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Y Zhang

Publications and source records attributed to Y Zhang.

At least 55 records · Page 3Linked to original sources

Widespread vascular production of C-reactive protein (CRP) and a relationship between serum CRP, plaque CRP and intimal hypertrophy.

OBJECTIVES: Evidence of local vascular production and a relationship between serum hsCRP levels and tissue expression of CRP in subjects with vascular disease would support a direct role for CRP in atherosclerosis. METHODS AND RESULTS: Vascular tissue from subjects undergoing coronary artery bypass grafting surgery (CABGS) (n=28) and carotid endarterectomy (CEA) (n=25) were studied. Histological samples were assessed for intima-media ratio (IMR) and CRP by immunohistochemistry. CRP mRNA was quantified by real-time polymerase chain reaction. CRP mRNA was seen in all plaques, non-atherosclerotic artery and atrium but no difference in mRNA expression was seen between plaque and non-atherosclerotic tissue. Serum hsCRP correlated with IMR (r=0.64, p=0.001) in non-atherosclerotic arteries and with plaque CRP staining (r=0.57, p=0.009) independent of age, BMI, lipids, diabetes and blood pressure. In a separate patient series, serum hsCRP was measured in aortic and coronary sinus blood from subjects undergoing CABGS or angiography (n=54). There was a coronary circulation hsCRP gradient ([mean+/-S.E.M.] aortic CRP 4.3mg/l+/-0.8 versus coronary sinus 5.8+/-1.2mg/l, p<0.05). CONCLUSIONS: Widespread vascular CRP mRNA expression, a correlation between serum hsCRP, intimal hypertrophy and plaque CRP, and a coronary hsCRP gradient suggest vascular secretion may contribute to serum CRP levels.

Aged↗

The ratio of medial to lateral tibial plateau bone mineral density and compartment-specific tibiofemoral osteoarthritis.

INTRODUCTION: Bone is thought to play an important role in osteoarthritis (OA) pathophysiology. Our aim was to look at specific features of OA and their relation to the ratio of medial:lateral tibial plateau bone mineral density (M:L BMD Ratio). METHODS: We examined our research question in the Framingham OA Study Cohort. All participants had BMDs and weight-bearing plain radiographs of the knees (2002-2005). M:L BMD Ratios were calculated using BMD from medial and lateral regions in the tibial plateau. Knee x-rays were read for osteophytes (OSTs), joint space narrowing (JSN), and sclerosis (Osteoarthritis Research Society International (OARSI) scoring system). Knees were classified as having medial and/or lateral JSN if they had JSN >or=1 in the medial and/or lateral tibiofemoral compartments, respectively. Medial and/or lateral OSTs were defined as medial and/or lateral tibial and/or femoral OSTs >or=2, respectively. Medial sclerosis and lateral sclerosis were defined as medial and lateral tibial sclerosis >or=1, respectively. We performed a logistic regression with medial JSN as the outcome and with M:L BMD Ratio groups as predictor variables, using the median group as the referent. Analyses were adjusted for age, sex, and body mass index (BMI). Generalized estimating equations were used to adjust for correlation between knees. Identical analyses were performed with medial OSTs, medial sclerosis, lateral JSN, lateral OSTs, and lateral sclerosis as the outcomes. RESULTS: Mean age of 1612 subjects (3048 knees) was 63.9 (Standard Deviation (SD)+/-8.9), 56% were women, and mean BMI was 28.5 (SD+/-5.5). M:L BMD Ratio was positively associated with medial JSN (P for linear trend <0.0001) and negatively associated with lateral JSN (P for linear trend <0.0001). The relations of the ratio with medial and lateral OSTs were j-shaped with P for quadratic trends <0.0001. There were also strong associations between M:L BMD Ratio and compartment-specific sclerosis (P for linear trends <0.0001) with most knees with medial and lateral sclerosis being in the highest and lowest M:L BMD Ratio groups, respectively. CONCLUSION: In summary, the extremes of the M:L BMD Ratio are strongly associated with individual radiographic features of OA. These findings add to existing evidence supporting the importance of understanding bone in OA pathophysiology.

Absorptiometry, Photon↗

Aluminium mobilization from acidic forest soils in Leigongshan area, Southwestern China: Laboratory and field study.

