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J Hescheler

Publications and source records attributed to J Hescheler.

At least 127 records · Page 7Linked to original sources
PubMed1993

Novel potent inhibitor of receptor-activated nonselective cation currents in HL-60 cells.

A pharmacological classification of receptor-activated nonselective cation channels has not been possible because of the lack of specific and potent pharmacological blockers. In dibutyryl-cAMP-differentiated HL-60 cells, we recently identified ATP- and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-stimulated cation currents that were blocked by an organic inhibitor of receptor-mediated Ca2+ entry, 1-beta-[3-(4-methoxyphenyl)-propoxy]-4-methoxyphenethyl-1H-imidazole hydrochloride (SK&F 96365), with an IC50 of about 3 microM. Here, we describe a new compound, (RS)-(3,4-dihydro-6,7-dimethoxyisoquinoline-1-gamma 1)-2-phenyl-N, N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]acetamide (LOE 908), that fully blocked these currents at 3 microM. Half-maximal inhibition of agonist-activated nonselective inward currents was seen at 40 nM LOE 908, whereas voltage-dependent K+ currents in undifferentiated HL-60 cells were blocked with an IC50 of 620 nM. fMLP-induced single-channel currents of 4-5-pS conductance were abolished when the excised inside-out patch was exposed to 3 microM LOE 908. The rank order of potency of cations blocking ATP- and fMLP-induced inward currents was Gd3+ > Ni2+ > Cd2+.

Acetamides↗
PubMed1993

Molecular mechanisms of somatostatin's inhibition of hormone release: participation of voltage-gated calcium channels and G-proteins.

Somatostatin is known to inhibit hormone release from various neuroendocrine cells. In order to understand the mechanisms underlying somatostatin's action we performed patch-clamp experiments in GH3 pituitary, rMTC 44-2 thyroid and BON carcinoid cells. Calcium-mediated hormone release depended on the intracellular calcium concentration and thus on the calcium influx through voltage-gated calcium channels. In addition to inhibiting the cAMP-dependent secretory pathway, somatostatin reduced the calcium inward currents and thereby hormone release. The inhibition of voltage-gated calcium channels by somatostatin was mediated by "signal transducing" Go proteins. Thus, somatostatin's actions on hormone release involve both cAMP and intracellular calcium as second messengers. Patch-clamp experiments of voltage-gated calcium channels allow functional studies on the coupling of somatostatin receptors to cellular effector systems.

Animals↗
PubMed1993

Hormonal modulations of calcium channel activity.

Hormones and neurotransmitters which modulate the membraneous influx of calcium into the cytoplasm interact with heptahelical receptors coupling to heterotrimeric G-proteins. Whereas early studies on cardiomyocytes demonstrated the involvement of a cAMP (cyclic adenosine monophosphate)-stimulated phosphorylation in the regulation of calcium channels, there is growing evidence for a direct coupling of G-proteins to these channels. Various approaches led to the identification of the subtypes of G-protein involved in these signal transduction processes. Intranuclear injections of antisense oligonucleotides hybridizing to the mRNA of G-protein subunits and, thereby, blocking the expression of these proteins showed a high specificity of the involved G-proteins, suggesting a selective processing of signals from receptors through G-proteins. Whereas hormonal inhibitions of voltage-dependent calcium channels are mediated by G-proteins of the G0-family, hormonal stimulations involve G-protein of the G1-family and protein kinase C.

Animals↗
PubMed1992

Formyl peptides and ATP stimulate Ca2+ and Na+ inward currents through non-selective cation channels via G-proteins in dibutyryl cyclic AMP-differentiated HL-60 cells. Involvement of Ca2+ and Na+ in the activation of beta-glucuronidase release and superoxide production.

