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Biomedical subjects

Ying Gao

Publications and source records attributed to Ying Gao.

At least 37 records · Page 2Linked to original sources
PubMed2006

Granule targeting of soluble tumor necrosis factor (TNF) receptor expressed during granulopoietic maturation in murine bone marrow cells.

In this experiment, we explored the potential of secretory lysosomes of hematopoietic cells to act as vehicles for immunomodulatory protein delivery at an inflammation site. We investigated whether exogenous soluble TNF-receptor 1 (sTNFR1) could be expressed in primary hematopoietic progenitor cells and become targeted for storage and secretion during granulopoietic differentiation. An sTNFR1 construct with a transmembrane domain (tm) and a cytosol sorting signal (Y) taken from CD63, was retrovirally transduced to lineage-negative murine hematopoietic bone marrow stem/progenitor cells. This process was followed by cytokine-driven granulopoietic maturation. The sTNFR1-tm-Y was found to be synthesized in precursor cells and to persist in mature granulocytes and monocytes/macrophages. Immunofluorescence-localization studies showed a granule pattern of sTNFR1-tm-Y in both precursor and mature granulocytes and secretion to phagosomes after ingestion of bacteria. Immunoelectron microscopy revealed co-localization between the sTNFR1-tm-Y and the primary (azurophil) granule marker myeloperoxidase. Collectively, our results demonstrated granule targeting, storage, and secretion of exogenous sTNFR1-tm-Y constitutively expressed during normal granulopoietic differentiation. These findings support the concept of using storage organelles of circulating hematopoietic cells as vehicles for targeting sites of inflammation with immunoregulatory agents.

Animals↗
PubMed2006

[Study on the chemical substrates of SFE extract from Rhizoma Cyperi].

OBJECTIVE: To extract the effective part of Rhizoma Cyperi and study the chemical constituents of diffrent parts. METHODS: The extract of Rhizoma Cyperi was obtained by SFE and dealed with molecular distillation, then the effective components was enriched. The chemical compositions were separated and identified by GC/MS. RESULTS: The content of volatile oil in the extract upgraded from 43.2% to 86.0% by molecular distillation, and the relative amount of cyperene and (+) -alpha-cyperone from 20.2% to 38.6%. Fatty acids was not found in Rhizoma Cyperi-MD1. CONCLUSION: The SFE of Rhizoma Cyperi could be refined with molecular distillation. The active ingredients, such as volatile oil and alpha-cyperolone, were remained effectively. The ineffective ingredients fatty acids were removed.

Carbon Dioxide↗
PubMed2006

[Present situation and thinking of studies on apoplectic aphasia].

There were different emphasis between Chinese medicine and Western medicine in the study of apoplectic aphasia, the study of Chinese medicine lay particular emphasis on treatment with more interfering methods but lacking unifying evaluation criteria; while studies of Western medicine lay particular emphasis on studies of mechanisms, classification and language rehabilitation of aphasia, etc.. Selection and application of scientific study methods are key to attain expectation results of studies, and deeply make studies of apoplectic aphasia, so as to explore and establish the model of integrated Chinese and western medicine study of aphasia, promote rehabilitation of language function and increase life quality of the patient of apoplexy.

Aphasia↗
PubMed2005

[Clinical features and outcomes of hyperthyroidism patients positive in propylthiouracil-induced antineutrophil cytoplasmic antibody].