Aluminium mobilization from acidic forest soils in the remote Leigongshan area in southwestern China was investigated in the field and by a laboratory batch experiment using sequential extractions with HCl solutions with pH of approximately 3.4. Experimental data showed that strongly organically bound aluminium (Alp-Alcu) decreased significantly after sequential extraction, whereas exchangeable aluminium (Alex) increased in all three horizons. In the A-horizon with higher base saturation (BS), dissolved aluminium exchanged with base cations (BCs) on soil complex, causing lower aluminium release but significant leaching of BCs. In AB- and B-horizon with lower BS, more dissolved aluminium remained in solution. Al3+ activities in both experimental soil extracts and field soil waters strongly deviated from those predicted by the gibbsite model (i.e., pAl = pKsp + 3.0 pH) despite a significant increase in Al3+ with a decrease in pH. The soil organic-bound aluminium model, using Alcu and Alp to account for differences in the size of available Al pools in the soil, gave considerably better fits to both experimental and field data. SOM-Al model, approved by using Alex instead of organically bound aluminium (i.e., Alp and Alcu), could depict the changes in Al activities most successfully. We have concluded that Alp-Alcu is the main source of aqueous aluminium, whereas Alex plays an important role in regulating aluminium solubility during soil acidification.

Aluminum↗

Indispensable amino acid concentrations decrease in tissues of stomachless fish, common carp in response to free amino acid- or peptide-based diets.

The premise that free amino acid or dipeptide based diets will resolve the nutritional inadequacy of formulated feeds for larval and juvenile fish and improve utilization of nitrogen in comparison to protein-based diets was tested in stomachless fish, common carp (Cyprinus carpio L.) larvae. We examined the postprandial whole body free amino acid (FAA) pool in fish that were offered a FAA mixture based diet for the duration of 2 or 4 weeks. We found that the total amount and all indispensable amino acids concentrations in the whole body decreased after a meal. We then fed juvenile carp with dietary amino acids provided in the FAA, dipeptide (PP), or protein (live feed organisms; brine shrimp Artemia salina nauplii, AS) forms. Histidine concentrations in the whole fish body increased in all dietary groups after feeding whereas all other indispensable amino acids decreased in FAA and PP groups in comparison to the AS group. Taurine appears to be the major osmotic pressure balancing free amino acid in larval freshwater fish which may indicate a conditional requirement. We present the first evidence in larval fish that in response to synthetic FAA and PP diets, the whole body indispensable free AA concentrations decreased after feeding. This study shows that amino acids given entirely as FAA or PP cannot sustain stomachless larval fish growth, and may result in depletion of body indispensable AA and most of dispensable AA. The understanding of these responses will determine necessary changes in diet formulations that prevent accelerated excretion of amino acids without protein synthesis.

Amino Acids↗

On the human CYP2C9*13 variant activity reduction: a molecular dynamics simulation and docking study.

Cytochrome P450 2C9 (CYP2C9) plays a key role in the metabolism of clinical drugs. CYP2C9 is a genetically polymorphic enzyme and some of its allelic variants have less activity compared to the wild-type form. Drugs with a narrow therapeutic index may cause serious toxicity to the individuals who carry such allele. CYP2C9*13, firstly identified by some of the present authors in a Chinese poor metabolizer of lornoxicam, is characterized by mutation encoding Leu90Pro substitution. Kinetic experiments show that CYP2C9*13 has less catalytic activity in elimination of diclofenac and lornoxicam in vitro. In order to explore the structure-activity relationship of CYP2C9*13, the three-dimensional structure models of the substrate-free CYP2C9*1 and its variant CYP2C9*13 are constructed on the basis of the X-ray crystal structure of human CYP2C9*1 (PDB code 1R9O) by molecular dynamics simulations. The structure change caused by Leu90Pro replacement is revealed and used to explain the dramatic decrease of the enzymatic activity in clearance of the two CYP2C9 substrates: diclofenac and lornoxicam. The trans configuration of the bond between Pro90 and Asp89 in CYP2C9*13 is firstly identified. The backbone of residues 106-108 in CYP2C9*13 turns over and their side chains block the entrance for substrates accessing so that the entrance of *13 shrinks greatly than that in the wild-type, which is believed to be the dominant mechanism of the catalytic activity reduction. Consequent docking study which is consistent with the results of the kinetic experiments by Guo et al. identifies the most important residues for enzyme-substrate complexes.

