Search PubMed⌕ Search

Biomedical subjects

Y Nakano

Publications and source records attributed to Y Nakano.

At least 73 records · Page 4Linked to original sources

Correlation of clinicopathological parameters and biological markers related to apoptosis and proliferative activity with a clinical outcome in squamous cell carcinoma of the larynx treated with concurrent chemoradiotherapy.

OBJECTIVE: This study was designed to determine whether biological markers related to apoptosis or proliferative activity are associated with the clinical outcome in patients with squamous cell carcinoma (SCC) of the larynx treated with concurrent chemoradiotherapy. METHODS: Immunostaining with antibodies specific to p53, bcl-2, bax, and MIB-1 was performed to evaluate expression of these proteins in formalin-fixed, paraffin-embedded specimens of 59 patients treated with concurrent chemoradiotherapy (carboplatin, 100 mg/m2, four to six times every week; total radiation dose of 40-65 Gy over 4-6.5 weeks). RESULTS: Multivariate analysis indicated that nodal status was a significant indicator of overall survival (OS: P = 0.001). Patients with bcl-2 positive tumors had better OS than those with bcl-2 negative tumors in both univariate (P = 0.002) and multivariate analyses (P < 0.001 ). In the univariate analysis, a considerable difference in OS was observed among the expressions of bax (P = 0.077), MIB-1 proteins (P = 0.071). and OS. but the difference was not statistically significant. CONCLUSION: This study indicates that nodal status is the major prognostic tactor in patients with SCC of the larynx treated with concurrent chemoradiotherapy. These results provide useful information for predicting prognosis. Further analysis of biological factors is needed to evaluate the value as predictive markers.

Apoptosis↗

Pulmonary embolism: comparison of gadolinium-enhanced MR angiography with contrast-enhanced spiral CT in a porcine model.

RATIONALE AND OBJECTIVES: The purpose of this study was to compare gadolinium-enhanced magnetic resonance (MR) angiography with contrast material-enhanced computed tomography (CT) for the detection of small (4-5-mm) pulmonary emboli (PE), with a methacrylate cast of the porcine pulmonary vasculature used as the diagnostic standard. MATERIALS AND METHODS: In 15 anesthetized juvenile pigs, colored methacrylate beads (5.2 and 3.8 mm diameter-the size of segmental and subsegmental emboli in humans) were injected via the left external jugular vein. After embolization, MR angiographic and CT images were obtained. The pigs were killed, and the pulmonary arterial tree was cast in clear methacrylate, allowing direct visualization of emboli. Three readers reviewed CT and MR angiographic images independently and in random order. RESULTS: Forty-nine separate embolic sites were included in the statistical analysis. The mean sensitivity (and 95% confidence intervals) for CT and MR angiography, respectively, were 76% (68%-82%) and 82% (75%-88%) (P > .05); the mean positive predictive values, 92% (85%-96%) and 94% (88%-97%) (P > .05). In this porcine model, PE were usually seen as parenchymal perfusion defects (98%) with MR angiography and as occlusive emboli (100%) with CT. CONCLUSION: MR angiography is as sensitive as CT for the detection of small PE in a porcine model.

Animals↗

CD4+ T cells are required for HSP65 expression in host macrophages and for protection of mice infected with Plasmodium yoelii.

We have reported that macrophages expressing heat-shock protein 65 play an essential role in protection of mice infected with Plasmodium yoelii. In this study, we investigated the function and expression mechanism of HSP65 in macrophages of mice infected with P. yoelii. C57BL/6 (B6) mice are susceptible to infection with the lethal (L) strain but resistant to infection with the non-lethal (NL) strain of P. yoelii. The percentage of apoptotic macrophages in mice infected with the L strain was higher than that in mice infected with the NL strain. However, the percentage was low in L strain infected mice if they acquired resistance to the infection by primary infection with the NL strain. That apoptosis was reversely correlated with HSP65 expression in splenic macrophages from mice infected with P. yoelii suggests HSP65 may contribute to protective immunity by preventing apoptosis of macrophages in malarial infection. Cell depletion/transfer experiments showed that CD4+ T cells, but not CD8+ T cells, gammadelta T cells, NK cells or NK T cells, were required for HSP65 expression in macrophages as well as for protection of mice infected with P. yoelii. In conclusion, HSP65 may play a role in preventing apoptosis of macrophages in mice infected with P. yoelii. CD4+ T cells are required for HSP65 expression and for protective immunity against P. yoelii infection.