OBJECTIVE: To analyze the clinical features and outcomes of hyperthyroidism patients positive in propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA). METHODS: The clinical data, including the clinical manifestations, treatment, and outcomes of 45 PTU-induced ANCA positive patients with hyperthyroidism were prospectively studied. RESULTS: Seventeen of the 45 patients had clinically evident vasculitis and 28 of the 45 patients were not complicated by vasculitis. In the vasculitis group, 13 patients (76.5%) had renal involvement manifested by hematuria, proteinuria, and renal insufficiency. 7 of them (41.2%) had lung involvement and 6 of them had hemoptysis. Perinuclear ANCA (p-ANCA) was detected in all 17 patients and 16 of them (94.1%) were anti-myeloperoxidase antibodies (MPO-ANCA) positive. PTU was discontinued in all 17 patients and the treatment was switched over to methimazole (MMI) in 6 patients. Four patients with severe organ involvement received prednisone and immunosuppressant for 6 to 12 months. No relapse or death occurred during the follow-up period (8 to 60 months with a median of 30 months). All the 17 patients achieved clinical remission except for two that developed end stage renal disease due to late diagnosis. 27 of the 28 patients without vasculitis (96.4%) were p-ANCA positive and 14 of them (50.0%) were MPO-ANCA positive. PTU treatment was discontinued in 24 patients and switched over to MMI treatment in 15 patients, and 4 patients continued to take low dose PTU. No vasculitis manifestation occurred during the follow-up period (3 to 36 months with a median of 20 months). However, the ANCA titer declined slowly in most patients in both groups. CONCLUSION: PTU treatment should be discontinued without delay in the PTU-induced ANCA positive patients with hyperthyroidism. Treatment can be switched over to MMI when necessary. Patients with severe organ involvement should receive prednisone and immunosuppressant. No vasculitis relapse is found during the follow-up after withdrawal of PTU. However, ANCA may keep positive for a long time.

Adolescent↗
PubMed2005

Expression and correlation of CD44v6, vascular endothelial growth factor, matrix metalloproteinase-2, and matrix metalloproteinase-9 in Krukenberg tumor.

AIM: To explore the expression and correlation of CD44v6, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2 and matrix metalloproteinase (MMP)-9 in Krukenberg and primary epithelial ovarian carcinoma. METHODS: The expressions of CD44v6, VEGF, MMP-2 and MMP-9 were detected by immunohistochemical method in 20 cases of normal ovarian tissues, 38 cases of Krukenberg tumor and 45 cases of primary epithelial ovarian carcinoma. RESULTS: The expression of CD44v6 (primary epithelial ovarian carcinoma tissue vs normal ovarian tissue: chi(2) = 4.516, P = 0.034; Krukenberg tumor tissue vs normal ovarian tissue: chi(2) = 19.537, P = 0.001) and VEGF (primary epithelial ovarian carcinoma tissue vs normal ovarian tissue: P = 0.026; Krukenberg tumor tissue vs normal ovarian tissue: chi(2) = 22.895, P = 0.001) was significantly higher in primary epithelial ovarian carcinoma tissue and Krukenberg tumor tissue than in normal ovarian tissue. The positive expression rate of MMP-2 and MMP-9 was 0% in the normal ovarian tissue. The positive expression rate of CD44v6 (chi(2) = 10.398, P = 0.001), VEGF (chi(2) = 13.149, P = 0.001), MMP-2 (chi(2) = 33.668, P = 0.001) and MMP-9 (chi(2) = 38.839, P = 0.001) was remarkably higher in Krukenberg tumor than in primary epithelial ovarian carcinoma. The correlation of CD44v6, VEGF, MMP-2, and MMP-9 was observed in primary epithelial ovarian carcinoma and Krukenberg tumor. CONCLUSION: CD44v6, VEGF, MMP-2, and MMP-9 are involved in ovarian carcinoma, gastric cancer and Krukenberg tumor. Detection of CD44v6, VEGF, MMP-2 and MMP-9 may contribute to the diagnosis of ovarian carcinoma, gastric cancer, and Krukenberg tumor.

Adult↗
PubMed2005

Peptide inhibitors of mammalian ribonucleotide reductase.

Mammalian ribonucleotide reductase (mRR) is a chemotherapeutic target. In common with other class Ia RRs, the enzyme is composed of two subunits (mR1 and mR2), with mR1 containing both the active site and allosteric effector sites and mR2 containing a stable tyrosyl radical that is essential for enzymatic activity. mRR is inhibited by Ac-FTLDADF (denoted P7), corresponding to the C-terminus of mR2, which competes with mR2 for binding to mR1. The enzyme has two physiologically important active forms, mR12mR22 and mR16(mR22)j (j=1-3), with high ATP concentrations favoring the latter. Here, we report on our progress in using structural and functional studies in conjunction with library screening to identify derivatives of tri-, tetra- and hexapeptides, and cyclic heptapeptides, having equal or significantly higher activities than P7 toward inhibition of one or both active forms. These identifications were made by screening candidate peptides both for their abilities to bind to mR1 competitively with P7 and to inhibit ribonucleotide reductase activity. A significant feature of both P7 and the newly identified derivatives is that they are stronger inhibitors of mR12mR22 than of mR16(mR22)j. For the tetrapeptides, this is due in part to their preferential binding to mR1 monomer. The possible application of these peptide derivatives in cancer chemotherapy, exploiting their preferential inhibition of mR12mR22, is considered.

