies to mouse immunoglobulin, led to an increase in the concentration of cytoplasmic free Ca2+ due to the release of Ca2+ from intracellular stores as well as the influx of Ca2+ from extracellular sources. Expression of interleukin 2 receptor and subsequently cell proliferation was observed upon incubation of thymocytes and splenic T cells with 8H3 antibody. Furthermore, 8H3 antibody induced the proliferation of double-negative thymocytes. These data collectively indicated that a cell surface antigen, 8H3, is involved in not only cell adhesion but also involved in the expression of immature as well as mature thymocytes.

QAOA for Max-Cut requires hundreds of qubits for quantum speed-up.

Computational quantum technologies are entering a new phase in which noisy intermediate-scale quantum computers are available, but are still too small to benefit from active error correction. Even with a finite coherence budget to invest in quantum information processing, noisy devices with about 50 qubits are expected to experimentally demonstrate quantum supremacy in the next few years. Defined in terms of artificial tasks, current proposals for quantum supremacy, even if successful, will not help to provide solutions to practical problems. Instead, we believe that future users of quantum computers are interested in actual applications and that noisy quantum devices may still provide value by approximately solving hard combinatorial problems via hybrid classical-quantum algorithms. To lower bound the size of quantum computers with practical utility, we perform realistic simulations of the Quantum Approximate Optimization Algorithm and conclude that quantum speedup will not be attainable, at least for a representative combinatorial problem, until several hundreds of qubits are available.

Electronic structure of the organic semiconductor Alq3 (aluminum tris-8-hydroxyquinoline) from soft x-ray spectroscopies and density functional theory calculations.

The element-specific electronic structure of the organic semiconductor aluminum tris-8-hydroxyquinoline (Alq(3)) has been studied using a combination of resonant x-ray emission spectroscopy, x-ray photoelectron spectroscopy, x-ray absorption spectroscopy, and density functional theory (DFT) calculations. Resonant and nonresonant x-ray emission spectroscopy were used to measure directly the carbon, nitrogen and oxygen 2p partial densities of states in Alq(3), and good agreement was found with the results of DFT calculations. Furthermore, resonant x-ray emission at the carbon K-edge is shown to be able to measure the partial density of states associated with individual C sites. Finally, comparison of previous x-ray emission studies and the present data reveal the presence of clear photon-induced damage in the former.

Analysis of T-cell receptor V region gene usage of cytotoxic T-lymphocytes and tumor-infiltrating lymphocytes derived from human autologous gastric signet ring cell carcinomas.

To determine the T-cell receptor (TCR) V alpha/V beta gene usage of the human autologous gastric tumor-specific cytotoxic T-lymphocytes (CTLs), we first established two pairs of tumor cell lines, HST2 and SSTW, from the malignant peritoneal effusions of signet ring cell carcinomas and their peripheral blood lymphocyte-derived tumor-specific CD8-positive CTL lines, TcHST2 and TcSSTW. TCR V alpha/V beta gene usage from these CTL was examined using the reversely transcribed-polymerase chain reaction method, demonstrating that the V alpha 7, V alpha 12, and V beta 20 transcripts were commonly detected. The fact that repeated antigenic stimulation by mixed lymphocyte-autologous tumor cell cultures brought about the specific cytolysis and the restricted TCR usage of TCR V alpha 7, V alpha 12, and V beta 20 strongly suggests that these TCR V region products participated in T-cell-cancer interaction. This restricted TCR V gene usage in the gastric signet ring cell carcinomas led us to examine further the frequency of TCR V alpha/V beta usage in 11 cases of in vivo tumor-infiltrating lymphocytes with this particular type of tumor. The data showed that V alpha 7, V alpha 12, V beta 6, and V beta 20 were also predominantly expressed among these tumor-infiltrating lymphocytes in vivo. However, it seemed that T-cells with these TCR V region products are not specific for the gastric signet ring cell carcinomas, since they also frequently infiltrate into noncancerous lesions, such as peptic ulcers. These data may suggest that T-cells with certain TCR V alpha/V beta products could preferentially infiltrate into the stomach tissue, while some of these T-cells may be cytotoxic to the neoplastic autologous tumor cells.

In vivo and in vitro studies of experimental ovarian adenocarcinoma in rats.