Animals↗

Frequency of failure to isolate Shigella spp. by the direct plating technique and improvement of isolation by enrichment in selenite broth.

In order to clarify the failure to isolate Shigella spp. by direct plating, we compared frequencies of Shigella spp. isolation by direct plating and by plating after enrichment in selenite broth. A total 67 strains were isolated in this study. The strains of 38 (56.7%) were isolated only by direct plating, and 25 (37.3%) strains were isolated by both direct plating and after enrichment. Four strains (6.0%) were isolated after enrichment but not by direct plating. Since 6% of isolated Shigella spp. were not isolated by direct plating, we recommend that direct plating and additional isolations from selenite broth should be performed. The significance concerning reduction of concentration of sodium selenite in enrichment broth is discussed.

Bacteriological Techniques↗

Characterization of a vitamin B12 compound from unicellular coccolithophorid alga (Pleurochrysis carterae).

A unicellular coccolithophorid alga, Pleurochrysis carterae, contained 125.4 +/- 1.2 microg of vitamin B12 per 100 g dry cell weight of the lyophilized algal cells. A vitamin B12 compound was purified from the lyophilized algal cells and partially characterized. The silica gel 60 TLC and reversed-phase HPLC patterns of the purified pink-colored compound were identical to those of authentic vitamin B12, but not those of vitamin B12 analogues inactive for humans. When 22-week-old B12-deficient rats which excreted substantial amounts of methylmalonic acid (75.5 +/- 12.3 mg/day) in urine were fed the P. carterae (10 g per kg diet)-supplemented diet for 12 d, urinary methylmalonic acid excretion (as an index of vitamin B12 deficiency) of the rats became undetectable and hepatic vitamin B12 level of the rats was significantly increased.

Animals↗

Inactive corrinoid-compound significantly decreases in Spirulina platensis grown in a cobalt-deficient medium.

Spirulina platensis NIES-39 was grown under open culture system in the presence or absence of CoSO(4) (12 microg/L) and/or vitamin B(12) (10 microg/L) to confirm whether CoSO(4) and/or vitamin B(12) stimulate or are essential for growth of the algal cells and for accumulation of vitamin B(12). The addition of CoSO(4) and/or vitamin B(12) could not affect both cell growth and cell yield of the alga. The amount of corrinoid-compound was increased significantly by the addition of CoSO(4) but not by vitamin B(12). A C18 reversed-phase HPLC pattern of the Spirulina corrinoid-compound increased by the addition of CoSO(4) was identical to that of authentic pseudovitamin B(12), which is inactive for human. These results indicate that the algal cells grown in the absence of CoSO(4) are suitable for use of human health foods because the inactive corrinoid-compound can be reduced significantly.

Chromatography, High Pressure Liquid↗

The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.

Adiponectin is an adipocyte-derived hormone. Recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where the gene encoding adiponectin is located. Here we show that decreased expression of adiponectin correlates with insulin resistance in mouse models of altered insulin sensitivity. Adiponectin decreases insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. This effect results from increased expression of molecules involved in both fatty-acid combustion and energy dissipation in muscle. Moreover, insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. We conclude that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy. These data also indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.

Adiponectin↗

Characterization of mouse GBP28 and its induction by exposure to cold.

OBJECTIVE: To investigate whether the expression of the novel adipose tissue-specific protein GBP28 in adipose tissue and serum are altered in mice under a variety of conditions. DESIGN: Mice were fed a high-fat diet for 4 weeks, fasted for 48 h or exposed at 4 degrees C. SUBJECTS: C57BL/6J mouse, male, 4--6 weeks old. MEASUREMENTS: GBP28 mRNA, GBP28 protein, blood glucose, insulin and fad pad weight of the mice. RESULTS: We first confirmed that the mouse has GBP28 and its characteristics are the same as human GBP28. Serum concentration and mRNA levels of GBP28 significantly increased in the mice exposed to cold. CONCLUSION: GBP28 may play a role in homeostasis, regulating body temperature and basal metabolic rate in response to changing environmental conditions. International Journal of Obesity (2001) 25, 75-83

Adiponectin↗

Granule-dependent killing of Toxoplasma gondii by CD8+ T cells.