Amino Acid Substitution↗

Influence of the first amplifier stage in MEA systems on extracellular signal shapes.

Recording of extracellular signals with planar metal microelectrodes (ME) has already been presented more than 30 years ago. To date, microelectrode array (MEA) systems are able to measure extracellular signals at about 64 sites, simultaneously. This enables monitoring of electrical activity of many cells in a large area. The extracellular recording technique has become a widely used method for neurological, toxicological or pharmacological studies. It already proved its potential to supplement the classical methods in electrophysiology. The interpretation of the recorded signal shapes in order to extract electrophysiological meaningful data--however--is still under discussion. In this article, we analyse the preamplifier circuit for extracellular recording of cardiac myocyte signals. We use a circuit model for the cell-electrode contact including the first amplification stage. In test experiments, we observe different signal shapes, when different shunt resistors are introduced at the input of the preamplifier. According to the frequency spectra of the recordings, we evaluate the transfer function between the source signal and the readout signal. As a result of our studies, an optimum readout electronics for originally, preserved extracellular signal shapes is proposed. Our amplifier design will be most valuable, if the use of small microelectrodes with high input impedances for in vitro as well as for in vivo experiments is desired.

Action Potentials↗

Increased chymotrypsin-like protease (chymase) expression and activity in placentas from women with preeclampsia.

Placenta-derived chymotrypsin-like protease (CLP/chymase) promotes endothelial P-selectin and E-selectin expression, which may be responsible for the increased neutrophil/endothelial interactions in preeclampsia (PE). However, little is known about this protease expression and production in human placenta. This study was undertaken to determine the distribution and gene expression of CLP in human placenta. Human placental tissues were obtained immediately after delivery from normal and PE pregnancies. We examined (1) CLP/chymase immunoactivity by immunohistochemical staining of villous tissue sections; (2) trophoblast mRNA and protein expression for chymase by RT-PCR and Western blot analysis; (3) chymase cDNA sequencing in isolated trophoblast cells (TCs); and (4) release of CLP by placental villous tissue cultured under 2% and 20% O(2). We found (1) CLP expression is mainly localized in the epithelial layer of syncytiotrophoblasts; (2) both mRNA and protein expression are significantly (p<0.05) upregulated in TCs isolated from PE vs. normal placentas; (3) TC chymase cDNA sequence and the deduced amino acid sequence are 100% identical to that reported for the human heart; and (4) villous tissue releases more chymotrypsin when cultured with 2% O(2). We conclude that (1) the DNA and protein sequence for chymase in placental trophoblast cells are the same as those reported in the human heart; (2) CLP/chymase expression is upregulated in TCs during PE; and (3) lowered oxygen condition promotes CLP release by placental TCs. Since chymase is a potent non-ACE angiotensin II producing enzyme, our data suggest that if placenta-derived CLP/chymase is released into the maternal circulation, it may contribute to the cardiovascular complications associated with PE.

Adult↗

alpha-lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells.

AIMS/HYPOTHESIS: The antioxidant compound alpha-lipoic acid (alpha-LA) possesses antidiabetic and anti-obesity properties. In the hypothalamus, alpha-LA suppresses appetite and prevents obesity by inhibiting AMP-activated protein kinase (AMPK). Given the therapeutic potential of alpha-LA for the treatment of type 2 diabetes and obesity, and the importance of AMPK in beta cells, we examined the effect of alpha-LA on pancreatic beta cell function. MATERIALS AND METHODS: Isolated rat islets and MIN6 beta cells were treated acutely (15-90 min) or chronically (18-24 h) with alpha-LA or the known AMPK-activating compounds 5'-amino-imidazole-4-carboxamide ribonucleoside (AICAR) and metformin. Insulin secretion, the AMPK-signalling pathway, mitochondrial function and cell growth were assessed. RESULTS: Acute or chronic treatment of islets and MIN6 cells with alpha-LA led to dose-dependent rises in phosphorylation of the AMPK alpha-subunit and acetyl CoA carboxylase. Chronic exposure to alpha-LA, AICAR or metformin caused a reduction in insulin secretion. alpha-LA inhibited the p70 s6 kinase translational control pathway, and inhibited MIN6 growth in a manner similar to rapamycin. Unlike AICAR and metformin, alpha-LA also acutely inhibited insulin secretion. Examination of the effect of alpha-LA on mitochondrial function showed that acute treatment with this compound elevated reactive oxygen species (ROS) production and enhanced mitochondrial depolarisation induced by Ca(2+). CONCLUSIONS/INTERPRETATION: This study is the first to demonstrate that alpha-LA directly affects beta cell function. The chronic effects of alpha-LA include AMPK activation and reductions in insulin secretion and content, and cell growth. Acutely, alpha-LA also inhibits insulin secretion, an effect probably involving the ROS-induced impairment of mitochondrial function.