When 7,12-dimethylbenz[a]anthracene-impregnated sutures were directly applied to the ovarian parenchyma of 8-week-old Sprague-Dawley rats (the clipping method), adenocarcinomas developed in 29 (39%) of the 75 rats during the 50-week observation period. When 20-methylcholanthrene was used, adenocarcinomas developed only in 1 (3%) of the 31 rats. Thus, the clipping method using 7,12-dimethylbenz[a]anthracene is satisfactory as an animal model of ovarian adenocarcinoma which comprises 85 to 90% of human malignant ovarian tumors. On the other hand, attempts were made to isolate cloned cell lines from these experimental ovarian adenocarcinomas in vitro, and two cloned cell lines were obtained. They were epithelioid and produced undifferentiated adenocarcinomas by back-transplantation into isologous newborn rats.

A comparative case-control analysis of stomach cancer and atrophic gastritis.

We conducted a comparative case-control analysis of stomach cancer and atrophic gastritis involving 427 cases with stomach cancer, 1414 cases with atrophic gastritis, and 3014 control subjects based on a questionnaire survey conducted for the subjects who received gastroscopic examination at Aichi Cancer Center Hospital from April 1985 to March 1989. The risk of atrophic gastritis in both males and females was not associated with any environmental factors. The risk of stomach cancer compared with the control subjects was positively associated with an intake of salted fish guts or cod roe [relative risk (RR) = 1.52, 95% confidence interval (CI) = 1.08-2.15] and smoking (RR for 20 or more cigarettes per day = 2.84; 95% CI = 1.79-4.51) and inversely associated with Western-style breakfast (RR = 0.68; 95% CI = 0.48-0.96) in males. Additionally, the risk of stomach cancer was inversely associated with a daily intake of raw vegetables (RR = 0.56; 95% CI = 0.34-0.94) in males when compared with the patients with atrophic gastritis as controls. Several environmental factors, such as intake of green-yellow vegetables, fruit, and meat, and a family history of stomach cancer, were only associated with intestinal types of cancer in females, whereas a clear difference between diffuse and intestinal types was not observed in males. The results of the present study suggest that risk factors for stomach cancer may be different from those for premalignant lesions.

Lymphoid cell subpopulations infiltrating into autologous rat tumors undergoing rejection.

Lymphoid cell subpopulations infiltrating into autografts of methylcholanthrene-induced sarcomas in rats immunized with autologous tumor cells were identified in terms of immunohistochemical and cytofluorographic techniques using various monoclonal antibodies raised against different classes of rat lymphohemopoietic cells. These antibodies included in this study directed to rat T-cell antigens corresponding to mouse Lyt-1 (RLyt-1) and Lyt-2,3 antigens (RLyt-2) and to W3/25 antigen expressed on a particular subset of rat T-cells with helper function, as well as to rat granulocyte-macrophage-specific antigen (RGM-1). Histological studies demonstrated that the autografts of highly antigenic tumors introduced to the primary hosts were completely rejected following massive immigration of lymphoid cells into the tumor sites, which was not observed in progressively growing, minimally antigenic tumors. These lymphoid cells found within regressing highly antigenic tumor autografts were identified mostly to be T-cells bearing RLyt-1 (approximately 70%), and more than two-thirds of these T-cells expressed RLyt-2 antigen. In contrast to T-cells, macrophages and B-cells, each of which could be recognized by the presence of either RGM-1 antigen or immunoglobulin on their cell surfaces, appeared to have a minimal role in the rejection of autochthonous tumors, as reflected by their less frequent appearance within the tumor tissues during the rejection process.

[New method for preparing proximal anastomotic system].

Heartstring is a useful device. However, the device failure at the time of loading the seal into the delivery device is a troublesome issue. To avoid this problem, we invent a new method using 2 tourniquets made of 5 mm-wide woven Teflon tapes and plastic tubes. Using our method, the loading procedure became easier and more reliable.

Genetic control of telomere integrity in Schizosaccharomyces pombe: rad3(+) and tel1(+) are parts of two regulatory networks independent of the downstream protein kinases chk1(+) and cds1(+).