Immunization of mice with live bradyzoites of a low-virulent Beverley strain of Toxoplasma gondii has been shown to increase CD8+ T-cell mediated immunity against a highly virulent RH strain. We found that preimmunization with an RH homogenate further enhanced this immunity. Using this model, we investigated the mechanism of CD8+ T-cell mediated protection against T. gondii infection. Splenic cells from mice immunized with RH homogenate and live bradyzoites stimulated apoptosis of RH-infected J774A.1 macrophages in vitro, and at the same time, the immunization significantly suppressed the proliferation of parasites within macrophages, as assessed by measuring 3H-uracil uptake by the parasites. Splenic cells from the immunized mice produced larger amounts of interferon-gamma (IFN-gamma) than did naive splenic cells; however, the production of nitric oxide (NO) by RH-infected macrophages was not enhanced. The elimination of CD8+ T cells from splenic cells significantly reduced their inhibitory action on parasite proliferation as well as their cytotoxic activity against RH-infected macrophages, but it did not affect the production of IFN-gamma. Treatment of CD8+ T-enriched splenic cells from the immunized mice with concanamycin A, but not an anti-Fas ligand monoclonal antibody, significantly reduced their anti-proliferative and killing capabilities, suggesting that the CD8+ T cells induced by immunization with RH antigen and live bradyzoites of the Beverley strain may exert protection against T. gondii infection at least in part through granule-dependent cytotoxic activities.

Animals↗

The renal metabolism of insulin: urinary insulin excretion in patients with mutant insulin syndrome (insulin Wakayama).

Many studies have shown that the kidney plays an important role in the metabolism of many proteins and small peptides. To understand insulin handling in the kidney, we examined urinary insulin excretion under several conditions in patients with mutant insulin syndrome (MIS; insulin Wakayama). Urinary excretion of insulin was studied using high-performance liquid chromatography analysis in patients with MIS. In these patients, most of the insulin extracted from a 24-hour urine collection and from urine collected after stimulation of insulin secretion by glucose or glucagon was normal insulin, whereas 90% of serum insulin is structurally abnormal (Leu-A3 insulin). On the other hand, arginine, which is known as an inhibitor of renal tubular reabsorption, increased urinary excretion of Leu-A3 insulin. The ratio of Leu-A3 and normal insulin in urine after arginine was similar to that in serum. A large amount of Leu-A3 insulin is excreted in urine when reabsorption of insulin at renal tubules is inhibited by arginine. These data indicate that normal and Leu-A3 insulin are filtered through the glomerulus with relatively little restriction. Using the fact that basal urine has a high concentration of normal insulin and an extremely low concentration of Leu-A3 insulin, which has less receptor-binding affinity, we speculated some possibilities. One possibility is that both forms of insulin are reabsorbed by the tubular cells, but with different efficiencies. Leu-A3 insulin absorption in more complete, and this suggests differences in the uptake pathways that may account for the differences in response to arginine infusions. Another possibility is that only normal insulin is secreted from tubules into urine which is mediated by receptors. Our results provide new insight into renal metabolism of insulin and showed that MIS is a useful model for studying it.

Adult↗

The positive inotropic and chronotropic effects of evodiamine and rutaecarpine, indoloquinazoline alkaloids isolated from the fruits of Evodia rutaecarpa, on the guinea-pig isolated right atria: possible involvement of vanilloid receptors.

