Biomedical subjects

S Ohno

Publications and source records attributed to S Ohno.

At least 505 records · Page 28Linked to original sources

PubMed1995

[Seroprevalence of HTLV-I in various ocular diseases in central Japan].

Recently human T-cell lymphotropic virus type I (HTLV-I) has been shown to be responsible for a kind of uveitis in southwestern Japan, where HTLV-I infection is highly endemic. To investigate further the association of HTLV-I with various ocular diseases, we studied HTLV-I seroprevalence in 1,350 patients in central Japan, where HTLV-I infection is not endemic. Of 1,350 patients with various ocular diseases, 40 (2.96%) were seropositive for the retrovirus. There was no statistically significant difference in HTLV-I seroprevalence among various ocular diseases. Four of 9 (44.4%) seropositive cases from southwestern Japan developed HTLV-I associated uveitis (HAU), whereas only 2 of 26 (7.7%) seropositive cases from central Japan developed HAU. The difference was statistically significant (p < 0.05). This suggests that the incidence of HAU could be influenced by environmental or hereditary factors. On the other hand, 3 of 7 (42.9%) patients with episcleritis showed HTLV-I infection.

Adolescent↗

PubMed1995

[Optic neuropathy in systemic lupus erythematosus (SLE)--analysis of 54 cases including our case].

A 46-year old woman with systemic lupus erythematosus (SLE) who had been treated with oral administration of prednisolone (7.5 mg/5 mg on alternate days) at our outpatient clinic suddenly developed a loss of visual acuity, visual field defect, and photophobia on Dec. 15th, 1993. When she was admitted three days later, she was diagnosed as having optic neuropathy, and immediate treatment with methylprednisolone (1 g/day for three days) followed by prednisolone (50 mg/day) resulted in complete disappearance of the above symptoms by Feb. 9th, 1994. As far as we know, fifty-three cases of SLE with optic neuropathy have been reported previously. The result of analysis of the 54 cases including our case indicates that rapid diagnosis and corticosteroid treatment in an early phase of optic neuropathy leads to significant improvement.

Female↗

PubMed1995

Clinicopathologic characteristics and outcome of adenocarcinoma of the human gastric cardia in comparison with carcinoma of other regions of the stomach.

BACKGROUND: Carcinoma arising in the cardioesophageal junction is a distinct clinical entity compared with tumors located in other regions of the stomach. This study was done to analyze the biologic characteristics of carcinoma of the gastric cardia compared with other gastric carcinomas. STUDY DESIGN: Clinicopathologic features and postoperative prognosis of 68 cases of carcinoma of the cardia were evaluated, in comparison with findings of tumors in other regions of the stomach. RESULTS: From 1975 to 1992, 68 (6.5 percent) of 1,042 patients with carcinoma of the stomach had adenocarcinoma of the cardia. Carcinoma of the cardia was characterized by a more advanced stage compared with carcinoma of other regions of the stomach. The incidence of early stage carcinoma (limited to the submucosal layer) was 11.8 percent in the cardia, 15.8 percent in the upper one-third, and 42.2 percent in the remaining middle and lower thirds of the stomach. When compared to carcinoma in other regions of the stomach, tumors of the cardia had a significantly poorer prognosis and there was a higher incidence of lymph node and hepatic metastasis. The five-year survival rates in patients with adenocarcinoma in the cardia, the upper one-third, and the remaining middle and lower thirds of the stomach were 35.3, 43.7, and 61.9 percent, respectively. Especially for patients with stage II and stage III disease, the prognosis was significantly worse with adenocarcinoma of the cardia than with carcinomas of the other regions of the stomach. CONCLUSIONS: Early detection is crucial to improve the survival of patients with carcinoma of the gastric cardia. Extended dissection of lymph nodes and aggressive postoperative chemotherapy in an attempt to prevent hepatic metastasis are highly recommended.

Adenocarcinoma↗

PubMed1995

[Rapid diagnosis of adenoviral conjunctivitis by enzyme-linked immunosorbent assay (Adenoclone)].