The Schizosaccharomyces pombe checkpoint gene named rad3(+) encodes an ATM-homologous protein kinase that shares a highly conserved motif with proteins involved in DNA metabolism. Previous studies have shown that Rad3 fulfills its function via the regulation of the Chk1 and Cds1 protein kinases. Here we describe a novel role for Rad3 in the control of telomere integrity. Mutations in the rad3(+) gene alleviated telomeric silencing and produced shortened lengths in the telomere repeat tracts. Genetic analysis revealed that the other checkpoint rad mutations rad1, rad17, and rad26 belong to the same phenotypic class with rad3 with regard to control of the telomere length. Of these mutations, rad3 and rad26 have a drastic effect on telomere shortening. tel1(+), another ATM homologue in S. pombe, carries out its telomere maintenance function in parallel with the checkpoint rad genes. Furthermore, either a single or double disruption of cds1(+) and chk1(+) caused no obvious changes in the telomeric DNA structure. Our results demonstrate a novel role of the S. pombe ATM homologues that is independent of chk1(+) and cds1(+).

Increased expression of S100A4, a metastasis-associated gene, in human colorectal adenocarcinomas.

The S100A4 gene (also known as pEL98/mts1/p9Ka/18A2/42A/calvasculin /FSP1/CAPL) encoding an S100-related calcium-binding protein is implied to be involved in the invasion and metastasis of murine tumor cells. In the present study, the expression of S100A4 in human colorectal adenocarcinoma cell lines (SW837, LoVo, DLD-1, HT-29, SW480, SW620, WiDr, and Colo201) and surgically resected neoplastic tissues was examined to investigate whether S100A4 plays a role in the invasion and metastasis of human tumor cells. Northern blot analysis using total RNA isolated from the adenocarcinoma cell lines revealed that five of the eight cell lines expressed substantial amounts of S100A4 mRNA. Normal colon fibroblasts (CCD-18Co) expressed little of the RNA. Using surgically resected specimens, it seemed that the amount of S100A4 mRNA in adenomas was nearly equal to that in normal colonic mucosa, whereas adenocarcinomas expressed a significantly higher amount of the RNA than did the adjacent normal colonic mucosa. Immunohistochemical analysis using formalin-fixed paraffin-embedded surgical specimens and monoclonal anti-S100A4 antibody demonstrated that none of 12 adenoma specimens were immunopositive, whereas 8 of 18 (44%) focal carcinomas in carcinoma in adenoma specimens and 50 of 53 (94%) adenocarcinoma specimens were immunopositive. Interestingly, the incidence of immunopositive cells increased according to the depth of invasion, and nearly all of the carcinoma cells in 14 metastases in the liver were positive. These results suggest that S100A4 may be involved in the progression and the metastatic process of human colorectal neoplastic cells.

Stimulatory interaction between vascular endothelial growth factor and endothelin-1 on each gene expression.

The precise regulation of cell growth in the vascular wall maintains vascular integrity, and its disruption leads to cardiovascular disorders including atherosclerosis and restenosis. Vascular endothelial growth factor (VEGF) is a specific mitogen for endothelial cells, and endothelin-1 (ET-1) is known to stimulate the proliferation of smooth muscle cells. The aim of this study was to explore a potential interaction between VEGF and ET-1 on each expression in vascular cells. VEGF enhanced preproET-1 mRNA expression and ET-1 secretion in bovine aortic endothelial cells (BAECs). Similarly, in rat vascular smooth muscle cells (VSMCs), ET-1 enhanced VEGF mRNA expression and stimulated VEGF secretion. ET-1-induced VEGF mRNA expression was abolished by a selective ET(A) receptor antagonist, BQ-485, but not by an ET(B)-selective blocker, BQ-788. It was also inhibited by pretreatment with actinomycin D but not by pretreatment with cycloheximide. Furthermore, the actinomycin D chase experiment revealed that ET-1 did not alter VEGF mRNA stability. Coculture of BAECs and VSMCs enhanced both ET-1 and VEGF gene expression in these cells, and the conditioned media from BAECs and VSMCs reproduced the augmentation of each gene expression, which was partially inhibited by BQ-485 or an antibody specific to VEGF. Our results indicate that VEGF and ET-1 have stimulatory interactions on each expression, which may play an important role in concomitant proliferation of endothelial and smooth muscle cells in the vascular wall.

Analyses of APG13 gene involved in autophagy in yeast, Saccharomyces cerevisiae.