Cardiotonic effects of evodiamine and rutaecarpine, constituents of the fruits of Evodia rutaecarpa Bentham Rutaceae, were evaluated on guinea pig isolated atria. Comparison with capsaicin, a vanilloid receptor agonist, revealed similar positive inotropic and chronotropic activity, as judged from antagonistic effects of the competitive vanilloid receptor (capsaicin receptor) antagonist capsazepine, the non-competitive vanilloid receptor antagonist ruthenium red, the calcitonin gene related peptide antagonist CGRP(8-37), the P2X purinoceptor antagonist PPADS, and various desensitization studies. Evodiamine and rutaecarpine produced transient positive inotropic and chronotropic effects on the guinea-pig isolated atria, followed by a desensitizing effect to additional administration. Dose-response relationships for evodiamine, rutaecarpine and capsaicin were obtained. All the compounds evoked positive inotropic and chronotropic effects in a concentration-dependent manner. Maximal contractions for evodiamine, rutaecarpine and capsaicin were observed at concentrations of 1 microM, 3 microM and 0.3 microM, respectively. The cardiotonic responses evoked by both evodiamine and rutaecarpine were shifted to the right by capsazepine, an established antagonist of vanilloid receptor (capsaicin-receptor). The effects of both evodiamine (1 microM) and rutaecarpine (3 microM) were abolished by pretreatment with a desensitizing dosage of capsaicin (1 microM), developing cross-tachyphylaxis between these compounds. The effects of evodiamine (1 microM), rutaecarpine (3 microM) and capsaicin (0.3 microM) were also significantly reduced by pretreatment with ruthenium red (10 microM) and CGRP (8-37) (10 microM). The effects of evodiamine, rutaecarpine and capsaicin were not affected by pretreatment with PPADS (100 microM), a highly selective P2X purinoceptor antagonist, and the possibility of the involvement of the P2X purinoceptor was excluded. These results suggest that the positive inotropic and chronotropic effects on the guinea-pig isolated right atria induced by both evodiamine and rutaecarpine could be attributed to their interaction with vanilloid receptors and the resultant release of CGRP, a cardiotonic neurotransmitter, from capsaicin-sensitive nerves as with capsaicin.

Alkaloids↗

Capsaicin-like anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist.

Evodiamine, a major alkaloidal principle of Evodia fruits (Evodia rutaecarpa, Rutaceae), showed vanilloid receptor agonistic activities comparable to capsaicin. The Chinese literature refers to Evodia fruits as a "hot nature" herb. In spite of the similarities in the actions of evodiamine and capsaicin in vitro, evodiamine has no perceptible taste, including a peppery hot taste. Therefore, the effectiveness of evodiamine and the extract of Evodia fruits in preventing obesity on male C3H mice, or male SD rats were examined. When evodiamine was supplemented at 0.03% of the diet and fed to mice for 12 days, the perirenal fat weight became significantly lower than in the control group. The epididymal fat mass was also decreased in the evodiamine diet group. When evodiamine was supplemented at 0.02% in the form of ethanol extract of Evodia fruits to the high-fat diet and fed to rats for 21 days, the body weight, the perirenal fat weight, epididymal fat weight, the levels of serum free fatty acid, total lipids in the liver, triglyceride in the liver, and cholesterol level in the liver were significantly reduced as compared with the control diet group. Furthermore, both lipolytic activity in the perirenal fat tissue and specific GDP binding in brown adipose tissue mitochondria, as the biological index of enhanced heat production, were significantly increased in the evodiamine fed rats. Fasting mice subcutaneously administered 1-3 mg/kg evodiamine showed decreased core body temperature by 1-2 degrees C. This hypothermic effect was prevented by the pretreatment of intraperitoneally administered 10 mg/kg capsazepine, a vanilloid receptor antagonist. On the other hand, food-sated mice subcutaneously administered 1-3 mg/kg evodiamine showed unchanged core body temperature and increased tail skin temperature by more than 5 degrees C, suggesting the increased energy expenditure by enhanced heat dissipation. In conclusion, we have demonstrated that a novel non-pungent vanilloid receptor agonist, evodiamine, mimics the characteristic anti-obese effects induced by capsaicin. Evodiamine would induce heat loss and heat production at the same time and dissipate food energy, preventing the accumulation of perivisceral fat and the body weight increase.

Adipose Tissue↗

Feeding dried purple laver (nori) to vitamin B12-deficient rats significantly improves vitamin B12 status.