In human neutrophils, the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) induces increases in the intracellular free Ca2+ concentration ([Ca2+]i) with subsequent activation of beta-glucuronidase release and superoxide (O2-) production. Results from several laboratories suggest that the increase in [Ca2+]i is due to activation of non-selective cation (NSC) channels. We studied the biophysical characteristics, pharmacological modulation and functional role of NSC channels in dibutyryl cyclic AMP (Bt2cAMP)-differentiated HL-60 cells. fMLP increased [Ca2+]i by release of Ca2+ from intracellular stores and influx of Ca2+ from the extracellular space. fMLP also induced Mn2+ influx. Ca2+ and Mn2+ influxes were inhibited by 1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SK&F 96365). Under whole-cell voltage-clamp conditions, fMLP and ATP (a purinoceptor agonist) activated inward currents characterized by a linear current-voltage relationship and a reversal potential near 0 mV. NSC channels were substantially more permeable to Na+ than to Ca2+. SK&F 96365 inhibited fMLP- and ATP-stimulated currents with a half-maximal effect at about 3 microM. Pertussis toxin prevented stimulation by fMLP of NSC currents and reduced ATP-stimulated currents by about 80%. Intracellular application of the stable GDP analogue, guanosine 5'-O-[2-thio]diphosphate, completely blocked stimulation by agonists of NSC currents. In excised inside-out patches, single channel openings with an amplitude of 0.24 pA were observed in the presence of fMLP and the GTP analogue, guanosine 5'-O-[3-thio]triphosphate. The bath solution contained neither Ca2+ nor ATP. The current/voltage relationship was linear with a conductance of 4-5 pS and reversed at about 0 mV. fMLP-induced beta-glucuronidase release and O2- production were substantially reduced by replacement of extracellular CaCl2 or NaCl by ethylenebis(oxyethylenenitrilo)tetra-acetic acid and choline chloride respectively. In the absence of Ca2+ and Na+, fMLP was ineffective. SK&F 96365 inhibited fMLP-induced beta-glucuronidase release and O2- production in the presence of both Ca2+ and Na+, and in the presence of Ca2+ or Na+ alone. NaCl (25-50 mM) enhanced the basal and absolute extent of fMLP-stimulated GTP hydrolysis of heterotrimeric regulatory G-proteins in HL-60 membranes. The order of effectiveness of salts in enhancing GTP hydrolysis was LiCl > KCl > NaCl > choline chloride.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1992

Insulin-like growth factor I modulates voltage-dependent Ca2+ channels in neuronal cells.

Insulin and insulin-like growth factors are neuroactive peptides. We investigated the effect of insulin-like growth factor I (IGF-I) on Ca2+ channel currents in 108CC15 neuroblastoma x glioma (N x G) cells and a possible role of protein kinase C (PKC). Whereas the native IGF-I enhanced the Ca2+ channel current density in N x G cells, the boiled IGF-I had no effect. The effect of IGF-I occurred after 1-2 h incubation and reversed within 24 h. Ca2+ channel currents recorded in control cells were mainly of a low-threshold fast inactivating type and showed a mean density of 5.9 +/- 0.3 pA/pF. Current density in cells incubated with IGF-I (0.2 micrograms/ml) for 2 h increased to 9.2 +/- 0.8 pA/pF. Ca2+ channel currents in cells treated with IGF-I showed an enhanced amount of a high-threshold slowly inactivating Ca2+ current type sensitive to the dihydropyridine isradipine and the snail toxin omega-conotoxin. The effect of IGF-I was suppressed by coincubation with the PKC inhibitors 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7) and staurosporin which were both without effect on current density in control cells. Whereas the inactive phorbol ester phorbol 12-myristate 13-acetate (PMA) failed to modulate Ca2+ channels in N x G cells, stimulation of PKC by the active phorbol ester PMA mimicked the effect of IGF-I. The effects of IGF-I and phorbol ester were not additive. Our data suggest an intracellular mechanism dependent on PKC and we propose a physiological relevance of the observed Ca2+ channel modulation by IGF-I in the neuroactivity of the peptide.

Calcium Channel Blockers↗
PubMed1992

Different beta-subunits determine G-protein interaction with transmembrane receptors.