We have isolated 14 apg mutants defective in autophagy in yeast Saccharomyces cerevisiae (Tsukada and Ohsumi, 1993). Among them, APG1 encodes a novel Ser/Thr protein kinase whose kinase activity is essential for autophagy. In the course of searching for genes that genetically interact with APG1, we found that overexpression of APG1 under control of the GAL1 promoter suppressed the autophagy-defective phenotype of apg13-1 mutant. Cloning and sequencing analysis showed that the APG13 gene encodes a novel hydrophilic protein of 738 amino acid residues. APG13 gene is constitutively expressed bot not starvation-inducible. Though dispensable for cell proliferation, APG13 is important for maintenance of cell viability under starvation conditions. apg13 disruptants were defective in autophagy like apg13-1 mutants. Morphological and biochemical investigation showed that a defect in autophagy of delta apg13 was also suppressed by APG1 overexpression. These results imply genetic interaction between APG1 and APG13.

Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae.

Autophagic protein degradation includes bulk protein turnover with dynamic membrane reorganization, in which formation of novel organelles autophagosomes play key roles. We have shown that Saccharomyces cerevisiae performs the autophagy in the vacuole, a lytic compartment of yeast, in response to various kinds of nutrient starvation. Here we show that the APG1 gene, involved in the autophagic process in yeast, encodes a novel type of Ser/Thr protein kinase. Our results provide direct evidence for involvement of protein phosphorylation in regulation of the autophagic process. We found overall homology of Apglp with C. elegans Unc-51 protein, suggesting that homologous molecular mechanisms, conserved from unicellular to multicellular organisms, are involved in dynamic membrane flow.

Structural and functional analyses of APG5, a gene involved in autophagy in yeast.

The APG5 gene of Saccharomyces cerevisiae was cloned from a yeast genomic library by complementation of autophagy defective phenotype of apg5-1 mutant. Structural analysis of the obtained genomic fragment showed that the APG5 gene encodes a novel hydrophilic protein of 294 amino-acid residues without apparent structural similarities to other proteins in the database. To examine its function, a null allele for APG5 (delta apg5) was constructed and introduced into yeast. delta apg5 cells germinated and grew normally in nutrient-rich condition, however, their viability reduced significantly upon the nutrient starvation. They were also shown to be defective in autophagy: they could not sequester autophagic bodies in the vacuole under nitrogen-starvation conditions. These phenotypes are identical to those found in the apg5-1 mutant. The lack of apparent phenotype in rich medium suggests that APG5 function is required only under nutrient starvation condition, however, Northern blot analysis showed that its expression levels remained unchanged after nutrient depletion.

Adsorption of human lysozyme onto hydroxyapatite. Identification of its adsorbing site using site-directed mutagenesis.

To elucidate hydroxyapatite-protein interaction, mutant human lysozymes in which the surface charge was modified by site-directed mutagenesis were used. Five mutant human lysozymes (K1A, K13A, K33A, R10A, R14A) were expressed in yeast. The chromatographic behavior of these lysozymes was studied with a HPLC hydroxyapatite column. Elution molarities of K1A and R14A mutants were greatly lowered. While Lys-13 and Arg-10 are located around Lys-1 and Arg-14, K13A and R10A mutants bound onto hydroxyapatite stronger than K1A and R14A mutants. In combination with an X-ray crystal structure of human lysozyme, it is concluded that the adsorbing site of human lysozyme is at the back of the active site and that Arg-14, Lys-1, Arg-10 and Lys-13 play important roles in binding.

Agreement of endoscopic findings and serum pepsinogen levels as an indicator of atrophic gastritis.

Serum pepsinogen I and II levels have recently become popular as indicators of atrophic gastritis in epidemiological studies. Previous studies show a significant association between serum pepsinogen levels and endoscopically diagnosed atrophic gastritis. This study assesses the level of agreement between the degree of atrophic gastritis as assessed by endoscopic examination and by serum pepsinogen assays. Study subjects were 200 outpatients at Aichi Cancer Center Hospital, Nagoya, Japan, who were endoscoped between February and August 1995. Agreement of the degree of atrophic gastritis was assessed by endoscopic examination and by serum pepsinogen levels. Agreement in assessing the extent of atrophic gastritis between the two methods was 57%, and the presence of atrophic gastritis was 79%. Serum pepsinogen assays identify the majority of patients with atrophic gastritis, although they are less useful in assessing the degree of atrophy in detail.