To clarify the bioavailability of vitamin B12 in lyophylized purple laver (nori; Porphyra yezoensis), total vitamin B12 and vitamin B12 analogue contents in the laver were determined, and the effects of feeding the laver to vitamin B12-deficient rats were investigated. The amount of total vitamin B12 in the dried purple laver was estimated to be 54.5 and 58.6 (se 5.3 and 7.5 respectively) microg/100 g dry weight by Lactobacillus bioassay and chemiluminescent assay with hog intrinsic factor respectively. The purple laver contained five types of biologically active vitamin B12 compounds (cyano-, hydroxo-, sulfito-, adenosyl- and methylcobalamin), in which the vitamin B12 coezymes (adenosyl- and methylcobalamin) comprised about 60 % of the total vitamin B12. When 9-week-old vitamin B12-deficient rats, which excreted substantial amounts of methylmalonic acid (71.7(se 20.2) micromol/d) in urine, were fed the diet supplemented with dried purple laver (10 microg/kg diet) for 20 d, urinary methylmalonic acid excretion (as an index of vitamin B12 deficiency) became undetectable and hepatic vitamin B12 (especially adenosylcobalamin) levels were significantly increased. These results indicate that vitamin B12 in dried purple laver is bioavailable to rats.

Animals↗

Characterization of vitamin B12 compounds from edible shellfish, clam, oyster, and mussel.

Vitamin B12 content of various edible shellfish was determined by both Lactobacillus leichmannii ATCC 7830 microbiological and intrinsic factor-chemiluminescence methods. The values determined by the microbiological method were 1.2-19.8 (M/C ratio) fold greater in the shellfish than the values determined by the chemiluminescence method. Vitamin B12 compounds were purified from most eaten shellfish, oyster (M/C, 1.5), mussel (M/C, 1.2), and short-necked clam (M/C, 2.7), and partially characterized. TLC and HPLC patterns of each red-colored vitamin B12 compound (M/C, 1.0-1.2) purified from these shellfish were identical to those of authentic vitamin B12. Although the higher values in the determination of vitamin B12 by the microbiological method may be due to the occurrence of vitamin B12-substitutive compounds, the edible shellfish would be excellent vitamin B12 sources judging from the values (> or = 6 micrograms/100 g) determined by the chemiluminescence method.

Animals↗

Treatment with cathepsin L inhibitor potentiates Th2-type immune response in Leishmania major-infected BALB/c mice.

Prior to the activation of CD4 (+) T cells, exogenous proteins must be digested by endo/lysosomal enzymes in antigen-presenting cells (APC) to produce antigenic peptides that are able to be presented on class II molecules of the MHC. Studies described here inspect the functional significance of cathepsin L inhibition for antigen processing and T (h) 1/T (h) 2 differentiation in experimental leishmaniasis. We first demonstrated using in vitro systems that cathepsin L is one of the candidate endo/lysosomal enzymes in processing of soluble Leishmania antigen (SLA) and that its specific inhibitor, CLIK148, modulated the processing of SLA. BALB/c mice are known to be susceptible to infection with Leishmania major. Interestingly, treatment of BALB/c mice with CLIK148 exacerbated the infection by enhancing the development of SLA-specific T (h) 2-type response such as production of IL-4 and generation of T (h) 2-dependent specific IgE/IgG1 antibodies. Moreover, addition of CLIK148 in incubation of a SLA-specific CD4 (+) T cell line with APC up-regulated the production of IL-4. However, CLIK148 did not exert any direct influence on the function of T cells themselves. Taken together, these findings suggest that treatment of host mice with CLIK148 affects the processing of SLA in APC, resulting in the potentiation of T (h) 2-type immune responses and thus leading to exacerbation of the infection. Furthermore, endo/lysosomal cathepsin L was found to be functionally distinct from previously described cathepsins B and D.

Adjuvants, Immunologic↗

Inflammatory responses to lipopolysaccharide are suppressed in 40% energy-restricted mice.