We evaluated an enzyme-linked immunosorbent assay test (Adenoclone) for the rapid diagnosis of adenovirus infection in 589 cases of acute follicular conjunctivitis. Of 255 cases of adenoviral conjunctivitis proven by positive virus isolation. Adenoclone was positive in 51.0% by visual determination and 40.4% by spectrophotometry. Twenty-seven of 130 cases giving visually positive results were interpreted to be negative by spectrophotometry. In 334 adenovirus-negative cases, Adenoclone was negative in 99.1% and 99.4 by visual and spectrophotometric determination, respectively. Adenoclone was less sensitive in cases of adenovirus 3, 4 or 37, infections than in those of adenovirus 8, and also showed lower sensitivity in cases presenting mild conjunctivitis. Adenoclone is a rapid and easy test with high specificity but low sensitivity, and thus the test seems to be helpful in diagnosing adenoviral conjunctivitis.

Adenovirus Infections, Human↗

PubMed1995

[Ultrastructural study of lens fiber cells by quick-freezing and deep-etching].

The ultrastructure of lens fiber cytoskeleton was studied by quick-freezing and deep-etching. Lenses of 5 Wistar male rats were divided into lens cortex and lens nucleus. Filamentous structures were clearly observed in the cortical fiber cells, which had diameters in 10 approximately 15 nm or about 5 nm. They showed a meshwork structure. On the other hand, the filamentous structures showed a linear, dense, and laminar pattern in the nuclear fiber cells. These ultrastructural changes of cytoskeletons may be related to the elongation and differentiation of lens fiber cells and may be important for maintaining transparency of the lens.

Animals↗

PubMed1995

[A case of Behçet's disease associated with aortic regurgitation and nephrotic syndrome].

A 50-year-old housewife with a main complaint of dyspnea was admitted to our hospital in September, 1992. In 1975, the patient developed aphthous stomatitis, genital aphthous ulcers, uveitis and erythema nodosum appeared and diagnosed as having Behcet's disease at Department of Dermatology of our hospital. Aortic regurgitation was pointed out in 1984. Hyperlipidemia appeared in January and Oral prednisolone was started in May, 1985. From April in 1987, proteinuria appeared. From January, 1988, urinal protein was greater than 300 mg/dl. Orthopnea appeared in July, 1992. Physical examinations revealed systolic and diastolic murmur and pretibial edema. Laboratory findings showed proteinuria (3.8 g/day) and hypoproteinemia (serum total protein 5.1 g/dl, serum albumin 3.1 g/dl). Microscopic findings of renal biopsy revealed mesangial proliferative glomerulonephritis and arteriosclerosis. Immunofluorescent studies demonstrated deposits of Apo B in the basement membrane and the mesangium. She was discharged from our hospital as proteinuria was decreased after a combination treatment with camostat mesilate 600 mg and SAIREITO 9.0 g. This patient developed nephrotic syndrome, which was caused by hypertension and hyperlipidemia in addition to Behcet's disease. This case is noteworthy because Behcet's disease is rarely complicated with nephrotic syndrome.

Anti-Inflammatory Agents↗

PubMed1994

One subspecies of the red junglefowl (Gallus gallus gallus) suffices as the matriarchic ancestor of all domestic breeds.

The noncoding control region of the mitochondrial DNA of various gallinaceous birds was studied with regard to its restriction fragment length polymorphism (RFLP) and sequences of the first 400 bases. Tandem duplication of the 60-base unit was established as a trait unique to the genus Gallus, which is shared neither by pheasants nor by quails. Unlike its close ally Gallus varius (green junglefowl), the red junglefowl Gallus gallus is a genetically very diverse species; the 7.0% sequence divergence was seen between those from Thailand (G. g. gallus and G. g. spadiceus) and the other from the Indonesian island of Java (G. g. Bankiva). Furthermore, the divergence increased to 27.83% if each transversion is regarded as an equivalent of 10 transitions. On the other hand, a mere 0.5-3.0% difference (all transitions) separated various domestic breeds of the chicken from two G. g. gallus of Thailand, thus indicating a single domestication event in the area inhabited by this subspecies of the red junglefowl as the origin of all domestic breeds. Only transitions separated six diverse domesticated breeds. Nevertheless, a 2.75% difference was seen between RFLP type I breeds (White Leghorn and Nagoya) and a RFLP type VIII breed (Ayam Pelung). The above data suggested that although the mitochondrion of RFLP type V was the main contributor to domestication, hens of other RFLP types also contributed to this event.