Regulatory GTP-binding proteins (G proteins) are membrane-attached heterotrimers (alpha, beta, gamma) that mediate cellular responses to a wide variety of extracellular stimuli. They undergo a cycle of guanine-nucleotide exchange and GTP hydrolysis, during which they dissociate into alpha-subunit and beta gamma complex. The roles of G-protein alpha-subunits in these processes and for the specificity of signal transduction are largely established; the beta- and gamma-subunits are essential for receptor-induced G-protein activation and seem to be less diverse and less specific. Although the complementary DNAs for several beta-subunits have been cloned, isolated subunits have only been studied as beta gamma complexes. Functional differences have been ascribed to the gamma-subunit on the basis of extensive sequence similarity among beta-subunits and apparent heterogeneity in gamma-subunit sequences. Beta gamma complexes can interact directly or indirectly with different effectors. They seem to be interchangeable in their interaction with pertussis toxin-sensitive alpha-subunits, so we tested this by microinjecting antisense oligonucleotides into nuclei of a rat pituitary cell line to suppress the synthesis of individual beta-subunits selectively. Here we show that two out of four subtypes of beta-subunits tested (beta 1 and beta 3) are selectively involved in the signal transduction cascades from muscarinic M4 (ref. 4) and somatostatin receptors, respectively, to voltage-dependent Ca2+ channels.

Animals↗
PubMed1992

Stable and functional expression of the calcium channel alpha 1 subunit from smooth muscle in somatic cell lines.

Voltage-activated calcium channels are membrane spanning proteins that allow the controlled entry of Ca2+ into the cytoplasm of cells. The principal channel forming subunit of an L-type calcium channel is the alpha 1 subunit. Transfection of Chinese hamster ovary (CHO) cells with complementary DNA encoding the calcium channel alpha 1 subunit from smooth muscle led to the expression of functional calcium channels which bind calcium channel blockers and show the voltage-dependent activation and slow inactivation and unitary current conductance characteristic of calcium channels in smooth muscle. The currents mediated by these channels are sensitive towards dihydropyridine-type blockers and agonists indicating that the calcium channel blocker receptor sites were present in functional form. The smooth muscle alpha 1 subunit cDNA alone is sufficient for stable expression of functional calcium channels with the expected kinetic and pharmacological properties in mammalian somatic cells.

Animals↗
PubMed1992

Inhibition of voltage-dependent Ca2+ channels via alpha 2-adrenergic and opioid receptors in cultured bovine adrenal chromaffin cells.

Adrenal chromaffin cells secrete catecholamines and opioids. The effects of these agents on whole-cell Ca2+ channel currents were studied, using bovine adrenal chromaffin cells kept in short term culture. Ca2+ channel currents recorded during voltage-clamp pulses from a holding potential of -80 mV to 0 mV were reversibly reduced by 10 microM epinephrine (in the presence of 1 microM propranolol) or 5 microM of the synthetic opioid, d-Ala2-d-Leu5-enkephalin (DADLE) by approximately 35% and 25%, respectively. The inhibitory action of epinephrine was mimicked by clonidine, reduced by yohimbine but not affected by prazosin. The DADLE-induced reduction of the Ca2+ channel current was antagonized by naloxone. The dihydropyridine (+)PN 200-110 (5 microM) reduced the Ca2+ channel current by approximately 40%; the Ca2+ channel current inhibited by (+)PN 200-110 was not further reduced by epinephrine. Intracellular infusion of guanosine-5'-O-(2-thiodiphosphate) and pretreatment of cells with pertussis toxin abolished the inhibitory effect of both epinephrine and DADLE. In membranes of adrenal chromaffin cells, four pertussis-toxin-sensitive G-proteins were identified, including Gi1, Gi2, Go1 and another Go subtype, possibly Go2. The data show that activation of alpha 2-adrenergic and opioid receptors causes an inhibition of dihydropyridine-sensitive Ca2+ channels in adrenal chromaffin cells. These inhibitory modulations are mediated by pertussis-toxin-sensitive G-proteins and may represent a mechanism for a negative feedback signal by agents released from the adrenal medulla.

Adrenal Glands↗
PubMed1992

Transient membrane hyperpolarizations due to spontaneous fluctuations of the cytosolic Ca2+ in osteoblast-like cells.