Allosteric Regulation↗
PubMed2005

[Vicissitudes of proportion and mortality of patients with pulmonary thromboembolism].

OBJECTIVE: To investigate the vicissitudes of the proportion and the mortality of patients with pulmonary thromboembolism (PTE). METHODS: To analyze respectively the data of 442 patients with PTE admitted to the Fuwai Hospital during the period 1974-2002 were analyzed retrospectively. RESULTS: The numbers of PTE in-patients every year during the 1970s and 48-79 cases in the early 2000s. The hospitalization constituent ratio of PTE was 0.1152% in 1970s and was 0.5866% in early 2000s. The age of onset ranged from 30 to 60. The tide age was from 30 to 60 in the male patients and from 40 to 60 in the female patients. The in-hospital mortality of PTE patients was descending from 20.0% in 1970s to 5.8% in early 2000s. The in-hospital mortality was 12.5% before 1990 and was 4.5% after 1990 (P = 0. 005). The in-hospital mortality rates of the male and female patients were 4.6% and 8.6% respectively (P = 0.09). The in-hospital mortality rates of the patients younger than 70 and elder than 70 were 5.5% and 19.0% respectively (P < 0.05). CONCLUSION: PTE The mortality of PTE, which attacks males more frequently than females, and the proportions of the number of PTE in-patients to the number of the whole in-patients increased and the in-hospital mortality increased during the past 3 decades.

Adult↗
PubMed2005

Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections.

CD1d-restricted natural killer T (NKT) cells are innate-like lymphocytes that express a conserved T-cell receptor and contribute to host defence against various microbial pathogens. However, their target lipid antigens have remained elusive. Here we report evidence for microbial, antigen-specific activation of NKT cells against Gram-negative, lipopolysaccharide (LPS)-negative alpha-Proteobacteria such as Ehrlichia muris and Sphingomonas capsulata. We have identified glycosylceramides from the cell wall of Sphingomonas that serve as direct targets for mouse and human NKT cells, controlling both septic shock reaction and bacterial clearance in infected mice. In contrast, Gram-negative, LPS-positive Salmonella typhimurium activates NKT cells through the recognition of an endogenous lysosomal glycosphingolipid, iGb3, presented by LPS-activated dendritic cells. These findings identify two novel antigenic targets of NKT cells in antimicrobial defence, and show that glycosylceramides are an alternative to LPS for innate recognition of the Gram-negative, LPS-negative bacterial cell wall.

Animals↗
PubMed2005

Antitumor effects of human ribonuclease inhibitor gene transfected on B16 melanoma cells.

Human ribonuclease inhibitor (RI) is a cytoplasmic acidic protein. The experiment demonstrated that it might effectively inhibit tumor-induced angiogenesis and inhibit tumor growth. Ribonuclease inhibitor is constructed almost entirely of leucine-rich repeats, which might be involved in unknown biological effects besides inhibiting RNase A and angiogenin activities. The exact molecular mechanism of antitumor on ribonuclease inhibitor remains unclear so far. In order to further understand the function of ribonuclease inhibitor and investigate the relationship with tumor growth, our study established a transfection of human ribonuclease inhibitor cDNA into the murine B16 cells by the retroviral packaging cell line PA317. The cell line transfected with a stably high expression of ribonuclease inhibitor was identified. We found that the transfected ribonuclease inhibitor could obviously inhibit cell proliferation, regulate cell cycle and induce cell apoptosis in vitro. Mice that were injected with the B16 cells transfected RI cDNA showed a significant inhibition of the tumor growth with lighter tumor weight, lower density of microvessels, longer latent periods, and survival time than those in the other two control groups. In conclusion, the results reveal the novel mechanism that antitumor effect of ribonuclease inhibitor is also associated with inducing apoptosis, regulating cell cycle and inhibiting proliferation besides antiangiogenesis. These results suggest that ribonuclease inhibitor might be a candidate of tumor suppressor gene in some tissues. RI could become a target gene for gene therapy. Our study may be of biological and clinical importance.