AMP-Activated Protein Kinases↗

Observation of a fast electron beam emitted along the surface of a target irradiated by intense femtosecond laser pulses.

A novel fast electron beam emitting along the surface of a target irradiated by intense laser pulses is observed. The beam is found to appear only when the plasma density scale length is small. Numerical simulations reveal that the electron beam is formed due to the confinement of the surface quasistatic electromagnetic fields. The results are of interest for potential applications of fast electron beams and deep understanding of the cone-target physics in the fast ignition related experiments.

Journal Article↗

Investigation of corannulene for molecular hydrogen storage via computational chemistry and experimentation.

Molecular simulations for hydrogen physisorption with corannulene molecules arranged according to their crystal structure result in good agreement with the weight-percent hydrogen stored as determined experimentally employing a 3-g sample of highly crystalline corannulene at ambient temperatures and 72 bar of pressure. Calculated enthalpies of adsorption for corannulene/hydrogen molecular systems obtained from ab initio calculations which take into account electron correlation via second-order Möller-Plesset perturbation theory are in good agreement with literature experimental enthalpies of adsorption for activated carbons interacting with molecular hydrogen. Ab initio results also show that corannulene molecules arranged in a sandwich structure are important for approximately doubling the binding energy of corannulene interacting with molecular hydrogen through a cooperative interaction. To test the effects of finite temperatures and pressures, stack arrays were used as input for molecular dynamics simulations and indicate that physisorption mechanisms including van der Waals forces and dipole-induced dipole interactions may yield enhanced adsorption capacity in relation to other carbon-based materials. These results will be instrumental in identifying interlayer separations of an array of corannulene or related molecules that may provide a high weight percent of physisorbed hydrogen.

Journal Article↗

Effect of cilnidipine on left ventricular function in hypertensive patients as assessed by tissue Doppler Tei index.

Tissue Doppler Tei index is pointed to be more effective in the evaluation of global cardiac function than systolic and diastolic measurements alone in various heart diseases. This study was designed to assess the effect of cilnidipine on left ventricular function in hypertensive patients by using this index. A group of 40 hypertensives (mean age 55+/-8 years, range: 35-65) and 16 controls (mean age 52+/-9 years, range: 36-65) were included. Hypertensives were classified into non-left ventricular hypertrophy (NLVH) group (25 patients) and left ventricular hypertrophy (LVH) group (15 patients), and treated with cilnidipine for 2 months. Before and after treatment, the participants were examined by echocardiography. Tissue Doppler Tei index was calculated as diastolic time interval measured from end of late diastole to origin of early diastole (a') minus systolic Sm duration (b') divided by b', that is Tei index = (a'-b')/b'. Thirty-seven hypertensive patients finished the treatment. Tei index was significantly higher in NLVH and LVH groups than in control group, and in LVH group than in NLVH group (0.44+/-0.07 vs 0.28+/-0.06, P < 0.001; 0.51+/-0.13 vs 0.28+/-0.06, P < 0.001; 0.51+/-0.13 vs 0.44+/-0.07, P < 0.05). After treatment, Tei index was significantly decreased (0.40+/-0.11 vs 0.46+/-0.10, P < 0.0001); systolic blood pressure and diastolic blood pressure were also decreased significantly. In conclusion, Tei index is impaired in hypertensives before development of ventricular hypertrophy and impairment is more prominent in hypertrophy. Cilnidipine can improve left ventricular function. Tissue Doppler Tei index is gaining importance in evaluating LV function after drug intervention in hypertensive patients.

Calcium Channel Blockers↗

Protein and cell micropatterning and its integration with micro/nanoparticles assembly.