Animals↗

PubMed1994

Specificity of the high affinity interaction of protein kinase C with a physiological substrate, myristoylated alanine-rich protein kinase C substrate.

Although myristoylated alanine-rich C kinase substrate (MARCKS), has been employed as an indicator for the activation of protein kinase C (PKC) in intact cells, little is known about its specificity for PKC family members. To address this question, we partially purified human MARCKS from baculovirus-infected cells and compared the kinetic parameters for phosphorylation by PKC isozymes, conventional PKC alpha (cPKC alpha), novel PKC delta (nPKC delta), nPKC epsilon, and atypical PKC zeta (apKC zeta), all of which are distributed in a wide variety of cells. cPKC alpha, nPKC delta, and nPKC epsilon efficiently phosphorylated intact MARCKS protein in vitro. The affinity of MARCKS for cPKC alpha, nPKC delta, and nPKC epsilon was extremely high and decreased in the order alpha > delta > epsilon with Km values of 10.7, 20.7, and 29.8 nM, respectively. The rate of phosphorylation also decreased in the same order. In contrast, a PKC zeta did not phosphorylate MARCKS efficiently, and we were unable to estimate the kinetic parameters. These results suggest that cPKC alpha, nPKC delta, and nPKC epsilon but not a PKC zeta are enzymes that phosphorylate MARCKS in response to PKC activators in intact cells. The structural requirements of MARCKS for efficient phosphorylation by these PKC members were then examined using a peptide that surrounds the phosphorylation site of MARCKS (peptide MARCKS). Interestingly, intact MARCKS showed a 90-150 times lower rate of phosphorylation by PKCs compared with peptide MARCKS, whereas the former showed a 40-180 times higher affinity for these PKC members. This implies that intact MARCKS protein retains a very high affinity for PKC with the sacrifice of its phospho-accepting activity. The structural requirements of PKC were then examined using a calpain-cleaved active fragment of nPKC delta. MARCKS was phosphorylated by the active catalytic fragment as efficiently as by intact nPKC delta, indicating that the kinase domain is sufficient for the high affinity interaction with intact MARCKS. However, gel overlay assay revealed that both intact nPKC delta and its regulatory domain bind to MARCKS, suggesting that both the kinase and regulatory domains of nPKC delta are involved in the high affinity interaction with intact MARCKS protein.

Amino Acid Sequence↗

PubMed1994

FK506 treatment of noninfectious uveitis.

PURPOSE: We studied the clinical effects of the immunosuppressive agent FK506 in patients with noninfectious uveitis. METHODS: This study was designed as a multicenter open clinical trial in Japan. Sixteen patients with noninfectious uveitis who had visited the Uveitis Survey Clinic of the Yokohama City University Hospital were given FK506. Eight had Behçet's disease; five, Vogt-Koyanagi-Harada syndrome; one, sympathetic ophthalmia; one, retinal vasculitis; and one, sarcoidosis. In patients with Behçet's disease, ocular attack score before and after therapy was compared to judge clinical status. For the other diseases, the ocular inflammatory symptoms were observed after the initiation of FK506 treatment. All patients underwent blood and urine examinations, electrocardiography, and chest x-rays before and after FK506 treatment. RESULTS: Of the patients with Behçet's disease, five improved, one remained unchanged, one deteriorated, and the status of one could not be determined. Of the patients with Vogt-Koyanagi-Harada syndrome, four improved, and one remained unchanged. The patient with sympathetic ophthalmia improved, the patient with retinal vasculitis remained unchanged, and the status of the patient with sarcoidosis could not be determined. Major adverse effects were sensations of warmth, hypomagnesemia, renal dysfunction, glucose intolerance, nausea, vomiting, and disorders of the central nervous system. All adverse effects disappeared or improved when FK506 was stopped or when the dosage was decreased. Renal dysfunction and glucose intolerance appeared when the blood level of FK506 was high. CONCLUSIONS: FK506 was effective in patients with uveitis, but it is important to monitor the occurrence of adverse effects.

Adult↗

PubMed1994

The multicentric occurrence of squamous epithelial dysplasia and squamous cell carcinoma in the esophagus.