Angiogenesis Inhibitors↗
PubMed2005

Mechanisms of action of peptide inhibitors of mammalian ribonucleotide reductase targeting quaternary structure.

Mammalian ribonucleotide reductase (mRR) is a chemotherapeutic target. The enzyme is composed of 2 subunits (mR1 and mR2) and is inhibited by Ac-FTLDADF (denoted P7), corresponding to the C-terminus of mR2, which competes with mR2 for binding to mR1. mRR has 2 physiologically important active forms, mR12mR22 and mR16(mR22)j (j = 1-3). Here we report on the mechanism of action of recently identified peptide derivatives having higher activities than P7 toward inhibition of one or both active forms. A significant feature of both P7 and these new inhibitors is that they are more potent vs. mR12mR22 than mR16(mR22)j. For some of these peptides, this is due in part to their preferential binding to the mR1 monomer. The possible application of these peptide derivatives in cancer chemotherapy is discussed.

Animals↗
PubMed2005

Anti-myeloperoxidase IgG subclass distribution and avidity in sera from patients with propylthiouracil-induced antineutrophil cytoplasmic antibodies associated vasculitis.

OBJECTIVE: Propylthiouracil (PTU) could induce MPO-ANCA-positive vasculitis. The aim of this study was to compare the IgG subclass distribution and avidity of MPO-ANCA in sera from patients with primary ANCA-associated vasculitis (AASV) and PTU-induced vasculitis. METHODS: Nineteen patients with primary AASV with MPO-ANCA and thirteen patients with PTU-induced vasculitis were enrolled in the current study. Sera in both active phase and remission were collected. Anti-MPO IgG subclasses were detected by antigen specific ELISAs using specific monoclonal antibodies as second antibodies, and MPO-ANCA avidity was assessed by antigen-inhibition ELISAs. RESULTS: In primary AASV, all four anti-MPO IgG subclasses could be detected in active phase with IgG1 (100%), IgG2 (73.7%), IgG3 (63.2%) and IgG4 (94.7%), and in remission, IgG1 and IgG4 subclasses in most patients remained positive. However, in PTU-induced vasculitis, anti-MPO IgG3 subclass could not be detected, the anti-MPO IgG subclasses in active phase were IgG1 (100%), IgG2 (61.5%) and IgG4 (46.2%). Furthermore, five out of the six patients (88.8%) with PTU-induced vasculitis with positive IgG4 subclass in active phase turned to negative in remission, however, only eight out of the fourteen patients (57.1%) with primary AASV turned to negative. The median avidity constant of MPO-ANCA was 56 (8.96 to >140) x 10(7) mol/l for patients with primary AASV and 0.7 (<0.28 to >140) x 10(7) mol/l for patients with PTU-induced vasculitis respectively. Furthermore, the relative levels of MPO-ANCA avidity were associated with elevation of ESR in primary AASV and were associated with BVAS scores in patients with PTU-induced vasculitis, respectively. CONCLUSION: MPO-ANCA IgG subclass distribution and avidity were different between patients with primary AASV and PTU-induced vasculitis. It was suggested that the mechanism of ANCA production in PTU-induced vasculitis was different from that in primary AASV, and the avidity of MPO-ANCA might be associated with disease activity.

Adult↗
PubMed2005

Genome analysis and functional characterization of the E2 and RING-type E3 ligase ubiquitination enzymes of Arabidopsis.

Attachment of ubiquitin to substrate proteins is catalyzed by the three enzymes E1, E2 (ubiquitin conjugating [UBC]), and E3 (ubiquitin ligase). Forty-one functional proteins with a UBC domain and active-site cysteine are predicted in the Arabidopsis (Arabidopsis thaliana) genome, which includes four that are predicted or shown to function with ubiquitin-like proteins. Only nine were previously characterized biochemically as ubiquitin E2s. We obtained soluble protein for 22 of the 28 uncharacterized UBCs after expression in Escherichia coli and demonstrated that 16 function as ubiquitin E2s. Twelve, plus three previously characterized ubiquitin E2s, were also tested for the ability to catalyze ubiquitination in vitro in the presence of one of 65 really interesting new gene (RING) E3 ligases. UBC22, UBC19-20, and UBC1-6 had variable levels of E3-independent activity. Six UBCs were inactive with all RINGs tested. Closely related UBC8, 10, 11, and 28 were active with the largest number of RING E3s and with all RING types. Expression analysis was performed to determine whether E2s or E3s were expressed in specific organs or under specific environmental conditions. Closely related E2s show unique patterns of expression and most express ubiquitously. Some RING E3s are also ubiquitously expressed; however, others show organ-specific expression. Of all the organs tested, RING mRNAs are most abundant in floral organs. This study demonstrates that E2 diversity includes examples with broad and narrow specificity toward RINGs, and that most ubiquitin E2s are broadly expressed with each having a unique spatial and developmental pattern of expression.