Micropatterning of proteins and cells has become very popular over the past decade due to its importance in the development of biosensors, microarrays, tissue engineering and cellular studies. This article reviews the techniques developed for protein and cell micropatterning and its biomedical applications. The prospect of integrating micro and nanoparticles with protein and cell micropatterning is discussed. The micro/nanoparticles are assembled into patterns and form the substrate for proteins and cell attachment. The assembled particles create a micro or nanotopography, depending on the size of the particles employed. The nonplanar structure can increase the surface area for biomolecules attachment and therefore enhance the sensitivity for detection in biosensors. Furthermore, a nanostructured substrate can influence the conformation and functionality of protein attached to it, while cellular response in terms of morphology, adhesion, proliferation, differentiation, etc. can be affected by a surface expressing micro or nanoscale structures. Proteins and cells tend to lose their normal functions upon attachment to substrate. By recognizing the types of topography that are favourable for preserving proteins and cell behaviour, and integrating it with micropattering will lead to the development of functional protein and cell patterns.

Biocompatible Materials↗

The identification of an internal ribosomal entry site in the 5'-untranslated region of p53 mRNA provides a novel mechanism for the regulation of its translation following DNA damage.

The tumor suppressor p53 plays a crucial role in maintaining the genetic integrity of the cell and in suppressing cell transformation. Its cellular levels are usually low and rise substantially in response to DNA damage. Although research on p53 induction following DNA damage has mainly focused on the post-translational modification of p53 by Mdm2, it is known that protein translation also contributes to p53 induction. However, the mechanisms underlying translational regulation of the p53 protein in response to DNA damage are still poorly understood. We show that p53 synthesis increases dramatically in MCF-7 cells treated with etoposide. Interestingly, this increase is accompanied by an increase in the association of the translation initiation factor eIF-4E with its binding protein 4E-BP1, an inhibitor of cap-dependent protein translation. We further identified an internal ribosomal entry site (IRES) located in the 5'-untranslated region of the p53 transcript, that is capable of driving the cap-independent translation of a downstream cistron encoding Firefly luciferase in a dicistronic expression vector. Moreover, we found that the activity of the IRES element increases in response to etoposide-induced DNA damage in MCF-7 cells. These findings provide a novel mechanism for the regulation of p53 translation in response to DNA damage.

5' Untranslated Regions↗

Bayesian modelling of an epidemic of severe acute respiratory syndrome.

This paper analyses data arising from a SARS epidemic in Shanxi province of China involving a total of 354 people infected with SARS-CoV between late February and late May 2003. Using Bayesian inference, we have estimated critical epidemiological determinants. The estimated mean incubation period was 5.3 days (95% CI 4.2-6.8 days), mean time to hospitalisation was 3.5 days (95% CI 2.8-3.6 days), mean time from symptom onset to recovery was 26 days (95% CI 25-27 days) and mean time from symptom onset to death was 21 days (95% CI 16-26 days). The reproduction ratio was estimated to be 4.8 (95% CI 2.2-8.8) in the early part of the epidemic (February and March 2003) reducing to 0.75 (95% CI 0.65-0.85) in the later part of the epidemic (April and May 2003). The infectivity of symptomatic SARS cases in hospital and in the community was estimated. Community SARS cases caused transmission to others at an estimated rate of 0.4 per infective per day during the early part of the epidemic, reducing to 0.2 in the later part of the epidemic. For hospitalised patients, the daily infectivity was approximately 0.15 early in the epidemic, but fell to 0.0006 in the later part of the epidemic. Despite the lower daily infectivity level for hospitalised patients, the long duration of the hospitalisation led to a greater number of transmissions within hospitals compared with the community in the early part of the epidemic, as estimated by this study. This study investigated the individual infectivity profile during the symptomatic period, with an estimated peak infectivity on the ninth symptomatic day.

Bayes Theorem↗

Landau-level splitting in graphene in high magnetic fields.

The quantum Hall (QH) effect in two-dimensional electrons and holes in high quality graphene samples is studied in strong magnetic fields up to 45 T. QH plateaus at filling factors nu = 0, +/-1, +/-4 are discovered at magnetic fields B > 20 T, indicating the lifting of the fourfold degeneracy of the previously observed QH states at nu = +/-4(absolute value(n) + 1/2), where n is the Landau-level index. In particular, the presence of the nu = 0, +/-1 QH plateaus indicates that the Landau level at the charge neutral Dirac point splits into four sublevels, lifting sublattice and spin degeneracy. The QH effect at nu = +/-4 is investigated in a tilted magnetic field and can be attributed to lifting of the spin degeneracy of the n = 1 Landau level.