BACKGROUND: The biologic significance of esophageal dysplasia has not yet been completely elucidated, especially regarding the process of multiple occurrences of squamous cell carcinoma. METHODS: The multiplicity of dysplasia in 73 patients with solitary carcinoma of the esophagus (Group I) and 21 with multiple carcinomas (Group II) was compared in surgically resected specimens. RESULTS: Thirty-nine second carcinomas were identified in 13 patients of Group II, and all were superficial. The incidences of five or more isolated dysplasias in cases without continuity to a carcinomatous lesion, was 6.8% and 66.7% in Groups I and II, respectively (P < 0.01). In a case with three or more carcinomas, the incidence increased to 84.6%. The coexistence of all grades of isolated dysplasias was observed in 10 patients (47.6%) in Group II but in only 6 patients (8.2%) in Group I (P < 0.01). CONCLUSIONS: These findings suggest that various degrees of evolving biologically related lesions, such as dysplasia and carcinoma, can occur multicentrically in the same esophagus.

Carcinoma in Situ↗

PubMed1994

Characterization of conventional protein kinase C (PKC) isotype expression during F9 teratocarcinoma differentiation. Overexpression of PKC alpha alters the expression of some differentiation-dependent genes.

F9 teratocarcinoma is a useful model for studying early embryogenesis since these cells can differentiate into primitive or parietal endoderm under the influence of retinoic acid or retinoic acid and cyclic AMP, respectively. We have found that three isoforms of protein kinase C (PKC alpha, -beta, and -gamma) were expressed in undifferentiated stem cells. When the cells were treated with retinoic acid either alone or in the presence of cAMP for 120 h, PKC alpha mRNA and protein levels increased, whereas those of PKC beta and PKC gamma became undetectable. These changes began within 24 h of drug treatment and were complete by 48-72 h. In order to determine the functional significance of the induction of PKC alpha during F9 differentiation, we established two stable transfectants that overexpressed PKC alpha protein between 4- and 5-fold compared to wild type cells. Characterization of these cell lines revealed an altered pattern of expression of some of the markers of F9 differentiation. The clone that had the highest amount of PKC alpha protein constitutively expressed mRNA for type IV collagen and c-Jun, which are not normally expressed until 24-48 h of treatment with differentiation agents. In the other overexpressing clone, these markers were induced much faster than in wild type cells. The growth rate of both overexpressing clones was less than wild type cells, while the expression of the PKC beta protein in these clones was similar to the levels found in differentiated F9 cells. However, other markers of differentiation, including the cellular morphology and levels of pST6-135 and c-myc RNA, responded to agents identically in both wild type and PKC-alpha-overexpressing clones. Therefore, overexpression of PKC alpha is not sufficient to induce full differentiation of F9 cells. However, our data suggest that certain pathways that lead to the expression of differentiation-dependent genes are regulated by PKC alpha protein levels.

Animals↗

PubMed1994

NF-kappa B and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene.

Expression of the human monocyte chemoattractant protein-1 (hMCP-1) is ubiquitous in various cell types and is increased by a wide variety of stimuli. We initially found that the effects of various stimuli, including IL-1 beta, TNF-alpha, and 2-O-tetradecanoylphorbol 13-acetate, on the expression of hMCP-1 mRNA were quite different among A172 glioblastoma cells, HT1080 fibrosarcoma cells, and SKLMS1 leiomyosarcoma cells. These findings suggested that hMCP-1 expression is regulated both in a stimulus-specific and a tissue-specific manner. To elucidate the mechanism underlying this stimulus-specific and tissue-specific regulation, we isolated a hMCP-1 5'-flanking genomic DNA fragment and sequenced it extensively up to bp 3011 upstream from the transcriptional start site. Among many putative cis-elements, we identified two cis-elements critical for the transcription of the hMCP-1 gene. The first element is a remote kappa B binding site located far upstream between bp -2612 and -2603 that was important for IL-1 beta-, TNF-alpha-, and 2-O-tetradecanoylphorbol 13-acetate-induced enhancer activity. Mutation at the kappa B consensus site resulted in a complete loss of these stimulus-induced enhancer activities. The second element is a GC box located between bp -64 and -59 that was important for the maintenance of basal transcriptional activity. Overexpression of rSp1 resulted in increased hMCP-1 transcriptional activity, possibly suggesting the role of Sp1 in controlling basal hMCP-1 transcription via this GC box. These results together indicate that hMCP-1 expression is controlled by at least two distinct regulatory elements: a kappa B site and a GC box that seem to be associated with stimulus-specific and tissue-specific regulation, respectively.