Arabidopsis↗
PubMed2005

Titre and affinity of propylthiouracil-induced anti-myeloperoxidase antibodies are closely associated with the development of clinical vasculitis.

Substantial evidences suggested that propylthiouracil (PTU) could induced anti-myeloperoxidase (MPO) antibodies in sera from patients with hyperthyroidism, however, only a subgroup of the PTU-induced anti-MPO antibody positive patients developed clinical evident vasculitis. The aim of this study is to compare the titres and affinities of PTU induced anti-MPO antibodies in sera from patients with hyperthyroidism with and without clinical vasculitis. Anti-MPO antibody positive sera from patients diagnosed hyperthyroidism with (n = 13) and without (n = 14) clinical evident vasculitis were collected. The titre was determined by MPO-ELISA and expressed as logarithm value (lgT). The affinity constant (aK) of anti-MPO IgG was measured by antigen inhibition assay. The titre and aK values were compared between patients with and without vasculitis. In patients with vasculitis, the mean lgT of anti-MPO antibodies was 3.62 +/- 0.66; the median aK was 4.47 x 10(7)M(-1). In patients without vasculitis, the mean lgT was 2.54 +/- 0.29; the median aK was 0.14 x 10(7)M(-1), and both were significant lower than those in patients with vasculitis (t = 5.464; P = 0.000 & z = -4.373; P = 0.000, respectively). We concluded that the titre and affinity of anti-MPO antibodies might be associated with the development of clinical vasculitis in patients with PTU-induced ANCA.

Adolescent↗
PubMed2005

[Clinical trial and evaluation on comprehensive treatment on attack in acute stage: report of 522 cases].

OBJECTIVE: To investigate the clinical effect of the comprehensive treatment to acute stage of attack. METHODS: On the basis of the previous observation, the study of the randomization control with general treatment, treatment on acupuncture and western medical treatment were carried out. A comprehensive treatment on overall traditional Chinese medical differentiation according to the superiority of every treatment was assessed and evaluated in 522 patients with attack. RESULTS: The comprehensive treatment of cerebral infarction was superior to the western medicine treatment. General treatment, treatment on traditional Chinese medical differentiation, acupuncture group revealed different improvement on neural function, daily viability, cognitive function in various extent. CONCLUSION: The comprehensive treatment that based on overall traditional Chinese medical differentiation has advantage and characteristic. It has positive combined action to the attack and relevant to clinical setting, easier to popularization and application. Various appraising amount form has different evaluating effects in different stage.

Acupuncture Therapy↗
PubMed2005

[Effects of quinidine on pinacidil-induced transmural dispersion of repolarization in canine right ventricular wall].