Journal Article↗

Transition to a virtually incompressible oxide phase at a shock pressure of 120 GPa (1.2 Mbar): Gd3Ga5O12.

Cubic, single-crystal, transparent Gd(3)Ga(5)O(12) has a density of 7.10 g/cm(3), a Hugoniot elastic limit of 30 GPa, and undergoes a continuous phase transition from 65 GPa to a quasi-incompressible (QI) phase at 120 GPa. Only diamond has a larger Hugoniot elastic limit. The QI phase of is more incompressible than diamond from 170 to 260 GPa. Electrical conductivity measurements indicate the QI phase has a band gap of 3.1 eV. Gd(3)Ga(5)O(12) can be used to obtain substantially higher pressures and lower temperatures in metallic fluid hydrogen than was achieved previously by shock reverberation between Al(2)O(3) disks.

Journal Article↗

Negative cell cycle regulator 14-3-3sigma stabilizes p27 Kip1 by inhibiting the activity of PKB/Akt.

The 14-3-3sigma (sigma) protein is a human cancer marker downregulated in various tumors, but its function has not been fully established. 14-3-3sigma is a negative regulator of cell cycle when overexpressed, but it is not clear whether 14-3-3sigma regulates cyclin-dependent kinase inhibitor p27(Kip1) to negatively affect cell cycle progression. Protein kinase B/Akt is a crucial regulator of oncogenic signal and can phosphorylate p27(Kip1) to enhance p27(Kip1)degradation, thereby promoting cell growth. Here, we show that 14-3-3sigma-mediated cell cycle arrest concurred with p27(Kip1) upregulation and Akt inactivation. We show that 14-3-3sigma blocks Akt-mediated acceleration of p27(Kip1) turnover rate. 14-3-3sigma inhibits Akt-mediated p27(Kip1) phosphorylation that targets p27(Kip1) for nuclear export and degradation. 14-3-3sigma inhibits cell survival and tumorigenicity of Akt-activating breast cancer cell. Low expression of 14-3-3sigma in human primary breast cancers correlates with cytoplasmic location of p27(Kip1). These data provide an insight into 14-3-3sigma activity and rational cancer gene therapy by identifying 14-3-3sigma as a positive regulator of p27 and as a potential anticancer agent.

14-3-3 Proteins↗

Molecular mapping of stripe rust resistance gene YrCH42 in Chinese wheat cultivar Chuanmai 42 and its allelism with Yr24 and Yr26.

Stripe rust, caused by Puccinia striiformis f. sp. tritici (PST), is one of the most devastating diseases in common wheat (Triticum aestivum L.) worldwide. The objectives of this study were to map a stripe rust resistance gene in Chinese wheat cultivar Chuanmai 42 using molecular markers and to investigate its allelism with Yr24 and Yr26. A total of 787 F2 plants and 186 F3 lines derived from a cross between resistant cultivar Chuanmai 42 and susceptible line Taichung 29 were used for resistance gene tagging. Also 197 F2 plants from the cross Chuanmai 42xYr24/3*Avocet S and 726 F2 plants from Chuanmai 42xYr26/3*Avocet S were employed for allelic test of the resistance genes. In all, 819 pairs of wheat SSR primers were used to test the two parents, as well as resistant and susceptible bulks. Subsequently, nine polymorphic markers were employed for genotyping the F2 and F3 populations. Results indicated that the stripe rust resistance in Chuanmai 42 was conferred by a single dominant gene, temporarily designated YrCH42, located close to the centromere of chromosome 1B and flanked by nine SSR markers Xwmc626, Xgwm273, Xgwm11, Xgwm18, Xbarc137, Xbarc187, Xgwm498, Xbarc240 and Xwmc216. The resistance gene was closely linked to Xgwm498 and Xbarc187 with genetic distances of 1.6 and 2.3 cM, respectively. The seedling tests with 26 PST isolates and allelic tests indicated that YrCH42, Yr24 and Yr26 are likely to be the same gene.

Alleles↗