The recently developed nystatin modification of the patch clamp technique allows stable whole-cell recordings without affecting the intracellular Ca2+ buffering capacity and thereby may provide a means to indirectly monitor spontaneous changes in the intracellular Ca2+ concentrations. To test this hypothesis, we applied the nystatin method to the well-characterized ROS 17/2.8 osteoblast-like cell system, where rises of the intracellular Ca2+ are known to cause transient hyperpolarizations via activation of Ca2+ -dependent K+ channels. Additionally to minor fluctuations (10-20 mV) around a mean potential of -42.1 +/- 4.2 mV, we observed spontaneously occurring, transient hyperpolarizations to membrane potentials as negative as -80 mV. These transient hyperpolarizations were not eliminated by Ca2+ entry blockers but abolished by intracellular infusion of 10 mM EGTA. Thapsigargin, a specific inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, hyperpolarized the cells close to the K+ reversal potential. Moreover, voltage-clamp studies revealed an intermittendly activating Ca2+-dependent K+ conductance. These results strongly suggest that the nystatin method is particularly suitable to study Ca(2+)-dependent channels and thereby spontaneous changes in the intracellular Ca2+.

Animals↗
PubMed1992

Inhibition of Ca(2+)-induced calcitonin secretion by somatostatin: roles of voltage dependent Ca2+ channels and G-proteins.

Somatostatin has recently been applied therapeutically for hypercalcitonemia in patients with calcitonin-producing tumours. Using calcitonin-secreting cells (C-cells) of the medullary thyroid carcinoma cell line rMTC 44-2, we investigated the inhibitory action of somatostatin on calcitonin release, cytosolic Ca2+ and Ca2+ channel currents. The Ca(2+)-induced rises of the cytosolic Ca2+ and calcitonin secretion were greatly inhibited by somatostatin or its stable analogue octreotide. The effects of somatostatin were pertussis toxin-sensitive. Under voltage clamp conditions, C-cells exhibited slowly inactivating Ca2+ channel currents. Bath application of 100 nM somatostatin reversibly reduced the Ca2+ channel current by about 30%. The Ca2+ channel current and its inhibition by somatostatin were not affected by intracellularly applied cyclic AMP. Moreover, pretreating the cells with pertussis toxin had no effect on the control Ca2+ channel currents but greatly abolished its inhibition by somatostatin. The data show that somatostatin suppresses the Ca(2+)-stimulated calcitonin secretion by inhibiting voltage-dependent Ca2+ channel currents and by lowering cytosolic Ca2+. These actions of somatostatin involve pertussis toxin-sensitive G-proteins and occur independently of changes in the cyclic AMP concentration.

Animals↗
PubMed1992

Single calcium channel currents of arterial smooth muscle at physiological calcium concentrations.

Entry of Ca through voltage-dependent Ca channels is an important regulator of the function of smooth muscle, cardiac muscle, and neurons. Although Ca channels have been extensively studied since the first descriptions of Ca action potentials (P. Fatt and B. Katz. J. Physiol. Lond. 120: 171-204, 1953), the permeation rate of Ca through single Ca channels has not been measured directly under physiological conditions. Instead, single Ca channels have typically been examined using high concentrations (80-110 mM) of another divalent charge carrier, Ba, so as to maximize the amplitude of the single-channel currents. Calculations of unitary currents at 2 mM Ca indicated that the single-channel currents would be immeasurably small (i.e., < 0.1 pA). We provide here the first direct measurements of single Ca channel currents at a physiological Ca concentration. Contrary to earlier estimates, we have found that currents through single Ca channels in arterial smooth muscle are 0.1-0.3 pA at 2 mM Ca and physiological membrane potentials. These relatively large unitary currents permit direct measurement of Ca channel properties under conditions that do not distort their function. Our data also indicate that Ca permeates these channels at relatively high rates in physiological Ca concentrations and membrane potentials.

Animals↗
PubMed1992

Extracellular Ca2+ sensing in C-cells and parathyroid cells.