OBJECTIVE: On the basis that pinacidil can produce an "all or none" repolarization in right ventricular wall of canine, to observe the effects of quinidine on the marked transmural dispersion of repolarization. Recent studies have shown that ventricular myocardium is composed of at least 3 electrophysiological distinct cell types: epicardial, endocardial, and midcardial cells. Differences in the response of the 3 cell types to pharmacologic agents and/or pathophysiological states often result in amplification of intrinsic electrical heterogeneities, thus providing a substrate as well as a trigger for the development of arrhythmias. The study was designed to observe the right ventricular transmural heterogeneity in vitro canine heart tissue preparation level. METHODS: The strips were isolated from the anterior wall of the right ventricular of canine. The preparations perfused with oxygenated (95%O(2)/5%CO(2)) Tyrode's solution. The tissues were stimulated at basic cycle lengths of 1000 ms. Standard microelectrode techniques were used. Transmembrane action potentials were recorded from epicardial, midcardial and endocardial cells respectively from right ventricular free wall of canine on different conditions [perusing with Tyrode's solution (Control), pinacidil (2.5 micromol/L), and quinidine (5 micromol/L) in turn]. RESULTS: Compared with that of endocardial cells, the action potentials of canine ventricular epicardial and midcardial cells had more obvious spike and dome morphology. Pinacidil (2.5 micromol/L) caused a loss of the dome of transmembrane action potentials and a marked abbreviation of the action potential duration (APD) in right ventricular epicardial and midcardial cells, especially in epicardial cells, but not in endocardial cells (n = 10). With pinacidil (2.5 micromol/L), in epicardial cells, phase 2 amplitude of action potentials decreased from (117.7 +/- 9.3) mV to (71.3 +/- 6.4) mV (P < 0.01), and 90% of the APD(90) decreased from (198.2 +/- 20.8) ms to (103.9 +/- 13.5) ms (P < 0.01). The transmural dispersion of action potential duration increased from (48.5 +/- 9.2) ms to (128.7 +/- 13.5) ms (P < 0.01). Quinidine (5 micromol/L) effectively prolonged the APD abbreviated by pinacidil, restored or partly restored the dome of transmembrane action potentials of epicardial and midcardial cells but not of endocardial cells (n = 10). In epicardial cells phase 2 amplitude increased from (71.3 +/- 6.4) mV to (106.6 +/- 7.7) mV (P < 0.01), and 90% of the APD(90) increased from (103.9 +/- 13.5) ms to (185.9 +/- 15.7) ms (P < 0.01). The transmural dispersion of action potential duration significantly decreased from (128.7 +/- 13.5) ms to (54.3 +/- 10.8) ms (P < 0.01). Quinidine reduced pinacidil-induced transmural dispersion of phase 2 amplitude and the APD in right ventricular wall of canine. CONCLUSION: By restoring the dome and the APD of the epicardial and midcardial cells action potentials, quinidine (5 micromol/L) could reduce the marked transmural dispersion of repolarization caused by pinacidil.

Action Potentials↗
PubMed2005

[Expression and biological significance of survivin and p63 in laryngeal squamous cell carcinoma].

OBJECTIVE: To investigate the expression of Survivin and p63 and their biological significance in laryngeal squamous cell carcinomas (LSCC). METHOD: The expression of Survivin and p63 in 47 cases of tumor tissues, adjacent and normal tissues were detected using in situ hybridization. RESULT: Percentage of Survivin expression was 59.6% (28/47), 25.5% (12/47) in tumor tissues and adjacent tissues respectively. In contrast, normal laryngeal tissues did not express Survivin. Over expression of Survivin was strongly associated with tumor grade, TNM stage and cervical nodal metastasis. Percentage of p63 expression was 91.5% (43/47), 93.6% (44/47), 57.1% (8/14) in tumor tissues, adjacent and normal tissues respectively. The expression of p63 was not related to any clinicopathological features. CONCLUSION: Survivin may play an important role in the pathway of carcinogenesis and progression of LSCC and it may be identified as a new therapeutic target. The up-regulation of the expression of Survivin predicts more invasion and poor prognosis. p63 has less effect on biological behaviors of LSCC.

Aged↗
PubMed2004

Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo.

Inhibitors in myelin play a major role in preventing spontaneous axonal regeneration after CNS injury. Elevation of cAMP overcomes this inhibition, in a transcription-dependent manner, through the upregulation of Arginase I (Arg I) and increased synthesis of polyamines. Here, we show that the cAMP effect requires activation of the transcription factor cAMP response element binding protein (CREB) to overcome myelin inhibitors; a dominant-negative CREB abolishes the effect, and neurons expressing a constitutively active form of CREB are not inhibited. Activation of CREB is also required for cAMP to upregulate Arg I, and the ability of constitutively active CREB to overcome inhibition is blocked by an inhibitor of polyamine synthesis. Finally, expression of constitutively active CREB in DRG neurons is sufficient to promote regeneration of subsequently lesioned dorsal column axons. These results indicate that CREB plays a central role in overcoming myelin inhibitors and so encourages regeneration in vivo.

Animals↗