Base Sequence↗

PubMed1994

The genome of the THE I human transposable repetitive elements is composed of a basic motif homologous to an ancestral immunoglobulin gene sequence.

Amplification of rearranged human immunoglobulin heavy-chain genes using the polymerase chain reaction resulted unexpectedly in the amplification of human transposable repetitive element genomes. These were identified as members of the THE I (transposon-like human element I) transposable element family. Analysis of the THE I sequences revealed the presence of several copies of the ancestral building block described > 10 years ago by Ohno and coworkers as the primordial immunoglobulin sequence. The frequency and degree of homology of the repeats of the basic unit were similar for the two genes, as well as for two murine intracisternal A particles. These findings suggest that both the transposable genetic elements and the immunoglobulin genes originated from a common ancestral building block.

Animals↗

PubMed1994

Multiple occurrence of carcinoma in the upper aerodigestive tract associated with esophageal cancer: reference to smoking, drinking and family history.

Smoking and drinking habits as well as family history were examined in 143 men with esophageal cancer, including 30 who had associated second cancers of the upper aerodigestive tract (UADT) and 113 who did not. The risk of second cancers of UADT associated with the main lesions of the esophagus was evaluated, using odds ratios (ORs). As a result, the ORs of second cancers for current smoking and drinking were 5.3 and 7.6 respectively. The ORs significantly increased to 12.7 and 14.7 in heavy smokers and in heavy drinkers respectively. Furthermore, the risk of second cancer also significantly increased (8-fold) in patients who had close relatives with UADT cancer, compared to those without family history of any cancer. However, there were no differences in smoking or drinking habits regardless of family history. Our data thus suggest that a family history of UADT cancer as well as heavy smoking and drinking are clearly associated with multiple occurrence of UADT cancer. Therefore, careful and frequent examination for appearance of any second lesions are required for patients in these high-risk groups.

Aged↗

PubMed1994

Activation of novel protein kinases C delta and C epsilon upon mitogenic stimulation of quiescent rat 3Y1 fibroblasts.

Rat fibroblast 3Y1 cells express at least three protein kinase C species, conventional PKC alpha (cPKC alpha), novel PKC delta (nPKC delta), and novel PKC epsilon (nPKC epsilon). The stimulation of quiescent 3Y1 cells by serum (or epidermal growth factor (EGF) but not 12-O-tetradecanoylphorbol-13-acetate (TPA) results in the induction of DNA synthesis. Upon stimulation by serum or EGF, endogenous PKC species showed no indication of activation such as translocation or down-regulation, whereas TPA or synthetic diacylglycerol caused activation of all these PKC species when judged by these criteria. The only indication of activation observed upon serum or EGF stimulation was an upward shift in the electrophoretic mobility of nPKC delta. The phosphorylation levels of endogenous PKC members determined by in vivo metabolic labeling experiments revealed increased phosphorylation of both nPKC delta and nPKC epsilon, but only a slight increase for cPKC alpha in response to serum or EGF. On the other hand, TPA caused increased phosphorylation of all three PKC species. Overexpression of these PKC members by introduction of the corresponding cDNA expression plasmids resulted in the enhancement of the cell response to TPA when monitored in terms of transcriptional activation through TPA- or serum-responsive elements. Such enhancement in transcriptional activation by overexpression of cPKC alpha, nPKC delta, or nPKC epsilon was also observed in response to diacylglycerol, indicating that all these PKC species are activated by diacylglycerol in cells. In contrast to these nonphysiological stimuli, serum (or EGF) stimulation of 3Y1 cells that overexpress the respective PKC members revealed a clear difference between cPKC and nPKC, in that overexpression of nPKC delta or nPKC epsilon resulted in a large increase in TPA- or serum-responsive element activation, whereas the overexpression of cPKC alpha increased activation only very slightly. These results indicate that the mitogenic stimulation of quiescent 3Y1 cells results in selective activation of endogenous nPKC members and that the modes of activation of cPKC and nPKC differ from each other.