An essential function of C-cells and parathyroid cells is to monitor the extracellular Ca2+ concentration. The Ca(2+)-dependent secretion of calcitonin (CT) and parathyroid hormone is known to be mediated by corresponding changes in the intracellular Ca2+ concentration. To address the question of whether Ca2+ influx through voltage-dependent Ca2+ channels couples the extracellular to the intracellular Ca2+, we applied the patch clamp technique to C-cells of the rMTC 44-2 cell line and to parathyroid cells of the PT-r cell line. The rMTC cells displayed dihydropyridine-sensitive, voltage-dependent, high-threshold Ca2+ channels which allowed ion influx even at the resting potential of about -40 mV. Increases of the concentration of the extracellular divalent cation or adding the Ca2+ channel agonist Bay K 8644 stimulated the steady state ion influx. In contrast, PT-r cells exhibited only fast inactivating, low-threshold Ca2+ channel currents with no steady state conductivity for Ca2+ at the resting potential of around -40 mV. We conclude that dihydropyridine-sensitive Ca2+ channels allow steady state transmembranous Ca2+ influx in C-cells, thereby increasing the cytosolic Ca2+ and CT secretion. Parathyroid cells, however, lack long-lasting Ca2+ channel currents and obviously sense the extracellular Ca2+ concentration by other mechanisms.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Thyrotropin-releasing hormone induces opposite effects on Ca2+ channel currents in pituitary cells by two pathways.

Thyrotropin-releasing hormone (TRH) stimulates pituitary secretion by steps involving a cytosolic Ca2+ rise. We examined various pathways of Ca2+ elevation in pituitary GH3 cells. By using the patch clamp technique in the whole-cell configuration and Ba2+ as divalent charge carrier through Ca2+ channels, TRH (1 microM) reversibly reduced the current by about 55%. This hormonal effect was prevented by infusing guanine 5'-[beta-thio]diphosphate (GDP[beta S]) intracellularly but not by pretreating the cell with pertussis toxin (PT). Since PT-insensitive guanine nucleotide-binding regulatory (G) proteins are known to mediate a hormone-stimulated inositol trisphosphate-mediated Ca2+ release from intracellular stores, we assume that the inhibitory effect of TRH on Ba2+ currents through Ca2+ channels is caused by the increased intracellular Ca2+. To prevent a Ca(2+)-release-dependent inhibition of Ca2+ channels, we preincubated GH3 cells in a medium free of divalent charge carriers and measured the Na+ current through Ca2+ channels. When fura-2 was used as indicator for the cytosolic Ca2+, TRH induced a release from intracellular stores only once and had no effect on the intracellular Ca2+ concentration during further applications. In line with this observation, TRH initially reduced the Na+ current through Ca2+ channels but stimulated it during subsequent applications. The stimulation was sensitive to GDP[beta S] and was abolished by pretreatment with PT, suggesting that the stimulatory action of TRH is mediated by a G protein different from the one that functionally couples the receptor to phosphatidylinositol 4,5-bisphosphate hydrolysis. In conclusion, the present data suggest that TRH increases the intracellular Ca2+ concentration by two interacting pathways, that release from intracellular stores causes a secondary blockage of Ca2+ channels, and that, especially with empty intracellular Ca2+ stores, Ca2+ channels are stimulated by a PT-sensitive G protein.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Involvement of pertussis toxin-sensitive G-proteins in the hormonal inhibition of dihydropyridine-sensitive Ca2+ currents in an insulin-secreting cell line (RINm5F).

Adrenaline inhibits insulin secretion via pertussis toxin-sensitive mechanisms. Since voltage-dependent Ca2+ currents play a key role in insulin secretion, we examined whether adrenaline modulates voltage-dependent Ca2+ currents of the rat insulinoma cell line, RINm5F. In the whole-cell configuration of the patch-clamp technique, dihydropyridine- but not omega-conotoxin-sensitive Ca2+ currents were identified. Adrenaline via alpha 2-adrenoceptors inhibited the Ca2+ currents by about 50%. Somatostatin which also inhibits insulin secretion was less efficient (inhibition by 20%). The hormonal inhibition of Ca2+ currents was not affected by intracellularly applied cAMP but blocked by the intracellularly applied GDP analog guanosine 5'-O-(2-thiodiphosphate) and by pretreatment of cells with pertussis toxin. In contrast to adrenaline and somatostatin, galanin, another inhibitor of insulin secretion, reduced Ca2+ currents by about 40% in a pertussis toxin-insensitive manner. Immunoblot experiments performed with antibodies generated against synthetic peptides revealed that membranes of RINm5F cells possess four pertussis toxin-sensitive G-proteins including Gi1, Gi2, Go2, and another Go subtype, most likely representing Go1. In membranes of control but not of pertussis toxin-treated cells, adrenaline via alpha 2-adrenoceptors stimulated incorporation of the photo-reactive GTP analog [alpha-32P]GTP azidoanilide into pertussis toxin substrates comigrating with the alpha-subunits of Gi2, Go2, and the not further identified Go subtype. The present findings indicate that activated alpha 2-adrenoceptors of RINm5F cells interact with multiple G-proteins, i.e. two forms of Go and with Gi2. These G-proteins are likely to be involved in the adrenaline-induced inhibition of dihydropyridine-sensitive Ca2+ currents and in other signal transduction pathways contributing to the adrenaline-induced inhibition of insulin secretion.