To elucidate the suppressive effects of energy restriction on the inflammatory responses to lipopolysaccharide (LPS), mice were divided into a control group (fed 5.0 g diet/d; 71 kJ/d) and a 40% energy-restricted group (fed 3.0 g diet/d; 43 kJ/d) at 8-wk of age. Four weeks later, 25 microg of LPS was intraperitoneally injected. After the LPS injection, interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha were elevated in serums in the 40% energy-restricted mice and in the controls, but the extent of the elevation was significantly lower in the restricted group. The LPS-induced expression of inducible nitric oxide synthase in the liver was significantly suppressed by the energy restriction. In addition, the LPS-induced elevations of serum aspartate and alanine aminotransferase activities, which are indexes of hepatic injury, were also significantly attenuated in the restricted group. Moreover, the extent of LPS-induced alterations in hepatic structure was less in the restricted mice than in controls. Serum corticosterone level in the restricted mice was higher than that in the controls before LPS treatment (P < 0.05). Furthermore, after LPS injection, the significantly higher level of corticosterone was maintained in the restricted mice, although the LPS treatment significantly enhanced the level even in the control group. These results suggest that the extreme inflammatory responses to endotoxin are prevented in the 40% energy-restricted mice, and corticosterone participates in the preventive effects.

Animals↗

Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock.

OBJECTIVE: To investigate the physiologic effects of exogenous vasopressin as a potential alternative to traditional high-dose catecholamine therapy for septic patients with vascular hyporeactivity to catecholamines. DESIGN: Prospective, case-controlled study. SETTING: Intensive care unit of a university hospital. PATIENTS: Vasopressin was infused in 16 critically ill septic patients who remained persistently hypotensive despite infusions of pharmacologic doses of catecholamines. INTERVENTION: Continuous intravenous infusion of vasopressin at 0.04 units/min for 16 hrs, in place of escalating the amount of catecholamines being infused. MEASUREMENTS AND MAIN RESULTS: After administration of vasopressin, systemic vascular resistance and mean arterial pressure were immediately and significantly increased in comparison with the values obtained just before vasopressin. When the vasopressin infusions were discontinued, mean arterial pressure decreased immediately and dramatically. We did not detect any obvious adverse cardiac effects during the vasopressin infusions. Vasopressin had no effect on other hemodynamic parameters or any of the metabolic parameters studied, including measures of oxygenation, plasma glucose, or electrolytes. Urine output increased significantly during the administration of vasopressin, although this effect may be nonspecific. Lactate concentrations decreased, particularly in the survival group, but the decreases were not significant. Overall survival was 56%. CONCLUSIONS: Low-dose vasopressin infusions increased mean arterial pressure, systemic vascular resistance, and urine output in patients with vasodilatory septic shock and hyporesponsiveness to catecholamines. The data indicate that low-dose vasopressin infusions may be useful in treating hypotension in these patients.

Adolescent↗

Calorie restriction reduced blood pressure in obesity hypertensives by improvement of autonomic nerve activity and insulin sensitivity.

Association between obesity and hypertension has been well recognized. A reduction in the body weight of over-weight hypertensive patients is a recommended lifestyle modification. The purpose of our study is to examine the relationship of insulin sensitivity and autonomic nervous activity with reduction of blood pressure by the calorie restriction. We evaluated the heart rate variability, nocturnal change of blood pressure and insulin resistance before and after a short-term low-calorie diet in 12 overweight essential hypertensives. After a week of standard diet (2000 kcal), 2 weeks of low-calorie diet (800 kcal) with normal sodium content induced a significant reduction in body mass index, triglyceride, fasting immunoreactive protein, homeostasis model assessment as an index of insulin resistance, and urinary excretion of sodium and potassium. Systolic blood pressure was significantly reduced both in daytime and night-time after the low-calorie diet (daytime, 134.5+/-6.0 to 122.0+/-4.1 mmHg; night-time, 126.8+/-5.2 to 113.4+/-7.2 mmHg). In daytime, diastolic blood pressure was also reduced (90.3+/-2.1 to 88.1+/-4.8 mmHg). Although heart rate was not significantly reduced, a rise of high frequency in night-time (346+/-82 to 572+/-108 ms2) and a fall of low frequency/high frequency in day-time (3.5+/-0.4 to 2.6+/-0.1) was significant after a low-calorie diet. In conclusion, weight loss by low-calorie diet with a constant intake of sodium, reduced blood pressure in obese hypertensives by improvement of vagal nervous activity and insulin resistance.

Adult↗