Animals↗

PubMed1994

Differential activation of adenylyl cyclase by protein kinase C isoenzymes.

Cyclic AMP production within cells is altered upon protein kinase C (PKC) activation; however, whether PKC directly modulates adenylyl cyclase (AC) catalytic activity has been controversial. Molecular studies have elucidated the existence of multiple PKC isoenzymes although the functional role of this diversity is not clear. Using purified PKC and AC isoenzymes, we demonstrate that PKC zeta directly phosphorylates type VAC, leading to an approximate 20-fold increase in its catalytic activity, a significantly larger enhancement than that achieved with forskolin (approximately 5-fold), the most potent activator of AC. When forskolin and PKC phosphorylation are combined, type V AC catalytic activity is increased 100-fold over basal levels. The two PKC isoenzymes (alpha and zeta) are additive in their capacity to activate AC, although PKC alpha is less potent than PKC zeta. Our data indicate that PKC can directly and potently regulate AC activity in an isoenzyme-specific manner, suggesting that direct cross-talk plays a major role in coordinating the activity of these two principal signal transduction pathways.

Adenylyl Cyclases↗

PubMed1994

Opposite effects of the overexpression of protein kinase C gamma and delta on the growth properties of human glioma cell line U251 MG.

In order to address the question of whether protein kinase C (PKC) is involved in the growth regulation of human glioma cells, we introduced PKC cDNA expression vectors into a human glioma cell line, U-251 MG, and established sets of stable cell clones that overexpress PKC gamma or delta. Cell clones obtained by the transfection of PKC gamma cDNA express 3.6 to 5 times more PKC activity than parental cells that express predominantly endogenous PKC alpha. These PKC gamma overexpressing cell clones show an increased rate of growth in monolayer culture, increased colony-forming efficiency on soft agarose, and increased DNA synthesis in response to epidermal growth factor and basic fibroblast growth factor. Cell clones obtained by transfection with PKC delta cDNA express 2 to 10 times more PKC than that produced endogenously. PKC delta overexpressing cells show a decreased rate of growth and decreased colony-forming efficiency. However, these PKC delta cell clones show no significant changes in responsiveness to the growth factors described above. These results clearly indicate that different PKC family members have distinct regulatory functions in cell growth and that PKC is involved in several aspects of the growth regulation of human glioma cells.

Cell Division↗

PubMed1994

Molecular and crystal structure of (2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-(1-->3)- [2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl-(1-->6)]- (2,4-di-O-acetyl-beta-D-glucopyranosyl)- (1-->3)-1,2,4,6-tetra-O-acetyl-beta-D-glucopyranose.

Crystals of the tetrasaccharide, (2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-(1-->3)- [2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl-(1-->6)]- (2,4-di-O-acetyl-beta-D-glucopyranosyl)-(1-->3)- 1,2,4,6-tetra-O-acetyl-beta-D-glucopyranose, belong to the monoclinic system, space group P2(1), with a = 12.709(4), b = 27.767(9), c = 9.567(4) A, beta = 105.07(2) degrees, and Z = 2. The crystal structure was solved by the direct method and refined by the full-matrix least-squares procedure to an R-value of 0.071 for 302- observed reflections in the X-ray data. All the four D-glucopyranose residues have the usual 4C1 chair conformations. The torsional angles at two (1-->3)-beta-linkages were phi(O-5-1-O-1-C-3) = -74 degrees and psi (C-1-O-1-C-3-C-2) = -122 degrees between the nonreducing and the middle residues, and phi = -67 degrees, psi = -111 degrees between the middle and the reducing residues. The orientation about the (1-->6)-beta-linkage was found to be phi(O5-C1-O-1-C-6) = -77 degrees, theta(C1-O-1-C-6-C-5) = 160 degrees, and chi(O-1-C-6-C-5-O-5) = 63 degrees (gt conformation). The primary acetate groups at C-6 of the reducing and the (1-->6)-branched residues were in the gt conformations (O-5-C-5-C-6-O-6 = 81 degrees and 84 degrees, respectively). On the other hand, the gg conformation was observed for the primary acetate group in the nonreducing residue (O-5-C-5-C-6-O-6 = 78 degrees).

Carbohydrate Conformation↗