Animals↗
PubMed1991

Assignment of G-protein subtypes to specific receptors inducing inhibition of calcium currents.

The inhibition of voltage-dependent Ca2+ channels in secretory cells by plasma membrane receptors is mediated by pertussis toxin-sensitive G proteins. Multiple forms of G proteins have been described, differing principally in their alpha subunits, but it has not been possible to establish which G-protein subtype mediates inhibition by a specific receptor. By intranuclear injection of antisense oligonucleotides into rat pituitary GH3 cells, the essential role of the Go-type G proteins in Ca(2+)-channel inhibition is established: the subtypes Go1 and Go2 mediate inhibition through the muscarinic and somatostatin receptors, respectively.

Animals↗
PubMed1991

Steady-state currents through voltage-dependent, dihydropyridine-sensitive Ca2+ channels in GH3 pituitary cells.

Ca2+ influx via voltage-dependent Ca2+ channels is known to be elicited during action potentials but possibly also occurs at the resting potential. The steady-state current through voltage-dependent Ca2+ channels and its role for the electrical activity was, therefore, investigated in pituitary GH3 cells. Applying the recently developed 'nystatin-modification' of the patch-clamp technique, most GH3 cells (18 out of 23 cells) fired spontaneous action potentials from a baseline membrane potential of 43.7 +/- 4.6 mV (mean +/- s.d., n = 23). The frequency of action potentials was stimulated about twofold by Bay K 8644 (100 nM), a Ca(2+)-channel stimulator, and action potentials were completely suppressed by the Ca(2+)-channel blocker PN 200-110 (100 nM). Voltage clamping GH3 cells at fixed potentials for several minutes and with 1 mM Ba2+ as divalent charge carrier, we observed steady-state Ca(2+)-channel currents that were dihydropyridine-sensitive and displayed a U-shaped current-voltage relation. The results strongly suggest that the observed long lasting, dihydropyridine-sensitive Ca(2+)-channel currents provide a steady-state conductivity for Ca2+ at the resting potential and are essential for the generation of action potentials in GH3 pituitary cells.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Electrophysiological properties of rat calcitonin-secreting cells.

The spontaneous electrical activity of calcitonin-secreting cells (C-cells) appears to play an important role in the coupling of fluctuations in the extracellular Ca2+ to changes in the intracellular Ca2+ concentration and thus for calcitonin secretion. Using the patch clamp technique, we have investigated the spontaneous electrical activity and the underlying ionic currents in C-cells of the rMTC 44-2 cell line. With 1.2 mM external Ca2+, the membrane potential was -46.1 +/- 1.7 mV (n = 58) and about 30% of the cells spontaneously fired action potentials. Rising the external Ca2+ to 1.8 mM caused the cells to depolarize to -42.1 +/- 2.1 mV (n = 56) and spontaneous electrical activity was seen in about 70% of cells. Under voltage clamp conditions, tetrodotoxin-sensitive voltage-dependent Na+ currents, outward-rectifying K+ currents and isradipine-, omega-conotoxin-sensitive as well as isradipine- and omega-conotoxin-insensitive Ca2+ currents were observed. These voltage-dependent currents appear to be the major ionic currents contributing to action potentials in C-cells and to participate in calcitonin secretion.

Action Potentials↗